Proceedings of the 29th European Paediatric Rheumatology Congress (2024)

Correspondence: S. Ringold

Pediatric Rheumatology 2023, 21(Suppl 2):O01

Introduction: The STOP-JIA study was designed to compare the effectiveness of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Consensus Treatment Plans (CTPs) for untreated polyarticular JIA (pJIA) in achieving ACR clinically inactive disease (CID) at 1 year. The CTPs differ in the timing of initiation of biologic disease modifying anti-rheumatic drug therapy (bDMARD).

Objectives: To measure the impact of CARRA STOP-JIA CTPs on clinical outcomes at 2 and 3 years.

Methods: STOP-JIA compared 3 CARRA CTPs in 400 children with pJIA: 1) Step-Up (SU) – starting conventional, synthetic DMARD monotherapy (csDMARD), adding bDMARD if needed after 3 months; 2) Early Combination (EC) – starting csDMARD and bDMARD within the first 3 months; and 3) Biologic First (BF) – starting bDMARD monotherapy and adding csDMARD if needed after 3 months. There was no randomization. Data were collected using the CARRA Registry approximately every 3 months for the first 12 months and every 6 months thereafter. Patients with 2 to 3 years of follow-up were included. The primary outcome was the percentage of children achieving CID off glucocorticoids at 2 and/or 3 years. Propensity score (PS) weighting was used to balance baseline differences in potential confounders between CTPs. Secondary outcomes included comparison of proportions of patients with clinical Juvenile Arthritis Disease Activity Score based on 10 joints inactive disease (cJADAS10-ID ≤ 2.5), clinical remission on medications (CRM; consecutive visits with CID ≥ 6 months), and proportion of time spent in CID or cJADAS10-ID.

Results: 325 participants had a 2- and/or 3-year visit (210 SU, 83 EC, 32 BF). Percentage of patients in CID at 2 years was 42% for SU, 58% EC, and 52% BF (p=0.03 for SU versus EC). CID differences were not statistically significant at 3 years. Likewise, there was no significant difference between CTPs for JADAS10-ID at 2 or 3 years. However, there were significant percentage differences in CRM, which were higher for EC compared to SU at 2 years (46.3% versus 28.8% [p=0.02]) and 3 years (66.1% versus 40.1% [p<0.01]), and for percentages of time spent in CID (42.8% versus 28.8% [p<0.01]) and cJADAS10-ID (52.5% versus 39.4% [p<0.01]) up to 3 years.

Conclusion: These data support improved effectiveness of EC versus SU and BF at 2 and 3 years for most outcomes. There were significant differences favoring EC versus SU in outcomes that reflected duration of time spent with less disease activity at 2 and 3 years, which may be most important in limiting disease burden. However, benefits of EC did not reach statistical significance for all comparisons. More research is needed to improve understanding of which pJIA patients will respond to a particular CTP in order to optimize outcomes.

Trial registration identifying number: NCT02593006

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

S. Ringold Employee with: Janssen Research & Development, LLC, G. Tomlinson: None declared, L. Schanberg Grant / Research Support with: BMS, Consultant with: Sanofi (DSMB), UCB (DSMB), V. Del Gaizo: None declared, K. Murphy: None declared, B. Feldman Consultant with: AB2Bio (DSMB), Pfizer (DSMB & Advisory Board), Janssen, Novo Nordisk, M.-S. Ong: None declared, M. Natter: None declared, Y. Kimura: None declared

Reference

1. Kimura Y, Schanberg LE, Tomlinson GA, Weiss PF, Riordan ME, Dennos AC, Del Gaizo V, Murphy K, Natter M, Feldman BM, Ringold S. The Childhood Arthritis & Rheumatology Research Alliance Start Time Optimization of Biologics in Polyarticular Juvenile Idiopathic Arthritis Study. Arthritis Rheumatol. 2021 Oct;73(10):1898-1909. PMID:34105312

Correspondence: R. Erkens

Pediatric Rheumatology 2023, 21(Suppl 2):O02

Introduction: HLA-DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and adverse drug reactions to biological therpay in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. These findings have spurred a debate among pediatric rheumatologists about the utility of pre-prescription HLA-typing to guide medication decisions for new-onset sJIA patients. Such decisions may include postponing and even forgoing highly effective biological therapy in new-onset sJIA patients who carry the commonly occurring HLA-DRB1*15 haplotypes.

Objectives: Here, we present HLA-DRB1 and IL1RN variant genotyping data from our prospective cohort of new-onset sJIA patients treated in a standardized manner with the recombinant IL-1 Receptor antagonist anakinra as first-line therapy. The objectives of the study were to describe the HLA-DRB1 background of our sJIA cohort in relation to disease course and to determine clinical inactive disease rates in the first 2 years of disease based on HLA-DRB1 background and IL1RN genetic variants.

Methods: HLA and IL1RN risk alleles were identified via whole genome sequencing. Treatment responses and complications were compared between carriers versus non-carriers.

Results: Seventeen of 65 patients (26%) carried HLA-DRB1*15:01, comparable to the general Dutch and European population. Furthermore we found enrichment for HLA-DRB1*11:01 (28%), a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 and 2 years were high (>80%), irrespective of HLA-DRB1 or IL1RN variants. One patient, an HLA-DRB1*15:01 carrier, developed sJIA-LD. Of the three patients with severe drug reactions to biologics, one carried HLA-DRB1*15:01. The prevalence of eosinophilia is common and did not significantly differ between HLA-DRB1*15:01 carriers and non-carriers at disease-onset (6.2% vs 14.9%, p=0.67) nor after the start of anakinra (35.3% versus 37.5% in the first 2 years of disease).

Conclusion: We observed high rates of CID using anakinra as first-line treatment irrespective of HLA-DRB1 or IL1RN variants. Only one of the 17 HLA-DRB1*15:01 carriers developed sJIA-LD, and of the 3 patients with drug reactions to biologics, only one carried HLA-DRB1*15:01. Although thorough monitoring for sJIA-LD and drug hypersensitivity in sJIA remains important, withholding effective biological therapy in new patients based solely on HLA-DRB1 or genetic IL1RN variants is not warranted.

Patient Consent

Yes, I received consent

Disclosure of Interest

R. Erkens: None declared, J. Calis: None declared, A. Verwoerd: None declared, S. De Roock: None declared, N. Ter Haar: None declared, L. Van der Veken: None declared, R. Ernst: None declared, H. Van Deutekom: None declared, A. Pickering Grant / Research Support with: SJIA Foundation, R. Scholman: None declared, M. Jansen: None declared, J. Swart Consultant with: Amgen, R. Sinha Employee with: President, Systemic JIA Foundation (unpaid), J. Roth: None declared, G. Schulert Consultant with: Novartis and SOBI, A. Grom Consultant with: Novartis, SOBI and AB2Bio, J. Van Loosdregt: None declared, B. Vastert Grant / Research Support with: SOBI, Consultant with: SOBi and Novartis

Correspondence: T. Miyamae

Pediatric Rheumatology 2023, 21(Suppl 2):O03

Introduction: In 2008, Tocilizumab (TCZ) was approved for systemic juvenile idiopathic arthritis (sJIA) as an intravenous formulation after its efficacy and safety were demonstrated in a clinical trial conducted in Japan between 2002 and 2008.

Objectives: This study aimed to comprehend the long-term prognosis of patients who participated in phases II (MRA011JP), III (MRA316JP), and III/IV (MRA324JP) of the clinical trial. A total of 149 participants were included in the study.

Methods: The primary endpoint of this study was the sustained frequency of TCZ administration throughout the prolonged observation period of sJIA. Secondary endpoints encompassed additional long-term prognostic determinants, such as therapeutic conditions, disease status including remission rate and clinical phenotype, complications, social adaptation, employment status, and quantification of health-related quality of life (HRQOL).

Results: Results were collected for 147 cases by April 2023. Among the 135 patients (61 male and 74 female) whose medical records were available and final diagnosis was sJIA, the median age of the study participants was 26.7 years at the time of the study, 4.3 years at the onset of sJIA, 9.2 years at the first administration of TCZ, 4.0 years from the onset to the first TCZ administration, and 9.8 years from the initiation of TCZ (all median values). Thirty-four (25.2%) were in medication-free remission, and 97 (71.9%) continued therapy. Of the 97 patients, 91 were treated with b-/ts-DMARDs. Tocilizumab was continued in 83 patients (61.5%), and six were switched to canakinumab (CAN) due to TCZ failure, side effects, or other reasons. Except for an isolated incident of sudden death, three cases resulted in a fatal outcome. Specifically, the causes of mortality were macrophage activation syndrome, sJIA-associated interstitial pneumonia, and disseminated aspergillosis. Forty-four (32.6%) transitioned from acute febrile sJIA to chronic arthritic sJIA, in which chronic arthritis was the primary pathology without systemic inflammation. Macrophage activation syndrome was developed in 33 patients (24.4%) during the clinical course. The most commonly observed complications were osteoporosis in 74 (54.8%), infection requiring hospitalization in 43 (31.8%), and hypertension in 28 (20.7%). The EQ-5D-5L score was 0.89 (mean). The final mean height was 156.6 cm for males and 144.0 cm for females, showing a significant short stature. The college/university enrollment rate was as high as 65.4%, and all but five students were employed.

Conclusion: After approximately a decade of observation, 71.9% of the patients remained under treatment, with 61.5% electing to receive TCZ. Conversion to chronic arthritic sJIA was detected in 32.6% of the patient population. Despite the presence of primary disease activity and associated complications, the level of social adjustment observed was satisfactory, implying a favorable impact of the administered treatment.

Patient Consent

Yes, I received consent

Disclosure of Interest

T. Miyamae Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Chugai Pharma, Novartis Farma, T. Kawabe Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, K. Nishimura Shareholder with: none, Grant / Research Support with: Chugai Pharma, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Novaritis Pharma, S. Hattori Shareholder with: none, Grant / Research Support with: Chugai Pharma, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, T. Imagawa Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, T. Ishii Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Chugai Pharma, S. Ito Shareholder with: none, Grant / Research Support with: Chugai Pharma, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Novaritis Pharma, Chugai Pharma, N. Iwata Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: ONO PHARMACEUTICAL CO., LTD., GlaxoSmithKline Plc., Y. Kamata Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, Y. Kamiyama Shareholder with: none, Grant / Research Support with: Chugai Pharma, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, M. Mizuta Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Novaritis Pharma, M. Mori Shareholder with: none, Grant / Research Support with: I belong to the department that is financially supported by Chugai, UCB Japan, CSL Behring, Abbvie Japan, Japan Blood Products Organization, AYUMI, Nippon Kayaku, and Asahi-Kasei. , Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: I have received lecture fees from MSD, Chugai, UCB Japan, Abbvie Japan, Japan Blood Products Organization, AYUMI, and Asahi-Kasei., A. Murase Shareholder with: none, Grant / Research Support with: Chugai Pharma, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, Y. Nakagishi Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: CHUGAI PHARMACEUTICAL CO.,LTD. Novartis Pharma K.K. AstraZeneca plc, T. Nakano Shareholder with: none, Grant / Research Support with: Maruho Co., Ltd 500,000 yen, Torii Pharmaceutical Co., Ltd 300,000 yen, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, S. Nakayamada Shareholder with: none, Grant / Research Support with: S. Nakayamada has received research grants from Mitsubishi-Tanabe, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: S Nakayamada has received consulting fees, lecture fees, and/or honoraria from Bristol-Myers, AstraZeneca, Pfizer, GlaxoSmithKline, AbbVie, Astellas, Asahi-kasei, Sanofi, Chugai, Eisai, Gilead Sciences, Boehringer Ingelheim., T. Nozawa Shareholder with: none, Grant / Research Support with: Chugai Pharma, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, T. Ohya Shareholder with: none, Grant / Research Support with: Chugai Pharma, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, N. Okamoto Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: N.O. has has received consulting fees from Daiichi Sankyo Company Limited; Eli Lilly Japan K.K.; and Swedish Orphan Biovitrum AB, Speaker Bureau with: N.O. has received honoraria or lecture fees from AbbVie Inc.; Amgen Inc.; Asahi Kasei Pharma Corporation; Astellas Pharma Inc.; AstraZeneca PLC; AYUMI Pharmaceutical Co., Ltd.; Bristol Myers Squibb; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Eli Lilly Japan K.K.; GlaxoSmithKline PLC; Mitsubishi Tanabe Pharma Corporation; Novartis Pharma K.K.; Pfizer Inc.; and Teijin Pharma Limited; ., K. Sato Shareholder with: none, Grant / Research Support with: Chugai Pharmaceutical Co., Ltd, Four times, average 1,800,000 yen, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Chugai Pharmaceutical Co., Ltd, One time, 100,000 yen, Y. Sugita Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, S. Takei Shareholder with: none, Grant / Research Support with: Chugai Pharcaceutical Co.Ltd., Eisai Co.Ltd., Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Glaxo Smith Klein Pharmaceuticals Ltd, Novartis Pharma K.K., AbbVie, Mitsubishi Tanabe Pharma Corporation, Ayumimi Pharmaceutical Co, Bristol-Myers Squibb, Eli-Lilly,K.K., Asahi Kasei Medical Co.,, Sanofi, K.K. , S. Tanaka Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, Y. Tanaka Shareholder with: none, Grant / Research Support with: Y. Tanaka has received research grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Behringer-Ingelheim., Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Y. Tanaka has received speaking fees and/or honoraria from Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, M. Tomiita Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, H. Umebayashi Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: Novaritis Pharma, Y. Yamasaki Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none, N. Nishimoto Shareholder with: none, Grant / Research Support with: I have received financial grants from Chugai Pharmaceutical Co. Ltd.,the product company of tocilizumab., Consultant with: I have been work as a paid consultant for Chugai Pharmaceutical Co. Ltd. ,the product company of tocilizumab., Employee with: none, Paid Instructor with: I have been a paid instructor for Chugai Pharmaceutical Co. Ltd. ,the product company of tocilizumab., Speaker Bureau with: I have been paid as a speaker for Chugai Pharmaceutical Co. Ltd. ,the product company of tocilizumab., S. Yokota Shareholder with: none, Grant / Research Support with: none, Consultant with: none, Employee with: none, Paid Instructor with: none, Speaker Bureau with: none

Reference

1. Yokota S, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008 Mar 22;371(9617):998-1006.

Correspondence: K. Tenbrock

Pediatric Rheumatology 2023, 21(Suppl 2):O04

Introduction: A treat-to-target approach is recommended for all forms of juvenile idiopathic arthritis (JIA), with the goal of achieving inactive disease within the first six months of treatment [1]. Treatments and outcomes in newly diagnosed children and adolescents with JIA are currently being studied as part of the ProKind-Rheuma project.

Objectives: To investigate whether the treatment goal of inactive disease is achieved in non-systemic JIA and what factors are associated with failure to achieve the goal.

Methods: ProKind-Rheuma is an ongoing multicentre, prospective, non-interventional observational study. Patients with newly diagnosed JIA were enrolled from January 2020 to June 2022 and are being followed prospectively. Physician- and parent-reported data are collected in a standardized way (e.g., disease activity with the cJADAS-10, functional limitation with the Childhood Health Assessment Questionnaire (CHAQ), quality of life with the PedsQL 4.0). Data from patients with non-systemic JIA and a follow-up (FU) at 6 months ± 6 weeks were included. Chi2-Test was performed for categorical variables, Students t-test for continuously distributed variables.

Results: Six-month FU data were available for 325 patients with non-systemic JIA (42% oligoarthritis, 35% polyarthritis, 8% enthesitis-related arthritis, 3% psoriatic arthritis, 3% other arthritis) recruited 1.2 (±2.1) months after diagnosis from 17 paediatric rheumatology centres.

At the FU, 43% had reached inactive disease according to the 2021 cJADAS cutoffs [2]. Conversely, more than half had not reached the treatment target, including 69% of oligoarthritis, 48% of polyarthritis, 53% of enthesitis-related arthritis and 43% of psoriatic arthritis patients. One third (35%) of patients still had moderate or high disease activity at FU.

There were no significant differences in age at onset, frequency of ANA or HLA-B27 positivity, cJADAS-10 or PedsQL 4.0 score at baseline, parental education level (>10 years), or time from symptom onset to diagnosis between those who did not reach treatment goal and those who did. However, those who did not reach the treatment target were more likely to have oligoarthritis (50% versus 30%, p=0.025), to receive DMARDs later (2.8±3.7 months versus 1.0±1.3, p=0.001) and were less likely to have a 50% decrease in cJADAS-10 score in the first three months of treatment (61% versus 80%, p=0.049) than those who achieved the treatment target.

Conclusion: Under current treatment conditions, less than half of patients achieve the goal of inactive disease after six months of treatment. It seems that especially patients with oligoarthritis need to be treated more effectively.

Patient Consent

Yes, I received consent

Disclosure of Interest

K. Vollbach: None declared, J. Klotsche: None declared, K. Tenbrock: None declared, G. Horneff Speaker Bureau with: Novartis, MSD, Pfizer, Roche, Sanofi, Sobi, Biogen, D. Föll: None declared, J. Haas: None declared, D. Windschall: None declared, T. Kallinich: None declared, F. Weller: None declared, S. Mrusek: None declared, K. Mönkemöller: None declared, M. Hufnagel: None declared, I. Földvari: None declared, A. Hospach: None declared, R. Trauzeddel: None declared, C. Schütz: None declared, N. Brück: None declared, J. Kümmerle-Deschner: None declared, P. Oommen: None declared, J. Brunner: None declared, F. Dressler: None declared, A. Klein: None declared, C. Rietschel: None declared, M. Klaas: None declared, M. Rühlmann: None declared, K. Minden Speaker Bureau with: Amgen, Novartis

References

1. Ravelli A, Consolaro A, Horneff G, et al. Ann Rheum Dis 2018;77:819-28.

2. Trincianti C, Van Dijkhuizen EHP, Alongi A, et al.; PRINTO. Arthritis Rheumatol 2021;73:1966-75.

Correspondence: L. Kearsley-Fleet

Pediatric Rheumatology 2023, 21(Suppl 2):O05

Introduction: Juvenile idiopathic arthritis (JIA) is the most prevalent inflammatory rheumatic disease in children and young people (CYP) (1, 2). Uveitis, or intraocular inflammation, is the most common extra-articular manifestation of JIA. If JIA-uveitis (JIA-U) is not diagnosed early and thus left untreated, major ocular complications such as cataracts, glaucoma, and blindness can occur (1, 2, 3).

Objectives: To describe the incidence and characteristics of JIA-U among a representative inception cohort of CYP with JIA enrolled in the Childhood Arthritis Prospective Study (CAPS).

Methods: CAPS, a prospective inception cohort study, recruited CYP aged <16 years with newly diagnosed inflammatory arthritis across seven UK rheumatology centres between January 2001 (4) and July 2019. Analysis included descriptive statistics of all children recruited from the five centres at which ophthalmic data were available. Detailed ophthalmic data were extracted from clinical records by a paediatric ophthalmologist and comprised visual acuity, date of detection of uveitis, inflammation severity at onset, ophthalmic treatment use, and the presence of and date of detection of ocular structural complications.

Results: Ophthalmic information was available for 1169 (66%) CYP with JIA recruited to CAPS, of whom 158 (14%) were identified as having uveitis. Most patients with JIA-U (N=158) were female (72%), of white ethnicity (76%), had oligoarticular JIA (58%), and had a history of a positive ANA blood test result (69%). The median time from JIA diagnosis to JIA-U diagnosis was 0.9 years [IQR: 0, 2.5] and the median age at JIA-U diagnosis was 5.7 years [IQR: 3.7, 8.8].

Of the 158 patients reporting uveitis, 94% had anterior uveitis and 6% had anterior and intermediate uveitis at presentation. Disease presented bilaterally in 107 children (68%), and of the 51 with initially unilateral disease, seven progressed to having bilateral disease. At detection of uveitis, complications (cataract, glaucoma, macular oedema, posterior synechiae, band keratopathy and or visual impairment) were present in 23 children (15%) and a further 30% (48/158) went on to develop complications [follow up range 2-10 years, IQR 5, 10]; 8 of these patients had complications at both baseline and follow-up.

Conclusion: This is the first analysis on ophthalmic data collected by the CAPS study and provides an opportunity to examine the characteristics of JIA-U in JIA patients in greater detail, with 40% of children with uveitis having sight-threatening complications.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

J. Jennycloss: None declared, L. Kearsley-Fleet: None declared, K. Hyrich Grant / Research Support with: Grants from Pfizer and BMS outside the submitted work., Speaker Bureau with: Honoraria from Abbvie , C. Ciurtin: None declared, F. McErlane: None declared, S. Lawson-Tovey: None declared, A. L. Solebo: None declared

References

1. Carvounis PE, Herman DC, Cha S, Burke JP. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol. 2006;244(3):281-90. 10.1007/s00417-005-0087-3.

2. Clarke SL, Sen ES, Ramanan AV. Juvenile idiopathic arthritis-associated uveitis. Pediatr Rheumatol Online J. 2016;14(1):27. 10.1186/s12969-016-0088-2.

3. Carlsson E, Beresford MW, Ramanan AV, Dick AD, Hedrich CM. Juvenile Idiopathic Arthritis Associated Uveitis. Children (Basel). 2021;8(8). 10.3390/children8080646.

4. Adib N, Hyrich K, Thornton J, Lunt M, Davidson J, Gardner-Medwin J, et al. Association between duration of symptoms and severity of disease at first presentation to paediatric rheumatology: results from the Childhood Arthritis Prospective Study. Rheumatology (Oxford). 2008;47(7):991-5. 10.1093/rheumatology/ken085.

Correspondence: C. Lafay

Pediatric Rheumatology 2023, 21(Suppl 2):O06

Introduction: Viral infections have been suggested as a potential trigger in pediatric uveitis, a rare disease. This led us to suggest that the coronavirus disease 2019 (COVID-19) pandemic could have been a potential cause for the emergence of newly diagnosed uveitis.

Objectives: We sought to examine whether the COVID-19 pandemic was associated with an increased incidence of uveitis in children and if this increased incidence was correlated with the beginning of the campain vaccination in june 2021. We then studied children with newly diagnosed uveitis prior to the COVID-19 pandemic to those who were diagnosed after March 2020, to see if there were any clinical or biological differences.

Methods: We performed a time-series analysis of patient records from a national hospital-based French surveillance system. All children younger than 18 years hospitalized for uveitis in France between January 2012 and March 2022 were included. The incidence of newly diagnosed uveitis per 100,000 children per trimester in France was analyzed by a quasi-Poisson regression. The incidence of sarcoidosis and acute tubulo-interstitial nephritis over the same period were used as control outcomes. A cohort of children diagnosed with uveitis at Robert-Debré Hospital was described to evaluate wether one specific type of uveitis increased and to compare the clinical and biological characteristics of uveitis diagnosed before and after the onset of the pandemic.

Results: During the study period, 2492 children were hospitalized for uveitis in France. The COVID-19 pandemic, which started in March 2020, was associated with a significant increase in the occurrence of uveitis (estimated cumulative change, 44.9%; 95% CI 11.4 to 78.4; P < .001). The increase in the incidence of pediatric uveitis started in October 2020, while the national immunization program targeting children aged less than 18 years began in June 2021. This increase involved all forms of uveitis, regardless of location, and their characteristics were similar to those diagnosed before the pandemic.

Conclusion: Our study evidenced a significant increase in the incidence of pediatric uveitis following the COVID-19 pandemic. This increase, occurring 6 months before the implementation of the COVID-19 national immunization program in children, suggests the independence of the vaccine regarding the resurgence of this rare disease.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Tugal-Tutkun I. Pediatric uveitis. J Ophthalmic Vis Res 2011; 6: 259–69.

2. Cunningham ET. Uveitis in children. Ocul Immunol Inflamm 2000; 8: 251–61.

3. Kanski JJ, Shun-Shin GA. Systemic Uveitis Syndromes in Childhood: An Analysis of 340 Cases. Ophthalmology 1984; 91: 1247–52.

4. Pivetti-Pezzi P. Uveitis in Children. Eur J Ophthalmol 1996; 6: 293–8.

5. Soylu M, Özdemir G, Anli A. Pediatric uveitis in Southern Turkey. Ocul Immunol Inflamm 1997; 5: 197–202.

6. Hamade IH, Shamsi HNA, Dhibi HA, Chacra CB, El-Asrar AMA, Tabbara KF. Uveitis survey in children. Br J Ophthalmol 2009; 93: 569–72.

7. Standardization of Uveitis Nomenclature for Reporting Clinical Data. Results of the First International Workshop. Am J Ophthalmol 2005; 140: 509–16.

8. De Groot-Mijnes JDF, Chan ASY, Chee S-P, Verjans GMGM. Immunopathology of Virus-Induced Anterior Uveitis. Ocul Immunol Inflamm 2018; 26: 338–46.

9. Groen-Hakan F, Babu K, Tugal-Tutkun I, et al. Challenges of Diagnosing Viral Anterior Uveitis. Ocul Immunol Inflamm 2017; 25: 715–25.

10. Babu K, Murthy G. Chikungunya virus iridocyclitis in Fuchs′ heterochromic iridocyclitis. Indian J Ophthalmol 2012; 60: 73.

Correspondence: V. Natoli

Pediatric Rheumatology 2023, 21(Suppl 2):O07

Introduction: Despite the established role of IFN-α in the pathophysiology of Juvenile-onset Systemic Lupus Erythematosus (JSLE), its utility as a tool for monitoring disease activity has not been explored extensively.

Objectives: To assess the utility of serum IFN-α as a potential marker of disease activity, and a predictor of disease flare in JSLE patients who have reached a low disease activity state (LDAS) or remission.

Methods: Serum samples from 291 participants were analysed, including 49 healthy controls (HCs), 95 JSLE, and 52 juvenile idiopathic arthritis (JIA) patients. IFN-α levels were determined using ultra-sensitive Single-molecule array (Simoa) digital ELISA. All serum samples were analysed in duplicates, the coefficient of variation (CV) was calculated, and samples with a CV>15 were excluded. Thus, 88 serum samples were excluded and 203 samples were included in the analysis (25 HCs, 85 JSLE (148 samples), 30 JIA patients). At each visit, JSLE patients were classified as either being in: a) remission, b) LDAS, or c) having intermediate or active disease. Clinical characteristics, demographics and disease activity scores were collected. Median IFN-α levels were compared between patient groups and disease activity state sub-groups, cross-sectionally. Time-to-flare was analysed cross-sectionally by linear regression, and the ability of the IFN-α and other traditional biomarkers (erythrocyte sedimentation rate/ESR, low C3, anti-dsDNA antibodies) in predicting flare at the following visit was assessed longitudinally by generalised linear mixed model.

Results: Median IFN-α levels were higher in the combined active/intermediate group (median 3,184 fg/mL, IQR 69-14,878) as compared to both the LDAS (586 fg/mL, IQR 52-1,317 fg/mL, p=0.036) and remission sub-groups (271 fg/mL, IQR 3-56, p <0.001). IFN-α levels were comparable between JSLE patients in remission and HCs (23 fg/mL, IQR 3-277, p=0.5). IFN-α concentrations were higher in all JSLE patients (median 603 fg/mL, IQR 11-2,643) as compared to JIA patients (median 3 fg/mL, IQR 3-103, p=0.001) and HCs (p=0.016). Abnormal serum IFN-α levels were defined as >871 fg/mL (mean serum HC IFN-α level + three standard deviations). Cross-sectional JSLE patients in remission or LDAS with abnormal IFN-α levels had a shorter time-to-flare over the subsequent six months (p=0.038), compared to patients with normal IFN-α levels. Longitudinally, multivariable analysis demonstrated high IFN-α to be the only predictor of flare at the next visit (p=0.040), whereas elevated ESR, low C3, and anti-dsDNA antibodies did not predict flares.

Conclusion: Serum IFN-α levels correlate with JSLE disease activity and facilitate identification of a sub-group of patients in remission or LDAS who are at increased risk of flare.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: C. Ciurtin

Pediatric Rheumatology 2023, 21(Suppl 2):O08

Introduction: Atherosclerosis is an early manifestation of cardiovascular disease (CVD) which can be detected in young people (YP), suggesting that cardiovascular risk (CVR) management should start earlier in life. Childhood onset systemic lupus erythematosus (cSLE) has a 100-300-fold increased CVD mortality vs. age-matched population. Although progress has been made in assessing CVR for primary prevention of CVD, there is less guidance for CVR assessment in YP.

Objectives: The survey aimed to explore paediatric rheumatologists' perspective on CVR assessment/management in YP with cSLE, as well as potential geographical differences.

Methods: A 17-question survey adressing the objectives above was distributed electronically through contact lists to the Paediatric Rheumatology European Society (PReS) and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) members. Respondents were asked to rate some of their choices from 5 - “very important” to 1 - “unimportant”. Findings are reported using descriptive statistics.

Results: Out of 170 respondents, 161 (95%) completed the survey (62% were from Europe, 34% from US/Canada and 4% from other countries). The majority (67%) were fully trained paediatric rheumatologists, 9% dually trained, 23% were paediatric rheumatology trainees and 1% allied health professionals; 72% respondents reported seeing up to 10 cSLE patients/month. There was a significant agreement that YP with cSLE have a higher CVR compared to age-matched population (95%), and that CVR assessment in cSLE is warranted (95%), with the annual assessment being the most preferred option (70%). Despite 50% of respondents not being aware of any CVD-risk scores, 90% agreed with the need of validating a CVR score in YP with cSLE, and 70% of respondents indicated that they would use such a tool to guide lifestyle changes, while 50% would use it to either assess response to CVR management interventions or calculate the patients’ theoretical CVR. Previous CVD events (99%), smoking (98%), obesity and hyperglycaemia (87%), atherosclerosis lesions on vascular scans (86%), hypertension and BMI (85%), and increased LDL-cholesterol level (79%) were the top factors rated as "very” or “moderately important" for CVR assessment in cSLE. The most preferred CVR management interventions were tight control of cSLE and diabetes (78%), increase in physical activity (77%), followed by diet (72%) and tapering steroids (65%), with 51% respondents supporting the use of statins. Interestingly, 66% rated deprivation (1) as "very” or “moderately important" in determining CVR (98% from US vs. 21% from Europe p<0.001) with no differences between trainees and consultants (78% vs. 80%, p=0.89). No other significant geographical or training level differences were noted.

Conclusion: This is the first worldwide survey investigating paediatric rheumatologists' perspective on CVR in cSLE, which provided preliminary evidence for good consensus for most of the proposed strategies for CVR assessment and management in cSLE. There was a significant geographical difference in recognising the role of patient’s deprivation in determining CVR, which may require further exploration.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Reference

1. Kimenai DM, et al. Circulation. 2022 Jul 19;146(3):240-248

Correspondence: J. Brunner

Pediatric Rheumatology 2023, 21(Suppl 2):O09

Introduction: In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in two subsequent enzyme steps by mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) to generate mevalonate pyrophosphate that is further metabolized to produce sterol and non-sterol isoprenoids. Biallelic pathogenic variants in the MVK gene result in the autoinflammatory metabolic disorder MVK Deficiency (MKD). So far, however, no patients with PMVK deficiency due to biallelic pathogenic variants in the PMVK gene have been reported.

Objectives: This study aims to report the first patient with proven PMVK deficiency, including the clinical, biochemical and immunological consequences of a homozygous pathogenic variant in the PMVK gene.

Methods: We performed whole exome sequencing and functional studies in cells from a patient who, upon clinical and immunological evaluation, was suspected of an autoinflammatory disease.

Results: We identified a biallelic homozygous variant in the PMVK gene of the patient (NM_006556.4: c.392T>C, p.Val131Ala). Pathogenicity was confirmed by functional studies in patient cells, which revealed a markedly reduced PMVK enzyme activity due to a virtually complete absence of PMVK protein. Clinically, the patient showed various similarities but also distinct features compared to MKD patients, and responded well to therapeutic IL-1 inhibition.

Conclusion: In this study we report the first patient with proven PMVK deficiency due to a homozygous loss-of-function variant in PMVK leading to an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of the systemic autoinflammatory diseases (SAID), characterized by recurrent fevers, arthritis and cytopenia and thus should be included in the differential diagnosis and genetic testing for SAIDs.

Trial registration identifying number: -

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Hansmann S, Lainka E, Horneff G, Holzinger D, Rieber N, Jansson AF, et al. Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German PRO-KIND initiative. Pediatr Rheumatol Online J. 2020 Feb;18(1):17.

2. van der Hilst JCH, Bodar EJ, Barron KS, Frenkel J, Drenth JPH, van der Meer JWM, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008 Nov;87(6):301–10.

3. ter Haar NM, Jeyaratnam J, Lachmann HJ, Simon A, Brogan PA, Doglio M, et al. The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry. Arthritis Rheumatol. 2016;68(11):2795–805.

4. Yıldız Ç, Gezgin Yıldırım D, Inci A, Tümer L, Cengiz Ergin FB, Sunar Yayla ENS, et al. A possibly new autoinflammatory disease due to compound heterozygous phosphomevalonate kinase gene mutation. Jt Bone Spine. 2023;90(1):2022–4.

Correspondence: M. Tordoff

Pediatric Rheumatology 2023, 21(Suppl 2):O10

Introduction: Juvenile idiopathic arthritis (JIA) encompasses a group of heterogenous diseases characterised by joint pain and swelling where symptom onset is before the age of 16. The disease occurs unequally in female and male patients with a ratio of 2:1 but incidence differs between JIA subtypes. The HLA region is reported to have a role within the immune response and has been associated with several autoimmune conditions, including JIA.

Objectives: To investigate the role of variants within the HLA region for JIA onset in females and males, using sex dimorphism analysis.

Methods: Genotyping data was available on 2052 females and 961 males with JIA, excluding systemic JIA patients, and 9196 controls (female = 5137, males = 4059). Amino acids, alleles and SNPs within the HLA region were imputed using SNP2HLA with a total of 7773 HLA markers available for analysis. The HLA sex dimorphism analysis combined sex-specific GWAS summary statistics using the GWAMA software package. Sex-specific summary statistics for this analysis were calculated using a logistic regression with three principal components as covariates within PLINK. This analysis provided a sex-heterogeneity p-value (p_het), which provides evidence to support the heterogeneity between effect estimates of females and males.

Results: In total, 139 variants within the HLA region passed the threshold (5x10^-8) for significant sex dimorphism. A large proportion of markers that were significant for sex dimorphism were located within HLA-B, including HLA-B27 (p_het = 9.7x10^-15), which is a well-established risk locus for enthesitis related arthritis (ERA). ERA is reported to occur more frequently in male patients and effect sizes at HLA-B27 suggest a male specific effect in this cohort (OR_female = 1.6, OR_male = 4.1). Amino acids within the YST motif of the HLA-DRB1 binding groove were also significantly sex dimorphic. Tyrosine at position 10 (p_het = 4.7x10^-19, OR_female = 1.9, OR_male = 1.2), serine at position 11 (p_het = 2.3x10^-11, OR_female = 1.9, OR_male = 1.2) and threonine at position 12 (p_het = 2.3x10^-11, OR_female = 1.9, OR_male = 1.2), make up the YST motif of DRB1. The effect sizes of the YST motif markers suggest that these markers contribute to JIA onset only in females. HLA-DRB1 at position 11 has been previously associated with JIA onset in a cohort of oligoarthritis and rheumatoid factor negative polyarthritis; these subtypes are more common in females.

Conclusion: In conclusion, this is the first fine-mapping of the HLA region in a sex dimorphism analysis for JIA susceptibility. This research has provided evidence of differing genetic risk factors for female and male JIA onset that align with clinical observations. However, further research is now required to understand the mechanism behind these findings. Defining the genetic architecture to JIA will aid disease classification and diagnosis of patients in the future.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. Charras

Pediatric Rheumatology 2023, 21(Suppl 2):O11

Introduction: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease primarily affecting children and adolescents. It can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. The exact pathophysiology remains unknown, and no disease-specific biomarkers exist.

Objectives: This study aimed to investigate CNO-associated variants in P2RX7, encoding the ATP-dependent trans-membrane K⁺ channel P2RX7, and their effects on NLRP3 inflammasome assembly, to explore potential for patient stratification and individualized care.

Methods: Whole exome sequencing in two CNO patients from the same family (mother and daughter), and target sequencing of P2RX7 in a large CNO cohort (N=190) were conducted. Results were compared with publicly available datasets and regional controls (N=1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release.

Results: Rare damaging mutations in P2RX7 were identified in two related CNO patients. Targeted P2RX7 sequencing identified 11 additional CNO patients with rare damaging variants. Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (up to 11 CNO patients) participants were over-represented when compared to 190 randomly selected healthy controls. Patients with rare damaging variants were younger and more frequently required treatment with 2^nd-line agents (DMARDs and/or bisphosphonates). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages expressing variant P2X7 exhibited altered potassium flux, inflammasome assembly, IL-1β and IL-18 release, and pyroptosis.

Conclusion: Rare damaging P2RX7 variants occur in a small subset of the here investigated CNO patients (5·7%). The genetically variable P2RX7 gene may represent a CNO risk allele. Observations argue for inhibition of inflammasome activation and/or cytokine blocking strategies and may allow future patient stratification and individualized care.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: M.-L. Frémond

Pediatric Rheumatology 2023, 21(Suppl 2):O12

Introduction: COPA syndrome is a recently described monogenic autoimmune disease due to heterozygous mutations in COPA. COPA syndrome demonstrates considerable phenotypic overlap with SAVI (STING-associated vasculopathy with onset in infancy) due to gain-of-function mutations in STING.

Objectives: Our aim was to gather a European cohort of COPA patients to better delineate the clinical phenotype of this rare monogenic disorder

Methods: Assessment of clinical, radiological, immunological and therapeutic data from 27 patients (13 families) with molecularly confirmed COPA syndrome.

Results: Twenty-seven individuals with pathogenic COPA mutations were included. Among them, 20 patients presented with at least one clinical manifestation evocative of COPA syndrome (clinical penetrance of 74.1%). Symptomatic patients were female in 13 (65%) cases with a median age at disease onset of 4 years (0-50). All COPA mutations were inherited in an autosomal dominant pattern except for one that occurred de novo. Pulmonary involvement was observed in 16 (80%) patients, with interstitial lung disease (ILD) in most cases (n=13, 65%), diffuse alveolar haemorrhage (DAH) in 5 (25%) individuals and the association of ILD and DAH in 3 (15%) patients. Twelve (60%) patients demonstrated joint involvement of variable severity: 4 (20%) individuals experiencing deforming arthritis including one requiring bilateral knee arthroplasty, 6 (30%) patients had polyarticular arthritis and two (10%) patients presented with isolated arthralgias. Renal disease was observed in three (15%) individuals, manifesting as either proliferative glomerulonephritis (n=2) or membranous glomerulonephritis (n=1). Previously undescribed features were noted i.e. cutaneous involvement - acral ulcers, vitiligo and nasal perforation (n=3, 15%), cardiac disease (n=2, 10%), gastrointestinal dysfunction (n=2, 10%), and cytolytic hepatitis (n=1). When tested, 14 (93.9%) patients had positive autoantibodies. When assessed, immunophenotyping showed a mild T-cell lymphopenia, with an excess of naive T CD8+ cells and a defect of memory T CD8+ cells. All patients explored exhibited elevated IFN alpha protein levels and high IFN signature scores. The IFN signature was mildly positive in half of the clinically asymptomatic individuals assessed. The majority (60%) of patients were treated with corticosteroids and immunosuppressants, ten (50%) received biotherapies and eight (40%) patients are currently under JAK1/2 inhibition.

Conclusion: We report the first European cohort of COPA patients. While confirming the core organ features (lung, joint and kidney) of COPA syndrome, our data expand the phenotype to include cardiac, skin and digestive features, further demonstrating the clinical overlap with SAVI and other type I interferonopathies.In view of current (JAK inhibitors) and potential future targeted therapies, we suggest a requirement to assess IFN pathway status and/or perform sequencing in the case of suggestive features, even in the absence of a familial history.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: M. Tusseau

Pediatric Rheumatology 2023, 21(Suppl 2):O13

Introduction: Systemic lupus erythematosus is an autoimmune disease characterized by the production of antinuclear antibodies and an increase in type I interferons. The exact cause of the disease is unknown, but genetic and environmental factors are thought to play a role. Over the past decade, we have been able to explore the Mendelian contribution to juvenile-onset SLE (jSLE) and show that 7% of jSLE is monogenic using a panel approach^1,2.

Objectives: The aim of this study was to explore a cohort of juvenile or familial lupus with a pangenomic approach to assess the diversity of genes involved in lupus and to evaluate the diagnostic rate of exome sequencing.

Methods: We selected patients from the National Lupus Biobank who met at least one of the following criteria: (1) male sex, (2) disease onset < 12 years, (3) family history of autoimmune disease, and performed whole exome sequencing in 118 families. In a diagnostic approach, we used in silico panels and then explored the dataset to identify novel genes involved in lupus.

Results: We identified pathogenic or probable pathogenic variations according to the American College of Medical Genetics classification in genes associated with inborn errors of immunity in 7 patients (ADAR, C1QA, PSTPIP1, IRAK4, PTPN11, COPA, IKZF3). A genetic diagnosis involving a gene never associated with lupus (MAN1B1, ETV6) was identified in 2 patients, explaining part of the phenotype but not the lupus. In addition, a research approach revealed numerous candidate genes, including SOCS1, PTPN2, and DOCK11, which were confirmed as responsible for the disease by collaborative and functional studies^3,4.

Conclusion: This study confirms the value of exome sequencing in pre-selected lupus patients with a diagnosis rate of more than 10% of monogenic SLE. It demonstrates the superiority of exome over panel in lupus, with genetic diagnosis of unexpected genes and the possibility of discovery-based approaches. Finally, the striking element is the high proportion of novel genes involved, demonstrating the dynamics of genetic discovery in this field.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Belot, A. et al. Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts. The Lancet Rheumatology2, e99–e109 (2020).

2. Omarjee, O. et al. Monogenic lupus: Dissecting heterogeneity. Autoimmunity Reviews18, 102361 (2019).

3. Hadjadj, J. et al. Early-onset autoimmunity associated with SOCS1 haploinsufficiency. Nat Commun11, 5341 (2020).

4. Boussard, C. et al. DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity. Blood blood.2022018486 (2023) doi:10.1182/blood.2022018486.

Correspondence: G. A. Robinson

Pediatric Rheumatology 2023, 21(Suppl 2):O14

Introduction: Cardiovascular disease is a leading cause of mortality for patients with systemic lupus erythematosus (SLE) through accelerated atherosclerosis. This is likely due to chronic inflammation and cardiometabolic defects that exacerbate with age. Mechanisms of atherosclerosis begin from an early age, particularly in young patients with juvenile-onset SLE, highlighting the importance of studying cardiometabolic risk over age in SLE.

Objectives: This study investigated detailed age-associated changes in the circulating metabolomic profiles of SLE patients and healthy controls (HCs).

Methods: Serum NMR metabolomics (>250 metabolites) of female SLE patients (n=164, age=13-72, mean age=37) and matched HCs (n=123, age=15-76, mean age=37) was assessed by linear regression and Venn analysis. Multiple t-tests (FDR-corrected) and MetaboAnalyst assessed unique metabolic changes and pathways by age group between patients/HCs (≤25, n=62/46; 26-49, n=50/46; ≥50, n=52/31). The impact of inflammation, SLE disease activity, and treatments on metabolites were also investigated. Disease-wide association analysis of metabolites of interest was performed using the Nightingale Atlas web-tool (data from the UK Biobank cohort).

Results: Twenty-five metabolites were significantly altered in all SLE age groups vs HCs, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets and HDL-associated apolipoprotein(Apo)A1 (p<0.0001). Importantly, ApoA1 correlated negatively with disease activity measures (SLEDAI, p=0.005; BILAG, p=0.0009; dsDNA, p=0.003). Strikingly, the metabolite signature was significantly associated with both atherosclerosis incidence and myocardial infarction (MI) mortality through disease-wide association analysis. Altered metabolites unique to different age groups in SLE vs HCs included reduced amino acids (≤25), increased very-low-density lipoproteins (26-49), and increased low-density lipoproteins (≥50). Separately, metabolites in the glycolysis pathway (p=0.004), including acetone, citrate, creatinine, glycerol, lactate, and pyruvate, had positive correlations with age in SLE patients, but not in HCs. Pyruvate (p=0.01) and lactate (p=0.009) were upregulated in prednisolone-treated patients, whilst citrate (p=0.002) and creatinine (p= 0.005) were downregulated in hydroxychloroquine-treated patients. Importantly, all of these SLE age-associated glycolysis metabolites had a significant disease-wide association with both type 1 and type 2 diabetes.

Conclusion: Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve disease and cardiometabolic outcomes. Biomarkers from the glycolytic pathway could decrease the adverse metabolic effects of current therapies.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: C. Kessel

Pediatric Rheumatology 2023, 21(Suppl 2):O15

Introduction: To date, several studies have validated the use of key biomarkers such as IL-18, CXCL9 and S100 proteins in diagnosis and monitoring of treatment response of systemic juvenile idiopathic arthritis (sJIA). Despite the promise of these biomarkers, their clinical utility is still limited by their overall lack of standardization.

Objectives: In this project we set out to cross-validate emerging systemic JIA biomarkers across different measurement platforms and different international centers to facilitate their wider introduction into routine clinical care.

Methods: In a first step healthy donor serum samples spiked with defined concentrations of recombinant S100 proteins, CXCL9, CXCL10, IL-18 and sCD25 were distributed in blinded manner among all participating centers (CARRA member sites: Cincinnati, Philadelphia, Toronto, Vancouver; PReS centers: Leuven, Muenster, Rome, Utrecht). Individual spiked protein levels were determined using locally established platforms including commercial ELISA, commercial/custom luminex, Ella and Mesoscale. In a second step patients’ samples enrolled in the FROST study will be distributed for respective biomarker analyses. All data will be analyzed for variances across different platforms and agreement across identical platforms in different labs.

Results: We observe extremely tight correlation of spiked IL-18 and CXCL9 levels with the amounts quantified by the employed measurement platforms (IL-18 R²=0.744-0.999, P<0.0001; CXCL9 R²=0.924-0.999, P<0.0001). However, the actual spike recovery of the individual assays varied substantially. While some assays met 90-100% spike recovery over almost the entire tested concentration range (1pg-500ng/mL), others consistently yielded high (approx. 500%) or low (approx. 60-70%) spike recovery. Further, our data determined the lower level of detection for each assay to provide consistent performance. At present, this analysis is extended to other spiked parameters and measurements in patients’ samples are in preparation.

Conclusion: Our spike recovery approach demonstrates - as expected - high correlation of individual assay results but widely divergent absolute concentrations measured. From our data we can now clearly identify assays with almost perfect spike recovery and calculate conversion factors for those that over- or underperform in their concentration output. This may allow for correction factors for IL-18 and CXCL9 levels (and others) quantified in future studies using the tested assay systems. We will further expand to utilize patient samples from the FROST study to validate the utility of correction factors. Altogether, the results from our study will enable wide interpretation and translation of respective biomarker data and pave the way towards their wider use in routine clinical practice and international collaborative studies.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

C. Kessel Grant / Research Support with: Novartis, Consultant with: Novartis and SOBI, R. Marsh: None declared, C. Wouters: None declared, P. Matthys: None declared, P. Proost: None declared, D. Foell Grant / Research Support with: Novartis, Pfizer and SOBI, Consultant with: Chugai-Roche, Novartis and SOBI, F. Minoia Consultant with: Novartis and SOBI, S. Canna Consultant with: AB2Bio and Novartis, G. Prencipe: None declared, C. Bracaglia Consultant with: Novartis and SOBI, F. De Benedetti Grant / Research Support with: AbbVie, Sobi, Pfizer, Roche, Sanofi, Novartis, Novimmune, Consultant with: AbbVie, Sobi, Pfizer, Roche, Sanofi, Novartis, Novimmune, D. Dissanayake: None declared, R. Laxer: None declared, S. Vastert Grant / Research Support with: Novartis and SOBI, Consultant with: Novartis and SOBI, K. Brown: None declared, D. Cabral: None declared, G. Schulert Grant / Research Support with: IpiNovyx, Consultant with: SOBI

Correspondence: P. Buthe

Pediatric Rheumatology 2023, 21(Suppl 2):O16

Introduction: Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that affects small- and medium-sized arteries of infants and children. Using biosamples from a phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki Disease (KD) patients, we recently identified leucin-rich-α2-glycoprotein-1 (LRG-1) as known trigger of endothelial activation and cardiac re-modelling to associate with IL-1β signaling in KD.

Objectives: In the present study we aimed to assess a potential role of LRG-1 in activation of human coronary artery endothelium in context of a complex inflammatory environment as in KD.

Methods: To mimic a multi-mediator inflammatory interplay, primary human coronary artery endothelial cells (HCAECs) were treated with patients’ (KD (n=8), sJIA (n=4), MIS-C (n=3)) serum conditioned medium or an inflammatory matrix (IM) from stimulated healthy control whole blood, with or without IL-1R1 (anakinra), IL-6R (tocilizumab), TNFa (adalimumab) or LRG-1 (magacizumab) neutralizing drugs or IVIGs and were analyzed for inflammatory activation or endothelial-mesenchymal transition (EndoMT) on gene expression level. IM samples (n=8), treatment naïve KD (n=10) or HC sera (n=10) were subjected to proximity extension proteomic analysis for cardiovascular and/or inflammatory markers (n=184).

Results: Proteomic analysis of KD sera (n=10) and IM (n=8) revealed elevation of 32 versus 45 inflammatory proteins, respectively, and shared 19 significantly upregulated markers. HCAEC culture with IM or patient sera resulted in inflammatory endothelial activation, which differed between KD, MIS-C and sJIA. Upon exposure to IM this was most efficiently abrogated by IL-1R1 inhibition, while particularly IL-6R and LRG-1 targeting as well as IVIG-treatment revealed no effect. However, inflammatory endothelial activation is closely linked to endothelial-to-mesenchymal transition (EndoMT), which is supported by respective signatures in our proteomic analysis of cardiovascular activation in KD sera (n=10). Among others, EndoMT can be mediated by TGFβ1-signaling. Yet, inhibition of LRG-1 as a modulator of TGFβ1-signaling did not impact EndoMT of HCAECs. Instead, particularly on the level of transition as well as mesenchymal markers, EndoMT was most consistently abrogated by IL-1R1 inhibition compared to other drugs or combinations of those.

Conclusion: While targeted LRG-1 inhibition had no effect on inflammatory HCAEC activation or EndoMT, both processes were profoundly impacted by anakinra treatment. These observations highlight a superior role of IL-1 signaling in EndoMT, particularly in context of a high-dimensional inflammatory environment, and complement our understanding of the cytokine’s prominent role in context of cardiovascular inflammation, arteriosclerosis, and myocardial fibrosis.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: F. Raggi

Pediatric Rheumatology 2023, 21(Suppl 2):O17

Introduction: In Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the mechanisms underlying the inflammatory processes within the joints and leading to polyarticular extension are poorly understood. However, the pathogenetic role of immune cells infiltrating the synovial environment is well known, and the involvement of extracellular vesicles (EVs) released by immune cells is being increasingly recognized. Many studies have focused on the effects of EVs released in synovial fluid (SF) of patients affected by adult rheumatic arthritis on disease progression. Immunologically active EVs are mainly released by macrophages (Mf) and T cells, participating in antigen presentation and immune regulation. A better understanding of the immunophenotypic profile of circulating and in situ infiltrated inflammatory cells in OJIA patients and of the surface protein cargo of released EVs may help earlier disease diagnosis and new therapeutic approaches.

Objectives: This study aimed at identifying specific immune cell subsets from samples of OJIA patients at disease onset, their activation markers, and expression of specific EV surface molecules, which could be used as indicators to predict polyarticular extension.

Methods: A total of 50 treatment-naïve OJIA patients was enrolled at the onset and followed-up for two years. Plasma (PL) and SF samples from 10 patients who presented an oligoarticular course (oOJIA) and 10 who developed a polyarticular course (pOJIA) were considered for the analysis. Mf and T cell subsets from PBMCs and SF mononuclear cells (SFMCs) were characterized by cytofluorimetry. Characterization of surface molecules of EVs isolated from SF and PL was carried out.

Results: SF-derived Mf in active joints of patients who developed pOJIA exhibit polarization toward the M1-like phenotype, as shown by predominance of the CD80 and the coexpressing CD80+/CD206+ or CD80+/CD163+ subsets respect to oOJIA patients associated with higher expression of the immunoregulatory receptor TREM1. No differences were observed in the M2 subsets between the groups of patients presenting the oOJIA and pOJIA course. PBMCs displayed the same percentage of M1 and M2, but higher presence of the CD206⁺/CD163⁺ subset in patients who developed pOJIA. A different state of T cell activation (HLADR⁺) in both PBMCs and SFMCs and a different ratio of Treg in the SMFCs were also observed in oOJIA and pOJIA patients providing discrimination between outcome groups, whereas no differences were detectable in the percentages of naive, central memory, effector memory, and terminally differentiated effector memory CD4⁺ and CD8⁺ subsets derived from SFMCs and PBMCs. Interestingly, analysis on EV surface cargo showed higher expression in pOJIA of the glycoproteins CD9, CD44, and CD11c whose relevance was demonstrated in adult arthritis where their targeting is proposed as drug delivery strategy in disease treatment.

Conclusion: These data suggest that the number of CD80+/TREM-1+ Mf and the Treg subset in the SF of OJIA patients at disease onset might be helpful for early prediction of persistent/extended-to-be patients. Similarly, the expression levels of specific surface markers on SF-derived EVs might have a potential predictive value. These data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new indicators for improving disease diagnostic accuracy.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: P. Brossard

Pediatric Rheumatology 2023, 21(Suppl 2):O18

Introduction: Macrophage activation syndrome (MAS) is a rare, life-threatening complication of rheumatic diseases that occurs most frequently in patients with Still’s disease (systemic juvenile idiopathic arthritis [sJIA] and adult-onset Still’s disease [AOSD]). MAS is characterized by overproduction of interferon γ (IFNγ) and other cytokines. Emapalumab, a fully human anti-IFNγ monoclonal antibody, is being investigated as a treatment for patients with MAS in rheumatic diseases.

Objectives: To develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to describe the PD effect of emapalumab in patients with MAS associated with sJIA/AOSD.

Methods: A PK model was developed using pooled data from 3 studies (n=58; 2709 samples): (i) an open-label, single-arm, phase 2/3 clinical trial of 45 patients who received emapalumab for primary haemophagocytic lymphohistiocytosis; (ii) a pilot, open-label, single-arm, phase 2 study of 14 patients who received emapalumab for MAS in sJIA; and a 1-year, long-term, follow-up study of patients from both studies. PK analysis was performed using nonlinear mixed effects modelling (NONMEM® version 7.5). Three linked PK/PD models were then developed on data from the 14 patients in study (ii) to characterize the relationship between emapalumab exposure and laboratory parameters associated with MAS, namely C-X-C motif chemokine ligand 9 (CXCL9), soluble interleukin-2 receptor alpha (sIL-2Rα), and ferritin. These PD parameters and their treatment-induced changes were characterized by turnover models. Parameters were assumed to be in steady-state at baseline with exposure-induced inhibition after treatment start. Predictive performance of the model was assessed using goodness-of-fit (GOF) plots and visual predictive checks (VPCs).

Results: Emapalumab PK was adequately described by a two-compartment model with first-order elimination that was constant at total IFNγ concentrations <~10⁴ pg/mL. Emapalumab clearance increased proportionally with total IFNγ concentrations. Estimated baseline levels of CXCL9, sIL-2Rα, and ferritin were 8400 ng/L, 6550 ng/L, and 15300 mg/L, respectively. A rapid PD response to changes in emapalumab concentration was observed. Emapalumab almost completely suppressed CXCL9, sIL2-Rα, and ferritin production (estimated reduction in synthesis rate: 98.3%, 87%, and 99.6%, respectively). Standard errors of all parameters obtained by a bootstrap procedure were <40% of their respective bootstrap means indicating good model precision. GOF plots and VPCs indicated good alignment between model predictions and observed concentrations for all parameters.

Conclusion: Population PK/PD modelling indicated that emapalumab rapidly suppresses CXCL9, sIL2-Rα, and ferritin production in patients with MAS associated with sJIA/AOSD.

Trial registration identifying number: ClinicalTrials.gov identifier: NCT01818492, NCT02069899 and NCT03311854.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

P. Brossard Employee with: Sobi, A. Facius Consultant with: Sobi

Correspondence: E. Aliyev

Pediatric Rheumatology 2023, 21(Suppl 2):PT001

Introduction: Chronic Non-bacterial Osteomyelitis (CNO) is an inflammatory bone disease described in the last decade and frequently encountered in rheumatology practice. Since the condition is not well known and often confused with malignancy and growing pains, it can be easily overlooked in practice. Therefore, auxiliary means are needed.

Objectives: In this context, our study aims to develop computer-savvy physician-friendly modeling for detecting the disease with the help of Artificial Intelligence (AI) and to test it on real individuals.

Methods: Eighty-three patients with CNO, nine patients with growth pain, nine patients with bone tumor, nine patients with juvenile idiopathic arthritis (JIA), and 30 healthy controls (HCs) who were followed up in Hacettepe University Pediatric Rheumatology Outpatient Clinics were included in the study. Data sets, including clinical and laboratory findings of the individuals at the time of diagnosis, were given as input to the AI model. Python® software language and Tensorflow® AI library were preferred for model development. Neural Network (NN) and Recurrent Neural Network (RNN) models were preferred in the development of Maverik. Maverik started with eight neurons and evolved to a 1000-neuron model with 84 inner layers at the end of the training. The laboratory and clinical results of the cases were digitized as 1, -1 (abnormal), and 0 (normal range). The data belonging to a total of 140 cases were increased 20-fold to 2800 with repetitions, 80% of which were randomized by the AI as training data and 20% as validation data. The homogeneity of the variables was tested by analysis of covariance (p=0.881).

Results: During the first minutes of model training, the error rate was approximately 0.44. In the following generations of Maverik, the error rate decreased to 0.019. This error rate was considered sufficient, and the training phase was terminated. Training continued autonomously in the latent phase. The training lasted a total of 62 minutes. The study was designed to be single blind. Thirty case data (data completely unfamiliar to the model) were asked to Maverik and the expert clinician, and their interpretations were compared. Regression analyses were performed between both groups to evaluate the diagnostic prediction success. Maverik accepted 70% and above as a definitive diagnosis of CNO, with a mean of 88.1% (71.33-96.3%). This rate was almost identical to the diagnostic acuity of clinicians (88.2% (5-100%)). There was no difference between Maverik's predictions and etalon diagnoses (p=0.812), and CNO was 100% successfully recognized in the disease. However, clinicians correctly recognized 15 of 17 CNO patients (88.3%). Maverik was not as accurate as clinicians in recognizing patients with growth pain, malignancy, and JIA in the mixed data set.

Conclusion: Our study is the first investigation in the literature to develop and test an AI model as a CNO diagnostic tool. The developed AI model performed better than the clinician in differentiating the CNO patient from the aforementioned differential diagnoses. This study shows that AI can help clinicians in the diagnostic stage and differential diagnosis. Maverik could not clearly distinguish the differential diagnoses because there were only HCs and CNO case data in the training set. The model will achieve better results with more data sets. In addition to all these, it seems likely that the model can be used as an additional diagnostic tool for clinicians outside the disciplines.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. Yazdany J, Bansback N, Clowse M, et al. Rheumatology informatics system for effectiveness: a national informatics-enabled registry for quality improvement. Arthritis Care Res (Hoboken) 2016;68:1866–73.

2. McMaster, C., Bird, A., Liew, D. F. L., Buchanan, R. R., Owen, C. E., Chapman, W. W., & Pires, D. E. V. (2022). Artificial Intelligence and Deep Learning for Rheumatologists. Arthritis & rheumatology (Hoboken, N.J.), 74(12), 1893–1905.

Correspondence: E. Aslan

Pediatric Rheumatology 2023, 21(Suppl 2):PT002

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is characterized by recurrent episodes of fever and self-limiting polyserositis [1]. Joint involvement and erysipelas like erythema are other major features, which are not rare in the course of disease. [2, 3]. Joint involvement is mainly in the form of non-erosive monoarthritis, which is frequently seen in the large joints of the lower extremities [2]. Moreover, 3-5%% of patients may develop chronic arthritis in the hips or knees [2, 4].

Objectives: In our study, we aimed to collect the demographic, clinical, and genetic data of patients with FMF. In the second-step analysis, we investigated the impact of various genotypes on the clinical features of FMF patients, with a special focus on joint involvement patterns.

Methods: A total of 782 patients were consecutively enrolled to the study according to their order of admission to the outpatient clinic between September 2022 and May 2023. The clinical, genetic, and laboratory data of 782 patients were obtained from patient files retrospectively and these data were also confirmed by patients/parents at the study visit. The study group was categorized into 2 groups: Group 1 (Patients carrying the 4 pathogenic MEFV variants [M694V, M694I, M680I, V726A] in a homozygous or heterozygous state) and Group 2 (FMF patients with other variants or no mutation).

Results: Of the 782 patients (292 in Group 1 and 490 in Group 2), 384 (49.1%) were female and the median age at disease onset and diagnosis were 3.0 (0.5-16) and 5.5 years, respectively. The frequency of colchicine resistance (n=15, 5.1% vs n=1, 0.2%; p<0.001), chest pain (n=80, 27.4% vs n=84, 17.1%; p=0.001), arthritis (n=93, 31.8% vs n=124, 23.3%; p<0.01), erysipelas like erythema (n=20, 6.8% vs n=10, 2.0 %; p=0.001), corticosteroid usage (n=10, 3.4% vs n=6, 1.2%; p<0.05), synthetic DMARD (n=20, 6.8% vs n=16, 3.3%; p<0.05) and biologic agent (n=61, 20.9% vs n=30, 6.1%; p<0.001) requirement were significantly higher in Group 1 than Group 2. Both of the patients (n=2) with renal amyloidosis were in Group 1. Patients in Group 1 were found to have a longer duration of arthritis and higher doses of colchicine were required in this Group.

Conclusion: FMF Patients with a pathogenic exon 10 mutation either in a homozygous or compound heterozygous state not only have higher rates of serositis, erysipelas like erythema and amyloidosis, but also tend to have more frequent joint involvement with a longer remission period.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Barut, K., et al., Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int, 2018. 38(1): p. 67-74.

2. Avar-Aydın, P.O., et al., The expanded spectrum of arthritis in children with familial Mediterranean fever. Clin Rheumatol, 2022. 41(5): p. 1535-1541.

3. Sozeri, B. and O. Kasapcopur, Biological agents in familial Mediterranean fever focusing on colchicine resistance and amyloidosis. Curr Med Chem, 2015. 22(16): p. 1986-91.

4. Özen, S., E.D. Batu, and S. Demir, Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management. Front Immunol, 2017. 8: p. 253.

5. Yildiz, M., et al., Evaluation of co-existing diseases in children with familial Mediterranean fever. Rheumatol Int, 2020. 40(1): p. 57-64.

Correspondence: K. Izawa

Pediatric Rheumatology 2023, 21(Suppl 2):PT003

Introduction: Cryopyrin-associated periodic syndrome (CAPS) comprises a spectrum of autoinflammatory disorders caused by gain-of-function mutations in NLRP3. Since 2009, genetic testing for autoinflammatory diseases has been provided as part of the Primary Immunodeficiency Database in Japan (PIDJ) project in Japan. Canakinumab was subsequently approved in 2011 for CAPS treatment.

Objectives: To assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan.

Methods: Clinical information was collected retrospectively, and the serum concentrations of canakinumab and were analyzed.

Results: A total of 103 patients were included in this analysis; 86 and 15 patients carried heterozygous germline and somatic mosaic mutations, respectively, and two were mutation negative. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with previous reports. Notably, 74.4% of patients achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment improved height gain, visual acuity, and renal function. However, 23.2% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, and two fatal cases were recorded. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory non-remitters developed inflammatory bowel disease unclassified (IBD-u) during canakinumab treatment. Dual biologic therapy with canakinumab and anti-TNF-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy.

Conclusion: This study provides one of the largest-scale epidemiologic datasets for CAPS. While early initiation of anti-IL-1 treatment is beneficial for improving disease prognosis, some patients do not achieve remission despite high serum concentration of canakinumab. Therefore, dual biological therapy may be an effective approach for such patients.

Patient Consent

Yes, I received consent

Disclosure of Interest

K. Izawa Consultant with: SOBI, Speaker Bureau with: Novartis, T. Miyamoto: None declared, Y. Honda: None declared, E. Hiejima: None declared, O. Ohara: None declared, J. Takita: None declared, T. Yasumi Speaker Bureau with: Novartis, Abbvie, R. Nishikomori Consultant with: Eli Lilly, Speaker Bureau with: Novartis

Correspondence: A. Kozlova

Pediatric Rheumatology 2023, 21(Suppl 2):PT004

Introduction: HSCT represents a well-characterized curative treatment option for classic inborn errors of immunity, affecting T and B lymphocytes. Yet, its applicability in monogenic autoinflammatory disorders, resistant to conservative treatment, is less studied, and its efficacy is not always obvious as many AID affect non-hematopoietic lineages as well

Objectives: To analyze HSCT results in a group of children with monogenic AID

Methods: We report HSCT results in 6 patients (2 males, 4 females), who underwent transplantation at our center to treat the following AIDs: PSTPIP1 defect – 3, MVK deficiency – 2, DNASE2 deficiency - 1. The latter patient underwent simultaneous kidney and hematopoietic stem cell transplantation. HSCT indications included lack of remission while on multiple lines of treatment in 3, myelodysplastic syndrome in 1, hemophagocytic lymphohistiocytosis development in 1, aplastic anemia and end-stage kidney disease in 1

Results: The age of disease onset was M 0 (0- 2,9) years, the age of HSCT M 10,1 (1,5- 12) years. The donors for the first HSCT were matched unrelated in 3 patients, haploidentical - in 3. Treosulfan-based conditioning was used in all patients. Graft rejection occurred in 3/6 patients, all of them underwent second HSCT: 2/3 - from matched unrelated, 1/3- from haploidentical donor. 1/3 died from HSCT complications after the second transplantation. Graft versus host disease (GVHD) occurred in 2/9 procedures. Currently 5 patients have 3,2 (2- 5,6) years follow-up, with full donor chimerism, full immune reconstitution and resolution of all AID symptoms

Conclusion: Based on our experience HSCT in AID represents challenging, yet potentially effective treatment. Conditioning and GVHD prophylaxis regiments require further investigation in a larger cohorts of patients

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: J. B. Kuemmerle-Deschner

Pediatric Rheumatology 2023, 21(Suppl 2):PT005

Introduction: Autoinflammatory diseases (AID) have been treated safely and effectively with the interleukin-1β inhibitor canakinumab (CAN) in controlled trials and routine clinical practice. The most common adverse event reported were infections.

Objectives: In this study infections and infection rates in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS) on CAN therapy were investigated in a real-world setting.

Methods: RELIANCE is a prospective, non-interventional, observational study in Germany enrolling pediatric (age ≥2 years) and adult patients with a clinically confirmed diagnosis of AID who routinely receive CAN. Efficacy and safety parameters are recorded at baseline and assessed at 6-month intervals.

Results: The present interim analysis is based on data from a total of n=232 patients including n=101 (44%) pediatric patients under 18 years diagnosed with autoinflammatory diseases enrolled in the RELIANCE registry. The median duration of CAN treatment before and during study in the pediatric cohort was 4 years (0−15 years).

Between 2017 and 2022, 898 adverse events (AE) were recorded in n=164 patients (71%). The incidence rate per 100 patient years (IR) was 163.82. Serious adverse events (SAE) were reported for n=35 patients (15%; 98 events, IR 17.88).

During the study, infections occurred in 54.5% of patients (55 patients, 131 AE, including 11 SAE). To closely monitor the impact of long-term CAN treatment on infection rates in pediatric patients, data from a total of n=53, 71, 83 and 80 pediatric patients enrolled in the study in 2019, 2020, 2021, and 2022 were compared. The IR of non-serious and serious infections in pediatric patients was 75.24 and 10.75 in 2019, and dropped to 44.90 and 4.99 in 2020, and 29.65 and 0.00 in 2021. The IR decrease might be caused by the periods of social distancing during the coronavirus pandemic in 2020 and 2021. In 2022, the IR of non-serious infections increased to 105.50 while the IR of serious infection stayed flat (IR 2.15). The course of upper respiratory tract infections IR in 2019, 2020, 2021, and 2022 was comparable to the IR of non-serious infections: 10.75, 8.32, 1.85, and 10.76. No cumulation of non-serious and serious infections under Canakinumab long-term treatment could be observed in the pediatric cohort.

Conclusion: Interim data of the RELIANCE study confirm that in the pediatric cohort the risk of infections including upper respiratory tract infections does not accumulate over 4 years under CAN treatment.

Patient Consent

Yes, I received consent

Disclosure of Interest

J. Kuemmerle-Deschner Grant / Research Support with: Novartis, AbbVie, Sobi, Consultant with: Novartis, AbbVie, Sobi, J. Henes Grant / Research Support with: Novartis, Roche, Consultant with: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, B. Kortus-Goetze Consultant with: Novartis, P. Oommen Grant / Research Support with: Novartis, A. Pankow: None declared, T. Kallinich Speaker Bureau with: Roche, T. Krickau Grant / Research Support with: Novartis, Consultant with: Novartis, Speaker Bureau with: Novartis, C. Schuetz Grant / Research Support with: Novartis, G. Horneff Grant / Research Support with: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Speaker Bureau with: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, I. Foeldvari Consultant with: Novartis, J. Rech Grant / Research Support with: Novartis, Sobi, Consultant with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, F. Weller-Heinemann: None declared, A. Janda: None declared, M. Hufnagel Grant / Research Support with: Novartis, F. Meier Speaker Bureau with: Novartis, F. Dressler Grant / Research Support with: Novartis, Consultant with: Abbvie, Mylan, Novartis, Pfizer, M. Borte Grant / Research Support with: Pfizer, Shire, I. Andreica Consultant with: Abbvie, Chugai, Novartis, UCB, Galapagos, Takeda, Astrazeneca, Lilly, Boehringer Ingelheim, Amgen, Sobi, Paid Instructor with: Astrazeneca, UCB, Speaker Bureau with: Abbvie, Chugai, Novartis, UCB, MSD, Lilly, Sobi, Astrazeneca, Amgen, Pfizer, Gilead, P. Wasiliew: None declared, M. Fiene: None declared, D. Windschall: None declared, J. Weber-Arden Employee with: Novartis, N. Blank Grant / Research Support with: Novartis, Sobi, Consultant with: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche

Correspondence: M. Macaraeg

Pediatric Rheumatology 2023, 21(Suppl 2):PT006

Introduction: SURF represents a heterogeneous group of disorders characterized by self-limited recurrent fevers and systemic autoinflammation without confirmed molecular diagnosis of a Hereditary Recurrent Fever syndrome, and not fulfilling criteria for Periodic Fever, Adenitis, Pharyngitis, Aphthous stomatitis syndrome (PFAPA), and is a cause of significant burden to affected families due to days of daycare or school missed for the child, and days of work missed for the parent. Very little is currently known about SURF, and many different phenotypes are likely encompassed by this term.

Objectives: Our primary objectives are to define the clinical manifestations, treatment responses, cytokine signatures, and genetic variants of SURF. Our secondary objective is to compare clinical manifestations and cytokine signatures of SURF patients to PFAPA.

Methods: We enrolled 47 patients followed at the Cincinnati Children’s Hospital (CCHMC) Autoinflammatory Treatment and Research Center with recurrent fever who met criteria for SURF and did not satisfy EULAR/PRINTO PFAPA classification criteria. Clinical course was followed over time. Cytokines were run using a multiplex Luminex assay. In some patients, whole exome sequencing was done, with focused analysis of 394 genes implicated in known inflammatory disorders as well as primary immunodeficiency syndromes. This research was approved by the Institutional Review Board of CCHMC and all patients or parents/guardians provided informed consent.

Results: Pharyngitis and adenopathy were present in a minority of SURF patients compared to PFAPA, while rash and arthralgias were significantly more common in SURF. There were no significant differences in serum levels of proinflammatory cytokines between SURF and PFAPA patients; however, SURF had more outliers with marked elevations in IL1b, IL6, IL8, IFNg, IL17a, IL18, and IL23. Hierarchical clustering shows a distinct subgroup of SURF patients with elevated IFNg, IL17a, IL12p70, and IL23 compared to PFAPA. Successful treatment strategies in SURF patients ranged from self-resolution to the need for anti-IL1 therapy. Genetic variants of unknown significance (VUS) were frequently found in patients with SURF, particularly in genes implicated in T and B cell development and function, granulocyte/monocyte function, immunodeficiencies, and IBD risk.

Conclusion: Our preliminary findings suggest SURF is a heterogeneous group of disorders that have distinct clinical and immunologic features, and treatment responses. We also find frequent VUS in pathways which may have relevance to disease pathogenesis, and possible associations to SURF endotypes. Further collaborative research is necessary to understand these SURF endotypes, what drives the disorder, and how physicians can better predict which treatment will be most successful for each patient.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: T. Moberg

Pediatric Rheumatology 2023, 21(Suppl 2):PT007

Introduction: Tonsillectomy is an established treatment for PFAPA today. Data on both short- and long-term impact are important when deciding if the child should undergo tonsillectomy or not. There is, however, a lack of data on follow-up, in particular on the long-term effects of the procedure.

Objectives: To describe the short- and long-term effects of tonsillectomy on PFAPA-episodes and PFAPA-related symptoms.

Methods: All patients diagnosed with PFAPA between 2006 and 2017 at the Queen Silvia Children's Hospital, NU Hospital Group and Skaraborg Hospital were identified. Medical records were reviewed and all patients that had undergone tonsillectomy after the onset of PFAPA were included. A structured telephone interview regarding PFAPA symptoms over time, the effect of tonsillectomy and symptoms at the time of follow-up was held with caregivers and patients ≥ 18 years of age. For patients <18 years of age at the time of follow-up, the interview was held with a caregiver only. Patients ≥18 years of age at follow-up were interviewed regarding present symptoms, and their previous caregiver regarding the effect of tonsillectomy and symptoms as a child.

Results: Out of 101 patients identified, 3 were excluded as they didn’t live in Sweden at follow-up. Of the remaining 98 patients, 86 (88%) accepted to participate in the study. Among patients ≥ 18 years of age that were interviewed, caregivers were unavailable in 4 cases, i.e., complete data set was available for 82 patients (84%).

Median follow-up time after tonsillectomy was 8.8 years (range 2.8-16.1) and median age at follow-up 14.8 years (range 6.0-28.8). Median age at onset of PFAPA was 1.8 years (range 0.1-16.0), median age at tonsillectomy 5.1 years (range 2.3-18.8) and median duration of symptoms at tonsillectomy 3.0 years (range 0.5-11.5). 58% of patients were male and 42% female.

Responses from caregivers showed that 36/82 (44%) of patients had complete resolution of all symptoms after tonsillectomy and symptoms did not return during the follow-up time. In 19/82 (23%) patients, the febrile episodes became milder or fewer after tonsillectomy, while in 17/82 (21%) patients, the febrile episodes disappeared, but other PFAPA-related symptoms persisted. In 9/82 (11%) patients, the febrile episodes disappeared but returned after a median time of 1 year (range 0,5-4,5 years). Finally, 1/82 patients (1%) did not have any effect of tonsillectomy.

Regarding symptoms at the time of follow-up, we found that 15/86 (17%) patients still had febrile episodes (>38°C). Out of them, twelve had episodes with regular intervals, two with irregular intervals and one had episodes triggered by exercise. Four patients were treated with colchicine, one with betamethasone and eight did not have any contact with healthcare providers. 17/86 (20%) still had regularly or irregularly recurring non-febrile PFAPA-related symptoms such as subfebrility, malaise, aphthae, pharyngitis, swollen lymph nodes, joint pain, abdominal pain and headache. Most described their episodes as similar to what they had experienced before tonsillectomy, but now milder and without fever. Twelve patients had recurring aphthae of whom nine had aphthae as their only symptom.

Conclusion: Tonsillectomy is an effective treatment for PFAPA. In some patients, however, the fever episodes reappeared and in some non-febrile symptoms of PFAPA continued. At long-term follow up, 17% still had febrile episodes and 20% still had other PFAPA-related symptoms. These results have implications when deciding if a child should undergo tonsillectomy or not, but also for the understanding of children with persisting or reappearing symptoms after tonsillectomy.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: S. Palmeri

Pediatric Rheumatology 2023, 21(Suppl 2):PT008

Introduction: Syndrome of undifferentiated recurrent fever (SURF) comprises a group of patients characterized by: i) recurrent fever episodes, ii) negative molecular analysis for genes associated with hereditary recurrent fevers (HRF), iii) absence or marginal incidence of the typical clinical features of PFAPA syndrome, iv) complete or good response to colchicine treatment.

Objectives: Aim of this study was to compare SURF, HRF and PFAPA patients enrolled in the Eurofever registry in order to identify evidence-based criteria that could help in the classification of SURF patients.

Methods: 59 pediatric SURF patients followed in a single tertiary center for Autoinflammatory diseases were enrolled in the Eurofever registry according to the inclusion criteria already published. A group of 188 pediatric patients (< 18 years of age) affected with confounding diseases (32 FMF, 32 TRAPS, 56 MKD, 31 CAPS and 37 PFAPA) validated by international experts has been used as historical disease control group. A decision trees approach was tested randomly splitting the available data in a training set (70%) and in an internal validation set (30%). The recursive partitioning (rPART) method was used to identify the optimal split of the data that would best classify autoinflammatory diseases patients into SURF or not SURF. Two fully grown decision tree classifiers with no limit on the complexity parameter were developed using i) a combinations of genetic and clinical data; ii) clinical data only with the exclusion of the genetic information. We then calculated the area under the receiver operating characteristic (ROC) curve (AUC), accuracy, sensitivity, and specificity of the decision tree classifier for predicting SURF vs NON-SURF.

Results: A total of 247 patients were included in the analysis and randomly split into a training set (N=186) and a validation set (N=61). All the performance values obtained in the training cohort and in the validation set are summarized in the Table 1. To support the decision tree results, an alternative model was created using a logistic regression model. The models including genetic information yielded better performance measurements compared to those without genetic information. According to the decision tree including the genetic analysis, the probability of being classified as SURF having a positive genetic test is 0%, while the same probability increased to 92% if the genetic test is negative and the patient does not present exudative tonsillitis. In the absence of a genetic test, patients showed a higher probability of being classified as SURF in the absence of triggers for episodes and pain at lymph nodes, negative family history, age of disease onset > 2 years, mean duration of episodes > 2.5 days. An external validation is ongoing.

Conclusion: Preliminary evidence-based classification criteria to differentiate SURF patients from the main causes of recurrent fevers in childhood are available. A decision tree including the genetic analysis yielded the highest accuracy. However, the decision tree was able to discriminate SURF patients from confounding diseases even in the absence of information on genetic analysis.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: C. Reiser

Pediatric Rheumatology 2023, 21(Suppl 2):PT009

Introduction: The National Pediatric Rheumatologic Database (NPRD) collects long-term data of children and adolescents including CNO. Scores are warranted to assess disease activity (DA) and inactive disease.

Objectives: To assess disease activity (DA) and outcome of CNO in the NPRD cohort with onset in childhood and adolescence using the recently proposed numeric composite disease activity score developed by the CARRA (1), in addition to a score adaptation including whole body MRI defined lesions.

Methods: From 2015-2021 patients with a confirmed diagnosis of CNO were included in this analysis and observed for up to 4 years. Here we report the first-year outcome, including denominators for active and inactive disease.

Results: 400 patients with a diagnosis of CNO were enrolled in the NRPD during the study period. The CARRA clinical DA score (CARRA CDAS) consists of the sum of three DA components (patient global DA and patient pain measured via numeric rating scale (NRS) + the number of clinical lesions). To underline the significance of the number of radiological lesions regarding long term outcome and therapeutic decisions, a score adaptation was considered, by exchanging the number of clinical lesions by MRI defined lesions: MRI CDAS (patient global DA, patient pain, MRI lesions). Inactive disease may be considered if each item of the scores shows a NRS below 1 and no lesions are noticed /detected. Compared to the CARRA Validation cohort, a mild to moderate DA could be shown. At baseline the CARRA CDAS is 6.7 (mean (standard deviation sd 5.4); median 5.5), compared to 4.9 ((4.9); 4) after one year.

Initial patient global DA (2.7), physician global DA (2.1) and clinical lesions (1.3) dropped to 2.0, 1.2, 0.9, respectively, MRI lesions, dropped from 2.2 to 1.8 after one year.

Conclusion: An improvement of DA was documented either in the individual score components, as well as in the newly set up CARRA CDAS as well as in the MRI CDAS, suggesting that the majority of CNO patients experiences an improvement in the first year of follow-up. Further score adaptation and validation, and the analysis of the complete follow up time of 4 years is planned. Composite numeric scores might help to describe CNO activity including inactive disease. The proposed composite CDAS/its variation might help to institute effective treatment modalities earlier.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Wu EY, Oliver M, Scheck J, Lapidus S, Akca UK, Yasin S, et al. Feasibility of Conducting Comparative Effectiveness Research and Validation of a Clinical Disease Activity Score for Chronic Nonbacterial Osteomyelitis. Rheumatology; 2022 Oct [cited 2023 May 12]. Available from: http://medrxiv.org/lookup/doi/10.1101/2022.10.03.22280351

Correspondence: Ö. Taş

Pediatric Rheumatology 2023, 21(Suppl 2):PT010

Introduction: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease characterized by recurrent, self-limiting episodes of fever and sterile serositis. Colchicine is the mainstay of treatment. Despite the maximum tolerated colchicine doses, approximately 5-10% of patients may respond inadequately to colchicine. Anti-IL-1 agents are important treatment options in these patients.

Objectives: Our aim is to investigate the characteristics of colchicine-resistant FMF patients who continue anti-IL-1 therapy and whose therapy can be discontinued.

Methods: Electronic medical records of colchicine-resistant FMF patients receiving anti-IL-1 therapy at two referral centers in Ankara were evaluated retrospectively. Demographic, clinical characteristics and disease severity of patients in whom anti-IL-1 treatment was continued and discontinued were compared. Disease severity was evaluated with the international FMF severity scoring system (ISSF).

Results: Among 64 colchicine-resistant FMF patients, 39 (61%) were female. The median age at the onset of symptoms was 3 years (6 months-15 years), age at the diagnosis was 5 years (6 months-16years), the mean follow-up duration was 117.05 ± 53.80 months and the mean duration of biological use was 44.65±30.53 months. All patients received colchicine therapy along with anti IL- 1 agent. Treatment of 26 (40.6%) patients was started with anakinra, 38 (59.4%) with canakinumab. Eighteen of the patients receiving anakinra were switched to canakinumab. During follow-up, anti-IL-1 treatment was discontinued in 23 (35.9%) patients. Mean duration of biological use in these patients was 35.39±24.18 months, and median follow-up period was 40 months (6-81) after the drug was discontinued. Re-treatment was initiated in 1 patient. All clinical and demographic characteristics, colchicine doses, pre and post-biological ISSF scores of both groups were compared. ISSF scores before biological treatment were significantly higher in whom biological therapy could not be discontinued (mean 4.03±1.59) compared to those who could be discontinued (mean 3.13±1.10) (p<0,009). Even it was not statistically significant, the age at disease onset was lower and leg pain was less common in the group of patients that biologic treatment could be discontinued (p=0,06).

Conclusion: There is no definitive recommendation for the optimal duration and discontinuation of biological therapy for colchicine-resistant FMF patients. Low ISSF scores before biological treatment may predict the discontinuation of biologic agents in colchicine-resistant pediatric FMF patients.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: H. I. Brunner

Pediatric Rheumatology 2023, 21(Suppl 2):PT011

Introduction: The phase 3, IV Golimumab in Pediatric Participants with Active Polyarticular-Course JIA Despite Methotrexate (GO-VIVA) study demonstrated that golimumab (GLM) 80 mg/m² at Week 0, 4 and every 8 weeks thereafter is well-tolerated and effective in children 2 to < 18 years of age with active polyarticular-course juvenile idiopathic arthritis (pcJIA) despite methotrexate over 52 weeks (W).

Objectives: To evaluate the pharmacokinetics (PK), immunogenicity, efficacy, and safety of GLM in GO-VIVA participants (pts) who continued into the long-term extension (LTE).

Methods: Pts from GO-VIVA who continued GLM 80 mg/m² IV q8w (max single dose 240 mg) after W52 were included. PK and immunogenicity were assessed through W244, and safety was assessed through W252. Efficacy measures included JIA ACR response from baseline (start of GLM), clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS-10) minimal disease activity (cJADAS-10 MDA), inactive disease (cJADAS-10 ID) and remission (≥ 6 continuous months of cJADAS-10 ID). These were analyzed using an intent-to-treat (ITT) approach through W116, due to a protocol amendment instituted during the LTE that limited efficacy data collected after W116. Non-responder imputation was used for missing data.

Results: Of the 127 pts treated, 112 (88.2%) continued into the LTE, and 69 (54.3%) completed GLM through W244 and had a W252 assessment. W244 median steady-state trough GLM concentration was 0.61 μg/mL (mean ± SD: 0.66 ± 0.569μg/mL; N=31). Median steady-state trough serum GLM concentrations ranged from 0.29 to 0.61 μg/mL, indicating that exposure was maintained over time. Median trough GLM concentrations at W244 were similar across different age categories and body weight quartiles. At each visit for which efficacy was evaluable, the majority of pts had JIA ACR 30 (72%-77%), JIA ACR 50 (71%-76%), and JIA ACR 70 (62%-68%) responses, and approximately 50% had JIA ACR 90. The majority of pts had cJADAS-10 MDA, 41%-49% achieved cJADAS-10 ID, and 28-33% achieved remission. Antibodies to GLM were detected in 56 (44.8%) of pts. Of these 56 pts, 35 were positive for neutralizing antibodies (Nab) with an overall incidence of NAb of 31% (35/112). No new or unexpected safety events were reported. 92.1% of pts experienced ≥ 1 AE. SAEs were reported in 19.7% of pts. One death (septic shock) occurred.

Conclusion: PK exposure through the end of the LTE was consistent to that observed through W52. Although analyses were limited by protocol modification, data through W116 suggest an efficacy benefit with additional treatment and achievement of clinically important endpoints for pts who continued in the LTE. GLM was generally well tolerated with an acceptable long-term safety profile through W252.

Trial registration identifying number: NCT02277444

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

H. Brunner Grant / Research Support with: The Cincinnati Children’s Hospital, where HBR works as a full-time public employee, has received contributions from the following industries in the past 3 years: Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, F. Hoffmann-La Roche, Janssen, Novartis, and Pfizer. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment to third parties, Consultant with: AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, F. Hoffmann-La Roche, Janssen, Merck, Novartis, R-Pharm, Sanofi, Speaker Bureau with: Novartis, Roche, GlaxoSmithKline , D. Lovell Grant / Research Support with: Janssen Research & Development LLC, Bristol Meyers Squibb, Roche Laboratories, Consultant with: United Bioscience Corporation, AstraZeneca, GSK, Pfizer (Consultant & Member of Advisory Board), Novartis, Speaker Bureau with: Novartis, Pfizer, S. Ringold Employee with: Janssen Research & Development, LLC, X. Xu Shareholder with: Johnson & Johnson, Employee with: Janssen Research & Development, LLC, E. Lam Shareholder with: Johnson & Johnson, Employee with: Janssen Research & Development, LLC, Y. Wang Shareholder with: Johnson & Johnson, Employee with: Janssen Research & Development, LLC, J. Leu Shareholder with: Johnson & Johnson, Employee with: Janssen Research & Development, LLC, A. Martini Consultant with: Eli-Lilly, EMD Serono, Janssen, Novartis, Pfizer, AbbVie, Idorsia, Boheringer, N. Ruperto Grant / Research Support with: The IRCCS Istituto Giannina Gaslini (IGG), where NR works as full-time public employee has received contributions from the following industries: Bristol Myers and Squibb, Eli-Lilly, F Hoffmann-La Roche, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties, Consultant with: 2 Bridge, AMGEN, AstraZeneca, Aurinia, Bayer, BMS, Celgene, Cambridge Healthcare Research (CHR), Domain Therapeutic, Eli Lilly, EMD, GSK, Idorsia, Janssen, Novartis, Pfizer, UCB, Speaker Bureau with: 2 Bridge, AMGEN, AstraZeneca, Aurinia, Bayer, BMS, Celgene, Cambridge Healthcare Research (CHR), Domain Therapeutic, Eli Lilly, EMD, GSK, Idorsia, Janssen, Novartis, Pfizer, UCB

Reference

1. Ruperto N, Brunner HI, Pacheco-Tena C, Louw I, Vega-Cornejo G, Spindler AJ, Kingsbury DJ, Schmeling H, Borzutzky A, Cuttica R, Inman CJ, Malievskiy V, Scott C, Keltsev V, Terreri MT, Viola DO, Xavier RM, Fernandes TAP, Velázquez MDRM, Henrickson M, Clark MB, Bensley KA, Li X, Lo KH, Leu JH, Hsu CH, Hsia EC, Xu Z, Martini A, Lovell DJ; Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organisation (PRINTO). Open-label phase 3 study of intravenous golimumab in patients with polyarticular juvenile idiopathic arthritis. Rheumatology (Oxford). 2021 Oct 2;60(10):4495-4507. doi: 10.1093/rheumatology/keab021. PMID: 33493312; PMCID: PMC8487314.

Correspondence: F. De Benedetti

Pediatric Rheumatology 2023, 21(Suppl 2):PT012

Introduction: A 12-week (W) open-label, dose-finding study evaluated three subcutaneous doses of sarilumab in two weight groups of pts with pcJIA (Group A/B: body weight ≥30 kg/ ≥10 kg–<30 kg])¹. Based on the results, Dose 2 (3/4 mg/kg every 2 weeks (q2w) for Group A/B) was selected for further evaluation in an extension phase and with additional pts.

Objectives: To present 1-year data of pcJIA pts who received Dose 2 from baseline (BL)

Methods: This phase 2b, open-label, multicentre study comprised a 12W core dose-finding phase and an extension phase. It enrolled pcJIA pts aged 2–17 years. Primary endpoint: sarilumab pharmacokinetic exposure from BL to W12. Secondary endpoints: JIA ACR response rate and safety

Results: Of 73 pts (Group A/B: n=42/31) treated, majority were female (79.5%) with mean (SD) age of 9.5 (4.7) years (Group A/B: 12.6 (3.0)/ 5.4 (3.1) years) at BL. Mean (SD) disease duration and cJADAS10 was 2.48 (3.28) and 20.07 (4.09), respectively. Among them, 17.8% had RF+ polyarticular JIA. Concomitant use of conventional synthetic DMARD (mainly methotrexate) and systemic glucocorticoids (GC) were noted in 84.9% and 13.7% of the pts, respectively; 19.2% pts had prior treatment with biologic DMARD (mainly TNFi).

The observed C_trough were comparable in both groups and were 7.49 to 9.47 mg/L at W12 and 11.6 to 14.2 mg/L at W48. JIA ACR 70/90 response rates were 80.9%/45.6% (Group A: 74.4%/43.6%; Group B: 89.7%/48.3%) at W12 and 93.8%/76.6% (Group A: 89.5%/68.4%; Group B: 100%/88.5%) at W48. Proportion of the pts who reported cJADAS-10≤2.5, clinically inactive disease (CID) as per Wallace criteria with no systemic GC use and clinical remission (CID for 6 consecutive months) at W48 were 73.4%, 60.9% and 51.6%, respectively.

Treatment-emergent adverse events (AEs) were reported in 95.9% of the pts at W48; infections (79.5%) were the most common. Grade 3/4 neutropenia (AE of special interest) were reported in 27.4% pts at W52; all of them recovered within a few days and were not associated with increased infection risk. Six (8.2%) pts experienced 9 serious AEs (acute sinusitis, bone tuberculosis, tonsillar hypertrophy, inguinal hernia, pancreatic pseudocyst, acute pancreatitis, JIA, ligament rupture, meniscus injury) which were deemed unrelated to study drug by investigators. AEs leading to permanent treatment discontinuation (9.6%, 7 pts) were mostly neutropenia. No deaths were reported.

Conclusion: At steady state in pcJIA pts with Dose 2, exposure was comparable among the two body weight groups and was similar to that with the 200 mg q2w in adult pts with RA. There was a clinically relevant improvement in disease activity, with more than half of pts achieving remission at W48. Safety was consistent with the known profile of sarilumab.

Trial registration identifying number: NCT02776735

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

F. De Benedetti Grant / Research Support with: AbbVie, Novartis, Novimmune, Pfizer, Roche, Sanofi, SOBI and UCB, Consultant with: Roche, SOBI and Novartis, I. Calvo Penadés Grant / Research Support with: AbbVie, Bristol-Myers Squibb, Clementia, MSD, Novartis, Pfizer, Roche and Sanofi, Speaker Bureau with: AbbVie, Novartis, Roche and SOBI; and has participated in advisory boards for AbbVie and Novartis, I. Nikishina Speaker Bureau with: Novartis, MSD, Pfizer, AbbVie, Hoffmann-La Roche, Janssen and Ipsen, I. Foeldvari Speaker Bureau with: Pfizer (also advisor), A. J. Spindler Speaker Bureau with: Eli Lilly, A. Kozlova: None declared, N. Rubio-Pérez Speaker Bureau with: AbbVie and Roche, P. Quartier Consultant with: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi (also member of a data safety monitoring board), and SOBI, Speaker Bureau with: AbbVie, Bristol-Myers Squibb, Chugai-Roche, Novartis, Pfizer, and SOBI, Z. Żuber: None declared, R. Barria Consultant with: Tecnofarma, Speaker Bureau with: Pfizer and Roche, D. Clemente Speaker Bureau with: Novartis and Roche, G. Vega Cornejo Grant / Research Support with: Bristol-Myers Squibb, Parexel, and Sanofi, K. Marzan Grant / Research Support with: Sanofi, Novartis and Pfizer, N. Liu Shareholder with: Sanofi, Employee with: Sanofi, C. Xu Shareholder with: Sanofi, Employee with: Sanofi, M. C. Nivens Shareholder with: Regeneron , Employee with: Regeneron , A. Giannelou Shareholder with: Regeneron, Employee with: Regeneron, B. Akinlade Shareholder with: Regeneron, Employee with: Regeneron, L. Baret-Cormel Shareholder with: Sanofi, Employee with: Sanofi

Reference

1. Benedetti FD, et al. Annals of the Rheumatic Diseases 2019;78:969-970.

Correspondence: T. Herlin

Pediatric Rheumatology 2023, 21(Suppl 2):PT013

Introduction: Inflammatory biomarkers have been suggested to reflect disease activity in juvenile idiopathic arthritis (JIA) and contribute to the prediction of clinical outcome.

Objectives: To evaluate serum biomarkers obtained early during disease as predictors for disease activity and remission status at long-term follow-up (FU) 18 years after disease onset.

Methods: Patients from the population-based Nordic JIA cohort study were recruited close to disease onset from defined regions of Nordic countries between 1997-2000. Clinical data and serum biomarkers were obtained at baseline (6 (-1/+2) months from disease onset) and at 18-yr FU. S100 proteins, and 14 other inflammatory biomarkers (cytokines, chemokines) were determined by multiplexed bead array assay. The analyzing laboratory in Münster was blinded for the patients’ clinical data. We estimated both univariate and multivariate logistic regression models on binary outcomes of disease activity and remission with baseline variables as explanatory variables.

Results: Of the 510 patients from the Nordic JIA cohort, serum samples from 236 patients at baseline were available. Median JADAS10 at baseline was 5.0 (IQR 2.0-11.0) compared to 2.0 (IQR 0.0-6.4) at FU. Inactive disease at 18-yr FU was observed in 58% and remission off medication in 39% of the patients. No significant difference in clinical characteristics between the group of patients with baseline serum samples and the remaining group without blood samples was found. Computing receiver operating characteristics (ROC) illustrating the area under the curve (AUC) for the prediction of active disease at 18-Y FU we found that significant levels of AUC were obtained for baseline levels of IL-1β, IL-6, IL-12p70, IL-13, MMP-3, S100A9 and S100A12 as well as for ESR, and number of active and cumulative joints at the baseline visit. Nested multivariate logistic regressions models were compared in analysis of variance. We compared a traditional clinical model (with the variables gender, age, joint counts, ESR/CRP) and a combined clinical and biomarker model (clinical variables as above plus 16 biomarkers obtained at baseline: IL-1ß, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17A, IL-18, TNFα, MMP-3; CCL-2, sCD25, GM-CSF, MPO, S100A9, S100A12). We found that the biomarkers significantly added to the explanatory value predicting the outcome regarding inactive/active disease at 18-yr FU (AUC increased from 0.59 to 0.80, p=0.024). Multiple regression analysis revealed S100A9 as the strongest predictor for active/inactive disease at long-term outcome, controlling for the other variables.

Conclusion: Biomarkers of inflammation obtained within the first 6 months after JIA onset may complement the characterization of disease activity and contribute to improved future prediction models of long-term outcome.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: K. Mclellan

Pediatric Rheumatology 2023, 21(Suppl 2):PT014

Introduction: Temporomandibular joint(TMJ) synovitis remains challenging in juvenile idiopathic arthritis(JIA) management. The American College of Rheumatology(ACR) 2021 JIA management guidelines identified TMJ involvement as a risk factor for poor outcome and conditionally as an indication to escalate systemic treatment.

Objectives: To review management of TMJ synovitis in our centre; identify the demographic with radiologically-proven TMJ synovitis, presence of damage and referral to maxillofacial services.

Methods: Case note retrospective review of children with TMJ synovitis confirmed radiologically at Great Ormond Street Hospital over 12-month period.

Results: 57 patients with JIA had a TMJ MRI; 45(79%) female. 12(17%) had MRI at diagnosis, 10(14%) within a year and 14(20%) 1 to 5 years from diagnosis. Indications for TMJ MRI were pain (71%), restricted movement (38%) and jaw swing (58%). 60% had other active joints.

The most common ILAR subtype with TMJ synovitis was oligoarticular JIA 26(46%) (18 ANA+), followed by polyarticular rheumatoid factor(RF)-negative 12(21%), enthesitis-related 6(11%), polyarticular RF-positive 4(7%), systemic 4(7%), psoriatic 3(5%) and inflammatory bowel disease-related 2(4%).

Of 58 JIA TMJ scans, 45(78%) were abnormal; 42(75%) had active synovitis and a further 2(3%) had biomechanical changes. 29/45(64%) had bilateral changes.

Of the 45 abnormal TMJ JIA scans, 44(98%) had synovial enhancement, 24(52%) condyle flattening/irregularity, 17(37%) erosions, 10(22%) oedema and 8(18%) effusion.

36/44(82%) JIA patients with radiologically-proven TMJ synovitis had a change in treatment; 26(72%) had other active joints. Of the 18 patients with TMJ synovitis, without other active joints,11 had a change in their medication; 6 started a biologic, 1 started methotrexate, 1 switched biologic and 3 had doses optimised; 7 had no change in management.

Of 44 JIA with TMJ synovitis, 7 were already under maxillofacial services and 14 new patients (38%) referred. 5 patients had surgical intervention, including 1 new referral.

Conclusion: Diagnosis of TMJ synovitis, with absence of early clinical findings, is challenging. In our cohort, 53% of JIA TMJ MRI scans had joint damage. Furthermore 64% had bilateral changes.

With a high proportion of abnormal scans, erosions and bilateral involvement, we highlight the importance of early MRI. TMJ synovitis should be systematically screened for using the published tools. We also raise the question of screening TMJ MRIs in a subset of JIA patients; oligoarticular JIA accounted for the highest proportion of TMJ synovitis in our cohort. Identifying subclinical TMJ synovitis is especially important in this cohort as this would influence management.

Intra-articular TMJ steroid injections have been shown not to reduce joint damage and may worsen osseous changes. In our JIA cohort with isolated radiologically-confirmed TMJ synovitis, 61% had a change in management. We suggest that all young people with TMJ synovitis should be referred to maxillofacial services for interdisciplinary management.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: F. Milatz

Pediatric Rheumatology 2023, 21(Suppl 2):PT015

Introduction: Previous studies have shown that growing up with rheumatic conditions can fuel dissatisfaction and psychological distress, which in turn affects disease self-management and treatment adherence [1].

Objectives: Primary objective of this study was to estimate the prevalence of anxiety and depression symptoms in adolescents and young adults (AYA) with juvenile idiopathic arthritis (JIA) and to identify correlates of conspicuous screening.

Methods: Initiated as part of the COACH multicentre observational study, outpatients aged 12 to 21 years participating in the National Paediatric Rheumatological Database (NPRD) were prospectively screened for mental health using the Patient Health Questionnaire-9 (PHQ-9) and the Generalised Anxiety Disorder Scale-7 (GAD-7). Scores ≥7 on either instrument were considered conspicuous. In order to consider potential seasonal and pandemic influences in the study period, correlates were identified by regression analysis adjusted for screening date.

Results: Data from 1,150 adolescents with JIA (mean age 15.6 ± 2.2 years; mean disease duration 7.2 ± 4.9 years, 69% female, 43% oligoarthritis, 26% polyarthritis) from 48 paediatric rheumatology centres were analysed. Overall, 32.7% (n=316) of AYA had conspicuous screening, of whom 30.4% (n=96) reported suicidal or self-harm thoughts (nearly 12% of all screened participants). One in three conspicuously screened patients was receiving psychotherapeutic (25.9%) and/or psychopharmacological (13.6%) treatment. Adolescents with conspicuous screening were older (15.8 vs. 15.2 years; p<.0001), more often female (81% vs. 64%; p<.0001) and overweight (25% vs. 17%; p=0.006). They had higher disease activity (physician global assessment on NRS 0-10; 1.7 vs. 1.2; p<.0001), more functional limitations (CHAQ; 0.44 vs. 0.14; <.0001), and rated their health status worse (NRS 0-10; 3.5 vs. 1.8; p<.0001) than inconspicuous screened patients. Females (OR 2.33 [CI 1.53-3.56]; p<.0001), older patients (OR 1.09 [CI 1.01-1.18]; p=0.026), patients with more functional limitations (OR 3.36 [CI 1.98-5.72]; p<.0001), and patients with worse subjective health status (OR 1.17 [CI 1.07-1.27]; p<.0001) were more likely to be conspicuously screened. Regular sports participation was associated with a lower likelihood of conspicuous screening (OR 0.69 [CI 0.49-0.98]; p=0.039).

Conclusion: A large-scale outpatient screening of adolescents and young adults with juvenile idiopathic arthritis in Germany uncovered a high prevalence of anxiety and depression symptoms., as well as psychological undertreatment. The need for routine screening to identify this issue and provide optional support to affected patients has become evident.

The COACH project was funded by the BMBF (01GL1740F) and the NPRD was financially supported by the German Children's Rheumatism Foundation, Abbvie, Chugai, GSK, Novartis and Pfizer to date.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Reference

1. Fair DC, et al. Depression and anxiety in patients with juvenile idiopathic arthritis: current insights and impact on quality of life, a systematic review. Open Access Rheumatol Res Rev 2019;11:237–52.

Correspondence: S. M. Orsi

Pediatric Rheumatology 2023, 21(Suppl 2):PT016

Introduction: The measurement of disease activity level is of central importance in the evaluation of the patient with juvenile idiopathic arthritis (JIA). The Juvenile Arthritis Disease Activity Score (JADAS) and its clinical version excluding the acute phase reactant (cJADAS) were validated and are increasingly used in clinical trials and routine practice. To allow score interpretation, cutoffs have been developed and subsequently validated for JADAS10 and cJADAS10 in RF- polyarthritis and oligoarthritis. The need to have cutoffs for other arthritis categories is increasingly evident.

Objectives: To validate the JADAS10 and cJADAS10 disease activity state cutoffs to separate the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with RF+ polyarthritis, PsA and ERA.

Methods: JIA children from 49 countries included in the EPidemiology, treatment and Outcome of Childhood Arthritis (EPOCA) study were considered. For PsA and ERA, the decision on whether to use oligoarthritis or polyarthritis cutoffs was based on the most frequent pattern of joint involvement at visit. Discriminative ability was assessed by calculating and comparing in each disease activity state the level of pain (0-10 VAS) and functional ability impairment (measured with the Juvenile Arthritis Functional Ability Score, JAFS, 0-45) and the frequency of patients satisfied with current disease state, starting a new medication, and having morning stiffness. Comparisons of quantitative variables among groups were made by Kruskal-Wallis test; Dunn’s test was used to assess differences between pairs of patient groups. Percentage data were compared by chi-squared test or Fisher’s exact test. Bonferroni’s adjustment was applied to explore post-hoc differences between pairs of patient groups.

Results: 309 children with PsA, 959 with ERA, and 382 with RF+ polyarthritis were included. 88% children with PsA and 91% with ERA had oligoarticular disease, at study visit; therefore, oligoarthritis cutoffs were used for these categories.

The level of pain and functional ability was significantly different among the JADAS-based disease states, with pain and JAFS scores increasing progressively from ID to HDA (Kruskal-Wallis test p <0.001). The percentage of patients who prescribed a new medication, with morning stiffness < 15 minutes, and who were satisfied with current disease state were different in the JADAS-based disease states. Paired comparison showed significant discrimination for most comparisons.

Conclusion: Both the JADAS10 and cJADAS10 cutoffs to define disease activity states validated for oligoarthritis and polyarthritis showed good discriminative validity in RF+ polyarthritis, PsA and ERA. These results preliminarily indicate that available cutoffs might be used for these categories of JIA.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: F. Ridella

Pediatric Rheumatology 2023, 21(Suppl 2):PT017

Introduction: The parent Juvenile Arthritis Disease Activity Score (parJADAS)¹ is a disease activity tool developed specifically for remote monitoring of patients with Juvenile Idiopathic Arthritis (JIA). It relies solely on the patient or parent perception of disease activity. Previous studies have demonstrated the excellent discriminant ability¹, reliability² and good criterion validity² of parJADAS.

Objectives: This study aimed to establish the cut-off values of moderate disease activity (MoDA) and high disease activity (HDA) for the parJADAS in patients with JIA.

Methods: The parJADAS (score range 0-40) is derived by summing four values: 1) parent’s assessment of disease activity on a 21-numbered circle 0-10 Visual Analogue Scale (VAS); 2) assessment of pain intensity on a 21-numbered circle 0-10 VAS; 3) proxy assessment of active joints, up to a maximum of 10 joints; 4) assessment of morning stiffness (MS) on a Likert scale, ranging from no MS (0 points) to > 2 hours of MS (10 points). The study dataset is composed of 8772 patients with JIA, which were enrolled in the the multinational study “Epidemiology, Treatment and Outcome of Childhood Arthritis” (the EPOCA study). At each visit, the attending physician subjectively categorized the patients into one of the following disease activity states: inactive disease (ID), minimal disease activity (MDA), moderate disease activity (MoDA), or high disease activity (HDA). The following methods were implemented to establish the cut-off values for parJADAS: 1) Mapping: the 25^th percentile value of the parJADAS in patients classified as MoDA or HDA, respectively; 2) Youden Index: Youden Index (J) identifies the maximum potential effectiveness of the biomarker through the Receiver Operating Characteristic (ROC) curve analysis. The proposed cut-offs for both MoDA and HDA were subsequently calculated as the mean of the two obtained values with the aforementioned methods, for each disease activity state.

Results: Data from a total of 2,146 patients with moderate disease activity (MoDA) and 343 patients with high disease activity (HDA) were analyzed. For MoDA, the obtained cut-off value using the mapping approach was 6.5. The ROC curve analysis demonstrated an area under the curve (AUC) of 0.829 (95% CI 0.821 to 0.837). The ROC analysis further yielded a Youden Index of 5, indicating a sensitivity of 82.5% and specificity of 68.9% for the identified cut-off value. Regarding HDA, the mapping approach yielded a cut-off value of 13.25. The ROC curve analysis showed an AUC of 0.870 (95% CI 0.863 to 0.877). The Youden Index was calculated as 9.5, indicating a sensitivity of 85.7% and specificity of 71.4% for the determined cut-off value. The proposed cut-off values for moderate disease activity (MoDA) and high disease activity (HDA) were determined as the mean of the values obtained from both the mapping approach and the Youden index approach for each disease state. For MoDA, the mean value was calculated to be 5.75, while for HDA, the mean value was determined as 11.375. These values were rounded to ≥5.5 for MoDA and ≥11 for HDA, representing the clinically relevant cut-offs for distinguishing between different disease activity states in Juvenile Idiopathic Arthritis (JIA) patients.

Conclusion: Tentative cut-off values for classifying the states of MDA and HDA using parJADAS were calculated. The obtained values will be tested in the validation analysis. Once validated, the cut-offs are ideally suited to identify subjects at risk of disease flare when remotely monitored with the parJADAS; subsequently, these are the patients to be soon referred to their Pediatric Rheumatology Center for a comprehensive clinical examination.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. Ridella et al. Annals of the Rheumatic Diseases, volume 78, Issue Suppl 2. Abstract “Discriminant ability of the parent version of the Juvenile Arthritis Disease Activity Score in a large multination cohort of patients with Juvenile Idiopathic Arthritis“

2. van Dijkhuizen et al. Arthritis Care Res (Hoboken) 2023 Feb;75(2):391-400. doi: 10.1002/acr.24855. „Validity and Reliability of Four Parent/Patient–Reported Outcome Measures for Juvenile Idiopathic Arthritis Remote Monitoring“

Correspondence: N. S. Shevchenko

Pediatric Rheumatology 2023, 21(Suppl 2):PT018

Introduction: Since September 2014, a medical reform has been initiated in Ukraine. At the beginning of 2022, the primary and secondary stages were reformed. Against this background, there are no clear data on the prevalence and incidence of rheumatic diseases in children, including juvenile idiopathic arthritis (JIA).The main feature of 2022 in Ukraine was the massive migration of the population. More than 10 million people became internally displaced persons: about 6.5 million became internally displaced persons, about 4 million more left the territory of Ukraine. The huge migration of displaced persons has placed a high strain on existing medical facilities in the western regions of the country and created additional barriers to accessing medical care.

Objectives: The purpose of the study was to clarify the state of specialized care for children with JIA.

Methods: An analysis was made of the work of specialists - pediatric rheumatologists of Ukraine on changes in the contingent of children with JIA for 2022.

Results: According to the data of 2017-2019, the number of children with JIA in Ukraine reached 2800 people. The current Ukrainian protocol for the treatment of JIA was introduced on July 22, 2012 ¹, and was based on the American Protocol for the Treatment of JIA - ACR 2011. In Ukraine, the concept of treat to target ² has been introduced, according to which basic biological anti-inflammatory therapy (BBT) is prescribed in case of ineffectiveness of traditional treatment for 3-6 months. Unresolved issues include an insufficient range of biological agents registered for pediatric patients. The second problem is the lack of recommendations on the appointment of BBT as a starting or monotherapy for certain types of JIA (systemic arthritis, polyarthritis, spondylarthritis with active enthesitis).

A sufficiently large number of children with JIA remain under the supervision of Ukrainian pediatric rheumatologists, despite the massive departure of patients from Ukraine to other countries. Among the total number of patients in Ukraine, children who fell ill in 2022 range from 15 to 20%. State funding for the treatment of children with JIA continues. Children receive BBT, including about 40% of patients who fall ill in 2022. Average number of patients with JIA who receive BBT in Ukraine is 30%. The main problem was the interruption of BBT for more than three months due to the closure of the medical institutions or the child's move to another place of residence. Activation of the inflammatory process occurred in 83.3% of such cases.

Conclusion: Despite the difficult situation in the health care system of Ukraine, which was the result of incomplete reform and military aggression, the work of pediatric rheumatologists in Ukraine continued, and the provision of biological therapy to patients with JIA is maintained. At the same time, it is necessary to improve the work of pediatric rheumatologists with a wider implementation of international recommendations.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. https://zakon.rada.gov.ua/rada/show/v0832282-12#top

2. Ravelli A, et al.,doi: 10.1136/annrheumdis-2018-213030.

Correspondence: S. J. W. Shoop-Worrall

Pediatric Rheumatology 2023, 21(Suppl 2):PT019

Introduction: The heterogenous presentation and variable clinical response of juvenile psoriatic arthritis (JPsA) to disease-modifying therapies suggests undiscovered subgroups within this disease. Nevertheless, JPsA is often studied under the umbrella of juvenile idiopathic arthritis, with few studies interrogating JPsA separately. To improve stratified treatment of this rare disease, such subgroups must be uncovered.

Objectives: To identify novel, phenotypically consistent subgroups of children and young people (CYP) with JPsA at the point of first contact with paediatric rheumatology.

Methods: CYP were initially selected if enrolled between January 2001 and December 2019 to the Childhood Arthritis Prospective Study, a UK, multicentre, prospective inception cohort of JIA. Those who had a physician’s diagnosis of JPsA at any time point through the 10-year follow-up were included, to allow for onset of psoriatic signs after initial diagnosis. At initial presentation to paediatric rheumatology, clinical features within the ILAR classification criteria for JPsA were collected: an active joint count and the presence or absence of psoriasis, dactylitis and nail abnormalities. Latent class analysis used these features to identify clusters of disease. Between one and ten clusters were tested and an optimal model selected based on statistical fit.

Results: Of 1,753 CYP with JIA recruited to CAPS within the study period, a total of 161 CYP had ever had a diagnosis of JPsA (n=97 diagnosed as JPsA at initial presentation to paediatric rheumatology). The majority were female (61%), of white ethnicity (94%) and the median age at initial presentation was 10 years (IQR 6, 13).

The optimal latent class model identified two clusters of JPsA. An oligoarticular cluster (90%, median active joint count (IQR): 2 (1,5)) had a higher proportion of CYP affected by psoriasis (Cluster 1: 29%, Cluster 2: 14%). A polyarticular cluster (10%, median active joint count (IQR): 20 (16, 27)) had a higher proportion with nail abnormalities (Cluster 1: 8%, Cluster 2: 27%). There were similar proportions of dactylitis among the clusters (Cluster 1: 18%, Cluster 2: 15%).

Conclusion: This study identifies two clusters of JPsA at initial presentation to paediatric rheumatology with differences in key features used to classify this disease. Such subgroups may have different experiences of disease, and future analysis will explore characteristics, alongside disease impact and response to therapy for these groups.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: M. Trevisan

Pediatric Rheumatology 2023, 21(Suppl 2):PT020

Introduction: Juvenile idiopathic arthritis (JIA) is an umbrella term encompassing different forms of arthritis that may have different pathological mechanisms. Hypergammaglobulinemia, reflecting B cell hyperactivity, has been described in JIA. Genetic studies of associations with HLA allele, immunologic studies focusing on B lymphocytes, and the presence of specific clinical features support the hypothesis that early-onset JIA (presenting before age 6 years) is a distinct clinical entity, regardless of the number of joints involved.

Objectives: We aim to study serum levels of immunoglobulins and in vitro production of immunoglobulins following B cell activation in patients with oligo-/poly-JIA (o-/p-JIA) diagnosed before the age of 6 years.

Methods: We enrolled patients with o-/p-JIA (n=34), aged matched healthy donors (HD) (n=19) and patients with systemic JIA (sJIA) (n=10), all younger than 6 years. Serum levels of IgG, IgM and IgA were retrieved from medical records of OPBG. B cells of o-/p-JIA patients and HD were activated in vitro for 7 days with CpG, concentration of secreted immunoglobulins was measured by ELISA.

Results: We focused on patients age 0 to 6 years, as B cell subsets and immunoglobulins levels of children younger than 6 years are still immature and differ significantly from children older than 6 years and young adults. Immunoglobulins levels were obtained at disease onset and before the initiation of any treatment for JIA. The median age in years was: HD 1.99 [IQR 1.37, 3.38], sJIA 2.76 [2.07, 3.64], o-/p-JIA 2.54 [1.66, 4.03] (ANOVA, p=0.28). Of the o-/p-JIA patients, 25 (73.5%) had oligo-JIA and 9 (26.5%) had poly-JIA; 28 (82.4%) were ANA positive and 14 (41.2%) developed uveitis. Levels of serum IgG were significantly higher in o-/p-JIA compared to HD and sJIA (median [IQR] mg/dL: HD 8.16 [6.67, 9.50], sJIA 7.40 [7.12, 12.27], o-/p-JIA 11.49 [10.10, 14.70], ANOVA p<0.001). We observed no differences between the 3 groups for IgM and IgA. When we divided o-/p-JIA patients according to number of joints involved and ANA positivity we did not observed significant differences for levels of IgG, IgM or IgA. PBMCs of 20 o-/p-JIA patients and 92 HD were stimulated in vitro for 7 days with the TLR9 agonist CpG, that induces B cell differentiation into plasmablasts. We observed significantly higher levels of IgG in the supernatant of stimulated cells of JIA patients than of HD (median [IQR]: HD 0.42 [0.12, 3.24], o-/p-JIA 2.75 [0.52, 9.05], t-test p=0.024). We observed no differences in the production of IgM and IgA.

Conclusion: Our data support the hypothesis of a hyperactive B cell compartment in patients with o-/p-JIA younger than 6 years. We observed higher levels of serum IgG and higher in vitro production of IgG by stimulated B cells in patients with o-/p-JIA than HD and sJIA patients. Further work is required to dissect the molecular pathways leading to B cell activation in o-/p-JIA.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Marasco, A&R, 2018

2. Marasco, EJI, 2017

3. Wouters, Clin Exp Rheumatol, 2002

Correspondence: V. Alexiou

Pediatric Rheumatology 2023, 21(Suppl 2):PT021

Introduction: The role of regulatory T cells (Tregs) is well established in juvenile idiopathic arthritis (JIA) pathogenesis. JIA studies have also shown that a pro-inflammatory subset of Th17 cells, expressing the marker CD161, is enriched in the synovial fluid (SF) of JIA patients and correlates with disease activity. Establishing transcriptomic signatures which faithfully infer the proportions of potentially pathogenic cells in JIA may be a valuable prognostic tool.

Objectives: To explore whether RNA sequencing (RNAseq) data can be used to predict the cellular proportions of Treg and CD161+ CD4+ T cell populations measured by flow cytometry in healthy and JIA peripheral blood mononuclear cells (PBMC) and SFMC of JIA patients.

Methods: Matched flow-cytometry and RNAseq data from PBMC (n = 158) and SFMC (n = 43) of JIA patients and PBMC (n = 39) from healthy controls were used for the modelling analysis. Specifically, Treg (CD4+CD25hiCD127lo) and CD161+ CD4+ proportions (% of CD4+ T cells) were measured by flow cytometry and CD4+ sorted RNAseq data of the same samples were used to predict the flow cytometry measured proportions. To provide biologically informed predictors, recent literature on Treg and CD161+ CD4+ T cell from heathy and disease states was reviewed to generate the cell-specific lists of genes which are differentially expressed compared to non-Treg and CD161- CD4+ subsets respectively. RNAseq data from sorted Tregs (CD4+CD25hiCD127lo) and conventional T cells (Tconvs) (CD4+CD25loCD127+) were generated from SFMC of JIA patients (n = 8) and PBMC from healthy controls (n = 3) and analysed to validate the literature-based Treg gene list across tissue and disease state. For the modelling analysis, the elastic net method was used for variable selection from the cell-specific gene lists to predict the flow-cytometry-measured proportions using the RNAseq data separately in SFMC and PBMC samples. The performance of the model was assessed by repeated cross-validation.

Results: A 42 Treg gene list generated from the literature review was able to cluster the sorted Tregs separately from the Tconvs regardless of tissue and disease origin. Preliminary analysis showed that the model is more predictive in SFMC samples (R = 0.77) than in PBMC samples (R = 0.37).

Conclusion: Biologically informed signatures are valuable in discriminating cell populations of interest at the transcriptional level regardless of cell origin and disease state. The preliminary data show that the predictive capacity of conventional modelling methods is limited, so alternative algorithms are being explored.

Patient Consent

Yes, I received consent

Disclosure of Interest

V. Alexiou: None declared, A. Callaghan: None declared, M. Kartawinata: None declared, E. Ralph: None declared, B. Jebson: None declared, M. Wilkinson: None declared, A. Radziszewska: None declared, H. Peckham: None declared, E. Rosser: None declared, C. Curtin: None declared, E. Vigorito: None declared, L. Wedderburn Grant / Research Support with: LRW Declares in kind contributions to CLUSTER by AbbVie, GSK, UCB, Sobi and Pfizer inc and non renumerated collaborations with Lilly and Novartis.

Correspondence: M. H. Attrill

Pediatric Rheumatology 2023, 21(Suppl 2):PT022

Introduction: Children and young people with Juvenile Idiopathic Arthritis (JIA) experience repeated inflammatory flares of their joints leading to pain, fatigue, reduced quality of life and ultimately joint destruction and disability. While therapeutics have improved, treatment still fails for 30-50% of patients.

Objectives: To unlock potential insight into JIA disease pathogenesis and novel treatment targets, we need to understand the cellular composition and specialised phenotype of synovial fluid mononuclear cells (SFMC) from inflamed joints, so that ultimately targeted treatment can restore the immunoregulatory balance.

Methods: Using 5-laser full spectrum flow cytometry, we designed and verified a 37-parameter panel to assess the cellular composition and phenotype between JIA SFMCs (n=18), JIA peripheral blood (PBMCs, n=52), as well as healthy control PBMCs (n=18). The panel identified monocyte, B, NK, and dendritic cell subsets in addition to CD4- effector (Teff), CD4+ conventional (Tconv) and regulatory T cell (Treg) phenotype. Unbiased high dimensional analysis was performed after pre-processing in FlowJo using the R package Spectre, allowing raw data integration, clustering through FlowSOM/Phenograph, dimensionality reduction via UMAP and quantitative statistical analysis and visualisation.

Results: We identified highly upregulated and JIA SF exclusive phenotypes across cell types by unbiased clustering. The Fc receptor CD16 was absent from SF monocyte and NK cell subsets, suggesting a lack of antibody-mediated action, which could help explain failure of antibody-mediated treatments. Two unusual subsets of dendritic cells were exclusively found in the inflamed joint, highly expressing 4-1BB, CD71, CD39 and Ki67, revealing maturation, proliferation, and adaptation to the inflammatory environment. SF T cells, including Tregs, and B cells highly expressed multiple activation markers and unique cell surface receptor combination exclusive to cells from the inflamed joint. A significant cluster of CD4- Teff expressed the transcription factor FoxP3, which has been indicated to promote changes in metabolic behaviour of CD8+ Teff within tumours to allow survival in an environment of restricted metabolic resources. Moreover, the transferrin receptor CD71, which is critical to increase iron metabolism and enables cellular survival and proliferation, was upregulated on the majority of cells from the inflamed joint.

Conclusion: High dimensional flow cytometry revealed phenotypic and metabolic adaptations of SF cell subsets and SF cells had unique cell surface receptor combinations, which may be used to target cells in the inflammatory environment in the future while sparing circulating cells. These findings may facilitate more targeted therapies to achieve treatment success for more children and young people with JIA and minimalizing systemic side effects.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: R. Caorsi

Pediatric Rheumatology 2023, 21(Suppl 2):PT023

Introduction: COVID-related Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory condition characterized by systemic inflammation with multiorgan failure, that can occur in children and young adults after COVID-19 infection. By now, different publications have provided evidence about the clinical manifestations, possible treatment and outcome of this condition, without analyzing the parameters associated to a increased risk of sequelae or death.

Objectives: To evaluate the presence of variables associated with a poor prognosis (sequelae or death) in patients with MIS-C, taking into consideration the age at disease presentation and the geographical origin of the patients.

Methods: Data regarding clinical manifestations, laboratory features, response to treatment and outcome of patients with MIS-C patients were collected by the Hyper-Ped registry, available online on PRINTO and ESID websites. Univariable and multivariable logistic regression analyses were assessed to identify possible factors associated with a poor prognosis in patients with MIS-C.

Results: 1009 patients, were analysed.

432 patients were form Western Europe (Belgium, Denmark, Italy, Portugal, Spain), 334 were from Eastern Europe (Bulgaria, Croatia, Czech Republic, Greece, Latvia, Russian Federation, Serbia, Slovenia, Turkey, Ukraine), 168 from Latin America (Argentina, Brazil, Mexico) and 75 from Other countries (Bangladesh, Egypt, India, Singapore).

The final model identified 9 variables associated to the outcome: patients coming from Other countries (OR 7.06) presented a higher risk for the outcome rather those from Western Europe. The presence of increased neutrophil count (OR 1.04), lymphopenia (OR 3.38), myocarditis (OR 3.74), coronary aneurism (OR 14.1), renal hypertension (OR 10.07) and palpable purpura (OR 7.85) is correlated with the outcome, as the need of respiratory support (OR 2.4). Prophylactic treatment with heparin (OR 0.22) is protective for the outcome.

Conclusion: From the analysis of the data of the registry, it appears that patients coming from less resourced country presented a poorer prognosis than the others. It’s reasonable that these results depends on the reduced possibility of access to intensive cares and to biological drugs. The presence of cardiac involvement, hypertension and hematological abnormalities are associated to a poorer outcome.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: M. Hamad Saied

Pediatric Rheumatology 2023, 21(Suppl 2):PT024

Introduction: Children with pediatric autoimmune inflammatory rheumatic disease are at higher risk for infections due to both their underlying disease and immunosuppressive treatments. At the same time, vaccinations pose a great challenge in this patient group due to lower immunogenicity secondary to their underlying disease, their immunosuppressive treatment and the concern about disease flares following vaccination

Severe COVID-19 illness can occur in these patients , especially among those with underlying comorbidities

Objectives: To evaluate immunogenicity, efficacy and safety of COVID-19 vaccination in patients with pediatric autoimmune inflammatory rheumatic disease (pedAIIRD).

Methods: A prospective cohort study was performed at the pediatric rheumatology department of the Wilhelmina Children’s Hospital in Utrecht. Vaccination dates, COVID-19 cases and vaccine-related adverse events (AEs) were registered for all pedAIIRD patients during regular control visits from March, 2021 – August, 2022. SARS-CoV-2 IgG antibody levels and T-cell responses were measured and clinical and drug therapy data were collected. Rate of COVID-19 disease was compared between vaccinated and unvaccinated patients.

Results: A total of 157 patients were included, of whom the majority had JIA (88%) and were vaccinated against COVID-19 (87%). Geometric mean concentrations (GMCs) of post-vaccine antibody levels against SARS-CoV-2 were above the threshold for positivity in patients who did or did not use biological agents at the time of vaccination, although the biological users demonstrated significantly lower antibody levels (adjusted GMC ratio: 0.38, 95% CI: 0.21 – 0.70). T-cell responses were adequate in all but two patients (8%), who received combination therapy of methotrexate with tocilizumab or methotrexate with adalimumab at the time of vaccination. The adjusted rate of reported COVID-19 was significantly lower for fully vaccinated patients compared to non-vaccinated patients (HR: 0.53, 95% CI: 0.29 – 0.97). JIA disease activity scores were not significantly different after vaccination, no serious AEs were reported.

Conclusion: COVID-19 mRNA vaccines were immunogenic (both cellular and humoral), effective and safe in a large cohort of pedAIIRD patients despite their use of immunosuppressive medication.

Trial registration identifying number: This study was approved by the UMCU Medical Ethical Committee (METC number 22-643). T-cell responses were measured in patients who gave informed consent in the Pharmachild study (METC number 11-499c).

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: K. Kapten

Pediatric Rheumatology 2023, 21(Suppl 2):PT025

Introduction: The SARS-CoV-2 pandemic revealed numerous limitations to the widely known and accessible methods of evaluating individual immunity, necessitating new diagnostic tools, such as a novel T-cell-based Interferon-γ Release Assay (IGRA), that is proposed to assess cellular immunity, in addition to standard serological testing.

Objectives: This study aimed to evaluate and compare humoral and cellular responses to the recent coronavirus infection in the cohort of children suffering from juvenile idiopathic arthritis (JIA). In addition, the authors aimed to assess the immunity provided by the SARS-CoV-2 vaccine, particularly, in individuals undergoing different treatment regimes.

Methods: This prospective study included 55 pediatric patients between the ages 2-16 with different types and various stages of JIA. The cohort group included children with both positive and negative history of Covid-19 infection, as well as vaccinated and unvaccinated individuals. The cellular response to the virus was measured using a specific quantitative IGRA in whole blood, while subsequently, the anti-SARS-CoV-2 ELISA test was performed, quantifying the levels of IgA, IgM, and IgG antibodies in serum.

Results: The research found a significant correlation between the cellular response to SARS-CoV-2 measured by the IGRA test and the levels of IgA (p<0.00003, R=0.537) and IgG (p<0.0001, R=0.668) antibodies, along with the detection of antibodies with the nucleocapsid protein (IgG NCP) (p<0,003, R=0,0399). Notably, no correlation with IgM antibodies titers in serum was observed. Regardless of the number of boosters administered, all vaccinated individuals developed a T-cell response to the mRNA vaccine (p=0.0016). The humoral response, specifically the levels of IgG antibodies in patients receiving biological treatment (adalimumab, baricitinib, etanercept, or tocilizumab) were significantly lower compared to the group not undergoing such therapy (p=0.0369).

Conclusion: The strong affinity of SARS-CoV-2 with mucosal membranes can be associated with a correlation between cellular response and IgA antibody levels. Hence, the sole testing of humoral immunity, by measuring IgG and IgM antibodies may no longer remain the most precise diagnostic method. IGRA proves to be a highly accurate tool in the assessment of individual immunity both after viral infection and vaccination. Additionally, the suppression of humoral response observed in biological treatment protocols may impact individual susceptibility to the virus, possibly proving to be a protective factor against the SARS-CoV-2 infection.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: E. Marasco

Pediatric Rheumatology 2023, 21(Suppl 2):PT026

Introduction: Vaccination-induced protection against infections relies on the capacity of generating specific antibodies and memory B cells (MBCs), which can rapidly respond to successive infections. TNF inhibitors (TNFi), used to treat patients with juvenile idiopathic arthritis (JIA), do not only dampen inflammation, but they have been shown to also inhibit the germinal center response and, thus, to decrease the frequency of MBCs.

Objectives: We aim to study the frequency of SARS-COV2 spike-specific MBCs following vaccination or infection in patients with JIA.

Methods: B cell phenotype and spike specific B cells was assessed on PBMCs by flow cytometry as previously described (Terreri, 2022).

Results: We enrolled 36 patients with a diagnosis of JIA according to the ILAR criteria. Twenty-two (61%) patients had a diagnosis of oligoarticular JIA, 12 (33%) patients had polyarticular JIA, 1 psoriatic JIA, and 1 ERA. Nine patients were on treatment with MTX, 27 were on TNFi (13 adalimumab, 11 etanercept, 1 golimumab, 2 infliximab). Twenty-seven patients (75%) were vaccinated with 3 doses of SARS-CoV2 mRNA vaccine, 5 patients (14%) received 2 doses of SARS-CoV2 mRNA, 4 patients (11%) refused vaccination and contracted COVD19. All vaccinated patients received a vaccine against the original strain (BNT162b2 or mRNA-1273). In total, 23 patients contracted COVID19, all patients showed only mild symptoms. We enrolled 11 healthy healthcare workers without history of autoimmunity(HD) who underwent mRNA vaccination for SARS-CoV2.

The frequency of high affinity MBCs specific for SARS-CoV2 was higher in HD than in JIA patients (mean (SD) of MBCs: HD 0.46 (0.21), JIA 0.30 (0.22), p=0.03). All high affinity MBCs specific for SARS-CoV2 were switched (mean frequency of high affinity IgM- MBCs were 91.4% for HD and 89.3% for JIA). A large fraction of high affinity MBCs specific for SARS-CoV2 reacted against the omicron strain, although the frequency was lower in JIA patients than HD (mean (SD) of MBCs: HD 63.37% (21.52), JIA 44.61% (25.42), p= 0.032). The frequency of low affinity MBCs specific for SARS-CoV2 was similar between the two groups (mean (SD) of MBCs: HD 0.63% (0.53), JIA 0.84% (0.91), p=0.458). Patients on TNFi showed a lower frequency of high affinity spike-specific MBCs than patients who were on MTX only (mean (SD) of MBCs: MTX 0.42% (0.25), TNFi 0.25% (0.20), p=0.04). Interestingly, patients who refused to get vaccinated and contracted COVID19, did not produce high affinity MBCs specific for SARS-CoV2 compared to patients who were vaccinated (mean (SD) of MBCs: JIA non vaccinated 0.05% (0.05), JIA vaccinated 0.33% (0.21), p=0.017).

Conclusion: Our data showed that mRNA vaccination was able to induce the generation of high affinity MBCs against SARS-CoV2 spike protein, although at a lower frequency than HD. COVID19 infection alone was not able to induce high affinity MBCs against SARS-CoV2, highlighting the importance of vaccination for patients with JIA.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Terreri, Cell Host Microbe, 2022

Correspondence: E. Marasco

Pediatric Rheumatology 2023, 21(Suppl 2):PT027

Introduction: Pediatric Sjögren's syndrome (pSS) is a rare disorder that is often diagnosed late due to the lack of validated diagnostic criteria and validated biomarkers. The pathogenesis is largely unknown, but there is evidence of involvement of both the innate and adaptive branch of the immune system. Immunological overactivity is central in the pathogenesis of pSS. Several studies showed the presence of B cells abnormalities in patients with SS with an expansion of naïve B cells and a decrease in the frequency of memory B cells.

Objectives: We set out to investigate the distribution of B cell subsets and B cell cytokines in patients with pSS at disease onset and at follow up visits.

Methods: A monocentric retrospective cohort study was conducted on 17 patients with pSS enrolled at the department of Rheumatology of Bambino Gesù Children's Hospital. Serum levels of BAFF were analyzed by ELISA. B-cell phenotype was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry.

Systemic disease activity was evaluated by ESSDAI (EULAR Sjogren's syndrome disease activity index) and Clinical-ESSDAI score (Clin-ESSDAI), according to 2020 EULAR recommendations; active disease was defined by ClinESSDAI ≥1 and remission by ClinESSDAI=0. As controls we selected age-matched people with no diagnosis of pSS or any other systemic autoimmune disease.

Results: Serum levels of BAFF were significantly higher in patients with pSS than the control group (p<0,05). We correlated levels of biomarkers with clinical and laboratory parameters: we observed a positive correlation between hypergammaglobulinemia and BAFF (rho=+0,80).

Analysis of B-cell subsets at disease onset revealed the expansion of a population of atypical memory B cells (p=0,00049) and reduction in lgM memory B cells (p=0,0034) compared to the control group. We, then, compared the distribution of B cell subpopulations at disease onset with samples obtained at follow-up for each patient: no significant differences were observed. We also investigated the distribution of Tfh cells in pateints with pSS and we observed a significant expansion of CXCR5-PD1hi Tfh.

Conclusion: Patients with pSS showed high levels of BAFF at disease onset. Alteration in B cell subsets are present in patients with pSS compared to controls, with an expansion of atypical memory B cells and Tfh. The B cell abnormalities are not affected by current treatment. Our data confirm an hyperactivation of B cells and B cell-derived chemokines and in patients with pSS and provide evidence for their development as biomarkers and to develop new therapeutic strategies amied at controlling B cell hyperactivation in pediatric patients with SS.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: G. Mastrangelo

Pediatric Rheumatology 2023, 21(Suppl 2):PT028

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C), also known as Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS), is one of the most serious complications associated with COVID-19. The clinical features of MIS-C are not unique and are commonly seen in childhood febrile conditions. Thus, there is a need to identify those febrile children with MIS-C to enable early diagnosis and treatment. In response to the health care emergency, a multidisciplinary team from The Hospital for Sick Children (SickKids) of Toronto developed a preliminary screening pathway for the evaluation of possible MIS-C.

Objectives: The primary objective is to determine if the SickKids screening pathway is sensitive and specific to identify patients with MIS-C from other febrile children with suspected but not confirmed diagnosis of MIS-C. The secondary objective of this study is to determine how the ACR MIS-C algorithm performs compared to the SickKids screening pathway in differentiating children with MIS-C from the febrile controls.

Methods: Retrospective case-controlled, cross-sectional study including children who have been assessed at SickKids with suspected or confirmed MIS-C from March 2020 to March 2022. The MIS-C group included all children meeting the most permissive case definition as per international MIS-C and PIMS definitions and adjudicated by our multi-disciplinary MIS-C working group; the febrile control group consisted of all patients with a history of three or more days of fever who were suspected of MIS-C and qualified for the SickKids MIS-C screening pathway, but did not fulfill criteria for MIS-C after adjudication by our multi-disciplinary group. SickKids and ACR pathways were retrospectively applied to both groups. The diagnosis result obtained using the pathways was compared with the final clinical diagnosis made using the WHO definition criteria, used as the gold standard. From the contingency table, sensitivity and specificity have been calculated along with a 95% confidence interval.

Results: 402 children (241 with MIS-C and 161 febrile controls) were included in the study. The median age was 4.18 years (IQR: 1.9 to 9.0) and 237 (60%) were male. For the SickKids screening pathway, the sensitivity was 62% (95%CI, 54.2% to 70.4%), and specificity was 91% (95%CI, 86.9% to 94.2%). The positive predictive value (PPV) was 79% and the negative predictive value (NPV) was 81%. Overall, the balanced accuracy was equal to 76%. The ACR screening pathway had 74% sensitivity (95%CI, 67.3% to 81.4%), and 99% specificity (95%CI, 98.1% to 100%), with PPV of 98% and NPV of 87%. The balanced accuracy was 87%.

Conclusion: The SickKids MIS-C screening pathway has a high specificity, but a low sensitivity and accuracy in capturing children with MIS-C at the onset of the disease. Overall, the ACR algorithm performs better at differentiating children with MIS-C from febrile controls.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: M. V. Mastrolia

Pediatric Rheumatology 2023, 21(Suppl 2):PT029

Introduction: MIS-C and KD share many clinical features although these conditions may diverge in terms of epidemiologic and biochemical parameters.

Objectives: To compare two cohorts of KD and MIS-C patients.

Methods: A prospective collection of demographics, clinical findings, treatment and outcome data of KD and MIS-C patients between November 1^st 2020 to February 28^th 2023 belonging to 8 Pediatric units was conducted. Additionally, for each patient a blood sample at disease onset (T0), and at recovery (T1) was collected to assess type 1 interferon score (IFN score) and serum cytochines: CXCL9, CXCL10, IL18, IFN gamma, IL6, IL1b.

Results: 87 patients (43 KD, 44 MIS-C) were included in the study. Age at onset was significantly higher in MIS-C compared to KD patients (mean 31±23 vs 94±50 months, p<0.001). No differences in gender and ethnicity were observed. Considering clinical manifestations, extremities abnormalities and mucosal involvement were more often recorded in KD patients (p=0.027; p<0.001). Neurological findings, in particular headache (p=0.002) and meningism (p=0.035), were significantly more frequent in MIS-C patients (p=0.002). Irritability was a typical clinical feature in the KD cohort (p<0.001).Gastrointestinal symptoms were more frequently observed in MIS-C group (p=0.013) as well as respiratory involvement (p=0.019) and splenomegaly (p=0.026). Conversely, gallbladder hydrops (p=0.01) and lymphadenopathy (p=0.07) more often occurred in KD patients.The frequency of cardiac manifestations overall was significantly higher in MIS-C group (p<0.001), although coronary arteries aneurisms were more frequently observed in KD patients (p=0.012). The length of stay was longer in MIS-C patients (mean 8.6±4.1 vs 14.5±6.9 days, p=0.002) and PICU admission was significantly higher (p<0.001) together with the need for inotropes (p=0.048). Steroids and intravenous anakinra were more frequently administered in MIS-C cohort (p<0.001). ASA antiplatelet treatment was more often adopted in KD (p<0.001) while anticoagulant prophylaxis with heparin in MIS-C patients (p<0.001). The lymphocyte count was significantly lower in MIS-C group (p<0.001), while the CRP value was higher compared to those of KD patients (p=0.001). IFN score and IL18 values at T0 were higher in KD patients (p=0.019; p=0.016), CXCL10 at T0 was more elevated in the MIS-C cohort (p=0.007). No other significant differences in the biomarkers values were detected at the different timepoints (T0-T1 interval median 6 days IQR 8.25) between the two groups. A significant decrease of CXCL9 and CXCL10 values from T0 to T1 in both KD (p=0.02; p=0.015) and MIS-C patients (p=0.004; p<0.001) was reported.

Conclusion: The epidemiological, clinical, and biochemical differences of our KD e MIS-C cohorts confirm previous reported data. The role of the tested biomarkers in distinguishing KD from MIS-C is not completely clarified even if a larger prospectively assessment could be useful to monitor the response to treatment throughout the disease course.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: A. M. Pesenacker

Pediatric Rheumatology 2023, 21(Suppl 2):PT030

Introduction: FOXP3+CD4+ regulatory T cells (Tregs) are crucial to maintain tolerance, however, in Juvenile Idiopathic Arthritis (JIA) Tregs are not fit for service, and thus fail to control inflammation leading to repeated inflammatory flares of joints, pain, loss of mobility, and ultimately joint destruction and disability.

Objectives: To understand why Tregs from the site of inflammation and blood of children and young people with active JIA fail to suppress inflammation, we investigated the co-inhibitory co-receptor TIGIT and co-stimulatory CD226, which may be utilised by Tregs to interpret cues from the microenvironment in inflamed joints to change action accordingly.

Methods: We assessed co-receptor and their ligand expression in JIA synovial fluid mononuclear cells (SFMCs) and peripheral blood MC (PBMCs) from active and inactive JIA patients and healthy controls at protein level utilising full spectrum flow cytometry, and mRNA level by nanoString. Moreover, TIGIT-CD226 interaction and ligand-dependency was assessed by luciferase-based NanoBiT® system and confocal microscopy in stably transduced cell lines.

Results: We showed by flow cytometry and mRNA expression that TIGIT and CD226 are mostly co-expressed in SF Tregs (>60% double positive). This double positive Treg subset could also be detected in PB of children with clinically active JIA but was near absent in healthy control and children with clinically inactive JIA. Interestingly, overall TIGIT and CD226 expression was increased in SF CD4- effector and CD4+ conventional T cells compared with blood, however only a small proportion of effector cells co-expressed both receptors. The co-receptor ligands CD155 (PVR) and CD112 (Nectin2) were also increased by mRNA (total SFMC) and protein on SF antigen presenting cell subsets. Since TIGIT and CD226 have proposed opposite cellular effects, we investigated co-receptor interaction, and established that TIGIT and CD226 interact in the absence of ligand, but this interaction increased 4.7-fold with CD155 availability. This ligand-dependent enhancement could be inhibited when using blocking antibodies for TIGIT-CD155 or CD226-CD155 binding (3.5/3.8-fold decrease from ligand alone). Moreover, we saw clear co-localisation of TIGIT and CD155, CD226 and CD155, as well as TIGIT, CD226 and CD155 triple co-localisation using confocal microscopy.

Conclusion: We have demonstrated that TIGIT and CD226 directly interact in cis when co-expressed. With TIGIT-CD226 co-expression mainly seen in JIA SF Tregs, this receptor-receptor interaction will likely alter Treg signalling, behaviour and functional outcome at the site of inflammation, while in healthy control blood Tregs the direct effects of TIGIT or CD226 predominate. Breaking this interaction could serve as a novel treatment target in JIA without interfering with TIGIT- or CD226-dependent functions when expressed as single co-receptor.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: E. Aliyev

Pediatric Rheumatology 2023, 21(Suppl 2):PT031

Introduction: Systemic Lupus Erythematosus (SLE) is a chronic, autoimmune-based disease characterized by multiple organ involvement and autoantibodies. Although it generally has typical findings, it is a complex disease to diagnose, and early diagnosis and treatment are essential in the disease process. The diagnosis of the disease is based on SLICC 2012 criteria. The artificial Intelligence (AI) model was tested in diagnosing the condition. Our study aims to develop a computer-based AI model to assist clinicians in diagnosis.

Objectives: Fifty SLE patients followed up in Hacettepe University Pediatric Rheumatology Outpatient Clinics, and 50 healthy individuals similar to them in terms of age and gender were included in the study. Data sets, including clinical and laboratory findings of the individuals at the time of diagnosis, were given as input to the AI model. Python® software language and Tensorflow® AI library were preferred for model development.

Methods: The concept of 'Neural Networks' (NN) is becoming increasingly widespread in AI studies. Morgaf used the 'Recurrent Neural Network' (RNN) model preferred. The most important difference of the RNN from other networks is that while training the model while processing the inputs at the moment Tn, it also remembers the inputs at the moment Tn-1 (Tn is any time unit). With this, error rates on the network are lower than in other models. The laboratory and clinical results of the patients were digitized as 1, -1 (abnormal), and 0 (normal range). One hundred data were increased 15 times to 1500 with repetitions, and 80% were separated as training data and 20% as validation data. Morgaf is designed as a model that builds an NN with 1024 neurons. The homogeneity of the variables was tested by covariance analysis (p=0.792). Regression analysis was performed for both homogeneously distributed groups and tested with Levene (p=0,147). During the model training, the error rate in the early training phase of the model was approximately 0.5. In the later generations of the model, the error decreased to 0.028. This error rate was considered sufficient, and the training phase was terminated. Training continued autonomously in the latent phase. The study was planned to be single blind. Thirty case data (data utterly foreign to the model) were given to Morgaf and simultaneously to expert pediatric rheumatologists, and their interpretations were compared. Prediction success was evaluated by performing regression analyses between both groups.

Results: Morgaf accepted 70% and above as a definitive diagnosis of SLE, averaging 93% (78-98%). It accepted 10% and below for a completely healthy case; the average was 1% (0-3%). To recognize diseases requiring follow-up, he set himself a range of 10%-70% and estimated the mean to be 33% (15-47%). There was no difference between Morgaf's estimates and actual diagnoses (p=0.297). He was 100% successful in recognizing lupus disease. This rate was the same as the diagnostic acuity of clinicians. Morgaf (93.3%) gave clearer recommendations for non-lupus cases than clinicians (70%) (p=0.034). Regression analysis showed that Morgaf (y=0.9264xi) was more successful in non-selective prediction than clinicians (y=0.7322xi).

Conclusion: Our study is the first in the literature to develop and test an AI model as a diagnostic tool for pediatric SLE. The developed AI model was at least as successful as pediatric rheumatologists in differentiating SLE patients from healthy controls and non-SLE patients. With this study, we have shown that Morgaf can help clinicians in the diagnostic and differential diagnosis. The model can also be a diagnostic tool for non-specialist clinicians. The plan to further develop Morgaf to reach a clinician-like diagnostic acuity (with visual and auditory data processing integration) is one of the project's future goals.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. Yones, S. A., Annett, A., Stoll, P., Diamanti, K., Holmfeldt, L., Barrenäs, C. F., Meadows, J. R. S., & Komorowski, J. (2022). Interpretable machine learning identifies paediatric Systemic Lupus Erythematosus subtypes based on gene expression data. Scientific reports, 12(1), 7433.

2. Wu, J., Yang, W., & Li, H. (2022). An artificial neural network model based on autophagy-related genes in childhood systemic lupus erythematosus. Hereditas, 159(1), 34.

Correspondence: B. Bader-Meunier

Pediatric Rheumatology 2023, 21(Suppl 2):PT032

Introduction: Juvenile Dermatomyositis (JDM) is a rare inflammatory autoimmune paediatric disease associated with a type I interferon (IFN) signature. Questions remain about the relative contribution of interferon alpha subtypes or interferon beta to the pathophysiology of the disease. Here, we addressed this question by quantifying IFN beta, IFNalpha 2c, and all 13 IFNalpha subtypes (Pan-A) in a longitudinal cohort of JDM patients.

Methods: This longitudinal study included 187 samples from 52 JDM patients. Autoantibody expression and clinical measures of disease activity were evaluated: Childhood Myositis Assessment Scale (CMAS), Manual Muscle Testing in 8 muscles (MMT-8) for muscle testing; skin score of Disease Activity Score (DAS) for the skin. Pan-A, IFN alpha2c and IFN beta were measured in the plasma of patients by digital ELISA (Simoa) using homebrew assays. Correlation between IFN-I titers and clinical scores was evaluated using Spearman’s test followed by a Bonferroni correction.

Results: All assays correlated with all clinical scores for the entire cohort. After stratification based on MSA expression (MDA5+: n=12, NXP2+ n=11, TIF1g+ n=10, None n=19), we observed in MDA5+ patients, a very strong association between the two IFN alpha assays and all three clinical scores. IFNbeta levels were also strongly correlated with all three scores in MDA5+ patients, but to a lesser extent compared to the two IFNbeta tests. The only significant correlation in the other 3 groups was the correlation between IFN beta titer and CMAS in a TIF1gamma positive patient.

Conclusion: The association between JDM disease activity and plasmatic IFN-I levels has been described in previous studies. Our results suggest that this effect was mainly driven by MDA5 positive patients challenging the role of IFN-I subtypes in the pathophysiology of MDA5 negative JDM patients. Ongoing work will try to identify the specific immune pathways that lead to dysregulated IFN-I responses in MDA5+ patients using functional immune assays.

Trial registration identifying number:

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: S. Khaldi-Plassart

Pediatric Rheumatology 2023, 21(Suppl 2):PT033

Introduction: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease affecting multiple organ systems, characterized by increased expression of type I interferon (IFN)- regulated genes (50%–75% of patients). The presence of anti-IFN-α autoantibodies (AAbs) has been reported in adult patients with SLE (5% to 27%). Interestingly, neutralizing Aabs anti-IFN-α has been reported and are associated with reduced IFN-αserum levels, a reduced disease activity and a history of severe infectious episodes (COVID-19 pneumonia or episodes of cutaneous herpes zoster) illustrating the clinical impact of these AAbs. To the best of our knowledge, no studies have been conducted thus far that report the presence of anti-interferon autoantibodies (Aabs) in pediatric patients with systemic lupus erythematosus (SLE).

Objectives: The aims of this study are to evaluate the presence of anti-IFN-alpha Aabs and their neutralizing capacities, and to identify clinico-biological manifestations associated with the presence of anti-IFN-alpha Aabs in a French multicentric cohort of pediatric patients with SLE.

Methods: We tested 143 biological samples from pediatric patients with SLE from the French national lupus biobank and performed IFN-α2 dosage (ELISA) and functionally tested the inhibitory capacities of each sera sample on IFN activity. We collected clinical data retrospectively from the PEDIALUP registry of the JIRcohort database.

Results: The presence of anti-IFN-α AAbs was detected by ELISA in 26 (18,2%) of the 143 patients. Neutralizing anti-IFN-α2 Aabs were present in 11 patients (7,7 %) and neutralizing anti-IFN-α2, anti-IFN-β or anti-IFN-ω Aabs in 18 patients (12,6%) with pediatric-onset SLE. Clinical data collected from 83 patients showed there was no signifcant difference in terms of gender or median age or disease duration between patients with or without ELISA-detectable anti-IFN-α Aabs. We compared 3 groups: ELISA-negative anti-IFN-α AAbs group (anti-IFN-αAabs <100 ng/ml)(N=64) ; ELISA-positive but non-neutralizing anti-IFN-α Aabs group (N=10) ; ELISA-positive and neutralizing anti-IFN-α Aabs group (N=9). We observed a trend of less disease activity in patients with ELISA positive and neutralizing anti-IFN-α Aabs group (no significant) and no significant difference related to infectious event. .

Conclusion: This is the first report on the presence of anti-IFN-α2 Aabs in patients with pediatric onset SLE (French multicentric cohort) (N=143). We observed high prevalence of neutralizing and non-neutralizing anti-IFN-αAAbs in pediatric onset SLE patients compared to pediatric controls. Further studies are required to address their place in the management and follow-up of jSLE in the future.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Zhang Q et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 23 oct 2020;370(6515):eabd4570.

2. Mathian A et al. Lower disease activity but higher risk of severe COVID-19 and herpes zoster in patients with systemic lupus erythematosus with pre-existing autoantibodies neutralising IFN-α. Ann Rheum Dis. 16 août 2022;annrheumdis-2022-222549.

3. Bradford HF et al. Inactive disease in patients with lupus is linked to autoantibodies to type I interferons that normalize blood IFNα and B cell subsets. Cell Rep Med. janv 2023;4(1):100894.

Correspondence: K. Nay Yaung

Pediatric Rheumatology 2023, 21(Suppl 2):PT034

Introduction: Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease with unpredictable disease course. It interferes with the balance between immunity and regulation, resulting in immune system dysfunction. Capturing its inherent heterogeneity can yield mechanistic insights to improve theragnostic strategies, especially when only two targeted biologics have been FDA-approved for SLE treatment despite numerous clinical trials. Furthermore, adult and paediatric SLE patients are usually studied in silos, with treatment for the latter group often extrapolated from adult data with no direct evidence of benefit.

Objectives: We aim to resolve the immunopathogenic complexity of SLE with high-dimensional mass cytometry (CyTOF) to study and dissect the adult-onset and childhood-onset SLE immunomes. We hypothesise that immune dysregulation in SLE is driven dually by impaired immunoregulation and lowered activation threshold for immune effector cells.

Methods: Peripheral blood mononuclear cells (PBMCs) were studied with a 43-marker CyTOF panel. The adult group comprised 26 SLE (timepoints: 40, median age: 39.5 years) and 23 age-matched healthy subjects. The paediatric group included 30 patients (53, 14 years) and 17 healthy. Quality check, batch-effect correction, cell clustering, annotation and visualisation after t-distributed Stochastic Neighbour Embedding (t-SNE) dimensional reduction were performed using our Extended Polydimensional Immunome Characterisation (EPIC) pipeline.¹ Cell frequencies are presented as a percentage of CD45⁺PBMCs with median and interquartile range. Statistical significance was defined as p<0.05 (Kruskal-Wallis test, Dunn’s multiple comparisons).

Results: Multiple derangements were noted in all major immune lineages but mainly in CD4⁺ T cells. Interestingly, there were no significant differences in the naïve (CD45RA⁺) and memory (CD45RA^-) natural regulatory T cells (T_regs) (CD3⁺CD4⁺CD25⁺FoxP3⁺CTLA4⁺TIGIT⁺PD1^+/-) between SLE and healthy except for an increase in memory T_regs in the paediatric population (SLE versus healthy: 1.16 [0.79 to 1.92]%; 0.48 [0.32 to 0.80]%, p<0.0001). Instead, memory T_reg-like cells (CD3⁺CD4⁺CD45RA^-CD25^-FoxP3⁺CTLA⁺) were enriched in SLE in both adults (2.33 [1.50-3.31]; 1.16 [0.94-1.71], p<0.001) and children (2.75 [1.90-4.36]; 1.28 [0.83-1.78], p<0.0001). Concurrently, CTLA4-expressing naïve and memory non-T_reg CD4⁺ T effector cells were significantly reduced in adult-onset SLE compared to healthy (naïve: 1.61 [0.85-2.63]; 4.65 [3.2-7.18], p<0.0001; memory: 0.54 [0.34-0.79]; 1.46 [1.00-2.06], p<0.0001).

Conclusion: With a multi-parametric unbiased approach, we identified derangements in the immunoregulatory and effector axes in SLE: inadequate natural T_reg response in both adult- and childhood-onset SLE, and an overall tolerance reset in adult-onset SLE. Future therapeutic strategies may need to focus on these to restore immune homeostasis. The concurrent study of adult- and childhood-onset SLE offers a unique opportunity to identify mechanistic commonalities that will be amenable to similar therapeutic strategies and dissimilarities that warrant different treatment approaches.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Yeo JG, Wasser M, Kumar P, Pan L, Poh SL, Ally F, Arkachaisri T, Lim AJ, Leong JY, Lai L, Yeo KT, Lee ESC, Chua CJH, Larbi A, Nyunt MSZ, Ng TP, Chiesa S, Gattorno M, Martini A, Paleja BS, Duterte CA, Chen J, Nay Yaung K, Tang SP, Ng SK, Yung CF, Tan AYJ, Lee SY, Ginhoux F, Albani S. The Extended Polydimensional Immunome Characterization (EPIC) web-based reference and discovery tool for cytometry data. Nature Biotechnology. 2020 Jun 1;38(6):679-84.

Correspondence: M. I. Petrone

Pediatric Rheumatology 2023, 21(Suppl 2):PT035

Introduction: JDM patients show upregulation of interferon (IFN)-stimulated genes and downregulation of several genes related to mitochondrial function, suggesting a link of mitochondrial dysfunction and muscle inflammation in idiopathic inflammatory myopathies (IIM). The mitokines GDF15 and FGF21 are induced in situations of muscle stress, particularly mitochondrial myopathies. One published study demonstrated that GDF15 is increased in serum and muscle of adult patients with IIM and unpublished data showed elevated GDF15 plasma levels in JDM patients.

Objectives: To investigate serum levels of mitokines GDF15 and FGF21 in JDM patients at diagnosis, before start of immunosuppressive and glucocorticoid treatment, and evaluate possible correlations with clinical and laboratory findings, as well as with IFN-related biomarkers (type I IFN score, CXCL10, CXCL9 and neopterin).

Methods: We collected blood samples of 16 treatment-naïve JDM patients enrolled at time of diagnosis. Serum levels of FGF21, GDF15, CXCL10, CXCL9 and neopterin were analyzed by ELISA (normal values: 0-200 pg/ml, 200-1000 pg/ml, <300 pg/ml, <150 pg/ml, <1.59 ng/ml respectively); expression of 6 IFN-induced genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) was measured by real-time PCR and used to calculate a type I IFN score. For each patient, the following clinical data were recorded: physician’s global assessment (PGA) of disease activity VAS (Visual Analogue Scale), Childhood Myositis Assessment Score (CMAS), serum levels of creatine phosphokinase (CK, IU/l), MSA (myositis specific autoantibodies) status. Correlations were determined by the Spearman’s rank correlation coefficient. Non-parametric tests were used for comparisons between 2 groups.

Results: Twelve out of 16 patients were female (75%). Median age at disease onset was 6.1 years [IQR 4.25, 9.82] and median disease duration at diagnosis 3.4 months [IQR 1.80, 7.12]. Eleven patients were positive for at least one MSA. Median FGF21 levels were in the range of normal values [54 pg/ml (IQR 30.75-393.5)], whereas median GDF15 levels where increased [1370 pg/ml (IQR 1022-2055)]. Median GDF15 levels tended to be higher in anti-NXP2pos patients (n=4) when compared to the anti-NXP2neg patients (n=12) (3675 vs 1264 pg/ml, p=0.069). GDF15 levels, but not FGF21, showed significant correlation with CK levels (r_S=0.61, p=0.013), PGA (r_S=0.55, p=0.026) and CMAS (r_S=-0.62, p=0.013). We found no significant correlations of GDF15 or FGF21 levels with IFN-related biomarkers.

Conclusion: In our cohort a significant proportion of JDM patients showed increased levels of GDF15, whereas median FGF21 levels were normal. GDF15 levels were highest in anti-NXP2+ patients. GDF15 levels were correlated to global and muscular disease activity. Our data support the potential use of GDF15 as biomarker for IMM.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. De Paepe B, Verhamme F, De Bleecker JL. The myokine GDF-15 is a potential biomarker for myositis and associates with the protein aggregates of sporadic inclusion body myositis. Cytokine. 2020 Mar;127:154966. doi: 10.1016/j.cyto.2019.154966. Epub 2020 Jan 2. PMID: 31901761

2. Duvvuri B, Pachman L, Morgan G, Hermanson P, Wang T, Lood C. Growth and Differentiation Factor 15, an emerging biomarker of mitochondrial dysfunction-associated myopathies: implications for Juvenile Dermatomyositis. ACR Convergence 2022. November 10-14, 2022. Philadelphia, PA, USA.

Correspondence: A. Radziszewska

Pediatric Rheumatology 2023, 21(Suppl 2):PT036

Introduction: SLE (Systemic Lupus Erythematosus) is a multisystem autoimmune disease characterized by production of autoantibodies against nuclear antigens. While the adaptive immune response has been studied extensively in SLE, there is limited and at times contradictory evidence for the role of natural killer (NK) cells in SLE and, in particular, in the more severe, juvenile phenotype (JSLE).

Objectives: The aim of this study was to investigate the phenotype and function of NK cells in patients with JSLE compared to age/sex-matched healthy controls (HCs) using flow cytometric and transcriptional profiling.

Methods: Peripheral blood mononuclear cells (PBMCs) were collected from JSLE patients (n=45, 15.2-32.2 years), and age/sex-matched HCs (n=66, 15.4-29.8 years). Ex vivo PBMCs were stained with anti-CD3, -CD8, -CD56, -perforin, -granzyme A, -granzyme B, -granulysin antibodies and analysed by flow cytometry. Annexin V and PI staining was used to detect NK cell apoptosis with and without IFN-α stimulation. Cytolytic activity of NK cells against CFSE labelled K562 target cells was assessed in a flow cytometric 4hr co-incubation assay. Statistical significance was calculated using Mann-Whitney U tests or t-tests as appropriate. Transcriptomic analysis of RNA sequencing data from purified NK cells from a subset of JSLE patients (n=12) and HCs (n=6) was performed using R software and the DESeq2 model.

Results: The proportions of total NK cells (p=0.00001) as well as perforin (p=0.00001) and granzyme A (p=0.0002) expressing NK cell populations were markedly diminished in JSLE patients. Reductions in NK cells in JSLE were associated with increased disease activity (SLEDAI) (r=-0.34, p=0.031). Transcriptomic analysis of NK populations from active and inactive JSLE patients (SLEDAI score cut-off 4) and HCs confirmed that disease activity was the main driver of differential gene expression in NK cells. NK cells from active JSLE patients compared to HCs had a high number of differentially expressed genes (n=239, p.adj<0.05) while NK cells from inactive patients were transcriptionally similar to those of HCs (n=4, p.adj<0.05). Although NK cytotoxic function appeared to be preserved in JSLE, NK cells from JSLE patients exhibited increased propensity toward apoptosis when stimulated with IFN-α (p=0.029).

Conclusion: This is the first study to show that the cytotoxic capacity and frequencies of NK cells were diminished in JSLE patients, and more so in active disease, characterised by profound NK cell transcriptomic differences. NK cells from JSLE patients were more susceptible to apoptosis which may, at least in part, explain the reduction of NK cells in JSLE.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. Shimbo

Pediatric Rheumatology 2023, 21(Suppl 2):PT037

Introduction: Childhood-onset systemic lupus erythematosus(cSLE) is an autoimmune disease characterized by multisystem involvements, breakdown of self-tolerance and overproduction of autoantibodies with significant clinical heterogeneity. Differences in clinical phenotypes are reported to be related to underlying immune dysregulation.

Objectives: We aimed to determine the immunological phenotypes of cSLE by lymphocyte subsets and cytokine profiles and to investigate the association between the immunological phenotypes and clinical manifestations.

Methods: Peripheral blood samples were obtained from 22 cSLE patients at their diagnosis. The healthy control (HC) group consisted of 7 age-matched children for lymphocyte subsets and 10 for cytokines. The clinical manifestations were collected from medical records retrospectively. Lymphocyte subsets were evaluated by multicolour flow cytometry and serum cytokine levels were determined by enzyme-linked immunosorbent assay.

Results: In cSLE patients, the proportions of memory B, NK, iNKT and γδT cells were significantly decreased, whereas αβT, Treg, activated T cells and plasmablasts were significantly increased. Both myeloid dendritic cells (DCs) and plasmacytoid DCs were decreased in cSLE. IL-18, CXCL9, sTNF-RII, IL-6, IFNα and BAFF were increased compared to HC. Lupus nephritis was related to increased CD8+ T cells and memory B cells, and chilblain lupus was related to decreased γδT cells. Increased IFNα was related to increased memory B cells (% of CD19+ cells), transitional B cells, plasmablasts, IgM memory B cells and NK cells. In terms of treatment response, the increased proportion of Th17 was related to a longer duration of PSL reduction.

Conclusion: cSLE exhibited characteristic lymphocyte subset profiles markedly different from HC. Clinical manifestations of SLE were associated with lymphocyte subsets and cytokines. Th17 proportion may be associated with treatment response.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: S. R. Veldkamp

Pediatric Rheumatology 2023, 21(Suppl 2):PT038

Introduction: The clinical management of juvenile dermatomyositis (JDM) patients is complicated by the heterogeneity in disease course, as well as the uncertainty regarding which patients can safely taper or discontinue immunosuppressive medication.

Objectives: We aimed to identify different disease trajectories with latent class mixed-effects models (LCMM), using clinical disease activity measures and two previously validated biomarkers Galectin-9 and CXCL10.

Methods: Longitudinal clinical and biomarker data of the first 60 months of follow-up (FU) were used of 81 JDM patients from 7 tertiary centers. Clinical data included scores for global disease activity (PGA), skin disease activity (aCAT), and muscle disease activity (CMAS). Biomarker (Galectin-9, CXCL10, CK) measurements were collected as part of regular care. The best LCMM for each variable was based on BIC value, maximum posterior probabilities, and clinical relevance.

Results: LCMM analysis of PGA scores identified 3 classes. PGA scores in class 1 (69%) steadily declined and stayed low, while in class 2 (20%) they declined and increased again around 20 months of FU. PGA scores in class 3 (11%) remained high. During FU, class 3 had significantly higher aCAT scores than class 1. Calcinosis occurred in 5%, 25% and 33% of class 1, 2 and 3, respectively. LCMM analysis of aCAT scores identified 2 classes. Patients in class 1 (78%) had gradually declining scores which then remained low, while patients in class 2 (22%) showed persistent skin disease activity. LCMM analysis of CMAS scores identified 2 classes. Patients in class 1 (54%) showed a slow but steady improvement of muscle disease during FU. Patients in class 2 (46%) had more serious muscle disease at baseline, but a faster improvement than class 1. Class 2 was defined by higher PGA scores and CK levels at baseline compared to class 1. Although LCMM analyses of Galectin-9 and CXCL10 were limited by a small number of measurements, two classes of CXCL10 could be identified. In class 1 (83%) CXCL10 levels steadily declined and remained low, while in class 2 (17%) levels initially declined, but increased again around 20 months of FU. Notably, all 3 patients in class 2 with available CXCL10 measurements after 25 months FU, flared (at 29, 32 and 45 months FU, respectively). Finally, a trend towards higher Galectin-9 levels was observed in PGA class 2 at 20 months FU, compared to class 1 PGA (no measurements available in PGA class 3).

Conclusion: LCMM analysis identified distinct disease trajectories in JDM patients that align with disease courses typically seen in the clinic: most patients achieve persistent remission, some experience flares, and a smaller subgroup has refractory (skin) disease. Rising levels of Galectin-9 and CXCL10 could be indicative of an upcoming flare. Combining longitudinal clinical and biomarker data can provide insights in underlying phenotypes and enable personalized treatment.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: C. Wibrand

Pediatric Rheumatology 2023, 21(Suppl 2):PT039

Introduction: Juvenile dermatomyositis (JDM) is a rare, serious systemic autoimmune condition, and much remains unknown about the pathogenesis of and the immune cell types and cell-specific pathways associated with disease.

Objectives: To increase knowledge of immune dysregulation in JDM with immunophenotyping at the cellular level using CITE-seq.

Methods: Multiplexed single cell RNA and protein sequencing was applied to 27 peripheral blood samples to simultaneously profile the gene and cell surface antibody (ADT) expression associated with JDM (n=15, samples=22) compared to healthy pediatric controls (HC)(n=5). Data processing steps included quality control, dimensional reduction, clustering, and cell type annotation using canonical ADT and gene markers. To determine JDM-associated changes, we performed: 1) cell type proportion analysis between individual groups (treatment naïve (TN), inactive, HC) (adjusted p-value < 0.05), 2) correlation analysis between cell type proportion and disease activity measures (p < 0.05), 3) differential gene and ADT expression analysis between TN JDM and HC for each cell type using DESeq2 (FDR < 0.05), and 4) gene overrepresentation analysis (GOA) with clusterProfiler (adjusted p value < 0.05).

Results: Using unsupervised clustering of 107,661 immune cells, we identified 29 clusters, which compromised 21 unique immune cell populations. TN patients had statistically significantly higher levels of transitional B cells compared to inactive JDM, and cell type proportion was positively correlated with disease activity measures. TN patients had significantly fewer NK and gd T cells than both healthy controls and inactive JDM, and cell type proportion was negatively correlated with disease activity measures. Tregs were significantly increased in TN JDM compared to HC. Although most differentially expressed genes were found within naïve B cells, monocytes, and specific T-cell subsets, including Tregs, many differentially expressed genes were shared among cell types, and GOA revealed overrepresentation of genes involved in type 1 interferon and interferon gamma pathways for most cell types. However, we found a characteristic heterogeneity in the interferon signature expression among patients. Analysis of differences in cell surface protein levels revealed upregulation of SIGLEC-1 and LAMP-1 on the surface of both CD14+ and CD16+ monocytes.

Conclusion: Alterations in immune cell composition within the B, CD4⁺ T, gd T, and NK cell compartments are associated with disease activity in JDM. Monocytes and naive B cells experience major gene expression changes during disease, but all cell types are heavily influenced by interferon signaling, although patient-specific expression patterns are observed. Future directions of this work include characterization of JDM-associated immunophenotypes at the transcriptomic and proteomic levels and network analysis.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: M. G. L. Wilkinson

Pediatric Rheumatology 2023, 21(Suppl 2):PT040

Introduction: JDM is a rare childhood autoimmune myositis, typically presents with proximal muscle weakness and skin manifestations. JDM is characterised by abnormal interferon (IFN) type I signalling and mitochondrial abnormalities contributing to the disease pathogenesis(1). There is a need for better treatments, with novel therapeutics targeting IFN and mitochondria pathways, being the clear candidates.

Objectives: This study aimed to define and validate a JDM mitochondrial gene signature, explore whether this signature is shared with juvenile idiopathic arthritis (JIA), and investigate the disease specificity of the signature.

Methods: Peripheral blood mononuclear cell (PBMC) samples were obtained from treatment-naïve JDM and JIA patients and age/sex-matched child healthy controls (controls). RNA sequencing (RNAseq) was performed from total tPBMC and sorted CD14⁺ cells. Dataset-1 comprised JDM pre-treatment (n=10), and controls (n=6). Dataset-2 comprised JDM pre-treatment (n=30), JIA pre-treatment (n=84) and controls (n=18). Within dataset-2 the JDM and conrtol data were included for both CD14+ monocytes and tPBMC, while for JIA only CD14+ data were analysed. Differentially expressed genes (DEG) were analysed using EdgeR. Linear regression analysis was performed by comparing the log fold change in JDM CD14+ monocytes to PBMC, and to JIA CD14+ monocytes.

Results: DE analysis of dataset-1 showed gene dysregulation in the mitochondrion gene ontology term (MGO) and upregulated IFN type 1 genes (n=13) in CD14+ monocytes from JDM pre-treatment compared to controls. Confirmed by investigating the MGO of 1438 expressed genes, comparing DEG from datasets 1&2, CD14+ monocytes JDM pre-treatment compared to controls. 130 DEG in dataset-1 and 92 in dataset-2 and the overlap was 37 genes (FDR≤0.05, FC≤-1.5 or ≥1.5). The combined mitochondrial and IFN type 1 signature (MIGS) consisted of 48 genes. In dataset-2 clear separation was observed on the TPM (transcript per million) of normalised gene counts for the defined MIGS from JDM pre-treatment and controls by hierarchical clustering. Regression analysis showed that CD14+ monocytes had similar MIGS expression to total PBMC when JDM pre-treatment was compared to controls (estimate=0.99,95%CI(0.89,1.09),p-value<2.2e-16). In JIA pre-treatment the MIGS expression in CD14+ monocytes was less than in JDM pre-treatment compared to the same controls (estimate=3.62,95%CI(3.22,4.02),p-value<2.2e-16).

Conclusion: This study identified and validated a dysregulated mitochondrial signature in treatment-naïve JDM CD14+ monocytes, further validated in PBMCs. This signature partly overlapped with the CD14+ monocyte signatures in treatment-naïve JIA, suggesting a degree of disease-specificity. This signature could have clinical implications as a biomarker of mitochondrial health in JDM, potentially useful for patient treatment stratification.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Wilkinson MGL, Moulding D, McDonnell TCR, et al. Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis Annals of the Rheumatic Diseases 2023;82:658-669

Correspondence: C. Bracaglia

Pediatric Rheumatology 2023, 21(Suppl 2):PT041

Introduction: Chronic parenchymal lung disease (LD) is a new emerging severe life-threatening complication of Systemic Juvenile Idiopathic Arthritis (sJIA). The number of sJIA patients with LD is apparently increasing and interestingly they are reported more frequently in North America. Data regarding frequency and features of sJIA-LD in Europe are not available.

Objectives: To evaluate the burden of sJIA associated LD in Europe.

Methods: Patients with diagnosis of sJIA with LD, including pulmonary alveolar proteinosis (PAP), interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), followed in European paediatric rheumatology centres were identified through a survey sent to the members of the MAS/SJIA Working Party.

Results: Data from 49 JIA-LD patients, diagnosed in 17 European paediatric rheumatology centres between 2007 and 2022, were collected. 48 patients were Caucasian and 1 was African-American; 31 were female. The median age at sJIA onset was 7 years and LD occurred after a median time of 3 years. 27 patients had a chronic persistent sJIA course, 21 had a polycyclic course and only 1 patient had a monocyclic course; 38 patients (77%) had active sJIA at time of LD diagnosis. During the disease course, 41 (84%) patients developed MAS, 18 (44%) of whom had MAS at sJIA onset and 24 (58%) had full-blown MAS at time of LD diagnosis; 31 (76%) patients had >1 MAS episode. 42 (86 %) patients were treated with at least one IL-1 or IL-6 inhibitor before LD diagnosis: 33 with anakinra, 26 with canakinumab, and 23 with tocilizumab; 20 (40%) patients experienced drug adverse reaction to a cytokine inhibitor: 14 to tocilizumab and 6 to anakinra. 39 (80%) patients developed ILD, 6 (12%) PAP and 4 (8%) PAH. 22 (45%) patients presented acute digital clubbing; 18 (37%) patients developed hypoxia and 9 (18%) developed pulmonary hypertension. A chest CT scan was performed in all patients with evidence of septal thickening, peri-bronchovascular thickening and ground glass opacities in the majority of patients (39, 25 and 28 patients respectively). In 22 patients a bronchoalveolar lavage was performed and 15 underwent a lung biopsy. The histopathological pattern was alveolar proteinosis in 5 patients, endogenous lipoid pneumonia in 5, vasculitis in 1 and fibrosis in 1. 45 out of 49 patients were treated with glucocorticoids (GCs) at time of LD diagnosis, and 39 received IL-1 and/or IL-6 inhibitor after the diagnosis (25 anakinra, 20 canakinumab, 16 tocilizumab). Around half of the patients (23, 47%) required ICU admission and 9 (18%) died.

Conclusion: Lung involvement is an emerging life-threatening complication of sJIA, patients are also reported in Europe. Prompt recognition is crucial and new therapeutic strategies are needed to reduce the risk and improve the outcome of this complication.

Patient Consent

Yes, I received consent

Disclosure of Interest

C. Bracaglia: None declared, F. Minoia Consultant with: Sobi, C. Kessel Grant / Research Support with: Novartis, Consultant with: Novartis, Speaker Bureau with: Sobi, S. Vastert: None declared, M. Pardeo Consultant with: Sobi, A. Arduini: None declared, S. Fingerhutova: None declared, I. Nikishina Speaker Bureau with: Pfizer, Roche, Novartis, Pfizer, Sobi, MSD, R-Pharm, Ipsen, O. Basaran: None declared, N. Kiper: None declared, M. Kostik: None declared, M. Glerup: None declared, R. Caorsi Consultant with: Sobi, Novartis, A. Horne: None declared, G. Filocamo Consultant with: Sobi, H. Wittkowski: None declared, M. Jelusic: None declared, J. Anton Grant / Research Support with: Sobi, Novimmune, Novartis, Abbvie, Pfizer, GSK, Roche, Amgen, Lilly, BMS, Sanofi, Consultant with: Sobi, Novimmune, Novartis, Pfizer, GSK, Speaker Bureau with: Sobi, Novimmune, Novartis, GSK, Pfizer, S. Khaldi-Plassart: None declared, A. Belot Consultant with: SOBI, Novartis, Roche, Pfizer, G. Horneff Grant / Research Support with: MSD, Novartis, Roche, Speaker Bureau with: Abbvie, Chugai, Lilly, Sanofi, Novartis, Pfizer, S. Palmer Sarott: None declared, E. Cannizzaro Schneider: None declared, L. Fotis: None declared, P. Dolezalova: None declared, A. Ravelli: None declared, S. Ozen Consultant with: Sobi, Novartis, Speaker Bureau with: Sobi, Novartis, F. De Benedetti Consultant with: Abbvie, Sobi, Novimmune, Novartis, Roche, Pfizer.

Correspondence: M. Correia Marques

Pediatric Rheumatology 2023, 21(Suppl 2):PT042

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a complex inflammatory condition of childhood. It can be complicated by macrophage activation syndrome (MAS), a secondary form of hemophagocytic lymphohistiocytosis (HLH). Studies have identified an enrichment of HLH variants in sJIA patients with MAS compared with those without it. However, the role of these variants in sJIA in general is not known.

Objectives: To determine whether rare variation in HLH genes contributes to the risk of developing sJIA.

Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in an established sJIA cohort using Illumina Nextera Custom Capture Assays and Illumina sequencers. Data processing and quality control were performed using a Genome Analysis Toolkit-based pipeline. Variants were filtered to retain high-quality, rare, protein-altering variation on Ensembl canonical transcripts. Healthy control exomes were extracted from dbGaP (phs000280.v8.p2). Rare variant association testing (RVT) was done with sequence kernel association test (SKAT). A burden test was also performed with the SKAT package. Significance was defined as p<0.05 after 100,000 permutations.

Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 2952 controls. Subjects were excluded if they had a monogenic disease, dissimilar genetic ancestry, or >10% missingness (total 45 cases, 28 controls). Analysis of the remaining 479 sJIA cases revealed 71 rare HLH gene variants, including recurrent ultra-rare (MAF<0.001) variants in LYST and UNC13D and a recurrent STXBP2 variant that has been linked to severe COVID-19. RVT comparing the variant distributions of sJIA cases and controls revealed a significant association with rare (MAF<0.01) variants of STXBP2 (p=0.019), and ultra-rare variants of STXBP2 (p=0.006) and UNC13D (p=0.045). Sub-analysis of patients with known MAS status showed that the distribution of rare variants of UNC13D was different in 32 sJIA patients with MAS than in 90 without it (p=0.0047) or 2930 controls (p=0.03). There was an increased frequency of individuals with ≥1 rare HLH variants in all sJIA groups (MAS positive 28%, MAS negative 21%, full cohort 20%) compared to the controls (17%). Similarly, the full cohort (p=0.009) and those with MAS (p=0.025) had a higher burden of HLH variants than controls, whereas those without MAS did not (p=0.12).

Conclusion: We found that the association of HLH variants with sJIA is not purely linked to MAS. STXBP2 was significantly associated with sJIA, while showing no association with MAS. Moreover, the frequency of HLH gene variants trended higher in MAS-negative sJIA than in control subjects. As seen in prior studies, UNC13D was associated with MAS. Taken together, this suggests that HLH variants may play a role in the pathophysiology of sJIA in general, and not only in MAS.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: T. Hinze

Pediatric Rheumatology 2023, 21(Suppl 2):PT043

Introduction: Systemic juvenile idiopathic arthritis (SJIA) is characterized by a pronounced dysregulation of immune-related peripheral blood gene expression. Canakinumab, an interleukin (IL)-1β blocking antibody, is clinically highly efficacious in most patients and can be successfully tapered in many. It is unclear how the presence of different gene expression signatures in patients with SJIA on canakinumab therapy relate to tapering success.

Objectives: The objective of this study was to identify differences in peripheral blood gene expression signatures in patients with SJIA who underwent successful canakinumab tapering and withdrawal versus those who did not.

Methods: In exploratory RNA seq analyses of 83 patient samples from an open-label randomized canakinumab trial (NCT02296424) or from a long-term extension trial of canakinumab (NCT00891046), and 10 paediatric healthy controls we identified candidate genes of interest associated with treatment outcomes. Subsequently, we studied 212 longitudinal whole blood RNA samples from the same cohorts via a custom 67 gene NanoString panel that was designed to represent identified candidate genes and various pathways (including neutrophil/innate immunity, Interferon (IFN) and/or erythropoiesis signatures). Correlation analyses and group comparisons were performed, considering various treatment outcomes, including success of canakinumab tapering and withdrawal.

Results: RNA seq analysis demonstrated that neutrophil/innate immunity signatures were reversible upon treatment with canakinumab. Using the NanoString dataset, correlation analysis across all samples showed clear neutrophil/innate immunity, IFN and erythropoiesis signatures. Treatment of active SJIA patients with canakinumab resulted in a lasting reversal of neutrophil/innate immunity and erythropoiesis signatures. When analysing 54 samples of patients with subsequent successful taper and discontinuation of canakinumab with 94 samples of patients with non-successful taper or discontinuation, there was significant differential expression of multiple genes with higher expression of erythropoiesis- and neutrophil/innate immunity-related genes in the non-successful group, whereas interferon-stimulated genes were not significantly different.

Conclusion: Canakinumab therapy seems to reverse prominent neutrophil/innate immunity-related and erythropoiesis gene expression signatures in patients with SJIA. Relatively higher expression of these signatures may signal a higher risk of non-successful canakinumab taper or discontinuation. This would need to be studied further.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

T. Hinze Grant / Research Support with: Research Support by Novartis Pharma AG, M. Saers: None declared, C. Hinze: None declared, C. Kessel Grant / Research Support with: Research Support by Novartis, C. Farady Employee with: Employee of Novartis, S. McCreddin Employee with: Employee of Novartis, M. Trautmann: None declared, W. Hartmann: None declared, D. Foell Grant / Research Support with: Research Support by Novartis

Correspondence: J. Ombrello

Pediatric Rheumatology 2023, 21(Suppl 2):PT044

Introduction: Still’s disease (systemic juvenile idiopathic arthritis in children and adult-onset Still’s disease in adults) is an enigmatic inflammatory condition that affects people of all ages. It is characterized by inflammasome activation and pyroptosis with elevation of interleukin (IL)-1 and gasdermin D, and it is often punctuated by striking elevation of IL-18. Increased interferon (IFN) signaling, a known driver of pyroptosis, has been described in Still's disease complicated by either macrophage activation syndrome (MAS) or an emergent form of lung disease with hypersensitivity (LD/DHR), but it is unclear whether IFN activation is an active participant or an epiphenomenon.

Objectives: Using pathway analysis of candidate causative genes identified by trio whole exome-sequencing (WES), we sought to explore the relationship between genetic variation and increased IFN signaling in Still’s disease.

Methods: We examined consecutive people with Still’s disease enrolled in an IRB approved research study at the NIH Clinical Center. Whole blood expression of 28 IFN-stimulated genes (ISG) was quantified with custom NanoString arrays and expressed as a normalized score. Trio WES was performed in probands and a list of candidate causative variants (protein-altering de novo, recessive or X-linked variants; popfreqmax frequency<0.01) was generated. Candidate gene lists were compiled for individuals in the top or bottom quartiles of ISG scores and subjected to pathway over-representation analysis (ORA) and network topology analysis (NTA) using the Web-based Gene Set Analysis Toolkit (webgestalt.org).

Results: ISG scores among Still’s patients were negatively skewed and the upper quartile included 15 people with high ISG scores. LD/DHR was more common in the top quartile than in the bottom quartile (0.6, 0.13; p=0.02), and it was strongly associated with HLA-DRB1*15 alleles. The rates of active disease, IL-18 above 15K, use of IL-1 directed therapy, HLA-DRB1*15 carriage and history of MAS did not differ significantly between the groups. Trio sequencing identified 83 candidate genes among subjects in the top ISG quartile. ORA of candidate genes from individuals in the top ISG quartile revealed enrichment in the macrophage activation (ratio=21.7, p=3.4E-7, FDR=0.0055), type I IFN biosynthetic process (ratio=77.9, p=6.7E-6, FDR=0.03) and myeloid leukocyte activation (ratio=5.0, p=1.9E-5, FDR=0.039) pathways. Most people in the top ISG quartile (11/15) had candidate causative variation within these 3 pathways. Several other relevant pathways, including chemokine production, regulation of IL-18 production, and nuclear factor-kappa beta (NF-KB) signaling, also had evidence of over-representation (p<0.0005, FDR>0.05). NTA demonstrated significant enrichment of several pathways, including the MyD88-dependent TLR signaling pathway (corrected p=0.0045). ORA and NTA of 81 candidate genes from 15 subjects with the lowest ISG scores did not reveal enrichment of any pathway.

Conclusion: In our cohort, high ISG score was associated with the presence of LD/DHR but not MAS. Using unbiased analysis of trio WES in a Still’s cohort, we observed that people with high ISG scores had specific enrichment of potentially causative variation in innate immune pathways, most notably type I IFN production, MyD88/TLR signaling, and macrophage/myeloid leukocyte activation. Together this suggests that causative or high effect genetic variants are operative in the pathophysiology of Still's disease, where they can promote enhanced IFN signaling and may predispose to LD/DHR.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. I. Rebollo-Giménez

Pediatric Rheumatology 2023, 21(Suppl 2):PT045

Introduction: Treatment of systemic juvenile idiopathic arthritis (sJIA) includes conventional synthetic (cs) and biologic (b) disease modifying anti-rheumatic drugs (DMARDs) in addition to glucorticorticoids as needed.However,evidence on safety data regarding these treatments in sJIA is scarce.

Objectives: To report the adverse events (AE) of at least moderate intensity, serious AE (SAE) and events of special interest (ESI) in sJIA patients in the initial 6-months of treatment from Pharmachild registry.

Methods: Inclusion criteria were children with sJIA as per ILAR criteria with at least 6 month of follow-up visits.Data was available from 1987 until December 2021.Patients were classified into 4 mutually exclusive groups according to their treatment in the initial 6 months from disease onset:1)glucocorticoids, 2)bDMARDs, 3)csDMARDS and 4)combinations of these drugs. AE were classified as the latest version of MedDRA dictionary(Version 23.1). Statistical analysis included descriptive statistics,incidence rates(95% CI),time to occurrence of AE with Kaplan-Meier survival curve, the log rank test and Cox multivariate regression model.

Results: A total of 701/992 (71%) children with sJIA were classified into 4 different treatment arms as follows: 1)glucocorticoids(N=161), 2)bDMARDS(N=69); 3)csDMARDs(N=65) and 4)combo(N=406). The demographic characteristics of the patients included in the 4 groups were comparable. bDMARDs patients had the shortest duration of disease and older age at diagnosis compared to the other groups. With regards to the treatment, glucocorticoids exclusively were used more commonly before 2011.

A total of 125 AE in 701 patients,39 serious AE (SAE) and 48 ESI were observed in the initial 6 months of treatment.The two groups with the highest rate of AEs were a)bDMARDs with 32 AE/65 patients and b)combined therapy with 86 AE/406 patients. Infections/infestations were the most common AEs (varicella, viral gastroenteritis, impetigo, otitis media, pharyngitis, salmonellosis, herpes zoster,influenza, mycoplasma/Coxiella/viral/Epstein-Bar infection, pneumonia, pneumonia cytomegaloviral, subcutaneous abscess, respiratory tract/upper respiratory tract infection and vascular device infection),with the following rate of AEs per patient per year (N, IR*100PY-95%CI): a)bDMARDs group (7, 32.94 [15.70 - 69.10]) b)combination therapy group (10, 5.72 [3.08 - 10.63]), and c)glucocorticoids group (2, 4.42 [1.11 - 17.69 ])with no infectious events reported in the csDMARDs group.Gastrointestinal disorders were most frequent in the bDMARDs group(N, IR*100PY-95%CI) (6, 28.24 [12.69 - 62.85]), followed by the combo group(4, 2.29 [0.86 - 6.10]). General disorders and administrations site conditions (drug intolerance, fatigue, injection site rash, injection site abscess sterile) were more common in the bDMARDs group, followed by combination therapy group. No relevant differences have been observed for other SOCs. Kaplan Meier's showed the bDMARDs group experienced more adverse events and sooner in time when compared to the other groups (log rank test p<0.).The risk of any AE was significantly higher in patients with bDMARDs, hazard ratio 8.8 (95% CI: 3.5 to 22.1).

Conclusion: Treatment of children with sJIA with bDMARDs or combination therapy was associated with a higher prevalence of AE, SAE and ESI when compared to treatment with csDMARDS or glucocorticoids only in the first six months of therapy. Infections were the most common AE, principally consisting of respiratory infections and injection site reactions.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: S. Rosina

Pediatric Rheumatology 2023, 21(Suppl 2):PT046

Introduction: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) is a composite disease activity (DA) score specifically validated for use in systemic juvenile idiopathic arthritis (sJIA). The sJADAS10 is calculated as the simple linear sum of the scores of the following 5 items: 1) physician global assessment of overall DA, measured on a 10-cm visual analog scale (VAS), where 0 = no activity and 10 = maximum activity; 2) parent/patient global assessment of child’s well-being, measured on a 10-cm VAS, where 0 = very well and 10 = very poor; 3) count of joints with active disease in a maximum of 10 joints; 4) ESR or CRP level, normalized to a 0-10 scale; and 5) modified Systemic Manifestation Score (mSMS), ranging from 0 to 10, where 0 = absence of systemic manifestations and 10 = maximum activity of systemic manifestations. The range of the sJADAS10 is 0-50.

Objectives: To develop and validate the cutoffs in the sJADAS10 that define the states of inactive disease (ID), low (or minimal) DA (LDA), moderate DA (MDA) and high DA (HDA) in sJIA.

Methods: A multinational cross-sectional sample of 378 patients with definite or probable sJIA was enrolled. At study visit, each patient was categorized subjectively by the caring physician as being in the state of ID, LDA, MDA, or HDA. A total of 400 visits were collected, that were then randomly split into two samples: a developmental sample (n=240), and a validation sample (n=160). Optimal cutoff values were determined in the developmental sample against the subjective physician rating of DA state, that was used as external criterion, by multiple methods (calculation of percentiles of cumulative score distribution, ROC curve analysis, Youden index, 90% fixed specificity and kappa agreement). The choice of final cutoffs was based on clinical and statistical grounds. Cutoff validation was conducted in the validation sample by assessing discriminative ability.

Results: The selected sJADAS10 cutoffs were <=2.9 for ID, <=10 for LDA, 10-20.6 for MDA, and >20.6 for HDA. In validation analyses, the cutoffs showed strong ability to discriminate among DA states defined subjectively by the parents, parents’ satisfaction/dissatisfaction with illness outcome, level of child’s pain, presence/absence of functional impairment, presence/absence of morning stiffness, and normal/reduced quality of life.

Conclusion: We developed the cutoffs in the sJADAS10 that define the main DA states in sJIA. The cutoffs revealed good metrologic properties in the validation sample, and are therefore suitable for application in clinical practice and research.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Reference

1. Tibaldi J, Pistorio A, Aldera E, Puzone L, El Miedany Y, Pal P, Giri PP, De H, Khubchandani R, Chavan PP, Vilaiyuk S, Lerkvaleekul B, Yamsuwan J, Sabui TK, Datta P, Pardeo M, Bracaglia C, Sawhney S, Mittal S, Hassan WA, Elderiny GF, Abu-Zaid MH, Eissa M, Sztajnbok F, das Neves Sztajnbok FC, Russo R, Katsicas MM, Cimaz R, Marrani E, Alexeeva E, Dvoryakovskaya TM, Alsuweiti MO, Alzyoud RM, Kostik M, Chikova I, Minoia F, Filocamo G, Farag Y, Lotfy H, Nasef SI, Al-Mayouf SM, Maggio MC, Magalhaes CS, Gallizzi R, Conti G, Shimizu M, Civino A, Felici E, Giancane G, Ruperto N, Consolaro A, Ravelli A. Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis. Rheumatology (Oxford). 2020 Nov 1;59(11):3505-3514. doi: 10.1093/rheumatology/keaa240. PMID: 32829413.

Correspondence: G. S. Schulert

Pediatric Rheumatology 2023, 21(Suppl 2):PT047

Introduction: Systemic juvenile idiopathic arthritis (SJIA) associated lung disease (SJIA-LD) is an emerging and life-threatening clinical problem with urgent unmet needs including prevalence, pathogenesis, disease biomarkers, influence of biologics, and outcomes.

Objectives: To define baseline clinical features and biomarker profiles of patients in the CARRA Registry SJIA-LD cohort.

Methods: Existing or newly enrolled CARRA Registry patients with SJIA and suspected, probable, or definite SJIA-LD were included in the cohort. In addition to standard Registry data, lung disease specific data was obtained using a standardized case report form through REDCap Cloud, and biosamples collected when available. Biomarker profiles were determined from plasma using a custom Luminex panel. This study was approved by the DCRI Reliant IRB and/or IRB of all Registry sites.

Results: 37 patients were enrolled in the SJIA-LD cohort, from 16 CARRA Registry sites in the US. 46% had definite (biopsy-proven), 36% probable, and 18% suspected SJIA-LD. Most common CT findings were ground glass opacities (55%) and peribronchovascular or septal thickening (41%). Of those who underwent lung biopsy, all had pulmonary alveolar proteinosis (PAP) and interstitial inflammation, and 40% had collagenous fibrosis. 77% had at least one definite episode of macrophage activation syndrome (MAS) (including 64% that met the 2016-SJIA-MAS criteria), 73% had more than one MAS episode, and 32% had subclinical MAS. MAS occurred prior to SJIA-LD diagnosis in 68% and coincided with it in 18%. More than 80% of patients remained on oral glucocorticoids. Physician global assessment of lung disease (PGALD) ranged from 0-8 (median 3.5) on a scale of 0-10 with 10 being most severe. 36% had PGALD of 0-2, while 27% had PGALD ≥5 reflecting severe disease. Overall health-related quality of life at enrollment was excellent in 26%, very good in 22%, good in 35%, and fiar in 17%.

Median serum IL-18 was markedly elevated at 24,336 ng/mL (IQR 4,147-49,275). Across all patient samples, SJIA-LD patients showed significantly increased plasma levels of IL-6, IL-12, IL-18, CXCL9, CD25, CCL11, CCL17, MCP-1, and MCP-3, compared to healthy control children. Cluster analysis defined 3 distinct groups of SJIA-LD patients. Group 1 (n=7) showed high levels of TNF, IL-6, IL-17, MCP-1 and 3, CCL11, and CCL17; group 2 (n=8) showed high IL-10, IL-12, IL-18, CXCL9, CXCL10, CD25, and CD163; and group 3 (n=10) showed high CCL15 and CCL25.

Conclusion: Patients in the CARRA SJIA-LD cohort represent a broad spectrum of clinical and radiographic features, disease activity, and treatment approaches. Recurrent MAS was common. Patients with SJIA-LD showed multiple distinct plasma biomarker patterns. This cohort will serve as an ongoing prospective cohort study of this emerging disease, to assess longitudinal disease progression and trajectories, as well as associated immune biomarkers and cellular populations.

Patient Consent

Yes, I received consent

Disclosure of Interest

E. Eloseily: None declared, A. Clark: None declared, M.-L. Chang: None declared, M. E. Riordan: None declared, A. Russell: None declared, M. Natter: None declared, S. Thornton: None declared, Y. Kimura: None declared, G. Schulert Grant / Research Support with: IpiNovyx, Consultant with: SOBI

Correspondence: M. Shimizu

Pediatric Rheumatology 2023, 21(Suppl 2):PT048

Introduction: Pediatric Rheumatology International Trials Organization (PRINTO) has recently proposed revision of the current International League of Associations for Rheumatology (ILAR) criteria for systemic juvenile idiopathic arthritis (s-JIA). The requirement of arthritis has been removed from being a mandatory criterion because arthritis may not be observed as the initial manifestation of s-JIA. In contrast, leukocytosis has been added as a laboratory criterion among the minor criteria.

Objectives: This study was aimed to evaluate the performances of PRINTO criteria compared to ILAR criteria for s-JIA, and also to evaluate whether serum IL-18 levels improve the diagnostic performance of classification criteria for s-JIA.

Methods: This multicenter, retrospective study was conducted at 11 pediatric rheumatology institutes in Japan. This study included 65 patients with s-JIA and 13 patients with inflammatory diseases presenting prolonged fever over 14 days and arthritis and/or evanescent erythematous rash including refractory Kawasaki disease, reactive arthritis, Takayasu arteritis, Tubulointerstitial nephritis, Yersinia pseudotuberculosis infection, cryopyrin associated periodic syndrome and ANCA associated vasculitis. ILAR and PRINTO classification criteria were applied to all patients and checked with experts’ diagnosis. Serum IL-18 levels were determined by enzyme-linked immunosorbent assay.

Results: PRINTO criteria demonstrated higher sensitivity (100% vs 58%) but lower specificity (15.4% vs 84.6%) compared to ILAR criteria. Sensitivity of ILAR criteria and specificity of PRINTO criteria were improved with the addition of serum IL-18 levels ≥ 4800pg/mL to 97% and 100%, respectively.

Conclusion: Serum IL-18 levels could improve the diagnostic performance of PRINTO and ILAR criteria for systemic juvenile idiopathic arthritis. PRINTO criteria with the addition of serum IL-18 levels ≥ 4800pg/mL might be the best diagnostic performance for s-JIA.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. Swoboda

Pediatric Rheumatology 2023, 21(Suppl 2):PT049

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a rare childhood chronic inflammatory disorder with risk for life-threatening complications such as macrophage activation syndrome (MAS) or lung disease (LD). An early study on cellular phenotypes in sJIA demonstrated defects in the lytic machinery of sJIA NK- as well as CD8^posT cells.

Objectives: To date there are still little data on CD8^posT cell phenotypes and function outside of MAS, and therefore we aimed at an ex vivo whole blood phenotyping approach of CD8^pos T cells in non-complicated sJIA. Beyond, we set out to investigate their interplay with neutrophils as a highly abundant inflammatory cell population in sJIA, which is also known to interfere with CD8^posT cell function in other context.

Methods: Heparinized whole-blood of sJIA patients' samples (n=33) and healthy controls (n=20) were analyzed for effector molecule (IFNγ, TNFα, perforin, granzyme B) and cell activation (CD25, CD38, CD69, HLA-DR) or exhaustion (CD152 (CTLA-4), CD160, CD218a (IL-18R), CD233 (LAG-3), CD279 (PD-1), CD366 (TIM-3)). Autologous CD8^posT cells and neutrophils (sJIA n=7, HC n=11) were co-cultured with a range of inflammatory stimuli for 48 and 72h and analyzed by flow cytometry as described above.

Results:Ex vivo, we initially observed sJIA CD8^posT cells to reveal reduced cytokine (IFNγ, TNFα) and lytic molecule (granzyme B, perforin) expression compared to healthy controls, while perforin expressing cells were increased in frequency among a subset of CD69^neg/loCD8^posT cells. Compared to HC, several of the observed ex vivo phenotypes were recapitulated upon co-culture of sJIA CD8^posT cells with autologous neutrophils in ratios reflecting neutrophil excess in disease. Among HCs, effector molecule expressing CD25^pos or CD69^posCD8^posT cells expanded upon co-culture with neutrophils and with (neutrophil-specific) inflammatory load, which was not observed with sJIA T cells. Instead, in co-cultures of sJIA cells, perforin and granzyme expressing CD8^posT cells increased in frequency and with (neutrophil) stimulation, particularly among CD25^neg/lo- and CD69^neg/loCD8^posT cells. These experiments suggest aberrant activation trajectories of sJIA CD8^posT cells, combined with sub-set specific increased cytotoxicity compared to healthy controls. Analyzing ex vivo cells for further activation and exhaustion markers reveals prominent overexpression of CD38, decreased expression of IL-18R and increased frequencies of PD-1^posCTLA-4^pos or PD-1^posTim-3^pos cells as prominent features of sJIA CD8^posT cells, which were even present among (long-standing) remission patients.

Conclusion: Our still preliminary data point towards overactivation and exhaustion as potentially inherent features of sJIA CD8^posT cells, which may impact cellular effector function in context of hyperinflammatory events.

Patient Consent

Yes, I received consent

Disclosure of Interest

A. Swoboda: None declared, S. Schleifenbaum: None declared, C. Hinze Consultant with: Novartis, H. Wittkowski Consultant with: Novartis, Takeda, Octapharma and CSL-Behring, D. Foell Grant / Research Support with: Novartis, Pfizer and SOBI, Consultant with: Chugai-Roche, Novartis and SOBI, C. Kessel Grant / Research Support with: Novartis, Consultant with: Novartis and SOBI

Correspondence: M. G. Villarreal

Pediatric Rheumatology 2023, 21(Suppl 2):PT050

Introduction: Systemic Juvenile Idiopathic Arthritis (sJIA) is conceptualized as an autoinflammatory disease. Lung disease (LD) is increasingly recognized in these patients.

Objectives: To describe frequency of LD in patients with sJIA. To compare sJIA patients with LD to those without it. To evaluate predictor variables for developing LD.

Methods: Patients with sJIA according to ILAR criteria were included, who had undergone at least one pulmonary HRCT (high resolution computed tomography). We reviewed their clinical charts and prospectively collected databases, recording demographic, clinical and biochemical features. Data were collected at baseline (time of diagnosis) and follow-up (at the time of HRCT). Outcome measures included: sJADAS (Systemic Juvenile Arthritis Disease Activity) and Juvenile Arthritis Damage Index (JADI). Presence of MAS (macrophage activation syndrome). Biological agents (anti-IL-1/anti-IL-6) and related adverse events also were recorded. LD was defined as suspected sJIA-LD based on objective findings on clinical examination (tachypnea, cough, or clubbing) or diffuse abnormalities on chest imaging according to Erkens et al. We compared variables between patients with and without LD using descriptive statistics, association tests and linear models for analysis.

Results: From a cohort of 32 sJIA patients, 18 (12F) met inclusion criteria, with median age at diagnosis was 5.2 (range 2.2-15.6) years. Median follow-up 4.7 years. At baseline, arthritis was present in 100%, fever 89%, rash 55%, lymphoproliferation 55%, enlarged lymph nodes 33%, hepatomegaly 11%, splenomegaly 17%, serositis 5%. Median sJADAS was 25 (16.5-37). At follow-up, arthritis was present in 66%, fever 22%, rash 11%, and enlarged lymph nodes and serositis 5%. Median sJADAS was 19 (0-37), JADI 0 (0-47). Thirteen (72%) patients received biological agents, of those three presented adverse events including anaphylaxis, hepatitis and local injection. Six patients had MAS. Ten patients (55%) had LD, but none of them presented with pulmonary symptoms. HRCT findings were: micronodules/nodules 54%, parenchymal thickening 45%, septal thickening 18%, bronchial wall thickening 9%, ground-glass opacities 9%, tree in bud opacities 9%. Enlarged lymph nodes (5 vs 1, p=0.04), lymphoproliferation (hepatosplenomegaly and enlarged lymph nodes) (9 vs 1, p=0.0037), and hemoglobin levels (9.2 vs 10.1 mg/dL, p=0.045) showed significant differences between patients with sJIA-LD and those without LD. Age at onset (4.9 vs 7.03 years, p=0.05) was a predictor variable to develop LD.

Conclusion: The frequency of sJIA-LD was high in our cohort of sJIA patients. There was a dissociation between clinical respiratory features and imaging findings. Patients with sJIA-LD presented more inflammatory features (lymphoproliferation and low hemoglobin levels) that mimicked autoinflammatory diseases.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: A. Oladapo

Pediatric Rheumatology 2023, 21(Suppl 2):PT051

Introduction: Macrophage activating syndrome (MAS) is a rare, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD). MAS (a form of secondary HLH) is associated with overproduction of proinflammatory cytokines, such as interferon gamma (IFNγ). The REAL-HLH study assessed the real-world utilization of emapalumab, an anti-IFNγ antibody, among patients in the US.

Objectives: To understand treatment patterns and outcomes in patients with MAS secondary to Still's disease treated with emapalumab in the real-world setting.

Methods: A retrospective medical chart review conducted across 33 US hospitals identified patients treated with ≥1 dose of emapalumab between Nov. 20, 2018, and Oct. 31, 2021. Data extracted on the subset of patients with MAS secondary to Still's disease from the time of emapalumab initiation to end of data availability, death, or study end (Dec. 31, 2021) were analyzed.

Results: Ten of the 105 enrolled patients presented with Still’s disease (sJIA, n=9; AOSD, n=1). Most patients were female (8/10; 80%) and white (6/10; 60.0%). At diagnosis, mean (SD) age was 5.6 (6.4) years, and 70% (7/10) of patients met the 2016 ACR MAS diagnostic criteria. At diagnosis, the patient with AOSD was 22 years. At time of emapalumab initiation, all patients had received or were receiving other HLH-related therapies, including corticosteriods and anakinra; 60% of patients were in the intensive care unit. Emapalumab was mainly initiated to treat refractory (4/10; 40%), recurrent (3/10; 30%), or progressive (2/10; 20%) disease. Median (range) time from diagnosis to emapalumab initiation and treatment duration were 13.0 (1, 101) and 65.5 (25, 367) days, respectively. Median (range) emapalumab starting, maximum single, and cumulative administered dose were 3.7 (0.9-5.9), 5.8 (0.9-6.6), and 53.2 (6.7-171.3) mg/kg, respectively. Median (range) number of emapalumab doses was 15.5 (2, 35). Majority of patients achieved normal levels of ferritin (5/10; 50%), fibrinogen (6/10; 60%), platelets (8/10; 80%), alanine transaminase (8/10; 80%), absolute neutrophil count (9/10; 90%), and absolute lymphocyte count (9/10; 90%) during treatment. Median time to 1^st normalization of these laboratory parameters ranged from 7 to 46 days. Overall survival and 12-month survival probability following emapalumab initiation was 90% (9/10). One patient died due to uncontrolled viremia, unrelated to the clinical condition for which emapalumab was used (investigator determined).

Conclusion: This is the first study to report real-world treatment patterns and outcomes among patients with MAS secondary to Still’s disease treated with emapalumab. A phase 3 clinical trial of emapalumab in patients with sHLH/MAS and underlying rheumatologic disease is ongoing (NCT05001737).

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

C. Allen Consultant with: Sobi, Inc., S. Chandrakasan Consultant with: Sobi, Inc., M. Jordan Consultant with: Sobi, Inc., J. Leiding Consultant with: Sobi, Inc., A. Oladapo Shareholder with: Sobi, Inc., Employee with: Sobi, Inc., P. Pednekar Consultant with: Sobi, Inc., K. Walkovich Consultant with: Sobi, Inc., J. Yee Employee with: Employed at Sobi, Inc. at the time the work was done

Correspondence: A. Doležalová

Pediatric Rheumatology 2023, 21(Suppl 2):PT052

Introduction: Features of periodic fever, aphthae, pharyngitis, adenitis syndrome (PFAPA) are common in our patients. Although majority fulfil PFAPA criteria, some can be classified as a syndrome of undifferentiated recurrent fever (SURF). Its precise characteristics as well as distinction from PFAPA are yet to be defined.

Objectives: To characterize clinical, biochemical and immune phenotype of children with PFAPA and SURF during febrile and afebrile interval in comparison with controls.

Methods: Patients with PFAPA and SURF were prospectively recruited within an autoinflammatory disease (AID) project. Blood was taken at defined points: febrile – within 24h from recorded fever >38.0^oC, afebrile – at least 2 weeks from the last fever. Otherwise healthy children with acute infections and patients with non-inflammatory conditions served as febrile and healthy controls (FC, HC). Sera were analysed for standard parameters (CRP, SAA, procalcitonin (PCT), ferritin, S100 proteins) and a 48-cytokine Bio-Plex panel. Patient sera were also analysed for glycosylation status of the individual glycoforms of bikunin (Bkn), a proteinase inhibitor often considered to be an acute phase protein.

Results: From the total of 287 AID patients 54 (18.8%) have one of hereditary periodic fevers, 179 (62.4%) have PFAPA, 54 (18.8%) undefined AID incl. SURF. In 9 PFAPA and 7 SURF patients (9/16 boys, mean age 8.9yrs) paired samples were available. In control groups (FC=7, HC=28) only one sample was analysed. In patients differences were found between febrile and afebrile samples at p<0.001 in the following: CRP, SAA, 100A8/9, ferritin, small and large Bkn glycoforms, IP-10, HGF, MIG, at p<0.01 in IL-1ra, IL-2ra, IL-18, M-CSF, at p<0.05 in IL-6, G-CSF, IL-12p40 (all higher at fever). PFAPA and SURF differed in neither febrile or afebrile samples. Febrile patients had significantly lower IL-13 than FC (p=0.0037). Afebrile patients had higher levels than HC at p<0.01 in IL-8, IL-18, GROa, TNF-b, TRAIL, at p<0.05 in IL-13, IL-17, G-CSF, IL-2ra. All CRP, SAA and PCT significantly correlated with S100A8/9, ferritin, IL-1ra, IL-6, G-CSF,IP-10, MIP-1a, IL-2ra, IL-12p40, IL-18. Both Bkn glycoforms inversely correlated with S100A8/9, ferritin, IL-2ra and M-CSF. Small and large glycoforms inversely correlated also with IP-10, IL-12p40, HGF, MIG and MIP-1a,IL-18, respectively.

Conclusion: We have shown that febrile PFAPA and SURF patients had increased amounts of multiple proinflammatory molecules, although none distinguished PFAPA from SURF in this small pilot cohort. Suppression of Th-2 associated cytokine IL-13 in febrile patients as well as changes in cytokines that have not been reported so far will have to be confirmed in larger cohorts and by single ELISA. For the first time we investigated glycosylation profiles in periodic fever patients and reported significant reduction of both Bkn glycoforms in febrile sera.

Acknowledgements

Supported by the Czech Health Research Council (AZV CR) grant NU21-05-00522 and SVV 260523.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: T. Kallinich

Pediatric Rheumatology 2023, 21(Suppl 2):PT053

Introduction: Treatment of autoinflammatory periodic diseases (AID) with the interleukin-1β inhibitor canakinumab (CAN) has been shown to be safe and effective in controlled trials and real-world setting.

Objectives: In the RELIANCE registry, long-term safety and efficacy of CAN in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS) on CAN therapy were investigated in routine clinical practice.

Methods: The RELIANCE registry is a prospective, non-interventional, observational study in Germany enrolling pediatric (age ≥2 years) and adult patients with a clinically confirmed diagnosis of AID who routinely receive CAN. Efficacy and safety parameters are recorded at baseline and assessed at 6-month intervals. To compare disease control between indications, parameters of 30 months visits were analyzed.

Results: In the present interim analysis, data were included from a total of n=232 patients with a diagnosis of CAPS, FMF, TRAPS and HIDS/MKD enrolled in the RELIANCE registry between October 2017 and December 2022. The median age of the total study cohort was 20.0 years (2−80 years). Most patients (n=198, 85 %) were CAN pre-treated when entering the study and the median duration of total CAN treatment before and during the study was 4 years (0−15 years).

Of 58/28/10/5 CAPS/FMF/TRAPS/HIDS patients with month 30 visits documented, 68/82/63/100% were in disease remission according to physician assessment. Patient-reported median disease activity and fatigue were low (1.5/1.5/1.5/0 and 3/2/4/0 on a 0−10 VAS scale). Inflammation markers (median) were within the limits of normal including neutrophil counts (2975/3420/3262/2897 n/μL). Statistical analysis confirmed similar efficacy across diseases in most parameters.

Even though these outcomes suggest an adequate disease control, an impact of the disease on patient´s social life was reported in 38/22/50/50% and negative influence on mood in 26/6/0/50% of patients.

Conclusion: The interim data of the RELIANCE study confirm sustained disease control of long-term treatment with CAN across all study indications. Even though disease activity measures suggest adequate disease control, patients´ social life and mood were negatively impacted by the disease.

Patient Consent

Yes, I received consent

Disclosure of Interest

T. Kallinich Speaker Bureau with: Roche, N. Blank Grant / Research Support with: Novartis, Sobi, Consultant with: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, J. Henes Grant / Research Support with: Novartis, Roche, Consultant with: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, B. Kortus-Goetze Consultant with: Novartis, P. Oommen Grant / Research Support with: Novartis, A. Pankow: None declared, T. Krickau Grant / Research Support with: Novartis, Consultant with: Novartis, Speaker Bureau with: Novartis, C. Schuetz Grant / Research Support with: Novartis, G. Horneff Grant / Research Support with: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Speaker Bureau with: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, I. Foeldvari Consultant with: Novartis, J. Rech Grant / Research Support with: Novartis, Sobi, Consultant with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, F. Weller-Heinemann: None declared, A. Janda: None declared, M. Hufnagel Grant / Research Support with: Novartis, F. Meier Speaker Bureau with: Novartis, F. Dressler Grant / Research Support with: Novartis, Consultant with: Abbvie, Mylan, Novartis, Pfizer, M. Borte Grant / Research Support with: Pfizer, Shire, I. Andreica Consultant with: Abbvie, Chugai, Novartis, UCB, Galapagos, Takeda, Astrazeneca, Lilly, Boehringer Ingelheim, Amgen, Sobi, Paid Instructor with: Astrazeneca, UCB, Speaker Bureau with: Abbvie, Chugai, Novartis, UCB, MSD, Lilly, Sobi, Astrazeneca, Amgen, Pfizer, Gilead, P. Wasiliew: None declared, M. Fiene: None declared, D. Windschall: None declared, J. Weber-Arden Employee with: Novartis, J. Kuemmerle-Deschner Grant / Research Support with: Novartis, AbbVie, Sobi, Consultant with: Novartis, AbbVie, Sobi

Correspondence: F. Lucioni

Pediatric Rheumatology 2023, 21(Suppl 2):PT054

Introduction: Macrophage activation syndrome (MAS) has been reported in up to 20-50% of patients diagnosed with Multisystem Inflammatory Syndrome (MIS-C). As clinical and laboratory features of MIS-C partially overlap with MAS, diagnosis may be challenging. The 2016 classification criteria for MAS in systemic juvenile idiopathic arthritis (sJIA) have been largely used to identify MAS in MIS-C; however, the diagnostic performance of existing MAS criteria has never been evaluated in MIS-C and no specific diagnostic criteria for MAS in MIS-C exist

Objectives: To evaluate prevalence, clinical and laboratory features, therapeutic approaches and outcome of MAS in patients with MIS-C

Methods: The HyperPED-COVID is an international registry coordinated by PRINTO, aimed to collect data on patients with MIS-C worldwide. In the case reported form, clinicians were asked to specify if MIS-C patients developed MAS. Demographic, clinical, laboratory data together with therapeutic choices and outcome were compared between patients with and without MAS. Chi-square, Fisher and Mann-Whitney test were used to analyze data, as appropriate.

Results: Currently, data regarding 1009 patients with MIS-C are available in the HyperPED-COVID registry; in 59 cases (5.8%) a diagnosis of MAS was made by the caring physician. Patients with MAS were more frequently collected from East-Central Europe centres (63% vs 31%, p <.0001); they were older (9.7 vs 7.9 years, p 0.003) and with a longer disease duration at MIS-C onset (10 vs 5 days, p <.001). As expected, in patients with MAS hepatomegaly and splenomegaly were more frequently reported than in non-MAS, albeit in low percentages (25% and 20%, respectively). Notably, MAS was characterized by a higher rate of myocardial dysfunction (34% vs 19%, p 0.008) and less mucocutaneous involvement (76% vs 89%, p 0.005). MAS patients had higher levels of ferritin (1085 vs 407 ng/ml, p <.0001) and lower platelet counts (137 vs 197 x 10⁹/l, p<.0001) compared with MIS-C without MAS. At MIS-C diagnosis 205 patients (20.3%) satisfied the 2016 MAS classification criteria, however 174 (84.8%) did not receive a MAS diagnosis from the caring physician. Patients with MAS were treated more aggressively, especially with glucocorticoids (97% vs 80%, p 0.002), and anakinra (42% vs 9%, p <.0001). Despite similar mortality and risk of sequelae, MAS required more frequently a circulatory support (44 % vs 26%, p 0.003).

Conclusion: Despite a prevalence lower than previously reported, MAS in MIS-C is associated with a more severe phenotype, requiring prompt diagnosis and aggressive treatment to avoid complications. Patients at higher risk are older and with a longer disease duration at MIS-C diagnosis. Further studies are needed to identify the best criteria to diagnose MAS in MIS-C

Patient Consent

Yes, I received consent

Disclosure of Interest

F. Lucioni: None declared, R. Caorsi: None declared, A. Consolaro: None declared, C. Speziani: None declared, F. Bovis: None declared, C. Bracaglia Consultant with: SOBI, Novartis, M. Cattalini: None declared, P. Brogan: None declared, C. Wouters: None declared, A. Taddio: None declared, F. Candotti: None declared, I. Meyts: None declared, F. De Benedetti: None declared, N. Ruperto: None declared, A. Ravelli: None declared, M. Gattorno: None declared, F. Minoia Consultant with: SOBI

Correspondence: M. F. Natale

Pediatric Rheumatology 2023, 21(Suppl 2):PT055

Introduction: Systemic Autoinflammatory diseases (SAIDs) are a group of rare disorders caused by dysfunction of the innate immune system and characterized by periodic or chronic systemic inflammation. Nowadays a lot of monogenic or polygenic autoinflammatory diseases are described. Nucleotide-binding oligomerization domain containing 2 (NOD2) is a gene, associated with Blau syndrome, Crohn’s disease (CD) and most recently with a polygenic autoinflammatory disease with onset in adulthood called NAID or YAO-Syndrome.

Objectives: to describe the characteristics of a pediatric cohort with autoinflammatory undefined phenotype carrying NOD2 gene variants, to compare them with the NAID adult cohort described in literature and to evaluate genotype-phenotype correlation

Methods: 28 pediatric patients with undefined autoinflammatory disease carrying NOD2 gene variants were enrolled. NOD2 variants classified as pathogenic for BLAU syndrome or with an high prevalence in healthy population (polymorphisms) were excluded. Demographic, clinical, instrumental, laboratory characteristics and therapeutic approaches were collected. Our data were then put in comparison with the adult cohorts.

Results: The 28 patients enrolled were stratified into three subgroups based on the position of the variants on the NOD2 gene: N-Terminal (1 patient), Exon 4 (15 patients) and C-Terminal (12 patients). The 15 patients whose variants were localized on Exon 4 (10 males) presented homogeneous clinical characteristics with involvement of some target organs : skin (87%), joints (80%), bowel (54%), eyes (27%) and lymphatic system (54%). In 73% fever was present . Inflammation markers were increased in all patients while no circulating autoantibodies or signs of immunodysregulation were found. The most effective first-line therapy were glucocorticoids ; in refractory or glucocorticoid -dependent patients, IL-1/IL-6 inhibitors were used with good response. The characteristics of pediatric patients were shown to be completely similar to the adult patient cohorts described in literature. The only statistically significant differences were found in oral aphthosis, more frequent in children, and sicca syndrome exclusive of the adult patients.

Conclusion: This is the first study that evaluate genotypic/phenotypic characteristics of pediatric patients with systemic autoinflammatory phenotype carrying NOD2 gene variants. A close genotype-phenotype correlation has not been identified but the analysis showed a higher weight of variants localized on exon 4: patients carrying variants localized on this exon seems to show an homogeneous phenotype . Our data, if confirmed by larger future studies and functional tests, could identify a new pediatric autoinflammatory disease with defined characteristics and with a targeted and effective therapeutic approach.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: S. Sener

Pediatric Rheumatology 2023, 21(Suppl 2):PT056

Introduction: Enthesitis is a common presenting feature in juvenile-onset spondylarthritis and juvenile idiopathic arthritis, especially in enthesitis-related arthritis (ERA).

Objectives: Based on the overlapping features between ERA and chronic nonbacterial osteomyelitis (CNO), we aimed to evaluate the presence of enthesitis in CNO patients by ultrasonography (US).

Methods: Patients who were followed up with the diagnosis of CNO in Hacettepe University Pediatric Rheumatology Department between January 2022 and December 2022. All CNO patients had clinical symptoms lasting >6 weeks with unifocal or multifocal inflammatory bone lesions, in addition, infections and malignancies had been excluded in these patients. They were evaluated by a pediatric radiologist with the US. The insertion sites of seven bilateral tendons (common extensor and flexor tendons of the forearm, quadriceps tendon, proximal and distal patellar tendon, Achilles tendon, and plantar fascia) were examined in detail. US examinations were performed according to the pediatric OMERACT enthesitis scoring system.

Results: Forty CNO patients were included in this study. The median (IQR) age of the patients at diagnosis and at the time of US assessment were 9.4 (3.8) and 10.5 (6.1) years, respectively (M/F:1.1). Thirty-three patients (82.5%) were receiving anti-inflammatory treatment at the time of US evaluation. And also, the majority of patients were in clinical remission (82.5%), and had acute phase reactants in the normal range (90%). None of the patients had clinical signs of enthesitis on physical examination. Human leukocyte antigen B27 (HLA-B27) was positive in 25% (6/24) of the patients tested. In addition, unilateral or bilateral sacroiliitis was present in 80% of patients in whole-body magnetic resonance imaging (MRI). In the US, enthesitis was detected in three CNO patients (7.1%) and radiologically in four (0.6%) of 560 enthesis sites. Three of the involved enthesis areas were Achilles tendons and one was quadriceps tendon. All three patients had radiologically proven bilateral sacroiliitis and had positive HLA-B27. All of the patients were in clinical remission under anti-inflammatory therapy. Therefore, no treatment changes were made according to the US findings only. But these patients were followed up with both clinical examination and the US at close intervals. In the first six-month follow-up, enthesitis findings in one of these patients had disappeared, while subclinical enthesitis was still present in the other two patients in the US.

Conclusion: This is the first study to research enthesitis in patients with CNO. Although enthesitis is a rare finding in CNO, the US can be a helpful follow-up tool in CNO patients as it can detect enthesitis. In addition, if a patient with CNO has enthesitis, it would be more appropriate to consider this patient as having CNO and ERA overlap syndrome.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Zhao DY, McCann L, Hahn G, Hedrich CM. Chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO). J Transl Autoimmun. 2021 Mar 20;4:100095. doi: 10.1016/j.jtauto.2021.100095.

Correspondence: N. Singh

Pediatric Rheumatology 2023, 21(Suppl 2):PT057

Introduction: Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders that predispose affected individuals to infections, autoimmunity, autoinflammation, and malignancies. The literature on autoimmunity in IEI in Indian subcontinent is limited hence there is need to highlight the clinical presentation and management of these patients.

Objectives: To study the profile of autoimmune manifestations and immune dysregulation in patients with IEIs at presentation or during follow-up.

Methods: This study was carried out at a tertiary care center in Southern India from February 2017 to January 2023. Data on IEI was entered in a pre-designed excel sheet. The clinical spectrum of autoimmunity, treatment & outcome details were analyzed.

Results: Three hundred nineteen patients (311 kindreds) were diagnosed with IEI based on relevant immunological tests and/or genetic tests. Male-to-female ratio was 1.9:1. The mean age at onset of first clinical presentation in children (<18 yrs) was 1.24 years (range 1 day - 18 years) and 19 years (range 19-62 years) in adults (>18 years). The most common IEI was Severe Combined Immunodeficiency (SCID) (n=44,12%) in children and Common Variable Immune Deficiency (CVID) (n=25, 7.9 %) in adults. Autoimmunity was noted in 80 (25%) patients during their course of illness. The mean delay at diagnosis was 8.2 years in ‘autoimmune cohort’ . This was statistically higher as compared to the rest of the study population (p <0.001). Molecular testing was performed in 234 patients by exome sequencing and a genetic variant was reported in 220 cases.

The most common autoimmune manifestations included inflammatory colitis(n=23), followed by autoimmune cytopenia(n=19), arthritis(n=13) and autoimmune endocrinopathy (n=10). Autoimmune skin manifestations included pyoderma gangrenosum(n=7), alopecia areata (n=4), vitiligo(n=3), bullous pemphigoid(n=1), dermatitis herpetiformis(n=1) and cutaneous vasculitis(n=1). Systemic lupus erythematosus(n=6), Kawasaki Disease(n=4), lymphoproliferation(n=3), and autoimmune hepatitis(n=3), CNS vasculitis (n=2), nephrotic syndrome (n=1), oral aphthosis (n=1), sarcoidosis(n=1), and uveitis(n=1) were also reported.

Patients received immunomodulation as IVIG (n=43), steroids (n=36), methotrexate (n=10), colchicine (n=6), cyclosporine (n=3), sirolimus (n=3), mesalamine (n=3), leflunomide(n=2), thalidomide(n=2), tofacitinib (n=2), mycophenolate mofetil (n=1), azathioprine (n=6) and dapsone (n=1). Biologics including rituximab(n=2), anakinra (n=2), tocilizumab (n=1), adalimumab (n=1), and infliximab(n=1) were also used. One patient received romiplostim for thrombocytopenia. The overall survival was 90% in the “autoimmune” cohort.

Conclusion: Autoimmunity is a frequent yet underrecognized manifestation of IEI. The inherent predisposition to develop infections makes management of autoimmunity challenging and hence immunomodulation with close monitoring is the only way forward for these patients.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: W. M. Suwairi

Pediatric Rheumatology 2023, 21(Suppl 2):PT058

Introduction: The E3 ubiquitin-protein ligase RNF31 OR HOIL-1-interacting protein (HOIP) is a ubiquitin ubiquitin-protein ligase component of the LUBAC complex. It conjugates linear polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B. Human HOIP is essential for the assembly and function of LUBAC complex and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells. Bertrand Boissonet al. and Jean-Laurent Casanova reported 3 patients with HOIL-1 mutations associated with systemic autoinflammation, sever immunodeficiency and muscle amylopectinosis. (1,2 )

Objectives: Describe a novel mutation in RNF31 gene (HOIP) that is associated with recurrent infection, hypogammaglobulinemia, mental subnormal and sever systemic autoinflammatory disease and macrophage activation syndrome. We describe the long-term outcome (7 years) post HSCT

Methods: Currently, 9 years old Saudi girl who presented since age of 2 weeks with recurrent episodes of febrile illness associated with recurrent viral and bacterial infections (pneumonia, cervical lymphadenitis, URTI, and urinary tract infections. AT the age of 14 month, she presented with sever systemic inflammation, significant colitis diarrhea and laboratory evidence of Macrophage activation syndrome ( s,ferritin >5000 up to14000) disturbed coagulation, low ESR and cytopenia. Bone marrow was reactive and no hemophagocytic cells were seen. Patient responded well to high doses of systemic steroid with partial response to anti- IL=6 (Tocilizumab) and no response to anti IL-1 (anakinra)

The initial WG was not informative. Later one WES identified a homozygous non-synonymous mutation in RNF31 gene (c.1657G>A p.Glu553Lys). Both patents are heterozygous for this mutation. It is predicted to be damaging by SIFT and other softwares. The mutation is novel and has not been reported in dbSNPs or ExAC database as well as Saudi genome database. This was later on confirmed by Sanger sequencing.

The patient went for HSCT at the age of 21 months and the doner was her elder sister. The systemic autoinflammatory disease and immunodeficiency were well controlled post HCST. She was observed to have autistic behavior and IQ assessment confirmed moderate developmental delay and need for special education program. She also has polymorphisms in thyroglobulin gene, which have been reported to be associated with autoimmune thyroiditis. She is currently on L thyroxin 50 Mic. On November 2022 she was admitted to PICU in acute heart failure post viral URTI. The poor recovery of depressed myocardial function (EF to 25%) is most probably related to amlyplectinosis.

Conclusion: Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. HCST can be curative for the systemic autoinflammation and sever immunodeficiency but unfortunately not to amylopectinosis and mental subormality

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Boisson, B. et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency immunodeficiency, amylopectinosis, and lymphangiectasia. J. Exp. Med. 212, 939–951 (2015).

2. Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13, 1178-1186 (2012)

3. Kalpana Manthiram, Qing Zhou, Ivona Aksentijevich & Daniel L Kastner. Monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nature immunology 18 832-842 (2017)

Correspondence: E. L. Verweyen

Pediatric Rheumatology 2023, 21(Suppl 2):PT059

Introduction: Interleukin (IL) 18 is a main driver of hyperinflammation in Macrophage Activation Syndrome (MAS), which arises as serious complication in inflammatory diseases such as systemic juvenile idiopathic arthritis (SJIA). As demonstrated by us and others, type 1 interferon (T1IFN) signaling can drive IL-18 expression in both murine models and human cells.

Objectives: Previous data on the role of T1IFNs in IL-18 expression have been generated in context of TLR4 (LPS) stimulations. Here, we aimed to investigate the impact of viral stimuli, which are considered possible triggers of MAS, as well as IL-1 blocking therapies, potentially distorting an IL-1-T1IFN balance, on IL-18 expression and release as well as on hemophagocytosis.

Methods: Primary human monocytes or heparinized whole blood were stimulated with LPS or viral-infection mimicking ligands to TLR3 (p:IC), TLR7 (R837), TLR7/8 (R848), TLR8 (ssRNA40) or TLR9 (CpG), either alone or in combination, and with or without IL-1 blocking drugs (anakinra, canakinumab) or TLR8 inhibitor (CU-CPT9a). Cytokine release and/or gene expression was analyzed using multiplex bead arrays and qRT-PCRs. Phagocytosis of erythrocytes (hemophagocytosis) was assessed in monocyte-erythrocyte cocultures by flow cytometry following stimulations as described above and intracellular CD235a staining.

Results: Human monocyte stimulation by R848 induced rapid and massive IL-18 expression and release, which was driven through joined NFκB and T1IFN-signaling. Selective TLR8-inhibition or stimulation with ssRNA40 underscored the importance of TLR8 signaling in this context, and we further identified TLR8 signaling as a main driver of hemophagocytosis by inflammatory monocytes. In contrast, the exclusive exposure to TLR3, -4, -7 and -9 ligands resulted in significantly less monocytic IL-18 expression and release as well as hemophagocytic events. Intriguingly, combination of LPS and selected viral signals mounted significantly higher monocytic IL-18 expression compared to LPS stimulation alone. In these cell cultures, additional IL-1R1 inhibition by anakinra already resulted in some elevation of IL-18 expression, while in human whole blood experiments we observed LPS-stimulation in combination with anakinra, but not canakinumab, to strongly exacerbate LPS-induced IFNα, IL-18 and IFNγ release.

Conclusion: Our data demonstrate how specific viral insults or IL-1R1 blocking therapy in the context of inflammation can set off the T1IFN-IL-18-IFNγ axis as hallmark of hyperinflammation in MAS.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

E. Verweyen: None declared, S. Schleifenbaum: None declared, V. Kienapfel: None declared, M. Schell: None declared, C. Hinze Speaker Bureau with: Pfizer, D. Foell Grant / Research Support with: Novartis, Pfizer, Sobi, Speaker Bureau with: Chugai-Roche, Novartis, Sobi, C. Kessel Grant / Research Support with: Novartis, Consultant with: Novartis, Sobi

Correspondence: Y. Vyzhga

Pediatric Rheumatology 2023, 21(Suppl 2):PT060

Introduction: The pathophysiology of AIDs is progressively updated, with new monogenic diseases being discovered every year and multiple treatment options available. The increasing experience has allowed us to estimate the risk of developing potential complications and safety issues associated with treatment. Therefore, prolonged drug use requires safety monitoring and tolerability of therapy in children affected by these disorders.

Objectives: The present study is aimed to evaluate the impact of safety events in the largest international registry for Autoinflammatory diseases, called Eurofever.

Methods: The Eurofever project was promoted in 2008 by the working group for autoinflammatory diseases of the Paediatric Rheumatology European Society (PRES). It started enrolment in 2009, in 2015, the registry was amended with the development of a longitudinal part and the inclusion of several items for the registration of the safety events. All safety events of moderate, severe, very severe intensity are reported in Eurofever, regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities (MedDRA, Version 23.1).

Results: Of the 4552 patients with AIDs enrolled in the registry since 2009, 2464 displayed complete safety information. In 1499 of them retrospective data (from disease onset to the enrolment in the registry) were available. The remaining, 965 patients were followed longitudinally, with a mean follow-up of 22.7 months (range 7.33 – 31.07). The group of AEs that was the most frequently reported was infections and infestations (94; 19.6 %), gastrointestinal disorders (66; 13.8 %), followed by nervous system disorders (41; 8.6 %) and general disorders and administration site conditions (35; 7.3 %). 82/479 events were reported as serious, with the highest number of infections and infestations as the most reported (25.6 %), followed by surgical and medical procedures (15.8 %), immune system disorders (14.6 %), injury, poisoning, and procedural complications, and blood and lymphatic system disorders (4.9 %). 112 (23.4 %) safety reports of special interest were reported, with the absolute prevalence of infections and infestations (76/112). Among the other events of special interest, we retrieved seven episodes (5.9 %) of MAS and six (5.0 %) cases of malignancies. The highest number (43.2 %) of safety events came from 103 patients with FMF. Meanwhile, among the patients with rarer SAIDs, such as DIRA, Blau syndrome, PAPA, and DADA2, safety events were also reported.

99 drug-related AEs were reported and described by treating physicians at the context of their severity, relation with event onset, and action taken toward the medication. The highest number of drug-related AEs were related to colchicine (31/99 reports, 31.3 %) and were reported from 15 FMF, 3 SURF, 2 MKD, and 1 PFAPA and 1 Behcet disease patients. The overall incidence of AEs associated to biologic DMARDSs, was of 40 (40.4 %) events. Among patients treated with synthetic DMARDs, the highest number of AEs reports came from those receiving methotrexate, diagnosed with CRMO, undefined AID and Behcet`s disease.

Conclusion: This study is the first attempt to overview available safety information on the management of patients with AIDs. Results stress the importance of long-term monitoring of treatments given to patients with AIDs. Reporting safety is mandatory due to high possibility that some potential safety events may remain undetected or unreported.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: H. Adiguzel Dundar

Pediatric Rheumatology 2023, 21(Suppl 2):PT061

Introduction: Nailfold capillaroscopy is the best method for the early diagnosis of connective tissue diseases, especially systemic sclerosis, and evaluation of microcirculation in children and adolescents. Although there are many studies to identify normal capillaroscopic findings in healthy adults, there are limited number of studies for normal reference ranges by age and gender in the children and adolescents.

Objectives: The aim is to define and standardize the nail bed capillary properties in healthy Turkish children and adolescents.

Methods: This multicenter cross-sectional pilot study included; 564 healthy children and adolescents from 5 pediatric rheumatology centers. Using the Dino-Lite CapillaryScope 200 Pro / MEDL4N Pro capillaroscopy device, two images of 1mm radial and ulnar edge were obtained from the 4^th fingernail bed of the non-dominant hand at 200x magnification. Capillary density, capillary morphology (i.e., capillary tortuosity, capillary crossing, giant capillary, capillary meandering and branched capillary), microhemorrhage and avascular area were the parameters. Also 3 consecutive capillaries from each image; arterial and venous limb diameter, loop diameter, capillary length, capillary width, and intercapillary distance were measured. The children included in the study were classified according to their age; Group 1: 5-7 years, Group 2: 8-10 years, Group 3: 11-14 years, and Group 4: 15-17 years old.

Results: A total of 1128 images were obtained from 564 healthy children included in the study and 3384 capillary measurements were made. A positive correlation was determined between age and capillary density (p<0.001, R=0.450, CI95% 0.398-0.503). Capillary density was significantly lower in Group 1 than in other Groups. Although there was significant difference between the age groups in terms of arterial and venous limb diameter, loop diameter, capillary length, intercapillary distance; there was no significant difference between age groups and capillary width (Table I). There was significant difference between age groups and presence of dilated capillary, capillary tortuosity, avascular area. In total 1128 image evaluations, dilated capillary in 8.7%, Capillary tortuosity in 14.4%, crossed capillary in 43.1%, micro-hemorrhage in 2.7%, avascular area in 4.8% (Table II). There is no capillary presented with meandering, giant capillary or branched capillary. There was a good level of agreement between the researchers, as 10 cases with 60 capillaries were evaluated with a good level of agreement.

Conclusion: This is the first study to evaluate capillary morphology in healthy Turkish children. This study also adds that some special forms such as micro-hemorrhage and avascular area, which is always named as pathological in adult age, can be seen in healthy children. These data will be guiding in capillaroscopic studies in various patient groups, particularly in children with collagen vascular diseases.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: F. Çakmak

Pediatric Rheumatology 2023, 21(Suppl 2):PT062

Introduction: Nailfold videocapillaroscopy (NVC) examination is a simple and non-invasive method used to evaluate microvascular architecture. Capillary density, capillary dimensions (total capillary width, arteriyal width, venous width, apical loop, intercapillary distance, capillary length), capillary arrangement, and capillaroscopic alterations (tortiosity, increased cross-section, meandering capillaries, branched capillaries, bushy capillaries, enlarged capillaries, giant capillaries, avascular area) are analyzed from the images of NVC. In children, capillary morphology is categorized into four categories as normal capillary morphology, minor abnormality, major abnormality, and scleroderma pattern.

Objectives: With this study, we aimed to enable clinicians who do not have sufficient experience in the field of capillaroscopy to make NVC morphological classification in patient follow-up with an artificial intelligence supported system and to use capillaroscopy more effectively in patient follow-up.

Methods: The archieve of NVC images of Istanbul University Istanbul Faculty of Medicine was analyzed retrospectively. Images were evaluated according to the Ingegnoli system by two different capillaroscopists. 92 normal morphologies, 20 minor disorders, 153 major disorders, and 17 scleroderma patterns, classified by consensus, were presented to artificial neural networks (ANNs). Since the minor disorder and normal morphology classes did not differ clinically, these two classes were combined as a single class, resulting in a total of 3 classes. 80% of the data was reserved for training and 20% for testing. The images were first resized to 512x512, and then right-left rotation, rotation and zoom data augmentation methods were applied to the images in the training data. Training was carried out for 30 epochs using the Resnet 101 model. The model was then evaluated on the untrained test data. Results were evaluated using performance measures such as accuracy, precision, recall, F1 score, and area under the ROC curve (AUC).

Results: In this study, capillary morphology was classified as normal capillary morphology, major disorder, and scleroderma pattern using the artificial intelligence method on capillaroscopy images. The model, which was evaluated on 66 data allocated for the test had 94% accuracy. Also, for the normal class, the AUC value is 0.962, the precision value is 0.90, the recall value is 1.00, the f1-score value is 0.95. For the major abnormality class, the AUC value is 0.946, the precision value is 0.97, the recall value is 0.90, f1-score value is 0.93. For the scleroderma pattern class, the AUC value was 0.987, the precision value was 1.00, the recall value was 0.86, and the f1-score value was 0.92.

Conclusion: Artificial intelligence assisted capillary morphology classification was able to place capillaroscopy images in the correct classes with high sensitivity. The lack of time to provide NVC evaluation during outpatient clinic controls will be overcome by saving time with this method.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: I. Foeldvari

Pediatric Rheumatology 2023, 21(Suppl 2):PT063

Introduction: Juvenile idiopathic arthritis (JIA) associated uveitis is the most frequent cause of uveitis in the paediatric population, and often presents as a silent chronic anterior uveitis, which can lead to blindness. Adherence to current screening guidelines is halted by difficulties in assessing specialised services. Additionally, current protocols are often complex and rely on the knowledge of disease biomarkers; information which may not be available to many paediatric ophthalmologists.

Objectives: The Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC) identified the need to simplify JIA screening so paediatric ophthalmologists with no access to detailed information on JIA subtype can carry out safe screening with confidence, while also enabling other eye care professionals to play a role if needed.

Methods: The group consisted of 10 rheumatologists and 8 ophthalmologists. A consensus meeting took place on January 2023 in Barcelona, Spain. A summary of the current evidence for JIA-associated uveitis screening was presented to the expert panel. Nominal group technique was used to reach consensus.

Results: The need for a practical but safe guideline for uveitis screening was identified by the panel. At the end of the discussion, three screening recommendations were proposed and approved by the voting members. They represent a standardised approach to JIA screening and only take into account the JIA age of diagnosis to determine the screening interval until adulthood.

Conclusion: By removing the need for the knowledge of the JIA subtype, ANA positivity or treatment status, the MIWGUC recommendations can be more easily implemented in the clinical practice by a paediatric ophthalmologist, or other trained eye care professionals, who may not work directly with rheumatology or uveitis specialist. This holds particular significance in areas with limited resources. However, the proposed protocol is less tailored to the individual than those it references.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. Walscheid K, Klotsche J, Tappeiner C, et al. Adherence to ophthalmological screening recommendations and course of uveitis in children with juvenile idiopathic arthritis: data from the Inception Cohort of Newly diagnosed patients with JIA (ICON-JIA) study. Clin Exp Rheumatol 2020;38:792–8. doi:32105591

2. Heiligenhaus A, Niewerth M, Ganser G, et al. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology 2007;46:1015–9. doi:10.1093/rheumatology/kem053

3. Angeles-Han ST, Ringold S, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis–Associated Uveitis. Arthritis Care Res (Hoboken) 2019;71:703–16. doi:10.1002/acr.23871

4. Leinonen S. A Nordic screening guideline for juvenile idiopathic arthritis-related uveitis. Acta Ophthalmol Published Online First: 2 December 2022. doi:10.1111/aos.15299

Correspondence: M. Ha

Pediatric Rheumatology 2023, 21(Suppl 2):PT064

Introduction: T-cells are important actors in the pathophysiology of chronic autoimmune arthritis and are abundantly present both in synovial fluid and synovial tissue in different arthritic diseases, such as juvenile idiopathic arthritis (JIA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and HLA-B27⁺ spondyloarthritis (SpA). T-cell receptors (TCRs) are pivotal in recognizing antigenic peptides and driving T-cell response against the antigens. Current research indicates that there exists an overlap between synovial fluid TCRs in adult SpA patients against self-antigens and microbial antigens [1]. The molecular mimicry theory hypothesizes that in these HLA-B27⁺ SpA patients, T-cells elicited after bacterial infection may target self-antigens presented on synovial tissue [2]. Similarly, recent research has indicated that CD8⁺ T-cells specific to Epstein-Barr virus (EBV), cytomegalovirus (CMV), and influenza virus were present in the synovial fluid of RA patients [3].

Objectives: The objectives of this study are (i) investigate whether TCRs against viral epitopes are present and enriched in the synovial fluid of chronic arthritis patients; (ii) examine whether there is TCR overlap between the different T-cell subsets (e.g., between CD4⁺, CD8⁺, and regulatory T-cells) in the same patient and also between different patients; (iii) assess how synovial fluid cell phenotype distribution differs between patient groups and across ages.

Methods: 21 patients were recruited in rheumatology centres in Flanders: 4 patients with oligo-articular JIA, 4 HLA-B27⁺ enthesitis-related JIA patients (JIA-ERA), 2 juvenile PsA patients, 4 adult PsA patients, 1 adult HLA-B27⁺ SpA patient, 3 RA patients, and 3 Lyme arthritis patients. Their synovial fluid was collected and processed into synovial fluid mononuclear cells (SFMC). Single-cell RNA-seq and TCR-seq were performed on the SFMC. Bulk TCR-seq was performed on the CD4⁺, CD8⁺, and regulatory T-cell fractions.

Results: Our data indicate that JIA-ERA and Lyme arthritis patients had the least TCR diversity compared to other arthritis groups (Shannon entropy index = 0.96 and 0.92 for JIA-ERA and Lyme arthritis, respectively), which agrees with their high number of expanded TCR clonotypes (more than 600 largely and hyperexpanded clones). Among all the identified T-cell phenotypes, Th1/Th17 cells had the most clonal expansion with more than 250 moderately expanded clonotypes (i.e., frequency 5-10), more than 500 largely expanded clonotypes (i.e., frequency 10-50), and more than 100 hyperexpanded clonotypes (i.e., frequency > 50). Th1/Th17 cells were also the dominant population among all patient groups, having the highest proportion out of the total T-cell count in JIA-ERA and PsA patients (31% and 19%, respectively). Furthermore, TCRs against viruses like EBV, CMV and even SARS-CoV-2 are present in the SFMC of paediatric and adult arthritis patients.

Conclusion: The findings in this study provide insights into how TCR repertoires differ between arthritis groups, patients’ ages, T-cell subsets, and whether viral/bacterial infection contributes to arthritis onset and flares. Such knowledge will greatly contribute to the understanding of T-cells' and TCRs' participation in the underlying pathophysiology of arthritis.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Yang, X. et al. Nature2022, 612, 771–777.

2. Bowness, P. Annu Rev Immunol2015, 33, 29–48.

3. Zheng, Z. et al. Ann Rheum Dis2023, 82, 438–440.

Correspondence: G. Horneff

Pediatric Rheumatology 2023, 21(Suppl 2):PT065

Introduction: There is growing evidence that effective therapy with early achievement of inactive disease improves the outcome of JIA. Therefore, a treat-to-target approach with the goal of achieving inactive disease within the first 12 months of treatment is recommended [1]. To support the implementation of such an approach in clinical practice, four consensus-based treatment pathways based on current clinical practice for pJIA were proposed [2].

Objectives: To investigate whether the recommended therapy pathways for pJIA are followed in daily routine and what the outcomes are.

Methods: ProKind-Rheuma is a multicentre, prospective, non-interventional observational study. Patients with newly diagnosed pJIA were enrolled from January 2020 to June 2022 and followed prospectively for up to 15 months. Physician- and parent-reported data were collected in a standardized way up to five times (e.g., disease activity with the cJADAS-10, functional limitations with the Childhood Health Assessment Questionnaire (CHAQ), quality of life with the PedsQL 4.0); data from patients with a follow-up time (FU) of more than 9 months were included in this analysis.

Results: A total of 170 pJIA patients (RF- polyarthritis: n=128, RF+ polyarthritis: n=23, RF unknown: n=19) were recruited 1.0 months (SD 1.8) after diagnosis from 17 paediatric rheumatology centres. Data on 12-month-FU were available for 83 patients. Patients improved significantly over time: mean cJADAS10 decreased from 16.4±6.1 to 2.8±3.6, CHAQ from 0.9±0.8 to 0.3±0.5 and PedsQL increased from 65.9±21.8 to 85.9±13.8. At the 6- and 12-month-FU, 51% and 59%, respectively, had inactive disease and 70% and 77%, respectively, had at least minimally active disease according to the 2021 cJADAS-10 cutoffs [3].

Approximately two-thirds of patients had been treated according to the proposed treatment pathways, with n=33 (40%) treated with MTX and, if required, an additional biologic (pathway or group I) or biologic monotherapy (group II) from month 3 at the earliest. The pathway with additional high-dose iv methylprednisolone pulse therapy (group III) and the pathway with additional intra-articular glucocorticoids in >4 joints (group IV) were followed in n=14 (17%) and n=6 (7%) patients, respectively. In group I/II, 24 (73%) achieved minimally active disease and 18 (55%) achieved cJADAS remission, in group III 8 (57%) and 6 (43%), and in group IV 3 (50%) and 1 (17%). At last FU, 15 patients (48%) in group I/II were taking biologics, 3 (60%) in group III and 6 (46%) in group IV. The patients, n=30 (36%), for whom no clear allocation to a treatment pathway was possible, had inactive disease in 52% and at least minimally active disease in 71% at the 12-month FU. About half (53%) were receiving biologics at this time.

Conclusion: A treat-to-target approach is currently being used for most patients with polyarticular JIA. In the majority of those, the disease was clinically inactive or minimally active after about 12 months of treatment. Further analysis is needed to confirm the results, to determine who is not achieving the treatment goal and why, and to determine which treatment pathways are most effective.

Patient Consent

Yes, I received consent

Disclosure of Interest

G. Horneff Speaker Bureau with: Novartis, MSD, Pfizer, Roche, Sanofi, Sobi, Biogen, K. Minden Speaker Bureau with: Novartis, Amgen, K. Tenbrock: None declared, D. Föll: None declared, K. Vollbach: None declared, A. Klein: None declared, J. Haas: None declared, D. Windschall: None declared, T. Kallinich: None declared, F. Weller: None declared, S. Mrusek: None declared, K. Mönkemöller: None declared, M. Hufnagel: None declared, I. Földvari: None declared, A. Hospach: None declared, R. Trauzeddel: None declared, P. Oommen: None declared, C. Schütz: None declared, N. Brück: None declared, J. Kümmerle-Deschner: None declared, J. Brunner: None declared, F. Dressler: None declared, J. Klotsche: None declared

References

1. Ravelli A, Consolaro A, Horneff G, et al. Ann Rheum Dis 2018;77:819-28.

2. Horneff G, Klein A, Ganser G, et al. Pediatr Rheumatol Online J 2017;15:78.

3. Trincianti C, Van Dijkhuizen EHP, Alongi A, et al.; Arthritis Rheumatol 2021;73:1966-75.

Correspondence: S. Pastore

Pediatric Rheumatology 2023, 21(Suppl 2):PT066

Introduction: The definition of psoriatic arthritis in pediatric patients (JPsA) is controversial.

Objectives: to describe clinical and laboratory characteristics and response to therapy in patients with JPsA.

Methods: retrospective multicentre observational study of pediatric patients meeting the ILAR criteria for psoriatic arthritis or criteria for enthesitis related arthritis (ERA) with psoriasis and/or family history of psoriasis in a first-degree relative. Clinical and laboratory data were collected in a structured anonymized database. Disease remission was defined according to the Wallace criteria.

Results: We included 71 patients (44 F, 27 M) followed at 3 Italian pediatric rheumatology centers. Disease onset occurred at a median age of 10 years (two peaks, 8 and 14 years). At the disease onset , Erythrocyte Sedimentation Rate (ESR) and/or C Reactive Protein (CRP) were elevated in 61% of patients (ESR in 58%, CRP in 34%). Antinuclear Antibodies (ANA) were positive in 31 of 66 tested patients. HLA B-27 was present in 10 of 50 tested patients. Disease remission was obtained in 69/71 patients, whilst two patients had only partial response due to intractable uveitis. In 20/71 (28.1%) disease remission was obtained with intraarticular steroid injections. A conventional disease modifying antirheumatic drugs (DMARDs) was effective in 23/71 patients (32.4%). Biological agents were needed to obtain disease remission in 36/71 patients (50.7%)

55 patients (77.5%) met the ILAR criteria for JPsA diagnosis, whilst 16 were undifferentiated (8 HLA B27 positive males with disease onset over 6 years of age and 8 with ERA). Dactylitis and/or tenosynovitis were more common in JPsA than in undifferentiated cases but the difference was not significant (64 vs 55%).

Unsupervised principal component analysis based on clinical features allowed identifying two cluster of disease respectively composed of 45 and 26 patients. The first cluster was characterized by early onset (before 12 years), predominant oligoarticular pattern with uveitis, familial history of psoriasis or psoriatic arthritis. The second group was characterized by predominant onset in adolescence, polyarticular pattern and psoriasis appearance often before the onset of arthritis. Tenosynovitis, enthesitis and axial involvement were also more common in the second cluster (50 vs 22; 31 vs 9%; 15% vs 0).

Conclusion: Many pediatric patients with arthropathies associated with psoriasis or family history of psoriasis don’t meet classification criteria for JPsA but display clinical overlap with it. Two major clusters have been identified among psoriasis-related arthropathies, based on the age at onset, number of involved joints and presence of psoriasis. Further studies will clarify whether the definition of these clusters may have any impact on future classifications of JPsA.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. I. Rebollo-Giménez

Pediatric Rheumatology 2023, 21(Suppl 2):PT067

Introduction: Recent studies have shown that ultrasound (US) detected tenosynovitis (TS) is frequent in patients with Juvenile Idiopathic Arthritis (JIA) and may be a very early feature of JIA at the disease onset. Currently, the diagnosis of JIA is based on the finding of arthritis and does not include inflammation of periarticular structures such as tendons. To date, the diagnostic significance of TS in patients with JIA is still unknown.

Objectives: To determine the diagnostic significance of ultrasound findings of TS in patients with JIA.

Methods: We conducted an observational multicentric cross-sectional study including JIA patients with disease onset between 2013 and 2016. Clinical characteristics, US scan, laboratory test results and Juvenile Arthritis Disease Activity Score for 10 joint counts (JADAS10) were collected in an encrypted database. Patients performed a musculoskeletal ultrasound scan of the wrists, fingers, and ankles for the assessment of tenosynovitis according to the OMERACT (Outcome Measures in Rheumatology) US definitions. We ran a logistic model with TS as response variable to identify clinical and demographic features associated to TS.

Results: Musculoskeletal US was performed in 167 new-onset JIA patients. US revealed the presence of synovitis in 101/167 patients (60.5%) while 72/167 patients had TS (43.1%) in the scanned joints. Nine out of 72 (12.5%) patients presented with isolated TS without joint involvement.

Ankle TS was detected in 81% (58/72) of the patients that presented TS whereas the wrist/hand’s tendons were affected in 19.4 % (14/72) of these patients.

At the bivariate analysis, the predictors of having TS at disease onset were: increased acute phase reactants, high baseline active joint counts, high disease activity based on JADAS score, and RF- polyarticular and oligoarticular ANA negative JIA ILAR category.

In the final multivariate analysis, RF- polyarticular JIA category was an independent predictor of TS (OR: 3.01; 1.11-8.43 p-value 0.031). In addition, higher values of JADAS corresponded to a higher risk of having TS (an increase of 1 in the JADAS-10 score corresponded to an increase of 11% in the risk of having TS, p-value 0.0019).

Conclusion: A significant percentage of JIA patients showed TS at disease onset. TS may be present as an isolated manifestation without joint involvement. Patients with polyarticular JIA and high disease activity had a significant higher rate of tendons involvement. Our results suggest a potential role of TS as a marker of severity at the disease onset. Longitudinal studies are needed to verify the prognostic value of TS on the disease course.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Reference

1. Rooney ME, McAllister C, Burns JF. Ankle disease in juvenile idiopathic arthritis: ultrasound findings in clinically swollen ankles. J Rheumatol. 2009 Aug;36(8):1725-9. doi: 10.3899/jrheum.080508. Epub 2009 May 1. PMID: 19411390.

Correspondence: N. Ruperto

Pediatric Rheumatology 2023, 21(Suppl 2):PT068

Introduction: Secukinumab has demonstrated efficacy and safety in patients with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) categories of juvenile idiopathic arthritis (JIA) for up to 2 years.¹ After completion of a 2-year primary study (JUNIPERA), a long-term extension (LTE) study was conducted to evaluate the continued efficacy and safety of secukinumab in patients with ERA and JPsA.

Objectives: Here we report the interim efficacy and safety results of the LTE study.

Methods: In the primary study, a total of 86 patients (2 to <18 years of age) received secukinumab up to week 12 in the open-label (OL) period.¹ JIA American College of Rheumatology (ACR)30 responders at week 12 (n=75) were subsequently randomised to secukinumab (n=37) or placebo (n=38) up to week 100 in study period 2. Those who flared after randomisation (secukinumab, n=10; placebo, n=21) received OL secukinumab in study period 3 up to week 100.¹ A total of 55 out of 61 patients who had completed the primary study consented to enter the LTE study, among which 54 patients received secukinumab (s.c.) (75/150 mg in patients <50/ ≥50 kg) every 4 weeks up to 4 years. Patients whose signs and symptoms were not fully controlled, as judged by the investigator in the LTE study, could have dose escalation of their secukinumab dose from 75 mg to 150 mg or 150 mg to 300 mg. Median Juvenile Arthritis Disease Activity Scores (JADAS)-27 were presented up to week 156 for efficacy, and adverse events (AEs) and serious AEs were presented for the entire treatment period up to the cut-off date (02-Feb-2022).

Results: The median (Q1, Q3) JADAS-27 improved from 14 (9.3, 19.0) at baseline to 0.7 (0.0, 1.5) at week 104 for patients receiving secukinumab in the primary study, which was maintained in the LTE study till week 156 (0.7 [0.2, 2.8]). There was a notable reduction in median JADAS-27 from high disease activity at baseline to minimal and inactive disease activity at week 12 and week 104, respectively. The inactive disease status achieved in the primary study was sustained till week 156 in the LTE study. A total of 19 patients had dose escalation in the LTE study: 8 patients from 75 mg to 150 mg and 11 patients from 150 mg to 300 mg. The overall exposure-adjusted incidence rate per 100 patient-years (PY) of treatment-emergent AEs was 98.4 PY in the entire JIA population. The most commonly reported AEs were nasopharyngitis (n=9, 16.7%) and arthralgia (n=8, 14.8%). One major adverse cardiovascular event, not related to the study drug, and 2 cases of uveitis were reported. No cases of Crohn’s disease or deaths were reported, and no patient discontinued treatment due to an AE.

Conclusion: With secukinumab treatment, the JADAS-27 inactive disease status was sustained from week 104 to week 156 in patients with JIA who had completed the 2-year primary study and enrolled in the LTE study. Safety data were consistent with adult and paediatric indications, with no new or unexpected safety signals.

Trial registration identifying number: NCT03769168

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

N. Ruperto Grant / Research Support with: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi, Consultant with: Ablynx, AstraZeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB, Speaker Bureau with: Ablynx, AstraZeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB, I. Foeldvari Consultant with: Novartis, BMF, Bayer, Genentech, Sanofi, Abbvie, Chugai, Medac, BMS, Pfizer, E. Alexeeva Grant / Research Support with: Novartis, Pfizer, Sanofi, MSD, AMGEN, Eli Lilly, Roche, Speaker Bureau with: Novartis, Pfizer, Sanofi, MSD, AMGEN, Eli Lilly, Roche, N. A. Ayaz: None declared, G. Schulert Grant / Research Support with: Novartis, Consultant with: Novartis, S. Ozen: None declared, A. Popov: None declared, A. V. Ramanan Speaker Bureau with: Roche, Sobi, Eli Lilly, UCB, Novartis, C. Scott: None declared, B. Sozeri: None declared, E. Zholobova Grant / Research Support with: Pfizer, Novartis, Speaker Bureau with: Abbvie, Pfizer, Roche, Novartis, S. Chakraborty Shareholder with: IQVIA, Employee with: IQVIA, X. Zhu Shareholder with: Novartis, Employee with: Novartis, R. Martin Shareholder with: Novartis, Employee with: Novartis, S. Whelan Shareholder with: Novartis, Employee with: Novartis, S. Kaur Shareholder with: Novartis, Employee with: Novartis, L. Pricop Shareholder with: Novartis, Employee with: Novartis, D. Lovell Consultant with: AstraZeneca, Wyeth, Amgen, Abbott, Pfizer, Hoffmann-La Roche, Novartis, UBC, Janssen, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Bristol Myers Squibb, AbbVie, Paid Instructor with: DSMB member: Forest Research, NIH-NIAMS, Canadian Arthritis Society, Speaker Bureau with: Abbott, Novartis, A. Martini Consultant with: Eli Lilly, EMD Serono, Janssen, Novartis, Pfizer, Abbvie, Speaker Bureau with: Eli Lilly, EMD Serono, Janssen, Novartis, Pfizer, Abbvie, H. Brunner Grant / Research Support with: Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, F. Hoffmann-La Roche, Janssen, Novartis, and Pfizer, Consultant with: Aurinia, Abbvie, AstraZeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, GlaxoSmithKline, F. Hoffmann-La Roche, Merck, Novartis, R-Pharm, Sanofi, Pfizer, Speaker Bureau with: Pfizer, Roche and GlaxoSmithKline

Reference

1. Brunner HI, et al. Ann Rheum Dis. 2023;82(1):154-160.

Correspondence: T. Schmidt

Pediatric Rheumatology 2023, 21(Suppl 2):PT069

Introduction: Little is known of the mechanisms driving monocyte and neutrophil activation in oligoarticular juvenile idiopathic arthritis (oJIA). Synovial fibroblasts (S-Fib) are recognized as key drivers of inflammation in adult arthritis, but little is known of their role in oJIA.

Objectives: To explore if S-Fib from oJIA patients induce activation in healthy monocytes and neutrophils.

Methods: S-Fib were isolated from the synovial fluid (SF) of n=10 patients with oJIA. Isolated S-Fib were primed or not with pooled cell-free SF (n=8-10) to mimic a disease relapse. They were subsequently analyzed by mass spectrometry, cytokine production and their ability to induce migration of monocytes and neutrophils. The influence of S-Fib on the healthy monocyte- and neutrophil phenotypes and function was studied in co-culture systems. These cells were subsequently analyzed using various assays believed to reflect key pathological events, such as cytokine production, T-cell activation, and reactive oxygen species (ROS) production.

Results: Compared to S-Fib alone, priming of S-Fib with SF induced production of IL-6 (p=0.0402), IL-8 (p=0.0344), and enhanced immune cell migration to supernatants (p<0.0346). Furthermore, S-Fib induced an inflammatory phenotype in healthy monocytes, such as production of inflammatory cytokines (p<0.0209) and an increased ability to induce T-cell proliferation (p=0.0351). Importantly, these effects were further enhanced by priming of the S-Fib prior to co-culture. Moreover, the effect of S-Fib co-culture on neutrophils were minor, although co-culture with SF-primed S-Fib prevented apoptosis (p=0.0069). Finally, S-Fib supernatants did not induce the observed monocyte phenotype, but monocytes had increased adhesion to SF-primed S-Fib (p<0.0001), suggesting a role of cell-cell contact.

Conclusion: Our data show a role for S-Fib in driving inflammation in childhood-onset arthritis by inducing pro-inflammatory monocytes and pro-longing neutrophil survival, processes potentiated by inflamed SF. These data further support that targeting cell-cell interactions could be a viable option to explore for novel treatment strategies in arthritis.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: P. Vega-Fernandez

Pediatric Rheumatology 2023, 21(Suppl 2):PT070

Introduction: Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease in children. Currently, clinical evaluation of arthritis is subjective and provider dependent. Musculoskeletal ultrasound (MSUS) is an objective imaging technique that can be used to assess joint inflammation.

Objectives: This study aims to validate a novel pediatric-specific MSUS scoring system[1] for the assessment of finger arthritis.

Methods: Children with a diagnosis of JIA who received a MSUS of the finger joints were eligible for this study. Clinical data collected included presence/absence of MCP arthritis on physical examination (PE), and physician- and patient- reported outcomes. A comprehensive finger MSUS examination, including B-mode and Power Doppler (PD) mode of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints was performed on all participants by an American College of Rheumatology MSUS certified pediatric rheumatologist. MSUS images were scored by pediatric MSUS experts, who were blinded to clinical and imaging information, as per recently published semiquantitative MSUS scoring system (0-normal to 3-severe)[1]. For the current report, MSUS was recorded abnormal if any of the B-mode images had a score equal or greater than 2 or if PD images had a score of 1-3. B-mode images with a MSUS scores of 0 and 1 and PD-mode scores of 0 were interpreted as normal. A subset of participants received an MRI with and without contrast of the fingers (2^nd through 5^th finger) immediately after MSUS performance. MRI of the MCP joint was scored as abnormal if there was presence of increased synovial thickening (ST) and joint effusion (JE) as per previously proposed MRI scoring systems [2, 3]. Spearman’s Correlations were used to calculate the associations between variables.

Results: Twenty-three children (mean age of 12.5 years) with JIA were enrolled in this study. In some instances, bilateral MCP’s examination was performed and recorded. For the current report 139 MCPs were analyzed. At the time of MSUS collection, 23 (16.6%) of the MCPs had arthritis by physical examination. A weak correlation between physical examination and MSUS was found (r=0.23, p=0.006). Of these 139 MCPs, 24 MCPs had MRI in addition to MSUS and physical examination. There was a weak correlation between MRI and physical examination (r=0.26, p=0.2). A strong moderate correlation between MRI and MSUS for the presence of MCP arthritis (r=0.62, p=0.002).

Conclusion: The weak correlation of MSUS synovitis with finger arthritis by physical examination and the moderate strong correlation of MSUS synovitis with contrast-enhanced MRI, suggest that MSUS provides an objective bedside assessment of MCP arthritis. MSUS has the potential to effectively inform JIA medical decision making real-time. Further analysis is underway.

Patient Consent

Yes, I received consent

Disclosure of Interest

P. Vega-Fernandez: None declared, K. Rogers: None declared, M. Quinlan-Waters: None declared, A. Cassedy: None declared, A. Meyers Consultant with: paid consultant for Pfizer, T. Ting: None declared

References

1. Vega-Fernandez, P., et al., Musculoskeletal Ultrasound in Childhood Arthritis Limited Examination: A Comprehensive, Reliable, Time-Efficient Assessment of Synovitis. Arthritis Care Res (Hoboken), 2023.75(2): p. 401-409.

2. Damasio, M.B., et al., MRI of the wrist in juvenile idiopathic arthritis: proposal of a paediatric synovitis score by a consensus of an international working group. Results of a multicentre reliability study. Pediatr Radiol, 2012. 42(9): p. 1047-55.

3. van Dijkhuizen, E.H.P., et al., Effect of the Inclusion of the Metacarpophalangeal Joints on the Wrist Magnetic Resonance Imaging Scoring System in Juvenile Idiopathic Arthritis. J Rheumatol, 2018.45(11): p. 1581-1587.

Correspondence: A. Albayrak

Pediatric Rheumatology 2023, 21(Suppl 2):PT071

Introduction: Juvenile Idiopathic Arthritis (JIA) and Familial Mediterranean Fever (FMF) are the most common autoimmune and autoinflammatory rheumatic diseases in childhood. Cardiorespiratory fitness, which is an important indicator of physical function, plays a critical role in health-related outcomes in children and adolescents with rheumatic disease. The need for extensive equipment and trained personnel, accompanied with the inability to assess large numbers of children at one-time makes the objective assessment of cardiorespiratory fitness in a clinic setting unmanageable. The Progressive Aerobic Cardiovascular Endurance Run (PACER) has become a routine test for predicting cardiorespiratory fitness in children with chronic disease.

Objectives: The aim of this study was to evaluate the cardiorespiratory fitness with PACER, to investigate feasibility of the PACER in patients with JIA and FMF and compare the results with healthy controls.

Methods: Sixty-seven (22 JIA, 20 FMF, 22 healthy) children and adolescents aged between 11 to 17 years old were included in the study. Cardiorespiratory fitness was evaluated with the PACER, which is a cardiorespiratory fitness test in FitnessGram Physical Activity Test Battery. Participants were instructed to run back and forth across a marked 20-m course in a straight line, pivot and turn on completing a lap, and pace themselves in accordance with an audio recording. Participants were instructed to continue running until the pace could no longer be maintained. Strong verbal encouragement was provided by research personnel to continue running as long as possible. Participants completed the PACER test individually. By using the FitnessGram “VO2 calculator” application, VO2 peak was calculated for each patient based on the number of laps that patients completed. Patients were then classified, according to the age- and gender-specific cut-off points of FitnessGram as Needs Improvement (NI)-Health Risk, NI and healthy fitness zone (HFZ). The SPSS Version 24.0 program was used for statistical analysis.

Results: The mean age of the children and adolescents diagnosed with JIA and FMF and healthy controls included in the study was 13.77±1.82, 13.75±2.02 and 14.96±0.73 years, respectively. The PACER results of patients with JIA and FMF and their healthy peers were shown in Table 1. Compared with their healthy peers, the PACER test results of children and adolescents with JIA and FMF were significantly lower (p<0.05). The PACER test results of children with JIA and FMF were statistically similar (p>0.05) and the scores of nearly all participants were significantly lower than the age-appropriate normal scores. When the FitnessGram Standards were applied, %85.7 of them and %72.7 of healthy controls were categorized in the “NI-Health Risk”, %11.9 of them and %22.7 healthy controls in the NI and only %2.4 of them and %4.5 healthy controls in the HFZ for VO2 health category.

Conclusion: Cardiorespiratory fitness was significantly affected in children and adolescents diagnosed with both JIA and FMF. Reduced cardiorespiratory fitness can be related to many factors such as pain, fatigue and low physical activity level. The PACER can be an alternative tool for assessing cardiovascular fitness in patients with JIA and FMF. Future studies are needed to determine the factors influencing cardiorespiratory fitness in patients diagnosed with JIA and FMF for understanding barriers and to clarify the fitness facilitators. We believe that focusing on physical activity and exercise programs for improving cardiorespiratory fitness may be beneficial in minimizing health risks in patients with JIA and FMF.

This study was supported within the scope of the Scientific and Technological Research Council of Turkey (TUBITAK) 1001-Scientific and Technological Research Projects Support Program (Project number: 121E690).

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: M. Ha

Pediatric Rheumatology 2023, 21(Suppl 2):PT072

Introduction: Paediatric rheumatology covers a broad range of local and systemic inflammatory diseases that are caused by autoimmune and/or autoinflammatory mechanisms. Children who present with rheumatic symptoms often pose several challenges to their physicians due to the diagnostic challenges caused by the heterogeneity of many rheumatic diseases, variable clinical presentations, and complex pathophysiology.

Objectives: The objective of this study is to improve the early diagnosis of paediatric rheumatic diseases via whole blood transcriptomics combined with machine learning. We aim to investigatethe gene expression of whole blood from children with rheumatic diseases and apply machine learning on the transcriptome data to develop classification models for identifying different disease groups [1].

Methods: The cohort included 41 control cases (i.e., children without viral infection or rheumatic diseases), 47 children with viral infection, and 147 children having different rheumatic diseases: chronic recurrent multifocal osteomyelitis (CRMO), deficiency of IL-1 receptor antagonist (DIRA), juvenile idiopathic arthritis (JIA), periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA), systemic JIA (sJIA), undifferentiated systemic autoinflammatory disorders (uSAID), acrocyanosis-vasculopathy, chilblains, interferonopathy, linear scleroderma, Lyme arthritis, raynaud, sarcoid, uveitis, and vasculitis. RNA sequencing was performed on whole blood collected from all participants. Analyses of differentially expressed genes, gene ontology enrichment, KEGG pathways, and Random Forest classifier development were conducted based on the transcriptomic data.

Results: Chemokine signalling was observed in acrocyanosis-vasculopathy and PFAPA patients. AMPK signalling (which mediates the cellular energy level) was found in CRMO and DIRA patients, while mTOR signalling (which regulates cell proliferation and differentiation) was exhibited in Lyme, PFAPA, and sJIA. Patients with acrocyanosis-vasculopathy, JIA, Lyme, PFAPA, raynaud, sJIA, and uSAID could be distinguished well from other rheumatic groups by Random Forest classifiers with high area-under-the-curve (AUC) values (AUC = 0.76 ± 0.18, 0.69 ± 0.16, 0.92 ± 0.13, 0.76 ± 0.22, 0.86 ± 0.25, 0.79 ± 0.22, and 0.94 ± 0.13, respectively). When comparing HLA-B27⁺ enthesitis-related JIA with other juvenile arthritis groups (i.e., psoriatic, oligoarticular, polyarticular, undifferentiated, and Lyme arthritis), cytokine receptor interaction, JAK-STAT, IL-17, and TNF signalling pathways were enriched. Random Forest classification between these groups showed AUC values in the range 0.73 – 0.81 in leave-one-out cross-validation.

Conclusion: Overall, our study indicates that blood transcriptomics combined with machine learning is a promising tool for paediatric rheumatic disease classification and diagnosis. Application of machine learning on other clinical and molecular data has potential toassist paediatric rheumatologists in predicting the course of diseases, identifying important risk factors, and estimating treatment responses.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Ha, M.K. et al. Pediatr. Rheumatol. 2022, 20, 91.

Correspondence: G. Horneff

Pediatric Rheumatology 2023, 21(Suppl 2):PT073

Introduction: Current polyarticular juvenile idiopathic arthritis (polyJIA) treatment options are not always sufficient in easing symptoms and reducing further damage.

Objectives: We evaluated treatment patterns in newly diagnosed patients with polyJIA, with a focus on changes possibly indicating inadequate achievement of treatment goals.

Methods: Using a retrospective observational cohort study on two non-overlapping longitudinal health claims databases (WIG2, Scientific Institute for Health Economics and Health System Research GmbH, and InGef, Institute for Applied Health Research Berlin GmbH), a representative sample of 3.5 and 4 million patients, respectively, was analysed. Incident polyJIA patients were identified with inpatient or outpatient ICD-10 GM (German modification) diagnosis codes M08.0 or M08.3. The prescription date was assigned to a given half-year (HY) period relative to the index (first diagnosis) quarter. For each HY period, the highest drug escalation treatment was categorized, based on the following hierarchy (highest to lowest escalation: bDMARDs, csDMARDs, GCs, NSAIDs, none). Results from baseline period and 3-year follow-up from both cohorts and data sets were pooled

Results: We identified 121 and 58 newly diagnosed polyJIA patients in the pooled data set (2014/2015) in the InGef and WIG2 databases, respectively. At one year before the first diagnosis, most patients were not being treated with any of the pre-defined medications (66% WIG2 and 71% InGef), but of those who were, most were being treated with NSAIDs (21% and 12%), with little change in the -1HY. In the first HY period after index, most patients in the population were being treated with a csDMARD (not a bDMARD), however there were still some patients (24% and 12%) receiving none of the investigated treatments at this time.

CsDMARD as the highest escalation drug used peaked in the first HY period after index, and (52% and 33%) while bDMARD use continued to increase throughout the 3-year follow-up. At 3HY following diagnosis, 40% and 26% of patients were treated (at highest escalation) with a csDMARD, and 24% and 19% with a bDMARD.

After about 3 years of follow-up, many patients were receiving none of the treatments (31% and 45%), however some were still taking csDMARDs (17% in both databases) and even more taking bDMARDs (36% and 18%). The proportion of patients taking bDMARDs peaked at the end of the 3-year follow-up in one dataset (WIG2, 36%) and at the 3HY mark in the other (InGef, 19%), however in the latter, remained high by the end of the follow-up (at 3 years, 18%).

Conclusion: Throughout follow-up over three years from diagnosis, there was an increasing use of bDMARDs, and use of csDMARDs (as highest escalation) remained over 17%, indicating a need for further advanced treatment options for a subset of the population.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

G. Horneff Grant / Research Support with: Novartis, Roche, MSD, Speaker Bureau with: Lilly, Pfizer, GSK, Sanofi, J. Borchert Grant / Research Support with: Research activities of WIG2 GmbH commissioned and financed by Pfizer Pharma GmbH, Employee with: WIG2 GmbH, J. Diesing Grant / Research Support with: Research activities of WIG2 GmbH commissioned and financed by Pfizer Pharma GmbH, Employee with: WIG2 GmbH, P. Klaus Shareholder with: Pfizer Pharma GmbH, Employee with: Pfizer Pharma GmbH, R. Heinrich Grant / Research Support with: Research activities of WIG2 GmbH commissioned and financed by Pfizer Pharma GmbH, Employee with: WIG2 GmbH, H. Dally Shareholder with: Pfizer Pharma GmbH, Employee with: Pfizer Pharma GmbH, C. Hagemann Employee with: During project phase; now former employee of Pfizer Pharma GmbH, S. Kock Employee with: InGef GmbH, T. Schönfelder Grant / Research Support with: Research activities of WIG2 GmbH commissioned and financed by Pfizer Pharma GmbH, Employee with: WIG2 GmbH

Correspondence: M. Klanjscek

Pediatric Rheumatology 2023, 21(Suppl 2):PT074

Introduction: Anakinra is a recombinant human interleukin-1 (IL-1) receptor antagonist; it blocks the activity of IL-1, a pro-inflammatory cytokine involved in the immune response. It is primarily used by subcutaneous injection in the treatment of several autoinflammatory conditions such as: Still's disease, familial mediterranean fever and cryopyrin-associated periodic syndromes (CAPS). Intravenous anakinra is used in clinical practice, especially for Macrophage Activation Syndrome (MAS)/Hemophagocytic Lymphohistiocytosis (HLH), despite this being an off-label route of administration. In acute and life-threatening diseases, the subcutaneous route is often problematic, absorption may be unreliable in patients with critical illness, peripheral oedema or anasarca and multiple painful injections are needed to achieve the high doses required. Intravenous administration of anakinra enables a higher and faster maximal plasma concentration to be achieved, compared with subcutaneous delivery. Some authors have already reported its effectiveness via intravenous administration in some specific pediatric clinical settings such as MAS/HLH.

Objectives: To collect the patients treated by intravenous anakinra in order to demonstrate the safety of intravenous administration of anakinra in a cohort of children affected by different inflammatory conditions.

Methods: This is a bicentric retrospective study. All pediatric patients treated with intravenous anakinra from January 1^st, 2017, to December 31^st, 2022, in IRCCS Maternal and Child Health Institute Burlo Garofolo in Trieste (Italy) and in the IRCCS Bambino Gesù Children’s Hospital in Roma (Italy) were enrolled. Data about quantitative characteristics related to drug administration (dosage administered, treatment duration), information regarding the hospital setting (admission or non-admission to the ICU), findings about the clinical response, presence or absence of side effects, their nature and the patient’s outcome were collected.

Results: Our case series includes 48 patients with different underlying clinical conditions; the most represented are MAS/HLH 40% and MIS-C 19%.

Side effects were observed in 7 out of 48 treated children (14%), in most cases they were represented by transient elevation of hepatic or pancreatic enzymes (5/48, 10%). One patient (1/48, 2%) exhibited a maculopapular rash and fever 20 minutes after the infusion, which resolved upon discontinuation of the medication. In another case (1/48, 2%) there was an immediate reaction with hypotension and vomiting, which resolved after administration of plasma-derived medicinal products (PDMPs) and antihistamine. Seven patients (14%) experienced an unfavorable outcome due to the progressive and untreatable nature of their underlying clinical condition, specifically sepsis (2/7), acute respiratory failure, post-transplant complications, cardiac arrest, DRESS and intractable HLH.

Conclusion: The intravenous use of anakinra in pediatrics could represent a more manageable and effective alternative in the treatment of some life-threatening acute clinical conditions, ensuring the possibility to administer a high dosage of the drug and its absorption even in critical settings. The intravenous administration of anakinra at a dosage of 2-20mg/kg/day has proven to be safe in our case series. Side effects demonstrate to be transient or pharmacologically manageable. It is necessary to expand this research involving other Centers in order to increase the number of cases and the statistical significance.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: C. Lavarello

Pediatric Rheumatology 2023, 21(Suppl 2):PT075

Introduction: Juvenile Fibromyalgia Syndrome (JFS) is a disabling condition characterized by widespread musculoskeletal pain, fatigue, sleep, cognitive and mood disturbances. A considerable proportion of patients with JFS experience gastrointestinal (GI) symptoms such as abdominal pain, bloating, and constipation (1). Although the association between fibromyalgia and Functional Gastro-Intestinal disorders (FGID) is well established in adults with fibromyalgia, so far no study has explored this association in JFS.

Objectives: To investigate the frequency of FGID in JFS patients and its impact of the disease burden.

Methods: JFS patients followed at our center between 2021 and 2023 were included in the present study. Patients underwent a multidisciplinary evaluation. We applied Rome IV criteria (2) to investigate type and frequency of FGID. The Children Depression Inventory (CDI) and the Multidimensional Anxiety Scale for Children (MASC) were used to evaluate presence and severity of mood disorders. Participants were asked to rate their average level of pain in the previous two weeks using the standard 100-mm pain Numerical Rating Scale (NRS) that ranges from 0 (no pain) to 100 mm (pain as bad as it can be). Self-report measures (100 mm NRS) were also used to rate the severity of symptoms in the following domains: fatigue, headache, symptoms severity upon awakening, and global assessment (PGA) of disease severity.

Results: We included 47 JFS patients (F 42) with median age at onset of 13.7 (IQR 11.3-15.2) and median age at JFS diagnosis of 15.6 (IQR 14.1-16.5). Thirty-nine out of 47 (87%) patients referred at least one gastrointestinal symptom. Abdominal pain (85.1%), nausea (44.7%), constipation (34%), pyrosis (31.9%), bloating (27.7%), postprandial nausea (27.7), and dyspepsia (25.5%) were more common Thirteen out of 39 (33.3%) reported a frequency of symptoms > 4 days a week and 20 out of 39 (51.3%) reported that these symptoms are limiting daily activities. 14 patients (29.8%) underwent invasive investigations (e.g. endoscopy). 28 patients (59.6%) met Rome IV criteria for at least one FGID: dyspepsia in association with IBS (18.5%), IBS (14.8%), functional dyspepsia (14.8%), functional constipation (3.7%), and functional abdominal pain not otherwise specified (48.2%). We found a trend of higher PGA in patients with JFS and FGID even if with a difference not statistically significant (p 0.06).

Conclusion: FGID were diagnosed in a significant percentage of JFS patients and have a relevant impact on disease severity. Most common FGID were IBS and functional abdominal pain not otherwise specified. Our results highlight the need for a multidisciplinary approach to the assessment of JFS patients. Elucidation of the common pathophysiologic mechanisms underlying these disorders could provide insights for the development of more comprehensive and targeted therapeutic approaches.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Erdrich S, Hawrelak JA, Myers SP, Harnett JE. A systematic review of the association between fibromyalgia and functional gastrointestinal disorders. Therap Adv Gastroenterol. 2020 Dec 8:13:1756284820977402. doi: 10.1177/1756284820977402. PMID: 33343707; PMCID: PMC7727037.

2. Thapar N, Benninga MA, Crowell MD, Di Lorenzo C, Mack I, Nurko S, Saps M, Shulman RJ, Szajewska H, van Tilburg MAL, Enck P. Paediatric functional abdominal pain disorders. Nat Rev Dis Primers. 2020 Nov 5;6(1):89. doi: 10.1038/s41572-020-00222-5. PMID: 33154368.

Correspondence: I. Maccora

Pediatric Rheumatology 2023, 21(Suppl 2):PT076

Introduction: Childhood non-infectious uveitis (cNIU) is a rare disease whose differential diagnosis is extremely challenging and need to take into account several systemic diseases including demyelinating disease. Therefore, a thorough assessment should be considered, because of the presence of White Matter Abnormalities (WMA) in these children is important as they are often treated with anti-TNFα therapy which could worsen these lesions.

Objectives: The aim of this study is to report the prevalence WMA in children with non-infectious uveitis (NIU).

Methods: We performed a retrospective chart medical review at Meyer Children’s Hospital IRCCS (Florence) and at the University Medical Center Utrecht, involving children with less than 18 years old, with cNIU that underwent a cerebral MRI before starting a systemic treatment. Clinical, laboratory and radiological data were collected. As main outcome we considered the brain MRI abnormality.

Results: From two tertiary centers, the UMC Utrecht and the Meyer’s Children’s Hospital, a total of 112 children (53 female), 35 (31.3%) with anterior uveitis, 30 (26.8%) with intermediate uveitis, one with posterior uveitis (0.89%) and 46 (41.1%) with panuveitis, were included. 91 have bilateral uveitis (81.25%). Among the 112 children, 96 (85.7%) have idiopathic uveitis, 8 Tubular interstitial associated uveitis (TINU) (7.14%), and 8 others (7.14%). The median age at onset of uveitis was 109 months (range 98-139). A total of 29 children (25.9%) showed WMA on cerebral MRI. Among these children with WMA, 8 have anterior uveitis (27.5%), 10 intermediate uveitis (34.4%), 11 panuveitis (37.9%). In addition, incidental findings included one patient with a glandule pineal lesion, five patients with cysts, two patients with gliosis, one patient with optic neuritis, one patient with venous angioma, one patient with optic nerve atrophy and one patient with plexus papilloma. None of the patients with WMA showed neurological symptoms when the brain MRI was performed. In total, 72.34% of all MRI abnormal findings were seen in non-anterior uveitis patients.

Conclusion: In both tertiary centers, white matter abnormalities were frequently found on cerebral MRI, especially in non-anterior uveitis patients. Typically, these abnormalities were asymptomatic, however it is critical to early identify possible brain involvement in order to choose the better treatment.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: A. Schvartz

Pediatric Rheumatology 2023, 21(Suppl 2):PT077

Introduction: Minor salivary gland biopsy (MSGB) is a common test in medicine, easily prescribed by both pediatric and adult specialists(1). Despite its simplicity, MSGB is not without risk. A prospective study about MSGB complications revealed 10% of it (7% for local pain and 3% for paresthesia) are persistent(2). Although the MSGB is a major criterion for the diagnosis of Sjogren's Syndrome (SS), multiple studies have outlined difficulties in standardization(3). SS is a rare disease in children and can differs from the adult counterpart. MSGB is also used for the diagnosis of sarcoidosis where it allows visualization of granulomas. Several studies have conflicting results for this indication(4,5). To our knowledge, no study has investigated the accuracy of MSGB in children in SS and sarcoidosis suspicions.

Objectives: The aim of our study was to analyze diagnostic performance of MSGB in children suspected of Sjogren’s syndrome or sarcoidosis.

Methods: We did a retrospective monocentric study on patients under 18 years old who had a MSGB between October 2011 and December 2021 at Bicêtre University Hospital tertiary center. Clinical and biological data were collected digitally. Indication was made by the clinician in charge of the patient. Histological analysis was done by a dedicated expert physician. Biopsy was considered positive if Chisholm-Mason score was superior or equal to 3, or focus score was superior or equal to 1 for suspicion of SS, according to the ACR/EULAR criteria, and if non caseified granulomas were present in cases of sarcoidosis.

Results: One hundred sixty-two MSGB were analyzed, 47 were pathological and 34 confirmed the initial suspicion. MSGB were divided into 2 groups according to indications. Among the 66 MSGB performed for suspected SS, 23 were positive and 13 were associated with a confirmed final diagnosis. Twenty patients (31%) had positive anti-SSA antibodies. MSGB was sensitive and specific (Se=81%, Sp=80). Anti-SSA antibodies improved specificity (98%), but no other parameters.

For sarcoidosis suspicion, 114 biopsies were performed, 21 (18%) were associated with the final confirmed diagnosis and 7/21 (33%) of them were positive. On 63 patients who had ophtalmological examination, 40 had granulomatous uveitis. MSGB was not sensitive but very specific (Se=33%, Sp=98%). The presence of granulomatous uveitis improved the sensitivity and specificity of the test and the 7 patients who had positive biopsies and granulomatous uveitis had confirmed sarcoidosis.

Conclusion: Minor salivary gland biopsy is a simple and moderate invasive test in children, which is a good confirmation diagnostic tool but should not be used as a screening tool in sarcoidosis. It does not provide added value in the event of suspicion of SS compared to other non-invasive parameters, especially anti-SSA antibodies.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. Pellegrini M, et al. Current Salivary Glands Biopsy Techniques: A Comprehensive Review. Healthcare 2022.

2. Lida Santiago M, et al. Frecuencia de complicaciones y rédito de la biopsia de glándula salival menor. Reumatología Clínica 2012

3. Wicheta S, et al. Discrepancies in Interpretation of the Minor Salivary Gland Biopsy in the Diagnosis of Sjögren Syndrome. Journal of Oral and Maxillofacial Surgery 2019

4. Blaise P, et al. Minor salivary gland biopsy in diagnosing ocular sarcoidosis. British Journal of Ophthalmology 2011

5. Bernard C, et al. Ocular sarcoidosis: when should labial salivary gland biopsy be performed? Graefes Arch Clin Exp Ophthalmol 2013

Correspondence: C. A. Tatar

Pediatric Rheumatology 2023, 21(Suppl 2):PT078

Introduction: Cyclophosphamide (CYC) with its immunosuppressive properties continues to be the drug of choice in patients with severe rheumatic disease, such as vasculitis and systemic lupus erythematosus (SLE). However, ovarian failure due to cytotoxicity of CYC remains to be a major concern in adolescent female patients with high probability of survival.¹

Objectives: To analyze the risk of ovarian failure in women, diagnosed with rheumatic diseases and treated with CYC during adolescence.

Methods: This is a single-center cross-sectional cohort study involving 21 female patients (age 12-29 years) diagnosed with rheumatic disease (15 with SLE and the remaining with systemic vasculitides) between 2000 and 2020 who received CYC therapy. History of illness, details of menstrual irregularities, serum levels of FSH, LH, estradiol and AMH was recorded in 21 patients, and transabdominal ultrasonographic assessment of ovarian and uterine volume, antral follicular count, endometrium thickness and corpus to cervix ratio were carried out in 18 patients on days 3-5 of the menstrual cycle. Analyses were stratified according to treatment with low and high cumulative CYC doses (< or = 3g and > 3g, respectively) as well as the presence of amenorrhea which was defined as the absence of menstruations for three or more consecutive cycles.

Results: Median age at diagnosis was 12 (4-17) years and at the onset of CYC initiation it was 13 (9-18) years. The median age at the time of current evaluation was 16 (12-29) years with a median duration of 4 (1-17) years between treatment onset (CYC) and evaluation. The median of cumulative CYC dosage was 3 (0,5-7) grams and treatment duration was 6 (1-22) months. Eight women (38,1%) developed transient amenorrhea during follow-up, however none had sustained amenorrhea. The distribution of cumulative CYC dose was the same across categories of amenorrhea. There were no statistically significant differences between serum FSH, LH, estradiol levels and sonographic findings of low and high cumulative CYC doses. Notably, the AMH was comparably lower in the group with history of amenorrhea (p=0,068) and with high cumulative CYC doses.

Conclusion: Our findings support that children’s ovaries are much more resistant to the gonadotoxic effects of CYC, which is inconsistent with adult data. However, low AMH levels may indicate a future risk of ovarian dysfunction necessitating watchful monitoring.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Ejaz, K., Abid, D., Juneau, P., Chu, J., Hasni, S. Use of gonadotropin-releasing hormone agonists for ovarian preservation in patients receiving cyclophosphamide for systemic lupus erythematosus: A meta-analysis. Lupus. 2022; 31(14), 1706-1713.

Correspondence: S. U. Ward

Pediatric Rheumatology 2023, 21(Suppl 2):PT079

Introduction: Determining clinically significant joint hypermobility in childhood presents a challenge to clinicians. Previous research has demonstrated an evolving phenotype whereby hypermobility and symptoms may further develop or resolve over time. This is the first study to map clinical characteristics of children and adolescents presenting with symptomatic hypermobility in tertiary rheumatology settings from an Irish perspective.

Objectives: Define the clinical characteristics of children and adolescents presenting with symptomatic hypermobility to tertiary paediatric rheumatology services in Ireland.

Methods: A prospective cross-sectional study was carried out on children and adolescents aged 6-16 years recognised as having symptomatic hypermobility determined by a paediatric rheumatologist. A structured interview and clinical measurements were conducted. Standardised assessments included screening for generalised hypermobility (Beighton score and Lower Limb Assessment Score (LLAS)), Foot Posture Index, the 6-minute walk test, Y-balance test, measurement of strength and endurance and motor skills screening (BOT-2 Brief). Parent and child questionnaires assessing pain, multidimensional fatigue and quality of life were also completed following strict protocols.

Results: Eighty participants (26 males, 54 females) were included. Mean age was 11.6±3 years (range 6.0-16.92). Generalised joint hypermobility (Beighton score of ≥6/9) was identified in 79% of participants, and a further 9% classified using the LLAS. The mean time from onset of symptoms to recognition of symptomatic hypermobility was 32±23 months (range 3-108 months). All participants reported pain in more than one joint for >3 months; most affected were the knee (73%) and ankle (55%). Comorbidities were common with 49% reporting three or more. The most common were neurodevelopmental (48.8%) and chronic pain (25%). Below average motor skills were identified in 44% of participants. Muscle strength and endurance were poor with only 24% and 32% respectively achieving within the normative range. Feeling tired ‘often’ or ‘almost always’ was reported by 46% of participants and finding it hard to keep attention ‘often’ or ‘almost always’ was reported by 30%. PedsQL generic core scores (60 ±18.22) were reduced compared to normative data (83±14.79).

Conclusion: This study identified long delays to recognition of symptomatic hypermobility and the significant burden of symptoms and comorbidities in children and adolescents. The high levels of neurodevelopmental diagnoses, poor motor skills and multidimensional fatigue are of particular concern in this population. Earlier recognition and standardised assessments within a biopsychosocial framework are needed to develop better care pathways to improve outcomes.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. Yekdaneh

Pediatric Rheumatology 2023, 21(Suppl 2):PT080

Introduction: Juvenile Idiopathic Arthritis (JIA) is a disease of unknown etiology that affects mostly the knee and ankle joints, causing inflammation, malposition, and deterioration in functional performance (1). Children with JIA are less physically active than their healthy peers, and even children with mild involvement may exhibit decreased functional capacity and delayed development of complex motor skills, which may lead to physical inactivity and reduced quality of life (2, 3). The 6-minute walk test (6MWT) is frequently used to evaluate functional performance in patients with JIA. The 6MWT is a continuous walking test that maintains a constant speed and is administered at the child's own pace, and therefore may create a certain monotony on the functional performance of children. This may affect the functional performance and prevent the correct interpretation of the test. At the same time, it is emphasized that alternative tests are needed because the evaluation procedures of the test are not practical enough (4).

Objectives: The aim of this study was to investigate whether the 30-second Sit to Stand Test (30STST) is an alternative tool for assessing functional capacity in patients with JIA.

Methods: 28 patients with JIA (13 girls, 15 boys) aged 11-16 years were included in the study. Functional capacity of the participants was evaluated with the 30STST, 6MWT, and 10 Stair Climb Test (10SCT). SPSS Version 24.0 program was used for statistical analysis.

Results: The mean age of patients with JIA was 13.64±1.78 years, and the mean of the 6MWT, 30STST and 10SCT was 495.82±105.41 meters, 12.57±2.44 seconds, and 9.73±2.83 seconds, respectively. Between 30STST and 6MWT a high (r=0.73 p<0.001) and between 30STST and 10SCT a moderately significant correlation was found (r=-0.39, p=0.03).

Conclusion: As a results of this study, a significant relationship was found between the 30STST and 6MWT and 10SCT in patients with JIA. We believe that 30STST may have the potential to be a valid and valuable alternative tool for evaluating functional capacity in clinical routine, as it offers a quick and easy assessment in a small area compared to other functional capacity tests for patients with JIA.

This study was supported within the scope of the Scientific and Technological Research Council of Turkey (TUBITAK) 1001-Scientific and Technological Research Projects Support Program (Project number: 121E690).

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Merker J, et al. Pathophysiology of Juvenile Idiopathic Arthritis induced pes planovalgus in static and walking condition: a functional view using 3D gait analysis. Pediatr. Rheumatol. Online J.13(1):21, 2015.

2. Hulsegge GH, et al. Fundamental movement skills, physical fitness and physical activity among Australian children with juvenile idiopathic arthritis. J Paediatr Child Health. 2015;51(4):425-32.

3. Pritchard L, et al. Reproducibility of the Six-Minute Walk Test in Children and Youth With Juvenile Idiopathic Arthritis. Arthritis Care Res. 2022;74(4):686-690.

4. Scalco JC, et al. PSYCHOMETRIC PROPERTIES OF FUNCTIONAL CAPACITY TESTS IN CHILDREN AND ADOLESCENTS: SYSTEMATIC REVIEW. Rev Paul Pediatr. 2018;36(4):500-510.

Correspondence: S. C. Bergkamp

Pediatric Rheumatology 2023, 21(Suppl 2):PT081

Introduction: The pathophysiological mechanisms for premature atherosclerosis in (childhood-onset) systemic lupus erythematosus ((c)SLE) are not completely understood (1). Besides traditional risk factors, the endothelium plays a major role (2). Recently we hypothesized that the endothelium stays in a dysregulated state in SLE, even with low disease activity (3). However, previous studies were mostly cross-sectional and only performed in adult SLE.

Objectives: To determine serum biomarkers of endothelial cell (EC) activation in longitudinal samples of (treatment-naïve) cSLE patients (active vs. low SLE Disease Activity Index (SLEDAI)) and to compare them with healthy controls. Second objective was to assess the correlation of these EC markers with disease activity overtime.

Methods: Patient data and blood samples were used from a multicentre longitudinal cSLE cohort. Disease activity was evaluated by SLEDAI-2K, with cut-offs for active (>4) versus low (≤4) activity. Levels of CXCL12 (SDF-1), TWEAK, VEGF, CXCL10 (IP-10), ADAMTS13, Angiopoietin-2, Pentraxin-3, E-Selectin, Thrombomodulin, P-selectin, CCL2 (MCP-1), VCAM-1, ICAM-1, vWF-A2 and Gas6 were measured in cSLE (t=1 and t=2) and in HC (1 sample). Patient groups and healthy controls were compared by t-tests and ANOVA, with significance for p < 0.05. Correlations between EC biomarkers and SLEDAI were calculated with Pearson correlations.

Results: 47 cSLE patients (n=30 treatment naive patients at t=1) and 42 HC were included. Mean age at diagnosis was 14 (± 2.3) years. Median time between t=1 and t=2 was 14.5 months (IQR 9-24 months). Median SLEDAI at t=1 was 12 (IQR 6-18), median SLEDAI at t=2 was 2.5 (IQR 2-6). Serum levels of Angiopoietin-2, CCL2 and VCAM-1 were higher in cSLE (at t=1, compared to HC), but did not correlate with SLEDAI. At t=1, serum levels of CXCL10 (p=0.01), Thrombomodulin (p=0.03) and VCAM-1 (p=0.01) were higher in the group with active cSLE, compared to those with low disease activity. At t=2, Angiopoietin-2, CCL2, CXCL10, GAS6, Thrombomodulin and VCAM-1 were significantly higher in cSLE compared to HC, despite low median disease activity at that time point.

Conclusion: Our results suggest that in cSLE, the endothelium maintains in an active state over time, even in state of low disease activity. These markers represent activation of ECs with vascular inflammation, EC activation and a pro-angiogenic state. This study could aid in unravelling a part of the pathophysiology of premature atherosclerosis in cSLE patients.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Ardoin SP, Schanberg LE, et al. Laboratory markers of cardiovascular risk in pSLE: the APPLE baseline cohort. Lupus. 2010 PMID: 20861207

2. Westerweel PE, Luyten RK, et al. Premature atherosclerotic cardiovascular disease in SLE. Arthritis Rheum. 2007 May; 1384-96. PMID: 17469095

3. Bergkamp SC, Wahadat MJ et al., J Inflamm (Lond). 2023 May 16;20(1):18. PMID: 37194071;

Correspondence: H. I. Brunner

Pediatric Rheumatology 2023, 21(Suppl 2):PT082

Introduction: Physician Global Assessment of Disease Activity (PhGA) are commonly used as outcome measures in pediatrics rheumatology. For cSLE, the traditional visual analog scale (range: 0 – 10; 0=inactive; 10= very active; PhGA_0-10) but also the SELENA-SLEDAI (range: 0-3; 0= none, 1=mild,2=moderate, 3=severe; PhGA_0-3) are used to measure treatment response, flare, and Lupus Low Disease Activity Status with PhGA_0-3<1.

Objectives: To compare the measurement properties of the PhGA_0-10 and the PhGA_0-3in cSLE and with scores of the SLEDAI-2k, and the SELENA-SLEDAI.

Methods: Secondary data analysis from a convenience sample of 100 cSLE followed every 3 months for up to 7 visits (1). Ratings of PhGA_0-10, PhGA_0- , parent assessment of patient well-being (ParGA ; range:0= very poorly, 10=very well), SLEDAI-2k and SELENA-SLEDAI were compared. After linear transformation of PhGA_0-10 to a 0-3 range (tPhGA_0-10) frequency of PhGA_0-3<1 were compared.

Results: In 601 visits, mean (SD)/median (range) of PhGA_0-10, PhGA_0-3, SLEDAI-2K, SELENA-SLEDAI were 2.13 (1.87)/2 (0-10), 0.79 (0.64)/1(0-3),4.63 (4.14)/ 4 (0-28) and 4.51 (4.1) / 4 (0-32). PhGA_0-10 were moderately correlated with PhGA_0-3 (r=0.73; p<0.0001; Figure 1) with more variability for PhGA_0-3>2. ParGA was weakly correlated with PhGA_0-10, PhGA_{0-3 ,} SLEDAI-2k and SELENA-SLEDAI scores (r = -0.34, -0.30, -0.19 and -0.20). SELENA-SLEDAI and SLEDAI-2k scores were highly (r=0.98) correlated with each other. However, SLEDAI-2K/SELENA-SLEDAI scores were weakly correlated with PhGA_0-3 (r=0.28/0.28; p <.001) and moderately correlated with PhGA_0-10 (r= 0.56/0.54; p <.0001). There were 490/497 of 601 visits with PhGA_0-3<1 / tPhGA_0-10< 1 [Kappa (SE)=0.59 (0.04), McNemar p=0.4].

Conclusion: Using the traditional PhGA_0-10 in cSLE yields almost identical LLDAS rates compared to the PhGA_0-3 . Given its closer association with the scores of disease activity indices in cSLE, use of the PhGA_0-10 may be preferable in pediatric populations.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Mina R, Klein-Gitelman MS, Nelson S, Eberhard BA, Higgins G, Singer NG, Onel K, Tucker L, O'Neil KM, Punaro M, Levy DM, Haines K, Martini A, Ruperto N, Lovell D, Brunner HI. Validation of the systemic lupus erythematosus responder index for use in juvenile-onset systemic lupus erythematosus. Ann Rheum Dis. 2014 Feb;73(2):401-6. PMID: 23345596.

Correspondence: J. Cognard

Pediatric Rheumatology 2023, 21(Suppl 2):PT083

Introduction: Childhood-onset systemic lupus erythematosus (cSLE) is a rare autoimmune disease that leads to significant morbidity. There is a lack of studies examining the use of Rituximab (RTX), a B-cell depleting agent, in the pediatric lupus population.

Objectives: The aim of this study was to retrospectively evaluate the current indications, efficacy, and adverse effects of Rituximab in the treatment of cSLE in within the Juvenile Inflammatory Rheumatism (JIR) cohort (Pedialup module).

Methods: We conducted a national retrospective study of medical records and data collected within the JIR cohort on patients treated by RTX at a their pediatric age, over a period from July 2009 to February 2022.

Results: A total of 41 patients received 132 courses of Rituximab over a 12 year period. 35 (85,4%) were female, with a mean age at diagnosis of 11,7 years. The median administration of RTX occured 16 months after diagnosis. At the initiation of Rituximab treatment, 87% of children had received or were receiving corticosteroids, 21% were on NSAIDs, 82% were on immunosuppressants (MMF, MTX, AZA, CYC, TAC) and 95% were on hydroxychloroquine. The primary indications were Lupus nephritis (51,2%), aggressive polyarthritis with steroid dependence (19,5%) and refractory cytopenia (12,2%). Additionally, 3 children (7,3%) were treated for neuropsychiatric disorders. SLEDAI clinico-biological disease activity score demonstrated statistically significant improvements at 3 and 6 months after RTX perfusion (p< 0,001 ; one-way ANOVA followed by Tukey’s multiple comparisons test), along with a cortisone-sparing effect (from 0,93 mg/kg to 0,39 mg/kg ; p=0,001) and improvements of relevant biomarkers. Treatment efficacy appeared to be more prononced in children with extra-membranous glomerulonephritis, although this subgroup was small (p=0,03). Adverse effects occurred in 17 % of patients, including 7,3% with anaphylactic reactions that resolved upon discontinuation of treatment. No cases of severe infection have been reported during the first 12 months follow-up. However, one year after the last known infusion, 48% of the children required an intensification of their background immunosuppressive treatment or initiation of a new therapeutic approach.

Conclusion: The use of RTX in cSLE appears to be safe and effective, particularly in the treatment of lupus nephritis, polyarthritis and refractory cytopenia leading to a reduction in disease activity and in steroid usage. Further studies and international collaboration are required to confirm and expend these data.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Sawhney S, Agarwal M. Rituximab use in pediatric systemic lupus erythematosus: Indications, efficacy and safety in an Indian cohort. Lupus. 2021 Oct

2. Tambralli A, Beukelman T, Cron RQ, Stoll ML. Safety and Efficacy of Rituximab in Childhood-onset Systemic Lupus Erythematosus and Other Rheumatic Diseases. J Rheumatol 2015

3. Watson L, Beresford MW, Maynes C, Pilkington C, Marks SD et al. The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE. Lupus 2015

Correspondence: I. Foeldvari

Pediatric Rheumatology 2023, 21(Suppl 2):PT084

Introduction: Juvenile systemic sclerosis (jSSc) is a rare disease in childhood. To date, no composite response index exists to assess treatment effect in jSSc patients. ACR CRISS score (probability of improvement ranging from 0 to 1 based on mRSS, FVC%, PtGA, MDGA and HAQ-DI) and revised ACR CRISS (rCRISS, proportion of patients who improve in ≥ 3/5 ACR CRISS core items by a certain percentage, e.g. 30%, except 5% for FVC) were developed by experts in the field as outcome measures in adult patients with SSc. In addition, the Ranked Composite Important Difference (RCID) score was recently introduced as anchor to the ACR CRISS.

Objectives: We aimed to study the applicability and performance of the ACR CRISS, rCRISS and RCID in a prospectively followed cohort of patients with diffuse cutaneous jSSc.

Methods: Data from the international jSSc inceptions cohort were used for this analysis. The ACR CRISS, rCRISS and RCID were calculated between baseline and 12-months follow-up according to the scoring algorithms. Missing values in the core items were estimated by multiple imputation by chained equations. Here we aimed to determine the value of the response measures to detect clinically change defined by the anchor questions about change (much better or little better versus almost the same, little worse or much worse) in patients overall health due to scleroderma since the last visit provided by the treating physicians and parents or patients (aged > 12 years).

Results: We included 95 jSSc patients with diffuse cutaneous subtype with available baseline and 12-months visit. Seventy-nine percent were female, the mean age at enrollment was 13.0 (3.8) and the mean disease duration was 3.1 (2.8) years. Among 95 patients, 57% were treated with steroids, 47% with methotrexate, 27% with MMF and 3% with a biological at baseline. ACR CRISS showed a ceiling effect (>.998) in 51% and a floor effect (<0.005) in 26% of patients. Patients who reported at least moderate improvement had a median ACR CRISS of 0.99 and in mean 2.6 (1.3) core items that improved by ≥20% from baseline to 12-months follow-up. The rCRISS 20/30/50 responses were 59%/49%/33% in patients who reported improvement and 25%/25%/8% in patients with worsening. The RCID was approximately normal distributed (mean 20.7, SD 43.4). Mean (SD) RCID for patients who reported worsening was -10.5 (38.6) vs RCID of 20.7 (45.2) for patients who reported improvement. RCID scores for physician reported anchors of worsening or improvement were 6.5 (44.2) and 18 (45.4) , respectively. The concordance between a positive RCID score and rCRISS 20/30 was moderate (rCRISS 20 and RCID, 43%, kappa=0.43; rCRISS 30 and RCID, 38%, kappa=0.36).

Conclusion: Our data confirmed the presence of a ceiling and floor effect of ACR CRISS as shown in studies of adult SSc patients. The CRISS, rCRISS and RCID response distinguished between patients who rated their disease course since last visit as worsened or improved. Future studies should focus on the determination of specific pediatric weights for the CRISS and RCID components rather than extrapolation from adult SSc. In general, the RCID offers a meaningful tool in order to determine response to therapy in future clinical trials in jSSc patients.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: E. Moraitis

Pediatric Rheumatology 2023, 21(Suppl 2):PT085

Introduction: In the recent years, healthcare is moving away from the traditional view of the patient as passive recipient of services. Organisations around the world have increased their efforts to involve patients and make their participation in healthcare active using various forms of engagement.

Objectives: The aim of this project was to describe the development of a peer support and partnership group for patients and families living with lupus, healthcare professionals and charity.

Methods: Lupus Café was an idea generated from feedback in the lupus clinics at Great Ormond Street Hospital (GOSH).Young people and families reported that they were feeling isolated living with lupus. At the appointments we offer multidisciplinary advice, support and information but young people were clear that they also want to hear from other young people about their experience of living with lupus.

GOSH is a LUPUS UK Centre of Excellence and due to our large cohort of patients with lupus, we were ideally situated to facilitate this support in partnership with LUPUS UK and allow families and young people to meet each other.

Lupus Café started in 2021 as a virtual meeting for patients above the age of 10 years and the name was chosen to capture the informal nature of the meeting. We subsequently organised a face-to-face meeting and extended the invites to patients and families from other UK centres. In 2022, with support from PReS Lupus Working Party, we organised the first ever international event for children and families living with lupus. The meetings were facilitated by a team of lupus nurse, psychologist, doctor and charity representatives. Detailed feedback was collected at each meeting and the agenda of the meetings was developed based on the suggestions provided in the feedback forms.

Results: We have facilitated 4 patient and families group events between 2021-2023, of which 3 virtual (one with international patient and clinicians participation from 3 continents) and one face to face event with national participation. The feedback was positive and 93% participants indicated that they wish to attend further meetings and 7% that they will maybe attend. The patients indicated as the most positive aspects “meeting others with lupus and getting advice from each other”, “sharing experiences”, “having questions answered by professionals and other parents”, “a lot of useful information and resources”, “hearing about research”. Clinical teams’ feedback revealed that listening to patients’ and families’ lived experience of the disease and healthcare journeys identified areas for service improvement and also increased their awareness of research priority areas.

Conclusion: The patient support groups improve the quality of life of young people. In addition, patient and charities partners can transform the clinical development process and should be embedded in the care of patients with rheumatic disease. They are mutually beneficial, educational, and the unique perspectives provided by patients’ lived experiences can inform clinicians’ and researchers’ approaches.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: D. B. Pandya

Pediatric Rheumatology 2023, 21(Suppl 2):PT086

Introduction: Lupus nephritis (LN) is more common and aggressive in paediatrics compared to adults¹. There are several studies in adults showing better outcomes with various immunosuppressive combinations in LN². There is scarcity of such data in paediatric LN³.

Objectives: To compare the outcome of childhood-LN with different immunosuppressives in two tertiary Paediatric Rheumatology Centres, Sir Gangaram Hospital (SGRH) and Great Ormond Street Hospital for Children(GOSH) at 12-months follow-up.

Methods: This is a retrospective study including 101(SGRH=61, GOSH=40) children with biopsy proven class III-IV-V-LN, treated between January-2011 to December-2021. Renal outcomes were assessed using the CARRA definitions of substantial response, moderate response and renal flare⁴. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and dose of steroids at onset were calculated. Statistical analysis was performed by T tests and Chi Square static with yates' correction.

Results: Median age of onset was 12.6years in SGRH and 13 years in GOSH. M:F ratio was 1:2.8 in SGRH and 1:4 in GOSH. Average SLEDAI at onset was significantly higher in GOSH-24.5 compared to SGRH-17(p<0.05). Intravenous (IV) pulse glucocorticoids (GC) were given in 49/61(80%) and 31/40(78%) in SGRH & GOSH respectively. Average dose of IV GC was significantly higher in GOSH-28.5 vs SGRH-8.4 mg/kg/day(p<0.05). Average starting dose of oral steroids was higher in SGRH-1 vs GOSH-0.8mg/kg/day(p<0.05). For Induction(0-6months), SGRH patients received six doses IV cyclophosphamide (CYC, N=18/61), Mycophenolate mofetil (MMF,N=39/61) and Rituximab(RTX,N=4/61) while GOSH patients received RTX+MMF(N=19/40), RTX+ two doses CYC(N=8/40), RTX+Azathioprin(AZA,N=4/40) and MMF(N=9/40). For maintenance(6-12months), SGRH patients received MMF(N=38/61), MMF+Tacrolimus(N=14/61), RTX(N=6/61) and AZA(N=3/61) while GOSH patients received MMF(N=24/40), RTX(N=8/40) and AZA(N=8/40). Overall, there is no significant difference in substantial response (p 0.38), moderate response (p 0.77) and off GC (p 0.85) between the two centres. There is no significant difference between CYC vs RTX+MMF in substantial response (p 0.88), moderate response (p 0.64), renal flares (p 0.37) and being off GC (p0.79).Similarly, no significant difference between CYC vs RTX+CYC in substantial response (p 0.92), moderate response (p 0.38), renal flares (p 0.44) and being off GC (p 0.97).

Conclusion: LN outcomes are comparable between the two centres, despite the significant differences in disease severity, dose of GC and choice of immunosuppressives at onset. Larger multicentre studies are needed to look into long-term efficacy and safety of the different immunosuppressive agents in paediatric LN.

Patient Consent

Yes, I received consent

Disclosure of Interest

D. B. Pandya Grant / Research Support with: I have been awarded by Asia Pacific League of Associations for Rheumatology (APLAR) and PReS EMERGE grants to work as an International Fellow at Great Ormond Street Hospital , London, UK. This project is an integral part of this fellowship. , M. Aggarwal : None declared, M. Marlais: None declared, E. Moraitis: None declared, S. Sawhney: None declared, C. Papadopoulou: None declared, M. Al Obaidi: None declared

References

1. VAH Sato et al , Lupus 2012 Aug;21

2. Jin Deng et al , Turk J Med Sci 2018 Oct 31

3. Aeagon et al , Lupus 2016 Apr 25

4. Rina Mina et al , Arthritis Care Res 2013 March 1

Correspondence: S. Reddy

Pediatric Rheumatology 2023, 21(Suppl 2):PT087

Introduction: Assessment of capillary abnormalities in Juvenile Dermatomyositis (JDMS) may provide us a sensitive diagnostic and also a valid indicator of disease activity. However, association of NFC changes with myositis specific autoantibodies (MSA) and myositis damage index are not known.

Objectives: To study the NFC findings of JDMS and to correlate it with disease activity scores like Childhood myositis assessment scale (CMAS), Manual muscle testing-8 (MMT-8), Muscle disease activity score (MDAS), Skin disease activity score (SDAS) and Myositis Damage Index (MDI).

Methods: We enrolled 44 children with JDMS and 25 healthy controls. Of the 44 cases, 10 children were newly diagnosed with JDMS and NFC was done at presentation and 2 monthly for duration of 6 months. NFC was done during follow-up for the remaining 34 patients. We performed NFC using Digital Capillaroscope with OptiPix^TM Capillaroscopy and assessed quantitative parameters like length, width and inter-capillary distance and qualitatively for abnormal capillary morphology. MMT8, CMAS, MDAS, SDAS and MDI were assessed at each visit.

Results: Capillary tortuosity, oedema, enlarged loops and ramification was seen in 88.6%, 15.9%, 72.7% and 56.8% in cases as compared to 68%, 4%, 8% and 8% in controls. Other parameters like avascularity (81.6%), micro-bleeding (54.5%), giant capillaries (29.5%), bushy capillaries (40.9%) were seen in only in cases. Of the 10 children with JDMS enrolled for prospective follow-up, we noted significant improvement only in capillary density at 6 months duration (p=0.002). Of the MSA subgroups (10 NXP2, 7 TIF-gamma, 5 MDA5, 3 SAE-1, 3 Mi2-beta), we noted higher proportions of microbleeding in the TIF-gamma subgroup. Of the total 61 instances in which the NFC is performed, we noted that capillary density, microbleeding, and giant capillaries correlated with both skin and muscle disease activity measures. Bushy capillaries correlated only with skin disease activity (p=0.009). We also noted that avascularity index (p=0.025) and capillary density (p=0.025) correlated best with myositis damage index

Conclusion: Our study reiterates that capillaropathy plays a significant role in pathogenesis of JDMS. Only capillary density and avascularity corelated with disease damage score (MDI). Longitudinal follow-up revealed capillary density as a marker of improvement of disease activity

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: G. A. Robinson

Pediatric Rheumatology 2023, 21(Suppl 2):PT088

Introduction: Patients with juvenile-onset systemic lupus erythematosus (JSLE, onset <18 years) typically have more severe disease and relatively higher cardiovascular and mortality risk compared to adult-onset patients. This could be associated with more predominant type-I interferon (IFN) signalling.

Objectives: We investigated the heterogeneity of type-I IFN transcriptomic signatures in JSLE patients and their relationship with inflammatory pathways and co-morbidities using multi-omic analysis.

Methods: RNA sequencing (UCL Genomics) was used to assess differentially expressed genes (DEGs, p<0.01) in peripheral blood mononuclear cells (PBMCs) between JSLE patients with low disease activity (n=29, mean age=19, SLEDAI<4) and healthy controls (HCs, n=8, mean age=18). Data was analysed by gene ontology pathway enrichment and network analysis, hierarchical clustering, receiver operating characteristic (ROC) analysis, and comparison of normalised gene counts. Proteomics (Olink) and Metabolomics (Nightingale) assessed serum proteins and metabolites, respectively, associated with inflammation and cardiovascular disease.

Results: JSLE patients had significantly enriched type-I IFN signalling pathways compared to HCs (p<0.0001) associated with a vast network of pro-inflammatory pathways. IFN scores correlated positively with proteomic (such as ICAM1 and VCAM1) and metabolic (such as glycoprotein acetyls and the Apolipoprotein(Apo)B:A1 ratio) biomarkers known to reflect inflammation and cardiovascular disease risk. Interestingly, IL-10 signalling was the most significantly upregulated pathway in JSLE patients (vs HCs) independent from IFN-associated DEGs. Despite low disease activity, patients clustered into a high (H-IFN, 66%) and low (L-IFN, 34%) IFN signature group using normalised gene counts and validated by IFN score (p<0.0001). There was no difference in IFN score between the L-IFN group vs HCs (ROC: p=0.53, AUC=0.59), in contrast to a significantly higher IFN score in the H-IFN group vs HCs (ROC: p<0.0001, AUC=1.00). 281 DEGs were upregulated in the H-IFN (vs L-IFN) group, where the most enriched pathways (aside from IFN signalling) were cell cycle associated, with top contributing genes REC8 and PSME2. Finally, there was no significant difference in 5-year average SLEDAI or serological measures of disease between IFN groups, supporting the pro-inflammatory role of type-I IFN signatures independent of standard measures of disease activity.

Conclusion: JSLE patients can be stratified based on type-I IFN signatures associated with proinflammatory mechanisms, cardiovascular disease risk, and upregulated cell cycle pathways even in low disease activity states. This suggests that targeted biomarker patient stratification or therapeutic interventions may prevent long-term consequences of molecular dysregulation underlying low/moderate disease activity in JSLE.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: A. R. Torres-Jimenez

Pediatric Rheumatology 2023, 21(Suppl 2):PT089

Introduction: The antiphospholipid syndrome is not well defined in pediatric population and there are no validated criteria at this age. The criteria for adults are specific but lack sensitivity when applied to children, so the incorporation of non-criteria clinical manifestations is important in the pediatric population.The preliminary classification criteria for antiphospholipid syndrome were recently shown in ACR convergence 2022. Its usefulness in the pediatric population is not yet known.

Objectives: Describe the frequency of thrombotic and non-thrombotic clinical manifestations, laboratory and treatment in patients with pediatric primary antiphospholipid syndrome. To test the classification criteria recently shown in ACR convergence 2022 in the pediatric population.

Methods: A retrospective study was carried out in patients with a diagnosis of primary antiphospholipid antibody syndrome, under 16 years of age, under follow-up by the pediatric rheumatology service of the General Hospital, National Medical Center, La Raza, from January 2013 to April 2023. The antiphospholipid syndrome was defined when it met the laboratory criteria of the Sidney criteria and the presence of thrombosis or non-criteria manifestations of the disease (hematological, neurological, cutaneous, renal, cardiac or pulmonary). Demographic, clinical, laboratory, treatment, and prognosis data were collected. Patients were classified according to the preliminary antiphospholipid syndrome criteria presented at ACR convergence 2022 to determine their usefulness in pediatric population.

Results: We report 51 patients, 35 female (69%) and 16 male (31%), mean age 12.24 years, evolution time 19 weeks. Thrombosis 11 patients (22%), 3 arterial and 8 venous. Only thrombotic manifestations in 2 (4%), only non-thrombotic manifestations in 40 (78%) and both in 9 (18%). Non-thrombotic manifestations; Hematologic: thrombocytopenia 35 patients (69%), autoimmune hemolytic anemia 24 (47%), Fisher-Evans syndrome 14 (28%), lupus anticoagulant with hypoprothrombinemia syndrome 2 (4%). Dermatological: livedo reticularis 28 (55%), skin ulcers 3 (6%), Raynaud's phenomenon 11 (22%). Neurological: epilepsy 1 (2%), migraine 4 (8%), chorea 1 (2%) and cognitive impairment 3 (6%). Renal in 8 (16%). Laboratory: prolonged aPTT 47 (92%), lupus anticoagulant 51 (100%), positive IgG anticardiolipin 36 (71%), positive IgM anticardiolipin 31 (61%). AntiB2GPI was performed in only 7 patients, being positive in all. Treatment: anticoagulation in patients with thrombosis, antiplatelet in 41 (80%), steroid 47 (92%), immunosuppressant 46 (90%) and rituximab 6 (12%). According to the preliminary criteria of antiphospholipid syndrome presented at ACR convergence 2022, it was possible to classify 26 patients (51%) with primary antiphospholipid syndrome, with the Sydney criteria only 11 patients (22%). If other hematological manifestations are added, giving the same value as thrombocytopenia to hemolytic anemia, as well as 3 points to the combination of hemolytic anemia and thrombocytopenia or to the lupus anticoagulant with hypoprothrombinemia syndrome, 13 more patients were added, classifying a total of 39 patients as primary antiphospholipid syndrome (76%).

Conclusion: The clinical characteristics of patients with pediatric primary antiphospholipid syndrome differ from those presented in adults, since non-thrombotic manifestations are more frequent in children. The criteria recently shown in ACR Convergence 2022 improve the classification of pediatric patients with primary antiphospholipid syndrome, but they still fail to classify half of the patients, so it is suggested to add other hematological manifestations to these in order to improve their usefulness in pediatric population.

Trial registration identifying number: 1

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: I. Tsulukiya

Pediatric Rheumatology 2023, 21(Suppl 2):PT090

Introduction: Some patients with juvenile dermatomyositis (JDM) demonstrate incomplete responses to conventional therapy and some experience disease recurrences. Patients with JDM who are refractory to corticosteroids or other immunosuppressive medications, including biologics such as rituximab and abatacept, face poor outcome and suffer from various sequelae of the disease. Therefore, it is important to find new treatments for refractory JDM. Studies have reported that type I interferon pathways are upregulated in patients with dermatomyositis, and it has been reported that JAK-inhibitors (JAKi) can inhibit interferon signaling and showed an overall good efficacy for refractory dermatomyositis patients.

Objectives: To evaluate the efficacy and safety of JAK-inhibitors in children with refractory dermatomyositis.

Methods: This was a single-center retrospective study, including 17 (7—male, 10—female) children with refractory JDM. Refractory JDM was defined as patients who failed two or more steroid sparing agents, including biologic agents, or high-dose steroids. They were all treated using JAKi combined with steroids and other immunosuppressive agents. A mean age of JAK-inhibitors initiation was 8,4 years (range 2,1 –16,7 years).

Results: Seventeen refractory patients with JDM treated with tofacitinib (n = 9) or upadacitinib (n = 8) were included. Median of duration of disease prior to initiation JAKi was 8,2 (IQR 5,0 – 13,8) months. At the baseline, patients received CS (n = 17), methotrexate (MTX, n = 2), hydroxychloroquine (HCQ, n = 2), mycophenolate mofetil (MMF, n = 6), cyclosporine A (CsA, n = 2). 8 (47%) patients had received previous bDMARDs; 9 (53%) were bDMARD naïve. The main indications for treatment were refractory muscle involvement (n = 7) and skin rash (n = 10). The skin rash and muscle weakness improved in 14/17 (82%) patients within 3 months of JAKi introduction. All responders could decrease the dose of steroid. The mean daily steroid dose decreased from 1,3 mg/kg/d (range 0,35-2 mg/kg/d) to 0,4 (range, 0,3-0,8).

All patients responded well to JAK-inhibitors with significant improvement in clinical and inflammatory indices without occurrence of severe adverse events.

Conclusion: This study showed improvement of muscle strength, resolution of cutaneous lesions, increased daily quality of life and successful tapering of steroids when JAK-inhibitors used. Tofacitinib and upadacitinib can be considered when treating refractory JDM cases. Further randomized controlled trials are warranted to assess its efficacy in JDM.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: Ö. Akgün

Pediatric Rheumatology 2023, 21(Suppl 2):PT091

Introduction: Behçet's disease (BD) is a chronic and recurrent multisystem inflammatory disease that can involve vessels of all sizes and types, classified as variable vascular vasculitis. Recurrent oral and/or genital aphthae, uveitis, ocular findings, and skin lesions are the main symptoms of BD.

Objectives: It is aimed to collect international data on the safety and efficacy of biologic therapies in patients with resistant/severe pediatric BD.

Methods: This study was designed to be retrospective, observational, multicenter, and international. Patients who received biologic therapy and met the "International Criteria for Behçet's Disease" and/or "Pediatric Behçet's Disease" and were diagnosed with BD before the age of 18 were included in the cohort.

Results: In the preliminary report, 69 patients who met the criteria of the study from 13 centers were included in the cohort. The mean age of the patients was 16±4.5 years, and 31.9% (22) of them were female. Ocular, mucocutaneous, and neurologic involvement were the most common reasons for starting biologic therapy (52.2%, 18.8%, and 14.5%, respectively). Anti-TNF-alpha agents were preferred first-line biological therapy in 66 (95.6%) patients, and interferon and IL-6, and IL-1 blockers were preferred in three patients. The median time to achieve remission of 59 patients with remission data was 3 months (IQR:2-6). A biological switch was performed in 8 (11.5%) patients for various reasons. Four patients using infliximab as the first biologic agent were switched to adalimumab treatment for resistant uveitis. Adalimumab treatment was started in one patient who was diagnosed with uveitis while receiving etanercept treatment. Etanercept treatment was started in one patient who developed a hypersensitivity reaction during adalimumab treatment. When uveitis developed in a patient using anakinra, adalimumab was switched. One (1.4%) of patients in the cohort were in remission without the drug, 58 (84.1%) were in remission with the drug, and 6 (8.7%) were in partial remission. 4 (5.8%) patients were resistant despite biological therapy.

Conclusion: Biological drugs are increasingly used in the treatment of pediatric BD. We observed that tumor necrosis factor-alpha inhibitors are the most commonly preferred biological agents. These treatments had an acceptable safety profile and high remission rates.

Trial registration identifying number: Ethics committee number:1653276

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Jennette, J. C., Falk, R. J., Bacon, P. A., Basu, N., Cid, M. C., Ferrario, F., ... & Watts, R. A. (2013). 2012

   revised international chapel hill consensus conference nomenclature of vasculitides.

2. Koné-Paut, I. (2016). Behçet’s disease in children, an overview. Pediatric Rheumatology, 14(1), 1-8.

3. Davatchi, F. (2012). Diagnosis/classification criteria for Behcet's disease. Pathology research international, 2012.

4. Batu, E. D., Sönmez, H. E., Sözeri, B., Aviel, Y. B., Bilginer, Y., & Özen, S. (2017). Paediatric rheumatology The performance of different classification criteria in paediatric Behçet’s disease. Clin Exp Rheumatol, 35(108), S119-S123.

Correspondence: K. Arora

Pediatric Rheumatology 2023, 21(Suppl 2):PT092

Introduction: Kawasaki disease (KD) is an acute systemic vasculitis of childhood. Both innate and adaptive immune pathways are involved in pathogenesis. Inflammasomes are innate immune system receptors that regulate the activation of caspase-1 and induce inflammation. There is a paucity of information on the role of inflammasomes in KD

Objectives: To examine the expression of inflammasomes (NLRP3, NLRC4 and AIM2, NLRP1, NLRP12), caspase- 1, PYCARD, Interleukin- 18 and Interleukin-1β (IL-1β) in treatment naive (pre intravenous immunoglobulin) and post IVIg treatment in children with KD.

Methods: 20 patients with KD were enrolled in the study. Diagnosis of KD was based on American Heart Association 2017 criteria. All patients were treated with intravenous immunoglobulin (IVIg) and aspirin. Pre IVIg (n=20) and, 4-6 weeks after treatment, post IVIg (n=20) blood samples were collected. Expression of inflammasome (NLRP3, NLRC4, AIM2, NLRP12, NLRP1), caspase 1, IL-18 and IL-1β were assessed by real time PCR in patients with KD and compared with normal controls.

Results: Real time PCR analysis was performed in 20 patients with KD (20 in acute stage; 20 post IVIg) and compared with 20 controls. There was a significant increase in AIM2 expression in patients as compared to controls. There was also increase in IL-1β and IL-18 expression in pre IVIg patients as compared to post IVIg patients. Significant decrease in NLRP12 expression in pre IVIg patients as compared to post IVIg patients. Based on previous data and keeping NLRP3 as key molecule we also grouped patients based on NLRP3 expression. Group 1 patients had reduced NLRP3 in Pre IVIg condition as compared to post IVIg and controls. AIM2 expression was also increased in Group 1 patients. Group 2 patients had significantly increased NLRP3 expression as compared to post patients leading to increased IL-1β expression.

Conclusion: Increased expression of NLRP3, caspase 1, IL-18 and IL-1β in patients with acute KD suggests activation of inflammasome pathway in pathogenesis of KD. Previous studies (Wang et.al) showed increase in AIM2 in serum of KD patients. There was found to be increase in AIM2 in our set of patients. Blocking of this pathway may provide another therapeutic target for KD.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Wang Z, Wang Q, Jin J, Rong X, Wu T, Qiu H, Wu R. The diagnostic role of AIM2 in Kawasaki disease. Clin Exp Med. 2021 Feb;21(1):41-47.

Correspondence: J. N. Bathia

Pediatric Rheumatology 2023, 21(Suppl 2):PT093

Introduction: Various risk scoring systems have been developed to predict Intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD), however, they have not been found to be useful in other ethnicities.

Objectives: The aim of the study is to produce a set of cutoff values for the parameters that would best predict IVIG resistance in Kawasaki Disease in the Indian cohort of patients.

Methods: The analysis involves predicting the IVIG resistance label of patients for different cutoff values of the parameters and calculating the accuracy of the predictions based on the ground truth labels.

The analysis tried to keep the basic framework of the 3 Japanese scoring methods in the new method proposed.

Dataset was divided into training and test datasets, with the training dataset having more data, and being used to produce the scoring mechanism, and testing dataset being used to compare accuracy of proposed new model to the established methods. The training dataset comprised of 70 patients, 22 being IVIG resistant. The testing dataset had 45,15 were IVIG resistant. Both datasets combined is called Full dataset. For each predictor used in all of the scoring methods, a list of possible points to be tested for being the potential new cutoffs in the scoring mechanism were generated.4 different scoring mechanisms were tested:

• Scoring based on original Kobayashi, where the cutoff (=/>5), all the original Kobayashi predictors (but new cutoff value predicted for each), and the greater/lower than signage corresponding to each predictor was re-used.

• On Sano and Egami, in a similar way.

• A new scoring method, using a structure similar to the established scoring methods, but selecting predictors based on Logistic Regression and testing different values of the cutoff for best performer.

For each mechanism, the corresponding predictors and their list of values on which to test them were used to generate a grid.

For each proposed mechanism, the set of predicted labels for IVIG Resistance was calculated iteratively for each set of points on the grid, and the sensitivity and specificity were calculated. The set of values of the predictors that resulted in the best prediction accuracy were noted.To allow the proposed cutoff values of predictors in the scoring mechanism to generalize well to unseen future data, a K-fold cross validation (with K=5) approach was used. The choice of predictor values that give the highest mean accuracy is chosen as optimal for the problem. This allows the proposed scoring mechanism to have high accuracy.For comparison purposes, on test dataset the original Kobayashi values performed as follows: On test dataset: Sensitivity= 0.66, Specificity=0.5 On full dataset: Sensitivity=0.75 Specificity=0.56

Results: The above analysis was done for all 4 of the proposed scoring mechanisms; the Kobayashi based approach produced best results. Using the same variables used in Kobayashi, and running an analysis on the training dataset, we came up with the following new values of the variables:

Sodium=133, fever=4 days, AST=100, Neutrophils=84%, CRP=17 mg/dl, age=21months, platelet=6 lacs.

The signs are what was used in the original Kobayashi study for each of the variables (eg. for Sodium it was <=). We had the following results on datasets: On test dataset: Sensitivity=0.8 , Specificity=0.43 On full dataset: Sensitivity= 0.9, Specificity=0.52

Conclusion: The proposed values can be seen to have better sensitivity than the original values on the dataset, and thus will act as a better guide for screening patients for possible IVIG resistance.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: E. Fedorov

Pediatric Rheumatology 2023, 21(Suppl 2):PT094

Introduction: The leading component in the pathogenesis of autoinflammatory diseases is, which includes systemic juvenile arthritis (sJA), an increase in interleukin 1ß.At the same time, cytokines form an interdependent network and an increase in one of the pro-inflammatory cytokines leads to hyperproduction of other pro-inflammatory cytokines. One of the important cytokines is the tumor necrosis factor(TNF). The determination of the levels of its soluble receptors in the blood allows us to indirectly assess the overexpression of TNF.

Objectives: to evaluate the levels of sTNF-RI and sTNF-RII in the blood sera of patients with sJA and monogenic autoinflammatory diseses(mAIDs) and their correlation with serum levels of commonly accepted markers of inflammation (C-reactive protein, Serum Amyloid A, Ferritin)

Methods: 114 patients were included in the study, 43 of them with sJA(38%): male/female 20/23; age of inclusion in the study 3-19 years, FMF 33 (29%) patients; male/female 15/18; age 3-37 years, CAPS 23(20%)patients; male/female 15/8; age 1-51 years,, TRAPS 15(13%)patients; male/female 8/7, age 4-51 years. The control group consisted of 5 children and adolescents with orthopedic pathology (scoliosis, pes planus) The diagnosis in all patients with mAIDs was confirmed by the detection of pathogenic alleles of the corresponding genes. sTNF-RI and sTNF-RII were determined in blood serum by ELISA using Invitrogen kits (Bender MedSystems GmbH, Austria): Normal values of sTNF-RI 1.47-4.16 ng/ml, sTNF-RII 3.4-10.8 ng/ml. CRP and SAA were determined by nephelometric method using Siemens reagents on the BN ProSpec Siemens analyzer, Germany. Ferritin was determined by the ELISA method using kits manufactured by Orgentec Diagnostika GmbH, Germany. Statistical processing was performed using the SPSS program. The reliability of the differences between the groups was assessed by the Kruskal-Wallis test. Correlation was estimated by Spearman Rank Order Correlations.

Results: The levels of sTNF-RI Me[Q1; Q3] in patients with sJA were 2.43ng/ml [1.95; 3.43], in patients with FMF 2.47 ng/ml [1.89; 2.71], CAPS - 2.24ng/ml [1.84; 2.93], TRAPS - 1.6 ng/ml [1.06; 3.11]. In the control group 1.63 ng/ml [1.38; 1.65]. According to the Kruskal-Wallis criterion, the differences in values between here and the control group (p=0,04), TRAPS and sJA (p=0,01) were statistically significant.

The levels of sTNF-RII Me[Q1, Q3] in patients with sJA were 7.15 ng/ml [3,28; 23,2], in patients with FMF 28,82 ng/ml [3,98; 82,2], CAPS - 8.55 ng/ml [4.32, 110.0], TRAPS - 26.81 ng/ml [8.72, 110.0]. In the control group 0,577ng/ml [0,46; 1,05]. According to the Kruskal-Wallis criterion, the differences in values between CAPS and the control group (p=0,04), TRAPS and the control group (p=0.004), FMF and the control group (p=0,007) were statistically significant.

In patients with sJA, there was a statistically significant (p<0.05) correlation of the level of sTNF-RI with CRP (r=0.73), with SA (r=0.64) and ferritin (r=0.66). In patients with CAPS, there was a statistically significant (p<0.05) correlation of the level of sTNF-RI with CRP(r=0.52), with SATA (r=0.51) and ferritin (0.45). A statistically significant negative correlation (r=- 0.8) was found between the level of sTNF-RII and CRP in patients with TRAPS.

Conclusion: the maximum concentrations of sTNF-RI were found in patients with sJA and FMF, the minimum in patients with TRAPS. The maximum serum concentrations of sTNF-RII were detected in patients with FMF and TRAPS, the minimum in patients with sJA. Statistically significant positive correlations of sTNF-RI concentration with generally accepted laboratory markers of inflammatory activity (CRP, SAA, ferritin) were found in patients with sJA and CAPS. In patients with TRAPS, a significant negative correlation was found between the concentrations of sTNF-RII and CRP. These data may indicate a different role of TNF in different AIDs

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: C. Foley

Pediatric Rheumatology 2023, 21(Suppl 2):PT095

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder, driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first line treatment.

Objectives: To describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course of patients with sJIA.

To identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not.

Methods: We used electronic institutional clinical record coding to identify all patients with a diagnosis of sJIA seen at GOSH over a 16-year period. Using the search terms sJIA, Still’s disease, systemic onset JCR (juvenile chronic arthritis) and AOSD, we identified patients diagnosed with sJIA, between 2^nd October 2005 – 21^st October 2021 inclusive. Medical notes were reviewed retrospectively. All patients with a final diagnosis of sJIA made by a consultant paediatric rheumatologist were included.

Patient demographics including age at diagnosis and sex were recorded. Symptoms and signs present at diagnosis informing the ILAR sJIA classification criteria were documented. Data on the active joint count, presence of early morning stiffness, presence of uveitis as defined by the standardisation of uveitis nomenclature working group, physician’s global assessment (PGA) of overall disease activity on a visual analogue scale 0 – 100 mm (0 = no activity; 100mm = maximum activity), erythrocyte sedimentation rate (ESR, mm/hour) and C-reactive protein (CRP, mg/litre) were also captured.

Time-points for data collection were: at diagnosis, 3-months post diagnosis, 1-year post diagnosis and last review. Clinical and laboratory data as outlined above were recorded for each time-point.

Clinically inactive disease (CID) was defined using the modified Wallace Criteria

Complications of particular interest were captured. These were frequency of macrophage activation syndrome (MAS), sJIA-associated lung disease (sJIA-LD), requirement for haematopoietic stem cell transplantation (HSCT), and deaths.

Descriptive statistics were reported as median and range or inter-quartile range (IQR) for continuous variables, and as absolute frequencies and percentages for categorical variables unless otherwise specified. Comparisons of quantitative variables between two groups were made by Mann-Whitney U test. Categorical data were compared using Fisher’s exact test. All statistical tests were 2-tailed; p values <0.05 were considered significant.

Results: A total of 76-children (female n=40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6–14.1); 36% (27/76) presented with suspected or confirmed MAS. A biologic disease modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n=21/76) of the cohort; however, at last review, 84% (n=64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n=67/76) of the cohort at last review, however only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3-months of diagnosis compared to those who did not (90% versus 53%, p=0.002).

Conclusion: Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARD. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: M. Held

Pediatric Rheumatology 2023, 21(Suppl 2):PT096

Introduction: Non-HLA gene variants may play an important role in the pathogenesis of IgA vasculitis (IgAV). Glutathione S-transferases (GSTs) are metabolic enzymes involved in cellular detoxification processes of potentially toxic and carcinogenic compounds. Deletions in GST reduce detoxification activity, and thus increase susceptibility to various diseases.

Objectives: To investigate the influence of gene polymorphisms GSTA1, GSTM1, GSTP1 and GSTT1 on IgAV susceptibility and clinical heterogeneity of the disease.

Methods: Clinical data were collected from database of IgAV patients from three Croatian centers for pediatric rheumatology. The Flexigene DNA set (Qiagen) was used to isolate DNA from whole blood. The presence of GSTM1 and GSTT1 polymorphisms was determined by polymerase chain reaction in patients and controls, while GSTA1 and GSTP1 genotyping was performed using the PCR-RFLP method (eng. Polymerase Chain Reaction – Restriction Fragment Length Polymorphism).

Results: The study enrolled 124 IgAV patients (67 girls and 57 boys) with median age at the time of diagnosis 6.3 (4.3-8.2) years and 168 age- and sex-matched controls without any history of autoimmune diseases. All patients had purpuric rash, 85.5% had joint involvement, 36.3% had gastrointestinal (GI) manifestations, while 29.8% developed nephritis. A statistically significant difference between patients and controls was observed in genotypes GSTP1 Ile/Ile (48.33% vs. 22.62%, p<0,001) and Leu/Ile (4.17% vs. 28.57%, p<0,001). A higher frequency of null GSTM1 genotype was observed in IgAV patients with GI system involvement in comparison to patients without GI system involvement (52.2% vs. 28.6%, p=0.014). The GSTP1 Val/Val genotype appeared significantly more often in patients who developed urological complications (acute scrotum) within disease course (60% vs. 40%, p=0,037).

Conclusion: The studied GSTP1 polymorphisms showed a possible association with a higher individual susceptibility to IgAV. GSTM1 genotype variants seem to be involved in the pathogenesis of GI manifestations of disease.

SUPPORT: Croatian Science Foundation Project IP-2019-04-8822.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: M. Kasap Cuceoglu

Pediatric Rheumatology 2023, 21(Suppl 2):PT097

Introduction: Takayasu arteritis (TA) is a chronic, inflammatory, granulomatous vasculitis that commonly affects the aorta and its major branches.¹ Diagnosis is difficult due to nonspecific symptoms at onset. Effective treatment is essential due to the high morbidity and mortality rates in follow-up.

Objectives: We aimed to identify demographic, clinical characteristics, and outcomes of pediatric TAK in a national cohort.

Methods: We conducted a multicenter retrospective cohort study in Turkey. The clinical data were collected from patients’ charts in six rheumatology centers. Patients who were diagnosed with TAK before 18 years of age were included in the study. All patients met the Ankara 2008 classification criteria.² ITAS 2010 score was used to evaluate disease activity.³

Results: Overall, 43 pediatric TAK (p-TAK) patients were included (86% female). The median age of symptom onset was 13.2 (1-14.4) years, with a diagnostic delay of 5 (1-57) months, and a median follow-up time of 42 (6-146) months. The most common symptoms at presentation were neck, back, or abdominal pain (n=17,39.5%), fever (n=11,25.5%), and hypertension (n=7,16.2%). 39 patients had elevated acute phase reactants. The most common angiographic type at diagnosis was type IIa (13/43) and the least frequent types were IV (n=4) and IIb (n=1). Median ITAS2010 was 12 (6-18) and 3 (0-12) at admission and at last control, respectively. At the last visit, ITAS 2010 was <3 in 13 patients.Treatment included corticosteroids (n=43,100%), conventional (n=28,65.1%) and biological disease-modifying anti-rheumatic drugs (n=35, 81.5%), and other immunosuppressive therapies (cyclophosphamide (n=19,44.1%)). The median duration of corticosteroid use was 31 (6-96) months. Antihypertensive and anticoagulant drugs were used by 27 and 23 patients, respectively.There was a switch between biologic drugs in 17 patients. The first biologic drugs were tocilizumab (n=16), adalimumab (n=10), and infliximab (n=7), and the median time for the first biological drug use was 18 (2-70) months. The most frequent second biologic drugs were tocilizumab (n=8) and adalimumab (n=6). The median duration of use was 24 (1-72) months. Surgical procedures were required in nine patients with severe disease refractory to medications. In follow-up angiographic imaging, there was deterioration in 14 patients, improvement in 7, and stable findings in 21 patients. 24 (55.8) patients had refractory disease. Only, 4 patients had drug-free remission. Two patients died.

Conclusion: Despite aggressive immunosuppressive therapy and use of biologic agents, complete disease control was achieved in a small portion of p-TAK patients.

Patient Consent

Yes, I received consent

References

1. Jennette JC, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. Jan 2013;65(1):1-11.

2. Ozen S. et. 2010. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis.;69(5):798-806.

3. Misra R. et al. 2013. Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010). Rheumatology (Oxford).52(10):1795-801.

Correspondence: C. Matucci-Cerinic

Pediatric Rheumatology 2023, 21(Suppl 2):PT098

Introduction: Behçet’s disease (BD) is an autoinflammatory disease characterized by a variable vessel vasculitis. In the past, several criteria have been created for adult BD classification. In 2015, the first PEDiatric Behçet’s Disease classification criteria, the PEDBD, were proposed by an international Expert consensus (1).

Objectives: to perform a validation of the PEDBD classification criteria in a cohort of internationally validated pediatric BD, through an international Expert-based consensus process.

Methods: 210 patients (70BD, 40 PFAPA, 35 FMF, 26 MKD, 22 TRAPS, 17 Undefined/SURF) were randomly selected from the Eurofever Registry. A set of 11 Experts evaluated the patients to assign a diagnosis: in the 1^st round, clinical and serological data were evaluated; in the 2^nd round genetic data were added; in the 3^rd round the other Experts’ votes and comments were shown. Using the expert consensus as gold standard (agreement>80%), the PEDBD, the ISG and the ICBD criteria were then applied to BD patients and to the confounding diseases in order to define their sensitivity, specificity and accuracy.

Results: An Expert agreement was found for 66.2% of patients. BD patients with an agreement (24) were considered as “confirmed-BD”, and those with a partial agreement (60-70%) as probable-BD (10). When comparing confirmed-BD patients with the confounding diseases, the presence of an older age at disease onset, oral ulcers (100%), genital ulcers (77%), skin manifestations (50%), a positive pathergy reaction (39%), posterior uveitis (27%), cranic nerve palsy (17%), retinal vasculitis and papillary oedema (8%), venous thrombosis (8%) and anal/perianal ulcers (8%) resulted BD distinctive elements. Fever was present in 50% of patients. HLA-B51 was positive in 69% of patients.

The ISG, ICBD and PEDBD criteria were applied to confirmed and probable-BD, and to the confounding disease group, showing a sensitivity of 0.50, 0.79 and 0.58, a specificity of 1.00, 0.97, 0.99, and an accuracy of 0.91, 0.94 and 0.92, respectively.

Conclusion: the PEDBD were extremely specific in classifying BD patients, while the ICBD had a better sensitivity, especially for patients with only bipolar aphtosis. One limitation is that specific monogenetic BS mimics were not included as disease controls, thus the true accuracy of all these criteria may be lower in practice. The complexity of childhood BD suggests larger prospective international cohorts to foster the performance of the criteria, and to understand if BD clusters and ethnic variables should be added to the criteria.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Koné-Paut I et al. Consensus classification criteria for paediatric Behçet's disease from a prospective observational cohort: PEDBD. Ann Rheum Dis. (2016) 75:958–64.

Correspondence: U. Meinzer

Pediatric Rheumatology 2023, 21(Suppl 2):PT099

Introduction: Kawasaki disease (KD) is an acute, febrile, systemic vasculitis of children that primarily affects medium-sized blood vessels with a tropism for the coronary arteries. Although the etiological factors remain unknown, infections have been suggested as the trigger of KD. Using correlation analysis, a recent study showed that in South Korea, outbreaks of several viral infections precede KD outbreaks. Studies on the temporal association between seasonal infections and KD in the epidemiological context outside of Asia are currently lacking, and data to assess the fraction of KD potentially attributable to seasonal infections are not available.

Objectives: We sought to calculate the fraction of KD potentially attributable to seasonal infections.

Methods: This cohort study used a population-based time series analysis from the French hospitalization database. We included all children aged 0 to 17 years hospitalized for KD in France over 13 years. The monthly incidence of KD per 10,000 children over time was analyzed by a quasi-Poisson regression model. The circulation of eight common seasonal pathogens over the same period was included in the model to analyze the fraction of KD potentially attributable to each pathogen.

Results: From January 1, 2007, to December 31, 2019, we included 10,337 children with KD and 442,762 children with the selected infectious diseases. In the KD cohort, the median age [IQR] was 2 [0-4] years, 6164 [59.6%] were boys. Adenovirus infection was potentially responsible for 24.4% [21.5-27.8] (p<0.001) of KD, Norovirus for 6.7% [1.3-11.2] (p=0.002), and RSV 4.6% [1.2-7.8] (p=0.022). Sensitivity analyses found similar results. Subgroup analyses revealed that these significant associations prevailed among children younger than 5 years.

Conclusion: This cohort study of data from a comprehensive national hospitalization database indicated that approximately 35% of KD was potentially attributable to seasonal infections.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: G. Nardini

Pediatric Rheumatology 2023, 21(Suppl 2):PT100

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a rare inflammatory disease of unknown etiology. Several uncontrolled studies showed that early treatment with anakinra is associated with a better outcome, according to the “window of opportunity” hypothesis. However, very limited scientific evidence is available on withdrawal strategy. So far, anakinra withdrawal modalities are heterogeneous among the different rheumatology centres.

Objectives: The aim of this study was to identify predictive factors of disease flare, as suggestive of persistent course of the disease, after anakinra discontinuation, in patients with systemic juvenile idiopathic arthritis (sJIA) who reached clinical inactive disease (CID) off glucocorticoids (GCs).

Methods: We retrospectively analyzed data of 39 consecutive sJIA patients followed in our center who withdrew anakinra after achieving CID off GCs for at least 6 months. All patients underwent a 24-month follow-up after discontinuation. They were subsequently divided into two groups based to the presence or the absence of disease flare during the follow-up. Demographic, clinical and laboratory data of the patients were evaluated in univariate and multivariate analysis as predictors of flare.

Results: Ten out of 39 patients (25.6%) flared after a median time of 7.9 months from anakinra discontinuation. In univariate analysis, disease duration ≥ 3 months at anakinra initiation (p=0.001), anakinra dose < 2 mg/kg/day (p=0.065) and abrupt withdrawal instead of tapering of anakinra (p=0.016) were associated with occurrence of flare after discontinuation. In the multivariate analysis, disease duration ≥ 3 months at baseline was the only variable significantly associated with flare after anakinra discontinuation (Odds Ratio 15.16, CI 95% 1.7-131.9; p = 0.014).

Conclusion: Our data show that early treatment with anakinra (3 months) is associated with lower risk of flare following discontinuation suggesting that early treatment may prevent development of a chronic persistent sJIA course.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

G. Nardini: None declared, D. Pires Marafon: None declared, C. Bracaglia Consultant with: Sobi, Novartis, E. Sacco: None declared, A. De Matteis: None declared, I. Caiello: None declared, G. Prencipe: None declared, F. De Benedetti Grant / Research Support with: Sobi, Abbvie, Novimmune, Novartis, Roche, Sanofi, Pfizer, Consultant with: Sobi, Novartis, M. Pardeo Consultant with: Sobi

References

1. Nigrovic PA. Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol 2014; 66:1405-13.

2. Pardeo M, Rossi MN, Pires Marafon D, Sacco E, Bracaglia C, Passarelli C, et al. Early Treatment and IL1RN Single-Nucleotide Polymorphisms Affect Response to Anakinra in Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol 2021; 73:1053-1061.

Correspondence: A. Albayrak

Pediatric Rheumatology 2023, 21(Suppl 2):PT101

Introduction: Juvenile Idiopathic Arthritis (JIA) is the most common childhood rheumatic disease and is characterized by joint swelling, pain, stiffness, muscle weakness and muscle atrophy. In children and adolescents with JIA, participation in physical activity plays an important role in managing functional, structural, and activity-related limitations caused by the disease (1). Despite this, it has been reported that patients with JIA cannot be able to reach the recommended level of physical activity, and lack of motivation is thought to be one of the main obstacles to participation in physical activity (2,3).

Objectives: The aim of this study was to compare the physical activity level and motivation for physical activity participation of JIA patients with their healthy peers.

Methods: Twenty-two patients (11 girls, 11 boys) diagnosed with JIA and 21 healthy peers (14 girls, 7 boys) aged 11-18 years were included in the study. The physical activity level of children and adolescents was evaluated with the Physical Activity Question Form and Physical Activity Questionnaire for Adolescents, and the motivation to participate in physical activity was evaluated with the Physical Activity Motivation Scale. SPSS Version 24.0 program was used for statistical analysis.

Results: The mean ages of patients with JIA and their healthy peers were 14.32±2.16 and 13.90±0.76 years, respectively. In the comparison between the groups, In patients with JIA, the physical activity level and motivation to participate in physical activity were statistically significantly lower compared to their healthy peers (p<0.05). In addition, 81.8% of the patients with JIA had "insufficient" physical activity levels.

Conclusion: Compared to their healthy peers, patients with JIA were found to have lower physical activity levels and motivation to physical activity participation. In patients with JIA, we believe that when evaluating participation in physical activity, motivational factors should be evaluated comprehensively and motivational facilitators should be taken into account when planning a physical activity program.

This study was supported within the scope of the Scientific and Technological Research Council of Turkey (TUBITAK) 1001-Scientific and Technological Research Projects Support Program (Project number: 121E690).

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

References

1. Kuntze, G., Nesbitt, C., Whittaker, J. L., Nettel-Aguirre, A., Toomey, C., Esau, S. et al. Exercise therapy in juvenile idiopathic arthritis: a systematic review and meta-analysis. Archives of Physical Medicine and Rehabilitation, 2018;99(1):178-193.

2. Lelieveld, O. T., Armbrust, W., Van Leeuwen, M. A., Duppen, N., Geertzen, J. H., Sauer, P. J. et al. Physical activity in adolescents with juvenile idiopathic arthritis. Arthritis Care & Research: Official Journal of the American College of Rheumatology, 2008;59(10):1379-1384.

3. Nørgaard, M., & Herlin, T. Specific sports habits, Leisure-Time physical activity, and School-Educational physical activity in children with juvenile idiopathic arthritis: Patterns and barriers. Arthritis Care & Research, 2019;71(2):271-280.

Correspondence: Z. Balik

Pediatric Rheumatology 2023, 21(Suppl 2):PT102

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic idiopathic inflammatory arthritis of childhood, and it often persists in adulthood. Disease exacerbations, joint damage, and extra-articular manifestations may lead to morbidities. A well-prepared transition to adult rheumatology is crucial to improve the ongoing care and well-being of patients.

Objectives: The aim of this study is to review the clinical findings, treatments, and follow-up processes of JIA patients who were transferred to adult rheumatology.

Methods: The medical records of the JIA patients transferred from the Department of Pediatric Rheumatology to the Department of Adult Rheumatology between January 2015 and May 2022 were retrospectively reviewed.

Results: A total of 107 patients (45 girls, 62 boys) were included in the study (Table 1). The most common diagnosis was enthesitis-related arthritis, followed by oligoarticular JIA. Comorbidity was present in 38 (35.5%) patients. The most common comorbidity was familial Mediterranean fever (n=17, 15.9%) followed by inflammatory bowel disease (n=3, 2.8%) and scoliosis (n=3, 2.8%). One hundred (93.5%) patients had peripheral and 60 (56.1%) patients had axial symptoms. Twenty-eight (26%) patients had extra-articular findings. In adult rheumatology, 46 (43%) patients were followed without any complaints. Thirty-four (31.8%) patients had axial and 39 (36.4%) patients had peripheral symptoms. Extra-articular findings were observed in 10 (9.3%) patients. In the pediatric rheumatology department, all patients received non-steroidal anti-inflammatory drugs (NSAIDs) as first-line therapy (Table 2). The most frequently used disease-modifying anti-rheumatic drug (DMARD) was methotrexate. Biological drugs were given to 72 (67.3%) patients. During the transfer, 53 (49.5%) patients were on biological drugs, 9 (8.4%) conventional DMARD, and two (1.9%) patients were on both. Forty-three (40.2%) patients were transferred without medication. In adult rheumatology, 31 (29.9%) patients were followed without medication. NSAIDs were used in 40 (37.4%) patients. The most frequently used DMARD was methotrexate. Biological drugs were prescribed to 57 (53.3%) patients. In adult rheumatology, 27 patients who were transferred without taking any medication did not require it. But 16 of them were needed for drugs. Seven of 16 patients required biologics. In the last appointment, 55 (51.4%) patients were using biological drugs.

Conclusion: In adult rheumatology, more than half of JIA patients had recurrent complaints. And at the last control, half of the transferred patients still required biological drugs. Thus, an uninterrupted follow-up is vital for the JIA patients transferred to adult rheumatology. Knowing the distinct phenotypes and managing the transition without interruption will contribute to the improvement of JIA prognosis.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Reference

1. Debrach AC, Rougelot A, Beaumel A, Cabrera N, Belot A, Duquesne A, et al. Comparison of paediatric and adult classification criteria in juvenile idiopathic arthritis during the transition from paediatric to adult care. Joint Bone Spine. 2021;88(1):105047.

Correspondence: R. P. Beesley

Pediatric Rheumatology 2023, 21(Suppl 2):PT103

Introduction: Low awareness that Children and Young People (CYP) may develop arthritis (Juvenile Idiopathic Arthritis, JIA) has been identified as a risk factor for delayed diagnosis and worse clinical outcomes. The level of community awareness in the UK has not previously been reported in scientific literature.

Objectives: To measure awareness that CYP may develop arthritis, providing a baseline against which to monitor improvements.

Methods: Ipsos UK, on behalf of UK charity Juvenile Arthritis Research, conducted an online survey about awareness of childhood arthritis among a representative quota sample of adults aged 16-75. Fieldwork was between 10-13 February 2023. Data were weighted to the known population proportions for adults aged 16-75 in the UK. This work was carried out in accordance with the requirements of the international quality standard for market research, the MRS Code of conduct, ISO 20252, and participants gave informed consent prior to taking part.

Results: A total of 2044 adults aged 16-75 in the UK completed the survey online. When asked about the earliest age ranges someone could get arthritis, overall 40% indicated age ranges under the age of 16. This was higher amongst female respondents (47% vs 33% of males), older respondents (52% of those aged 45-75 vs 29% of those aged 16-44), and those from a White ethnic group (43%, compared to 23% among ethnic minority groups). Respondents were more likely to be aware the earliest someone could get arthritis is under the age of 16 if they had arthritis themselves (60%) or knew someone with arthritis (43%). However, only 19% of respondents were aware that children under the age of 5 can get arthritis.

Overall, 29% of respondents were aware that some types of arthritis can affect your eyesight; awareness of this extra-articular complication was also higher amongst those with arthritis (34%).

A total of 18% of respondents reported having arthritis themselves, and 55% claimed to know an adult with arthritis. In contrast, only 3% claimed to know of a child aged 15 or under with arthritis, although this was higher amongst parents of children aged 17 or under living in their household (7%).

Significant differences between ethnic groups were identified, with respondents from ethnic minority groups less likely to be aware the earliest that someone could get arthritis is under the age of 16 (23%, compared to 43% of those from White ethnic groups). Respondents from ethnic minority groups were also more likely to believe incorrect assumptions about arthritis to be true – such as ‘arthritis can be cured’ (25% compared to 6% of those from White ethnic groups), ‘blood tests can always confirm a diagnosis of arthritis (38% compared to 24% of those from white ethnic groups), and ‘X-rays can always confirm a diagnosis of arthritis’ (44% compared to 30% of those from white ethnic groups).

Conclusion: Awareness that children and young people under the age of 16 can get arthritis is low amongst the general population. Low awareness can lead to delays in diagnosis. Increasing awareness is therefore vital, and the #ThinkJIA campaign, school-based toolkits, and community-led initiatives developed by Juvenile Arthritis Research can be used to increase awareness of JIA. Targeted resources to increase awareness amongst ethnic minority groups should be considered. Ongoing review and monitoring, using these 2023 data as a baseline will be important to assess the efficacy of future awareness activities.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: M. M. Delliou

Pediatric Rheumatology 2023, 21(Suppl 2):PT104

Introduction: Previous data on Juvenile Idiopathic Arthritis (JIA) -the predominant type of Juvenile Rheumatic Diseases- report that this chronic disease affects both patient and family life. Relevant Greek data focusing on the family perspective are limited.

Objectives: To investigate the experience of parenting a child diagnosed with JIA, the interplay between JIA, family relations and everyday life, and coping behaviors regarding potential life changes.

Methods: This is a qualitative research study based on semi-structured in-depth interviews with parents of an offspring with JIA. The interview domains were: a. the experience of JIA diagnosis over time, b. the relationship between parents, the JIA patient and siblings, c. the impact of JIA on everyday life, d. their coping mechanisms. Interviews were transcribed, coded and analyzed anonymously in compliance with ethics research guidelines and following the principles of the interpretative phenomenological analysis.

Results: Nine parents (M:F, 3:6) aged 39-51 years (mean= 47), were included in the study. Their educational level differed: 3/9 had a high-school diploma, 5/9 a Bachelor’s degree and 1/9 a Master’s one. Interviews lasted 25 to 60 minutes. Our findings show that JIA led to the creation of strong bonds between parents, siblings, and the patient (9/9). JIA created confusion within families in early stages of the disease and frequently raised disagreements on issues related to medication (4/9). The parental focus on JIA minors occasionally fired jealousy of the healthy siblings (3/9). Additionally, JIA altered the family members’ daily life by shifting their focus on disease management (9/9) and frequently forced affected minors to modify their activities (4/9). The upcoming stress led parents to various coping mechanisms (9/9). 3/9 parents sought reliable information from Health Professionals, 6/9 shared their experience with other JIA affected families and 7/9 searched psychological support. Alternatively, 2/9 found intrafamilial discussions equally effective. 2/9 parents tried to maintain a positive attitude towards minor daily issues and disease management by developing easily understood and less frightening ways to present JIA impact to their minors. Impressively, 5/9 reported that JIA eventually had a positive impact by teaching the family to re-evaluate and re-prioritize problems and to appreciate moments of happiness. Finally, parents presented minors with JIA as fighters who developed discipline, empathy and diversity acceptance (4/9).

Conclusion: JIA post-diagnosis presents a challenge for parents introducing changes in relations and everyday life. However, most families gradually adjusted and accepted JIA acknowledging some beneficial effects. These findings can assist Health Professionals in supporting families with JIA and parents to develop constructive scenarios for the co-living with the chronic disease.

Patient Consent

Yes, I received consent

Disclosure of Interest

None declared

Correspondence: S. Francis

Pediatric Rheumatology 2023, 21(Suppl 2):PT105

Introduction: In recent years, there has been a shift of focus in health, from illness to well-being. How we feel physically and mentally is one of the most important factors for our overall wellbeing and how we can manage and deal with diagnosis and changes in health makes a difference. A gardening group was piloted for children and young people attending a 2-week rheumatology rehabilitation programme. The aim of the group was to promote physical and mental wellbeing for children with a chronic rheumatological condition. Gardening is an activity which can be graded and adapted based on the child or young person’s abilities. It can be done seated or standing, using fine, gross motor and cognitive skills. It is also a sustainable activity.

Objectives: - Recent well-being research suggests that building the following 5 actions into our day to day lives is important for wellbeing: connect, be active, take notice, keep learning, giving. Gardening is an activity which encompasses all of these.

- Better physical health through exercise and learning how to use or strengthen muscles to improve mobility and upper limb strength.

- Improved mental health through a sense of purpose and achievement. Reduction of stress and anxiety.

- The opportunity to connect with others, reducing feelings of isolation or exclusion.

- Acquiring new skills and learning about growing food and nature.

- Just feeling better for being outside, connecting to nature, reducing time in hospital accommodation and time on electronic devices.

Methods: The pilot group ran over a 13-week period, located at a local community garden next to the hospital, for 90 minutes/session. It was facilitated by 2 occupational therapists/student and the head gardener. Activities varied depending on the season, sowing seeds, pricking out, watering, sweeping leaves, seed bombs, arts and craft related activities. The practice of self-management strategies related to rheumatology conditions was also included; warm up exercises, breathing exercises, upper limb stretches. Practice of Pacing and joint protection.

Results: We evaluated the pilot through looking at attainment and engagement and asked children to rate their experience. Overall the pilot was a success with many children keen to return. Thirteen sessions were carried out between July and November 2022, with 32 patients attending. Average attendance 2.5 children per group. Children attended 1-2 sessions. The 14 older children who completed an evaluation, all reported a sense of achievement.

Conclusion: To our knowledge this is the first piece of work considering the therapeutic benefit of gardening in paediatric rheumatology. Gardening offers many therapeutic benefits; promoting well-being, the opportunity to leave the hospital environment and is a sustainable activity. We aim to embed it in the rehabilitation programme permanently and open it up to other patients, such as rheumatology inpatients.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. Aked et al (2018) Five ways to well-being: Communicating the evidence.NEF economics as if people and the planet mattered. SDU Strategy https://networks.sustainablehealthcare.org.uk/occupational-therapy-sustainable-practice-network-ot-susnet/blog/2014/12/house-agrees

2. Soga et al (2016) Gardening is beneficial for health: A Meta-analysis. Preventative medicine reports 5 (2017) 92-99.

3. Thrive: Using gardening to change Lives: www.thrive.org.uk

4. Van Den Berg AE (2011) Gardening promotes neuroendocrine and affective restoration from stress. Journal of health psychology. Jan; Vol. 16 (1), pp. 3-11.

Correspondence: D. Ghio

Pediatric Rheumatology 2023, 21(Suppl 2):PT106

Introduction: A key part of the research process is the invitation and recruitment to studies. However, little is known about how and why young people decide to take part. Your Rheum is a UK young person’s advisory group, providing young people aged 11-24 and diagnosed with rheumatic condition(s), the opportunity to input into rheumatology research.

Objectives: To identify what information young people need to know when deciding to take part in research studies. Also, to co-produce strategies for future studies, in reaching young people to invite them to take part in research.

Methods: At a virtual Your Rheum meeting eight young people, (F=7, M=1, age range 12-24) took part in group discussions, sharing their experiences of taking part in research and their decision process. Online tools Mentimeter and Miro were used to aid conversations and share ideas.

Results: The majority of young people had experience of taking part in research as a study participant (n=5). Deciding to participate in research included the following considerations: benefit/impact (will the research help them/others); connecting with others (meeting other young people); research topic (important/relevant to them, passionate about); which is then balanced against convenience (was the research opportunity easy to find, will taking part be easy and quick), and reimbursement (incentives for participation, will I be valued). The clinic environment was highlighted as a good and trustworthy recruitment strategy – being approached by a member of the research team was considered ideal, even if it was someone they had not met previously. However, whilst the young people discussed being open to hearing about research opportunities, they reflected that they are rarely exposed to these invitations or hearing about current research. Many recalled little discussions of research at their clinical appointments, particularly when ‘young’ in a paediatric or adult clinic.

Conclusion: It is essential to understand the perspectives of intended study participants, to plan successful recruitment strategies. This not only includes how they take part but why they take part. Young people consider multiple factors about themselves and others before deciding to participate in research. Also, if young people are not aware of research, they can not take part in it. Ensuring we consider these factors when designing our studies and recruitment strategies is beneficial to all involved. Co-produced recruitment strategies would aid inclusive (and increased) research participation.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: R. Lee

Pediatric Rheumatology 2023, 21(Suppl 2):PT107

Introduction: Education, vocational development and early employment experiences are important stages of adolescence and young adulthood (AYA). They are key developmental milestones which inform and shape self-identity and impact outcomes in adulthood, such as employment participation. In addition, these non-medical factors are well recognised social determinants of health. Healthcare professionals are considered well positioned to support the vocational needs/issues of AYAs with long-term health conditions (LTHCs). However, it is important to understand more about how a healthcare professional currently support the vocational needs of AYAs with LTHCs, in a healthcare setting to inform practice and interventions.

Objectives: To explore how communication about education, vocational readiness and employment feature in real-world paediatric rheumatology clinical consultations, between healthcare professionals, children/young people and parents.

Methods: In this qualitative study real-world clinical consultations were audio-recorded across three paediatric and adolescent rheumatology departments in the UK and transcribed verbatim for analysis. Consultations took place in-person or virtually between June-December 2021. A thematic analysis approach was taken to identify themes and sub-themes within consultation communication, using NVivo software to manage the analysis process.

Results: 30 clinical consultations were analysed. Healthcare professional’s predominantly raised topics of conversation related to school/careers/employment (n=18/30). Five key themes were identified; 1. Mechanisms to start communication about vocational development 2. Direct and indirect support from healthcare professional in vocational development issues, 3. Career specific guidance, 4. Transitioning healthcare alongside vocational development, 5. Disclosure about past positive and negative experiences related to vocational issues.

Conclusion: Healthcare professionals are in a key position to support the vocational development needs of AYAs with LTHCs, although to date, it has not been clear in the literature how vocational development communication occurs in real-world clinical settings. It is evident from this novel data, that a range of components of communication pertaining to vocational development are raised in the healthcare setting. Further work is needed to explore how these components relate to existing interventions such as a transitional care plan.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. Migowa

Pediatric Rheumatology 2023, 21(Suppl 2):PT108

Introduction: Delay in diagnosis and access to specialist care is a major problem for many children and young people with rheumatic disease in sub-Saharan Africa. Most children with symptoms of rheumatic disease present to non-specialists for care. There is an urgent need to understand and scale-up paediatric rheumatology knowledge and skills amongst non-specialist healthcare workers to promote early diagnosis, prompt referral, and management.

Objectives: We explored strategies from the perspective of healthcare workers in Kenya to improve the clinical care offered to pediatric rheumatology patients.

Methods: We conducted 12 focus group discussions with clinical officers (third-tier community health workers) nurses, general practitioners and paediatricians across 6 regions in Kenya. Interviews were conducted on zoom, audio-recorded, transcribed, and analyzed using MAXQDA software.

Results: A total of 68 individuals participated; 11 clinical officers, 12 nurses, 10 general practitioners, 27 paediatricians and 7 others. Most (n = 53) were female, and the median age was 36 years (range 31–40 years). Fifty per cent of the participants (34 of 68) worked in public health facilities across 6 regions of Kenya. Our study revealed the need for patient-centred interventions, health worker interventions and health system interventions.

Patient interventions proposed included individual patient education and psychosocial support. Proposed broader community interventions included outreach advocacy campaigns, financial support, prompt identification and referral of cases.

Health worker interventions recommended include clinical interventions aimed at availing diagnostic, management, referral and follow up guidelines. Educational interventions for the health workers should focus on symptom identification, management strategies and communication skills.

Health system interventions include availing diagnostic tools, improving access to care and promoting integrated holistic clinical care.

It was proposed that the interventions be delivered through a blend of in-person session, virtual platforms and social media forums.

Conclusion: Improving outcomes for pediatric rheumatology patients would require an integrated approach which is context specific for the various regions that still lack access to clinical care.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: K. Mördrup

Pediatric Rheumatology 2023, 21(Suppl 2):PT109

Introduction: In Sweden, approximately 2000 children are living with Juvenile Idiopathic Arthritis (JIA)¹. About 200 children are diagnosed every year. When the child is diagnosed, the families often experience loneliness and lack of information, with few resources available to help them². However, information provided at the time of diagnosis can be difficult to remember³. Therefore, families require repeated information and supportive care⁴. Against the background, a one-year Juvenile Arthritis support program (JASP-1) was developed, consisting of 7 patient-and family-centered visits planned during the first year after JIA diagnosis.

Objectives: To describe the levels of children’s and parent’s satisfaction after completing the Juvenile arthritis support program (JASP-1) and compare outcomes with children and parents who received standard care.

Methods: Children diagnosed with JIA and their parents were offered the opportunity to participate in the JASP-1 from the time of diagnosis and the following year. One year after JIA diagnosis, the children and/or their parents were invited to answer a study-specific questionnaire comprising 16 questions. The questionnaire assessed their experiences with the information, communication, participation, and emotional support they had received during the first year with JIA. In order to compare outcomes, the questionnaire was answered by both participants in JASP-1 and patients and parents receiving standard care.

Results: Totally 56 children, along with their parents, participated in the JASP-1, while 24 received standard care. In all 16 questions the participants in JASP-1 reported higher levels of satisfaction with their care compared to those receiving standard care. In 9 of the 16 questions, the results showed significant differences. Some examples on questions with significant differences include the assessment of the child’s health condition, whether they received information about how the health condition could affect everyday life, and if they have had the opportunity to receive supportive care if needed.

Conclusion: The children and parents who participated in the JASP-1 expressed higher satisfaction levels with the care they received compared to those who received standard care. Based on these findings, we conclude that the JASP-1 is likely an effective way to support children and parents after diagnosis and has the potential to improve quality of care within pediatric rheumatology.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

References

1. https://barnreumaregistret.se/for-patienter/information-om-barnreumatism/

2. Yuwen, W., Lewis, F. M., Walker, A. J., & Ward, T. M. (2017). Struggling in the Dark to Help My Child: Parents' Experience in Caring for a Young Child with Juvenile Idiopathic Arthritis. J Pediatr Nurs, 37, e23-e29. 10.1016/j.pedn.2017.07.007

3. Heath-Watson S and Sule S. Living with Juvenile Idiopathic Arthritis: Parent and Physician Perspectives. Rheumatology and therapy. 2018; 5: 1-4.

4. van Dijkhuizen EHP, Egert T, Egert Y, et al. Patient's experiences with the care for juvenile idiopathic arthritis across Europe. Pediatr Rheumatol Online J. 2018; 16: 10.

Correspondence: M. Nørgaard

Pediatric Rheumatology 2023, 21(Suppl 2):PT110

Introduction: Incidence of Temporomandibular joint (TMJ) involvement in patients with Juvenile Idiopathic Arthritis (JIA) is high and frequently impair joint/muscle function, leading to joint degeneration, dentofacial deformities and mandibular growth disturbances. Orofacial symptoms and functional impairment of TMJ and surrounding tissues are seen in 26-74% of cases. No treatment consensus exists and modalities varies from counselling to surgery. Improving aesthetics, function and pain reduction seems effective. However, intervention studies are sparse and heterogeneous, leading to low evidence, and little is known about effectiveness of physiotherapy (PT) in children with TMJ-arthritis.

Objectives: To assess effects of orofacial PT and self-managed exercise programs in JIA-patients with TMJ-involvement, and degree of patient compliance to this treatment.

Methods: Individual PT-treatments were performed once weekly for eight weeks with PT-modalities according to clinical features, using intra-/extra-oral manipulation, orofacial massage, muscle strengthening, muscle/tissue stretching, relaxation techniques etc. An individualized self-managed exercise program was performed daily.

Results: Ten JIA-patients (all females) aged 12-18 years with acute/chronic arthritis in one/both TMJ(s) participated. Nine of 10 patients had bilateral TMJ-involvement. TMJ-symptoms were pain, dysfunction, clicking/crepitation, decreased joint range of motion (ROM), muscle disturbances etc. Two patients reported more pain in non-/least affected TMJ (overuse), and two patients had excessive ROM in affected TMJ(s) (less use/hypermobility). All patients reported orofacial muscle/tissue pain during treatment of specific muscles, predominantly mm. pterygoids (external/internal), supra-/infra-hyoids and masseters. More patients had decreased ROM of cervical joints and/or pain in neck muscles (mm. scalene, sternocleidomastoids etc.).

Pain intensity (VAS 0-10) decreased in 6/10 patients (mean decrease 1,89 (range 0.7-3.9)). In 3 patients, intensity increased 0.5, and in one patient 4.0 (disease flare). Pain frequency (NRS 0-4) decreased in 8/10 patients (mean decrease 1.25 (range 1-3)), whereas 2/10 had steady levels (3).

In all patients, interventions were well tolerated, and all reported diminishing PT-related symptoms during intervention period. Compliance to PT-interventions/home exercises were 100%/95-100%, respectively. All patients reported improvements of overall symptoms during intervention period, especially own competence in obtaining improvements with specific PT-tools.

Conclusion: The eight-week intervention with physiotherapy and self-managed exercises improved patients´ symptoms of TMJ-arthritis, notably their competence in managing them. Thus, physiotherapy should be considered part of standard care in TMJ-arthritis, though more studies are warranted.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: M. J. Pedersen

Pediatric Rheumatology 2023, 21(Suppl 2):PT111

Introduction: Previous studies have shown conflicting results on school performance and academic achievements among children with juvenile idiopathic arthritis (JIA). No study has to our knowledge investigated school performance of children with JIA compared to healthy peers on a national level.

Objectives: We aimed to compare the results of the National Danish School Testing and final 9^th grade exams in the subjects Danish and mathematics between children with JIA and their peers. Further to study possible differences across parental socioeconomic status (SES).

Methods: A population-, register-based cross-sectional study was performed. The study population included all children participating in at least one National School Testing in reading or mathematics between 2^nd and 8^th grade from 2011 to 2019 (n = 812,461). A limit of at least five hospital contacts with a diagnosis code of JIA (ICD-10 codes DM08 and DM09) before the date of the test was used to define JIA patients in our study. Linear regression was used to estimate differences in mean test scores between children with JIA and their peers on the different school grade levels and subjects. Analyses of the final exam grades were stratified on SES variables to test for interaction.

Results: Fifteen hundred forty-one children with JIA participated in at least one National School testing. The results of the National Danish School Testing showed no significant difference in scores between children with JIA and children without JIA in reading (mandatory in grade 2, 4, 6, and 8). In mathematics there was no statistically significant difference in the school test results in 3^rd and 8^th grade but children with JIA scored almost 2 points lower (coefficient -1.73 95% CI [-3.33; -0.13]) than their peers in mathematics in 6^th grade. We found no statistically significant differences in the mean grades of the final 9^th grade exams in neither Danish nor mathematics between children with JIA and children without JIA. Family income was the only SES factor affecting the association between JIA and final exam grade scores. For children living in high income families children with JIA had higher average exam scores than peers but for children living in middle income families children with JIA had lower average exam scores than peers. Children with JIA of low income families did not differ statistically significant from their peers.

Conclusion: Children with JIA perform as good as their peers in school. Family income was the only SES factor associated with the final exam results.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest

None declared

Correspondence: A. Sanipaitiene

Pediatric Rheumatology 2023, 21(Suppl 2):P001

Introduction: Juvenile idiopathic arthritis (JIA) is chronic autoimmune disorder characterized by inflammation of one or more joints leading to stiffness, swelling, and pain. Early JIA diagnosis and treatment can improve outcomes. Many other diseases can mimic initial episode of JIA; thus, it is crucial to identify early signs of chronic disease.

Objectives: We aimed to determine distribution of symptoms and treatment as well as most frequent diagnostic tests in patients presenting with joint pain to a pediatric emergency department (PED).

Methods: Retrospective data analysis from electronic healthcare record system was conducted. Data of all children presenting to PED complaining of joint pain January 2018-February 2022 were analysed. Cases were divided into two groups: children progressing to chronic form of the disease (JIA), and those who did not (nJIA). Statistical data analysis was performed using SPSS 29.0. P value <0.05 was considered significant.

Results: Data of 110 children (55 JIA, 55 nJIA) were analysed; 63.6% were female. Median age was 12 (6-15) and did not differ in both groups. Median days from the onset of symptoms did not differ (61d as for JIA vs 31d as for nJIA, p>0.05). Pain was predominant symptom in both groups (92.73%-JIA; 89.1%-nJIA). Children complained of joint swelling and joint stiffness more frequently in JIA group compared to nJIA (74.5% vs 47.3% and 41.8% vs 29.1% respectively).

In PED, CBC was performed in 99.09% (n=109) cases, ESR in 93.64% (n=103). However, only eosinophil count was higher in JIA compared to nJIA (0.2x10*9 (0.1;0.32) vs 0.13x10*9 (0.08;0.2)). All were referred to pediatric rheumatologist. During follow-up, ANA was tested in 84.5% (n=94). 54.5% (n=61) had positive result of which 62.3% were from JIA group. In PED, 105 children (95.5%) received joint ultrasound. Effusion was found in 75 patients (71.4%), of which 56% belonged to the JIA group. In the same group, one joint involvement prevailed (n=30, 60%), polyarthritis was diagnosed only in 3 patients (6%). Less than half of nJIA patients (n=22, 40%) presented with no joint pathology in ultrasound. All patients were prescribed NSAIDs in PED.

Conclusion: Our research uncovered that the pain symptom predominated in both patients with subsequent JIA and without at the visit to PED. None of investigations in PED was able to identify chronic disease. Therefore, all patients suspected of nontraumatic joint pain should be referred to pediatric rheumatologist.

Patient Consent

Not applicable (there are no patient data)

Disclosure of Interest