Spectrum of Clinical Research in Juvenile Idiopathic Arthritis: A Cross-Sectional Analysis of Registered Studies in Clinicaltrials.gov and Clinicaltrialsregister.eu

The management of juvenile idiopathic arthritis (JIA) has improved tremendously in recent years due to the introduction of new drug therapies but remains complex in terms of non-pharmaceutical issues. In order to determine the direction of scientific progress by characterizing the current spectrum of ongoing clinical research in JIA, we analyzed all ongoing studies in the field of JIA—registered in clinicaltrials.gov and clinicaltrialsregister.eu—concerning sponsoring, enrollment, duration, localization, and particularly objectives. The close of the database was 7 January 2021. After identifying double-registered studies, n = 72 went into further analysis. Of these, 61.1% were academia-sponsored and 37.5% were sponsored by the pharma industry. The majority of the studies was of the interventional type (77.8%), while others (22.2%) were observational. The median planned enrollments were 100 participants (interventional studies) and 175 participants (observational studies), respectively. The duration differed remarkably from one month to more than 15 years, with a median of 42.5 months. A total of 61.1% of studies were located in a single country, and 38.9% were in several. Europe and North America clearly dominated the study localizations. The study objectives were DMARDs (56.9%), followed by diagnostics and disease activity measurement (18.1%), and medication other than DMARD (12.5%), besides others. Studies on DMARDs were mainly sponsored by industry, predominantly interventional studies on established and novel biologics, with several on specific issues such as systemic JIA and others. The spectrum of registered studies is currently centered on drug therapy and diagnostics, while other issues in JIA play a subordinated role in current research. Drug development was transferred from adult rheumatology into the JIA population with little innovation for children. Future research should take specific pediatric needs better into account.

Challenges in Diagnosing COVID-19 Related Disease in Pediatric Patients With Rheumatic Disease

Objectives Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe condition associated with coronavirus disease 2019 (COVID-19). Here we aimed to raise awareness for the symptoms of MIS-C in patients with rheumatic diseases, emphasizing the challenges of the differential features. Methods We retrospectively evaluated the demographic and clinical characteristics, laboratory and imaging findings, treatments, and outcomes of six MIS-C patients with previous rheumatic disease. Results Three of the patients had familial Mediterranean fever (FMF), one had juvenile dermatomyositis (JDM), one had systemic juvenile idiopathic arthritis (JIA), and another patient had oligoarticular JIA. All FMF patients presented with fever and abdominal pain, two also had chest pain. The patient with systemic JIA presented with fever, rash, and myalgia. All patients had elevated inflammatory markers and high d-dimer levels. Chest imaging of two FMF patients showed infiltrations compatible with pneumonia. One FMF patient had mildly decreased systolic functions with a shortening fraction of 48% in his echocardiography. Intravenous immunoglobulin and methylprednisolone were administered to all patients. Anakinra was given to four patients. Conclusions Clinical and laboratory signs of MIS-C may overlap with the findings of various rheumatic diseases, and this may cause a delay in diagnosis.

P034 Macrophage activation syndrome in Juvenile Idiopathic Arthritis

Objectives To describe the epidemiological, clinical-biological, and therapeutic characteristics of children with systemic JIA complicated with a macrophage activation syndrome (MAS). Methods It was a retrospective study, including children with JIA followed at the pediatric rheumatology unit of the children's hospital in Tunis for 22 years (January 1999 to December 2020), and presented MAS during their follow-up. Results We included 40 patients with JIA. Nineteen children (47.5%) presented MAS during the disease. They are 11 boys and 8 girls, with a sex ratio of 1.3. The mean age was 5.31 years (range: 0.66–10.83 years). The circumstances of the occurrence were variable. MAS was inaugural in 10 patients. Three of our patients presented MAS twice. MAS was definitive with clinical and biological markers in 12 cases and only biological in 7 cases. Seventeen of our patients were treated with intravenous Corticosteroids. Seven Childs among them received, in combination, Immunoglobulins (IG). We prescribed a biological treatment in 3 patients. We have mourned only one death. Conclusion MAS is a severe complication of JIA and is the leading cause of death.

P016 Updated Clinical Practice Guidelines for JIA management adopting Treat to Target approach: the Egyptian College of Paediatric Rheumatology initiative

Background There is an unmet need from paediatric rheumatologists and rheumatologists, managing children with JIA, for a well formulated guidelines aiming at achieving better outcomes of their patients. To establish adequate and easily adopted guidelines in management of different variants of JIA in a relatively low resources country. Method This study was carried out to achieve an Egyptian expert consensus on a treat-to-target management strategy for Juvenile Idiopathic Arthritis using Delphi technique. The preliminary scientific committee identified a total of 17 key clinical questions according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) approach. An evidence-based, systematic, literature review was conducted to compile evidence for the benefits and harms associated with JIA treatments. The core leadership team identified researchers and clinicians with expertise in JIA management in Egypt upon which Experts were gathered from different governorates and health centres across Egypt. Delphi process was implemented (2-rounds) to reacha consensus on the management recommendations of Egyptian JIA patients. Results: An online questionnaire were sent to expert panel (n = 27), of whom 26 participated in the two rounds. At the end of round 2, a total of eighteen (18) recommendation items, categorized into 4 sections to address the main 4 JIA categories, were obtained. Agreement with the recommendations (rank 7–9) ranged from 83.2–100% (average 86.8%). Consensus was reached (i.e. ≥75% of respondents strongly agreed or agreed) on the wording of all the 18 clinical standards identified by the scientific committee. Algorithms for the management of JIA polyarthritis, oligoarthritis and systemic JIA have been suggested. Conclusion A wide and representative panel of experts established a consensus regarding the management of JIA in Egypt. The developed guidelines provide a comprehensive approach to the management of JIA for ll Egyptian healthcare professionals who are involved in its management for follow up and frequent evaluation of these guidelines.

P010 Clinico-epidemiological characteristics and outcomes of Juvenile Idiopathic Arthritis (JIA) patients in Kenya: data from the KAPRI registry

Background Pediatric rheumatic diseases pose a significant disease burden upon children and their families (1–3). They lead to physical disability and diminished quality of life (1–3). Determination of the burden and clinical characteristics of these diseases is a critical first step to improving access to care and optimizing use of existing health systems for the well-being of these patients (4). This is in line with the goal of the Bone and Joint decade (2000–2010) aimed at increasing recognition and understanding of the impact of musculoskeletal diseases (5,6). The Kenya Pediatric Rheumatology Registry (KAPRI) offers a unique opportunity to pioneer and spearhead a systematic and organized format to inform policy and better healthcare provision. Our objective was to determine the patient characteristics, clinical features and outcomes of Juvenile Idiopathic Arthritis (JIA) patients assessed at the Aga Khan University Medical College East Africa from March 2019 to December 2020. Methods Data of JIA patients on age, gender, laboratory and clinical features at diagnosis and treatment options offered were extracted from the database. A further detailed chart review was undertaken to determine the proportion of patients who achieved remission or minimally active diseases. Results Among the 207 patients enrolled thus far, 16 (7.7%) were diagnosed to have JIA. Majority of the patients were females (75%; n = 12) with a mean age of 7 years and 3 months (Range : 1 year—13 years 7 months). All patients had joint pain and swelling as the initial presenting complaints. Majority of the patients had polyarticular JIA (75%, n = 12). The other 4 patients were oligoarticular (n = 2) and systemic JIA (n = 2). Among the polyarticular JIA patients (n = 12), only 3 (25%) were rheumatoid factor (RF) positive and 1 was antinuclear antibody (ANA) positive. The oligoarticular and systemic JIA patients were all negative for antinuclear antibody, rheumatoid factor and cyclic citrullinated peptide antibodies (anti-ccp). Seven patients (43.8%) required biological therapies; tocilizumab (n = 2: systemic JIA), adalimumab (n = 2: polyarticular JIA), etanercept (n = 2: polyarticular JIA) andtofacitnib (n = 1: polyarticular JIA). One patient with systemic JIA on tocilizumab developed herpes simplex which was successfully managed with oral acyclovir. All the other patients did not develop any infections, allergic reactions or any other untoward events as adverse outcomes following the use of biological therapies. Five patients have attained remission as illustrated in the table below. Two patients have been lost to follow up. Conclusion Seronegative polyarticular JIA was the predominant form of JIA observed with a predilection to affect more girls and boys. Over a period of 2 years, remission has been attained among 31.25% of the patients (5 of 16) with use of synthetic disease modifying anti-rheumatic drugs and biological therapies.

P030 Impact of methotrexate on growth in children with Juvenile Idiopathic Arthritis

Background Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic inflammatory disease which could be responsible for functional impairment and severe growth disturbance. Conventional disease-modifying antirheumatic drugs, such as methotrexate (MTX), may improve growth velocity especially by regulating systemic inflammation. The objective of this study was to evaluate the effect of MTX on growth parameters in pre-pubertal children with JIA and to determine the factors affecting the growth velocity. Methods We assessed height and changes in the height standard deviation score (SDS) at disease onset, at the onset of MTX and at the last follow-up visit in a cross-sectional study of JIA children. All patients were pre-pubertal when MTX began and were followed for at least 6 months afterward. We compared growth parameters (height, growth rate, weight and body mass index (BMI)) in responders and non-responders to MTX. The growth rate was defined as the number of millimeters of height acquired during 1 year. Associations between changes in the height SDS and discrete variables were evaluated using χ2 or Fisher’s exact tests. The significance level was set at 0.05. Results We enrolled 36 pre-pubertal children with JIA (34 boys and 12 girls) who had been treated with MTX orally. Median patient age was 6.2 years [4–13] at the onset of MTX and 8.4 years [6.1–14.9] at the latest follow-up. The median disease duration was 2.7 years [2.5–5.3]. Twenty-one patients (58.3%) had oligoarticular JIA, 2 patients (5.5%) had systemic JIA, 10 (27.7%) had polyarticular JIA and 3 (8.3%) had enthesitis-related arthritis. Nineteen children (52.7%) had received corticosteroids during an average period of 1.7 years [0.6–3] with a mean of 10 mg/day of prednisone or equivalent. The median duration of MTX at the latest follow-up was 3.1 years [0.62–5.5] with a mean MTX dose of 10 mg/m2/week [10–15]. Twenty-eight patients responded to MTX treatment and 8 did not. There were no significant differences between the responders and non-responders for age at treatment initiation, disease duration and mean MTX dose. At MTX onset, no significant differences between the two groups in terms of height (P = 0.52), growth rate (P = 0.08), weight (P = 0.74) and BMI (P = 0.9) were found. One year after MTX therapy, mean height (0.2 vs -1.1; P = 0.03), mean growth rate (0.5 vs –2.9 SDS; P = 0.01), mean weight (0.4 vs -2.3 SDS; P = 0.01) and mean BMI (0.6 vs -1.9; P = 0.04) were significantly higher in the responder group than in non responders, respectively. At the latest follow-up, this increase was significantly maintained for growth rate (P = 0.001) and height (P = 0.002) in the responder group. In the multivariate analysis, patients who required >10 mg/m2/week of MTX, systemic JIA and patients with reliance on steroids had a significantly lower growth velocity after the onset of MTX (P < 001, P = 0.02, P = 0.02 respectively). Conclusion In our study, the increase in growth parameters in pre-pubertal children with JIA was associated with a better control of the disease activity under MTX therapy.

Spectrum of Clinical Research in Juvenile Idiopathic Arthritis: a Cross-Sectional Analysis of Registered Studies in Clinicaltrials.gov and Clinicaltrialsregister.eu

Management of Juvenile idiopathic arthritis (JIA) has improved tremendously in recent years due to the introduction of new drug therapies but remains complex also in terms of non-pharmaceutical issues. In order to determine the direction of scientific progress by characterizing the current spectrum of ongoing clinical research in JIA, we analyzed all ongoing studies in the field of JIA registered in clinicaltrials.gov and clinicaltrialsregister.eu concerning sponsoring, enrollment, duration, localization, and particularly objectives. Close of database was 7 January 2021. After identifying doubled-registered studies, N=72 went into further analysis. Of these, 61.1% were academia-sponsored and 37.5% by pharma industry. The majority of studies was of interventional type (77.8%), while others (22.2%) were observational. Median planned enrollments were 100 participants (interventional studies) and 175 participants (observational studies), respectively. Duration differed remarkably from one month to more than 15 years with a median of 42.5 months. 61.1% of studies were located in a single country, 38.9% were in several. Europe and North America clearly dominated study localizations. Study objectives were DMARDs (56.9%), followed by diagnostics and disease activity measurement (18.1%), and medication other than DMARD (12.5%), besides others. Studies on DMARDs were mainly sponsored by industry, predominantly interventional studies on established and novel biologics, with several on specific issues like systemic JIA and others. The spectrum of registered studies is currently centered on drug therapy and diagnostics, while other issues in JIA play a subordinated role.

Burden of comorbid conditions in children and young people with juvenile idiopathic arthritis: a collaborative analysis of 3 JIA registries

Objectives Burden of comorbidities are largely unknown in JIA. From 2000, national and international patient registries were established to monitor biologic treatment, disease activity and adverse events in patients with JIA. The aim of this analysis was to investigate in parallel, for the first time, three of the largest JIA registries in Europe/internationally—UK JIA Biologic Registers (BCRD/BSPAR-ETN), German biologic registers (BiKeR/JuMBO), multinational Pharmachild—to quantify the occurrence of selected comorbidities in patients with JIA. Methods Information on which data the registers collect were compared. Patient characteristics and levels of comorbidity were presented, focussing on four key conditions: uveitis, MAS, varicella, and history of tuberculosis. Incidence rates of these on MTX/biologic therapy were determined. Results 8066 patients were registered into the three JIA registers with similar history of the four comorbidities across the studies; however, varicella vaccination coverage was higher in Germany (56%) vs UK/Pharmachild (16%/13%). At final follow-up, prevalence of varicella infection was lower in Germany (15%) vs UK/Pharmachild (37%/50%). Prevalence of TB (0.1–1.8%) and uveitis (15–19%) was similar across all registers. The proportion of systemic-JIA patients who ever had MAS was lower in Germany (6%) vs UK (15%) and Pharmachild (17%). Conclusion This analysis is the first and largest to investigate the occurrence of four important comorbidities in three JIA registries in Europe and the role of anti-rheumatic drugs. Combined, these three registries represent one of the biggest collection of cases of JIA worldwide and offer a unique setting for future JIA outcome studies.

Interfering with interferons: targeting the JAK-STAT pathway in complications of systemic juvenile idiopathic arthritis (SJIA)

Systemic JIA (SJIA) is distinguished from other forms of JIA by the prevalence of the severe, life-threatening complications macrophage activation syndrome (SJIA-MAS) and lung disease (SJIA-LD). Alternative therapeutics are urgently needed, as disease pathogenesis diverges from what is observed in SJIA, and currently available biologics are insufficient. SJIA-MAS, defined by a cytokine storm and dysregulated proliferation of T-lymphocytes, and SJIA-LD which presents with lymphocytic interstitial inflammation and pulmonary alveolar proteinosis, are both thought to be driven by IFNs, in particular the type II IFN-γ. Involvement of IFNs and a possible crosstalk of type I IFNs with existing biologics indicate a distinct role for the JAK-STAT signalling pathway in the pathogenesis of SJIA-MAS and SJIA-LD. Here, we review this role of JAK-STATs and IFNs in SJIA complications and discuss how new insights of ongoing research are shaping future therapeutic advances in the form of JAK inhibitors and antibodies targeting IFNs.

Association between high mobility group box 1 protein and juvenile idiopathic arthritis: a prospective longitudinal study

Objective To analyze the levels of high mobility group box 1 (HMGB1) protein on different courses of juvenile idiopathic arthritis (JIA). Methods In our prospective longitudinal study, children with JIA were included with their blood samples collected at the first visit, 1-month, 3-month, and 6-month follow-up, respectively. Samples were also collected from healthy controls and children with reactive arthritis at the first visit. Levels of HMGB1 were determined using enzyme-linked immunosorbent assays. Clinical disease characteristics and routine laboratory findings were analyzed as well. Results A total of 64 children were enrolled, of whom 31 (48.4%) were female. The median age at the first visit for participants with JIA was 9.25 years (range, 1.42–15.42) and the median duration of disease was 2.38 months (range, 1.53–49.31). Serum HMGB1 levels at the first visit were significantly elevated in children with systemic JIA compared with other groups, and so were in enthesitis-related arthritis versus healthy controls. Significant correlations were established at the first visit between HMGB1 levels and duration of disease, C-reactive protein, percentage of neutrophils, and ferritin. Data from all samples revealed that serum HMGB1 levels in JIA were significantly associated with erythrocyte sedimentation rates, C-reactive protein, percentage of neutrophils, and disease activity scores. Conclusions Serum HMGB1 may be associated with clinical disease activity of JIA and specifically increased at the first visit in children with systemic JIA, suggesting its function as a sensitive inflammatory marker. Further large-scale studies are warranted to explore its spectrum in JIA.