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Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are considered the same disease, but a common approach for diagnosis and management is still missing., Methods: In May 2022, EULAR and PReS endorsed a proposal for a joint task force (TF) to develop recommendations for the diagnosis and management of sJIA and AOSD. The TF agreed during a first meeting to address four topics: similarity between sJIA and AOSD, diagnostic biomarkers, therapeutic targets and strategies and complications including macrophage activation syndrome (MAS). Systematic literature reviews were conducted accordingly., Results: The TF based their recommendations on four overarching principles, highlighting notably that sJIA and AOSD are one disease, to be designated by one name, Still's disease.Fourteen specific recommendations were issued. Two therapeutic targets were defined: clinically inactive disease (CID) and remission, that is, CID maintained for at least 6 months. The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors associated to short duration glucocorticoid (GC). MAS treatment should rely on high-dose GCs, IL-1 inhibitors, ciclosporin and interferon-γ inhibitors. A specific concern rose recently with cases of severe lung disease in children with Still's disease, for which T cell directed immunosuppressant are suggested. The recommendations emphasised the key role of expert centres for difficult-to-treat patients. All overarching principles and recommendations were agreed by over 80% of the TF experts with a high level of agreement., Conclusion: These recommendations are the first consensus for the diagnosis and management of children and adults with Still's disease., Competing Interests: Competing interests: BF: AbbVie, Amgen, Biogen, BMS, Celltrion, Fresenius Kabi, Galapagos, Gilead, Janssen, Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Roche-Chugai, Sandoz, Sanofi-Genzyme, SOBI, UCB, Viatris; SM: BMS, Lilly, SOBI; JA: Sobi, Novartis, Roche, Pfizer, AbbVie, Lilly; AB: Boehringer Ingelheim, Novartis, AbbVie, Fresenius Kabi, GlaxoSmithKline; CB: SOBI; TC: AbbVie, Novartis, Roche; LD: AbbVie, Amgen, Astra-Zeneca, Boehringer-Ingelheim, BMS, Lilly, Galapagos, GlaxoSmithKline, Janssen, Kiniksa, Novartis, Pfizer, SOBI; ADB: Lenovo; EF: AbbVie, BMS, Galapagos, Lilly, Medac, Novartis, Sanofi, UCB, Pfizer, Roche, SOBI; DF: Boehringer-Ingelheim, SOBI, Novartis, Werfen Innova; MG, SGL, FM, FOR, SV: Novartis, SOBI; RG, AG: Novartis; IJ: Amgen, Lilly, Novartis, SOBI; PN: BMS, Brickell Bio, Cerecor, Exo Therapeutics, Miach Ortho, Novartis, Pfizer, SOBI, UpToDate, American Academy of Pediatrics; SO: Novartis, SOBI, Pfizer; PQ: Amgen, AbbVie, BMS, Roche-Chugai, Lilly, Novartis, Pfizer, Sanofi, SOBI, Health Events; PR: AbbVie, BMS, Janssen, Novartis, SOBI; SS: Novartis, SOBI, CSL Behring, Takeda, BioCryst, Biotest; M-ET: Boehringer-Ingelheim, Pfizer, Lilly, MSD, SOBI, Janssen, BMS, Fresenius Kabi, Galapagos, AbbVie; CW: Novartis, SOBI, UCB; LC: Meda Pharma, Angelini Pharma, Pfizer, SANOFI-AVENTIS, Fresenius Kabi, Galapagos; FDB: SOBI, Novartis, Apollo, Kiniksa, Sanofi, Roche, Elixiron, Regeneron; ADM, SB, KL, CL, ES, T-CW: none., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ on behalf of EULAR.)

Aims: To analyse the prescription of biologics (bDMARDs) in chronic inflammatory rheumatic diseases (CIRD) from Tunisian National Health Insurance (CNAM) data and to estimate their direct costs and associated factors., Methods: One hundred and nine consecutive patients who received at least one bDMARDs during a six-month period from January to June 2022 were analysed. Clinical and therapeutic parameters as well as data related to the choice of bDMARDs were identified. Direct costs were assessed. Excess costs were considered if the monthly costs exceeded 2200 Tunisian dinars (TD) per patient., Results: The most common CIRD was axial spondylarthritis (AS) in 44% and rheumatoid arthritis (RA) in 37.6% of cases. Juvenile idiopathic arthritis represented 2.7% of cases. In Tunisia, prescribing of bDMARDs is concentrated in the coastal regions and follows the distribution of rheumatologists. Certolizumab pegol was the most prescribed agent in 45% of cases. No significant association was found between the choice of bDMARD and the characteristics of patients, CIRD or prescribers. The total monthly cost of bDMARDs was 225,535 ± 1269 TD. Overspending was significantly associated with initial high DAS28 in RA and young age and total hip replacement in AS., Conclusion: Prescription of bDMARDs in CIRD is mainly for AS and in the coastal regions of Tunisia. The burden is considerable, partly due to the high cost of biologics. Data from this study may enable public health managers to better allocate the limited resources available for patient care and to develop medico-economic strategies to reduce health care costs.

Background: Juvenile idiopathic arthritis (JIA) is a common chronic rheumatic disease in children, requiring careful management to reduce both short- and long-term morbidity. In this study, our objective was to assess the clinical features of patients diagnosed with JIA who received intra-articular corticosteroid injections (IACI)., Methods: In this retrospective study, we evaluated the clinical and laboratory characteristics of 225 JIA patients monitored from January 2012 to October 2023 at a tertiary care center. We focused on patients who underwent intra-articular corticosteroid injections (IACI) as part of their treatment. Triamcinolone hexacetonide (TH) was used due to its demonstrated safety and efficacy., Results: Our analysis revealed that IACI, particularly utilizing TH, was a widely employed and effective adjunct therapy, contributing to rapid symptom relief and local disease control. Patients receiving IACI exhibited earlier symptom onset, younger age at diagnosis, longer follow-up durations, and higher cumulative treatment burden ( p  < 0.001, p  < 0.001, p  < 0.01, p  < 0.001 respectively). Despite inconclusive acute-phase reactants, a higher frequency of ANA positivity and elevated initial lymphocyte counts were associated with increased IACI use ( p  < 0.001, p  < 0.001 respectively). Importantly, on a joint basis, a high percentage of arthritis remission following IACI underscores its efficacy and favorable safety profile., Conclusions: Notably, the high percentage of arthritis remission achieved with intra-articular corticosteroid injections (IACI) on a joint-specific basis highlights its efficacy and favorable safety profile. A lymphocyte count exceeding 5000/mm 3 at the time of diagnosis may serve as an early indicator for considering intra-articular steroid administration. These findings emphasize the need for nuanced and individualized treatment strategies in JIA management to optimize outcomes for affected children.

Objectives: Given the limited tocilizumab (TCZ) treatment data for systemic juvenile idiopathic arthritis (sJIA) in China, we evaluated the long-term efficacy and safety of TCZ in Chinese patients with sJIA., Method: In this multicentre, interventional Phase IV study, patients with sJIA and inadequate clinical response to non-steroidal anti-inflammatory drugs/corticosteroids received TCZ infusions every 2 weeks based on body weight (< 30 kg, 12 mg/kg; ≥ 30 kg, 8 mg/kg), over a 52-week open-label period and an 8-week safety follow-up period. The primary endpoint was the proportion of patients with a JIA American College of Rheumatology (ACR) 30 response and absence of fever at Week 12., Results: Sixty-two patients were enrolled and treated (12-mg/kg group, 34; 8-mg/kg group, 28). At Week 12, 87.1% (95% confidence interval 78.8%-95.4%) of patients had JIA ACR 30 response and absence of fever; Week 52 results were similar. The proportion of JIA ACR 30/50/70/90 responders rapidly increased at Week 12, up to Week 52. High-sensitivity C-reactive protein (hsCRP) levels decreased within 4 weeks; 44/58 patients (75.9%) with elevated baseline hsCRP recovered at Week 52. Childhood Health Assessment Questionnaire pain scores, disability index scores, and mean corticosteroid dose decreased over time. Height standard deviation score changes at Week 52 indicated catch-up growth. Most adverse events (AEs) were mild (serious AE incidence, 17.7%). No deaths or macrophage activation syndrome occurred., Conclusion: This is the first multicentre trial to report the efficacy and safety of TCZ in Chinese patients with sJIA at 52 weeks. No new safety concerns were found., (© 2024. The Author(s).)

Objectives: In recent years, the distinct clinical presentations and elevated mortality rates of various subtypes of juvenile idiopathic arthritis (JIA) with pulmonary involvement have garnered significant attention. This study aimed to elucidate the clinical characteristics of pulmonary involvement in patients with JIA to improve clinicians' knowledge., Methods: This single-centre retrospective study analysed the baseline data, treatment options, follow-up of sixty patients of JIA with pulmonary involvement in China. Patients with interstitial lung disease (ILD) were further classified in accordance with the 2013 American Thoracic Society/European Respiratory Society International multidisciplinary consensus on idiopathic interstitial pneumonia., Results: Sixty patients (5.03%) with JIA were complicated with pulmonary involvement. The highest subtype was systemic JIA (sJIA, 63.3%), followed by rheumatoid factor (RF)-positive polyarthritis (pJIA, 25.0%). The incidence of macrophage activation syndrome (MAS) was 21.6%. The most common diagnosis was ILD (90%). Respiratory symptoms/signs were initially experienced by 61.7% of the patients, and respiratory support was required by 21.7%. High-resolution CT classification of sJIA revealed non-specific interstitial pneumonia (NSIP) and organising pneumonia. High-resolution CT classification of pJIA was NSIP and usually interstitial pneumonia (UIP). Patients were treated with NSAIDs, along with glucocorticoids, DMARDs, and biological agents. The survival rates after 1 and 5 years were approximately 93.3% and 90.0%, respectively., Conclusions: Patients with JIA with pulmonary involvement present with early onset, high mortality rate. JIA patients should undergo physical examination thoroughly and high-resolution CT scans, lung function tests for evaluating and monitoring the occurrence and development of pulmonary involvement in early stages to improve prognosis.

Objective: Despite treatment advances, pain remains a serious problem for many children with juvenile idiopathic arthritis (JIA). To better understand pain in children with JIA and identify potentially modifiable factors, this study evaluated Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference (PI) and its relationships with other pain measures and demographic, clinical, psychosocial, and functional variables., Methods: This cross-sectional, observational, multicenter study used descriptive statistics and a mix of bivariate and multivariable analyses to describe PI and characterize relationships with other measures and variables., Results: Among 355 children with JIA, 27% reported moderate or severe PI and 13.3% reported daily pain. PI correlated with other pain measures. Increasing age, decreasing disease duration, and increasing number of active joints, as well as presence of active disease, steroid treatment, and biologic treatment, were associated with greater PI. All PROMIS psychosocial and functional measures were associated with PI in the expected direction except for PROMIS Pediatric Physical Activity, which showed no association. In multivariable analyses, only PROMIS Fatigue, PROMIS Mobility, and the exploratory interaction of PROMIS Anxiety and disease-modifying antirheumatic drug treatment were significant., Conclusion: Moderate and severe PI was prevalent in this sample of children with JIA. PI increased with age and indicators of disease activity, but was more strongly associated with increasing fatigue and decreasing mobility. Findings support the use of PI as a short, easily administered multidimensional pain measure as part of routine clinical care. Fatigue, mobility, and disease activity should be assessed further when PI is high., (Copyright © 2024 by the Journal of Rheumatology.)

Objective: To characterize and describe clinical experience with childhood-onset non-infectious uveitis., Study Design: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared., Results: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated ( p  < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use., Conclusion: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Objectives: Methotrexate (MTX) is the most used drug to treat children and adults with arthritis and its use is burdened by adverse effects. The MTX intolerance severity score (MISS) was developed in English to identify patients who are intolerant to MTX. The aim of this study was to translate and validate the MISS in Italian., Methods: The Italian version of the MISS was developed following the "guidelines for process of cross-cultural adaptation of self-reported measures". The Italian version of the MISS was validated in 125 patients with juvenile idiopathic arthritis (JIA) followed at the Rheumatology Unit of Bambino Gesù Children Hospital. We assessed the construct validity and calculated the internal consistency of the Italian MISS. We performed ROC analysis to assess the overall performance of the Italian MISS., Results: We translated and adapted the MISS to the Italian language. The Italian MISS showed a very good internal consistency as shown by a Cronbach α of 0.87 (95% CI, 0.84-0.90) and a composite reliability of 0.89 (95% CI, 0.83-0.91).The Cohen's κ was 0.81 (95% CI, 0.71-0.91), suggesting a very good construct validity. The ROC analysis showed an area under the curve (AUC) of 0.97 (95% CI, 0.93-0.99). A threshold of 6 to define intolerant patients, showed a sensitivity of 98.3% and specificity of 81.2%., Conclusions: We developed the Italian version of the MISS and showed its validity and reliability to identify patients intolerant to MTX in clinical practice and in a research setting.

Macrophage activation syndrome (MAS) is one of the most severe complications of systemic juvenile idiopathic arthritis (sJIA). Around 10% of patients with sJIA exhibit systemic symptoms accompanied by macrophage activation syndrome (MAS), but it may occur subclinically in another 30-40%. In this article, we present a case of a 3-year-old girl diagnosed with sever MAS as an onset of sJIA complicated by disseminated intravascular coagulation (DIC). First symptoms of sJIA were observed about 5 months before setting the diagnose, and it was resembling urticaria. A comprehensive allergological diagnostics were conducted, but no cause for the skin changes was identified. A few weeks before admission to the hospital, the girl was presented with a high fever. During the hospital stay, viral, bacterial, and fungal infections were ruled out. However, the findings indicated significantly elevated markers of inflammation (ferritin, CRP, ESR) in the conducted tests. Meanwhile, swelling of the feet and ankle joints was also observed. Based on Ravelli criteria, we set the diagnosis of MAS in a course of sJIA. We implemented treatment with steroid pulses, followed by cyclosporine; however, her clinical condition did not improve. Despite intensive treatment, skin petechiae were observed twice, and laboratory tests revealed a very high INR along with an extremely low level of fibrinogen. The patient required multiple plasma transfusions and clotting factor administrations. Due to the severe condition of the girl, we initiated biological treatment with anakinra, after which the child's condition gradually improved. In this case, we want to present how dynamic and life-threatening the course of MAS can be. In the discussion, we are also comparing our approach and the applied treatment with the currently available knowledge., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To report pharmacokinetics (PK), immunogenicity, clinical effect, and safety of intravenous (IV) golimumab in children with active polyarticular-course juvenile idiopathic arthritis (pcJIA) who participated in A Study to Evaluate the Pharmacokinetics, Efficacy and Safety of Intravenous Golimumab in Pediatric Participants With Active Polyarticular Course Juvenile Idiopathic Arthritis Despite Methotrexate Therapy (GO-VIVA)'s open-label, long-term extension (LTE) through week 252., Methods: GO-VIVA participants who continued IV golimumab (80 mg/m 2 every 8 weeks) after week 52 were included. PK and safety were assessed through week 244 (last dose) and week 252, respectively, and clinical response through week 116. Clinical outcomes included JIA-American College of Rheumatology (ACR) responses and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10). Binary outcomes used nonresponder imputation, and other descriptive analyses used observed data., Results: Of 112/127 (88.2%) participants entering the LTE, 69 completed the week 252 visit. Median steady-state trough golimumab concentrations were generally maintained from week 52 through week 244 (range 0.3-0.6 μg/mL). Antigolimumab antibody rates were consistent through week 52 (39.2% [49/125]) and week 244 (44.8% [56/125]). Week 52 JIA-ACR 30/50/70/90 response rates (75.6% [96/127], 74% [94/127], 65.4% [83/127], and 48.8% [62/127], respectively) were generally maintained through week 116 (72.4% [92/127], 71.7% [91/127], 63.8% [81/127], and 50.4% [64/127], respectively), when the median cJADAS10 was 1.6 and 56.7% (72/127) of participants achieved cJADAS10 ≤ 5 (minimal disease activity). Rates (per 100 patient-years) of serious adverse events and serious infections through week 252 were 7.7 and 3.9, respectively., Conclusion: GO-VIVA LTE participants experienced adequate PK exposure and stable safety and immunogenicity. The majority of participants experienced no more than minimal residual disease activity. Data suggest IV golimumab treatment provided durable clinical response through week 116, with an acceptable risk-benefit profile., (Copyright © 2024 by the Journal of Rheumatology.)

Background: Interstitial lung disease (ILD) is a serious complication in systemic juvenile idiopathic arthritis (SJIA). This study aimed to identify the clinical characteristics and prognosis of SJIA-ILD., Methods: A two-center retrospective cohort study was conducted on patients newly diagnosed with SJIA in China from October 2010 to December 2021. Clinical characteristics, laboratory parameters, outcomes, and relapse rates were compared between ILD and non-ILD groups., Results: A total of 176 children with SJIA were included, including 35 in ILD group and 141 in non-ILD group. The median age at onset of SJIA was 5.8 years (range 4.4-9.5) in patients with SJIA-ILD. It exhibited higher incidences of cervical spine (28.6%) and hip involvement (40.0%) in ILD group (P = 0.031 and P = 0.029, respectively). The incidence of macrophage activation syndrome (MAS) in ILD group reached up to 40%, significantly elevated than that in non-ILD group (P = 0.047). Children with ILD demonstrated a stronger inflammatory response and were more prone to developing lymphopenia (P = 0.009), requiring more combination therapy (P = 0.006) to control disease activity. 54.3% of patients received biologic therapies, with only three patient receiving biologics (one with IL-6 blockade, two with TNF inhibitor) prior to ILD onset and none receiving IL-1 blockade. The median follow-up duration was 6.0 years (range 3.9-9.5). The proportions of patients with SJIA-ILD achieving clinical inactive disease without glucocorticoids within 6 to 12 months of the treatment were significantly lower than control group (45.7% vs. 70.2%, P = 0.006). In ILD group, only 54.3% of patients achieved complete remission, and 17.1% were in a non-remission state, among whom two deaths from respiratory failure. There was no significant difference in disease relapse rates between the two groups (P > 0.05)., Conclusions: Patients with SJIA-ILD exhibited heightened inflammation, increased hip joint and cervical spine involvement, and were more susceptible to developing lymphopenia and MAS, suggesting a relatively poor prognosis. They required a prolonged time to control inflammation and more aggressive treatment strategies to achieve inactive status. The unsatisfactory rate of complete remission highlighted an urgent need for focused clinical strategies., (© 2024. The Author(s).)

Background: Methotrexate (MTX) intolerance in juvenile idiopathic arthritis (JIA) frequently leads to discontinuation due to anticipatory and associative gastrointestinal symptoms. Eye Movement Desensitization and Reprocessing (EMDR) has successfully been used in MTX intolerance, with lasting effects but frequently diminishing efficacy over time. BLAST (bi-lateral alternating stimulation tactile) wristbands utilize a similar process to EMDR. The aim of this study was to determine if utilization of BLAST wristbands could improve and prolong the effect of EMDR on patients with MTX intolerance., Methods: Consecutive patients admitted to the German Center for Pediatric and Adolescent Rheumatology with JIA and signs of MTX intolerance from October 2016 until March 2024 were included in this study. Treatment was performed using an adapted 8 phase EMDR protocol implementing BAST wristbands. Initial patients were treated with EMDR, subsequent patients additionally with BLAST wristbands. Health-related quality of live was determined using the PedsQL. Measurements of MISS (Methotrexate Intolerance Severity Score) and PedsQL were taken at 4 time points: directly before and after (MISS only) treatment, as well as 4 and 12 months after treatment. Changes in MISS and PedsQL were compared using descriptive statistics and repeated measures ANOVA., Results: 87 patients with MTX intolerance were included, 53 in group 1 without BLAST wristbands and 34 in group 2 which were concurrently treated with BLAST wristbands. All patients reported marked improvement of MTX intolerance symptoms (mean MISS score group 1: 15.0 ± 5.5 before treatment, 1.3 ± 1.5 after treatment, group 2: 16.8 ± 5.6 and 2.5 ± 2.5, respectively). After 4 and 12 months, MISS in group 1 was 8.1 ± 7.1 and 8.7 ± 8.4, and in group 2: 7.1 ± 6.3 and 6.5 ± 5.7. A repeated measures ANOVA showed a significant difference between the MISS results over time (F(3,114) = 64.6, p < 0.001), and also demonstrated a significant difference of the PedsQL results between the two groups over time (F(2,64) = 8.9, p < 0.001)., Conclusion: Treatment with Eye Movement Desensitization and Reprocessing (EMDR) could present an effective treatment of MTX intolerance, and using BLAST wristbands, further potential improvement is possible., (© 2024. The Author(s).)

Objectives: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study., Methods: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0., Results: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48., Conclusions: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48., Trial Registration Number: NCT01500551., Competing Interests: Competing interests: HIB has received research grants from Bristol Myers Squibb, Novartis and Pfizer; is an employee of Cincinnati Children’s Hospital Medical Center; has received consulting fees or other remuneration from AbbVie, AstraZeneca/MedImmune, Bayer, Biocon, Boehringer Ingelheim, Bristol Myers Squibb, Cerecor, Eli Lilly, EMD Serono, Janssen, Novartis, Pfizer, Roche, R-Pharm and Sobi; and is a member of speaker bureaus for Novartis and Pfizer. JDA has received honorarium from Novartis. JFB has received research grants from AbbVie, Bristol Myers Squibb, Janssen, Pfizer and Roche. ALB is a member of speaker bureaus for AbbVie, Novartis and Roche. RC has received consulting fees or other remuneration from AbbVie, Bristol Myers Squibb, Eli Lilly, GSK, Novartis, Pfizer, Roche and Sanofi. GS has received consulting fees or other remuneration from Novartis and Sobi and research support from IpiNovyx. CN has received research grants from AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GSK, Pfizer and UCB. MV-DM is an employee of Clínica de Investigacion en Reumatologia y Obesidad, SC. HP, CC, CWh, KeK and SL are employees and stockholders of Pfizer. AW was an employee and stockholder of Pfizer at the time of this analysis. AM has received consulting fees or other remuneration from Aurinia, Bristol Myers Squibb, Eli Lilly, EMD Serono, Janssen and Pfizer. DL’s institution, the Cincinnati Children’s Hospital Medical Center, has received research grants from Bristol Myers Squibb, Janssen, Novartis, Pfizer, Roche and UBC; and has received consulting fees or other remuneration from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Novartis, Pfizer, Takeda and UBC. DL is also a data safety and monitoring board member or chairperson for the National Institutes of Health and the Canadian Arthritis Society. NR has received honoraria for consultancies or speaker bureaus from Ablynx, AstraZeneca/MedImmune, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EMD Serono, F Hoffmann-La Roche, GS, Janssen, MSD, Novartis, Pfizer, R-Pharm, Sanofi, Servier, Sinergie and Sobi. The IRCCS Istituto Giannina Gaslini, where NR works as a full-time public employee, has received contributions from Bristol Myers Squibb, Eli Lilly, F Hoffmann-La Roche, GS, Janssen, Novartis, Pfizer and Sobi; this funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties. EA-A, GC, WDLP, LJ, ÖK, KaK, RR-C, JCRR, LW-W, JEW and CWo have declared no conflicts., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: Although treatments for juvenile idiopathic arthritis (JIA) have seen considerable advancements, there remains a lack of clear guidelines on withdrawing medications. This study aimed to investigate the current strategies for discontinuing non-systemic JIA treatment., Methods: A web-based questionnaire was distributed to members of the Pediatric Rheumatology Association of Japan., Results: According to 126 responses, the most significant factors influencing JIA treatment tapering were the duration of clinically inactive disease, medication toxicity, and a history of arthritis flares. Respondents were often cautious about discontinuing medication if symptoms, e.g. 'morning stiffness' or 'intermittent joint pain', persisted. Among subtypes, oligoarticular JIA was more amenable to treatment tapering, whereas rheumatoid factor-positive polyarticular JIA proved less amenable. Most respondents started medication tapering after a continuous clinical inactive duration exceeding 12 months, and >50% of them required >6 months to achieve treatment discontinuation. Additionally, 40% of the respondents consistently underwent imaging before treatment tapering., Conclusions: The relative risks of treatment continuation and withdrawal should be considered, and decisions should be made accordingly. To obtain improved understanding of and more robust evidence for the optimal strategies for safely discontinuing JIA treatment, it is crucial to continue investigations including long-term outcomes., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research., Methods: This prospective observational cohort study was conducted at nine pilot sites between February 2020 and August 2022. Patients with JIA-associated CAU (JIA-U) were treated according to either the MTX or TNFi CTP. Uveitis activity and medication use were recorded at 0, 3, and 6 months. We assessed patient enrollment rates, CTP arm selection, uveitis control, and quality of data collection. We also evaluated CTP arm selection in a retrospective cohort of similar JIA-U patients enrolled in the CARRA Registry during the same study period., Results: Seventeen patients were included in the pilot cohort. Eight were treated with the MTX CTP (4 oral MTX, 4 subcutaneous MTX), and 9 with the TNFi CTP (9 received standard-dose adalimumab, none selected high-dose adalimumab or infliximab). Uveitis was controlled in 13 of 17 patients by 6 months. Query of the CARRA-wide Registry identified 42 patients with JIA-U who were treated according to the MTX or TNFi CTPs. Among these, 26 were treated with MTX (8 oral, 18 subcutaneous) and 16 with TNFi (12 standard dose adalimumab, 2 high dose adalimumab, and 2 infliximab)., Conclusion: Both the MTX and TNFi uveitis CTPs can practically be implemented in clinical settings and are currently being utilized across Registry sites. However, in patients starting TNFi therapy, all pilot study participants and most patients across the CARRA Registry were treated with a standard dose of adalimumab. This consensus on the treatment approach underscores its broad acceptance but also limits the applicability of the uveitis TNFi CTP for comparative effectiveness research., (© 2024. The Author(s).)

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatic disease in children, and adalimumab is one of the primary treatment options. Although it is widely used for inflammatory diseases, there is limited research on its safety and efficacy in patients with psychiatric disorders or in those with inflammatory diseases who also have comorbid psychiatric conditions., Case Report: We report a 12-year-old adolescent boy who presented with emotional instability for 1 year, exacerbated leading to hospital admission in the past month. Upon detailed evaluation after admission, it was found that the patient's emotional fluctuations may be related to the use of Adalimumab. Follow-up after psychiatric inpatient treatment revealed that the patient did not experience emotional excitement again after discontinuing Adalimumab., Conclusions: Although tumor necrosis factor-α inhibitors have positive effects on the emotional, cognitive, and physical functions of patients with inflammatory diseases, their use may induce mood swings in patients with comorbid mood disorders. This is particularly important for adolescents with rapid mood changes, where greater caution is required. Further research is necessary to clarify the correlation between the adverse effects of these drugs and their impact on patients with bipolar disorder., (© 2024. The Author(s).)

Objectives: To determine features and frequency of ultrasound (US)-detected tenosynovitis in ankles with clinically active disease and to investigate whether its detection may affect the achievement of inactive disease in patients with new-onset juvenile idiopathic arthritis (JIA)., Methods: The study included children with new-onset JIA and clinically active disease of the ankle. Based on US, patients were stratified as having isolated arthritis or as having tenosynovitis irrespective of the presence of concomitant arthritis in the ankle. Estimation of patients who were able to achieve clinically inactive disease 6 months after starting treatment was assessed by the Kaplan-Meier method. Cox model was used to calculate hazard ratio (HR) and 95% confidence interval (CI). Reliability of US was tested using kappa statistic., Results: Forty-five patients were recruited. On US, tenosynovitis of the ankle was detected in 28 patients (62.2%); isolated arthritis was found in 17 patients (37.8%). The medial and lateral tendon compartments were the tendon sites most frequently inflamed. Patients with tenosynovitis had similar likelihood of those without tenosynovitis to achieve clinically inactive disease (60.7% and 58.8%, respectively; HR 1.12, 95%CI:0.51-2.45). In the subanalysis excluding patients who were given biologics, the probability of experiencing inactive disease was slightly higher for patients with tenosynovitis compared to those without (64.7% and 54.5%, respectively; HR 1.56, 95%CI: 0.58-4.24). The rate of US reliability was high., Conclusions: US-detected tenosynovitis is frequent in ankles with clinical arthritis at JIA onset but does not impair the chance of achieving clinically inactive disease in the early disease phase.

Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease in childhood, and is associated with uveitis in up to 20-25% of cases. Typically, the uveitis is chronic, asymptomatic, non-granulomatous and anterior. For this reason, screening for uveitis is recommended to identify uveitis early and allow treatment to prevent sight-threatening complications. The management of JIA associated uveitis requires a multidisciplinary approach and a close collaboration between paediatric rheumatologist and ophthalmologist. Starting the appropriate treatment to control uveitis activity and prevent ocular complications is crucial. Current international recommendations advise a step-wise approach, starting with methotrexate and moving on to adalimumab if methotrexate alone is not sufficient to control the disease. If the uveitis remains active despite standard treatment other therapeutic options may be considered including anti-IL6 or other anti-TNF agents such as infliximab, although the evidence for these agents is limited., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Catherine Guly reports a relationship with Eli Lilly and Company that includes: consulting or advisory, funding grants, and speaking and lecture fees. Athimalaipet V Ramanan reports a relationship with Eli Lilly and Company that includes: consulting or advisory, funding grants, and speaking and lecture fees. Athimalaipet V Ramanan reports a relationship with AbbVie Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Athimalaipet V Ramanan reports a relationship with Pfizer that includes: consulting or advisory, funding grants, and speaking and lecture fees. Athimalaipet V Ramanan reports a relationship with Alimera Sciences Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Athimalaipet V Ramanan reports a relationship with Roche that includes: consulting or advisory, funding grants, and speaking and lecture fees. Athimalaipet V Ramanan reports a relationship with Novartis that includes: consulting or advisory, funding grants, and speaking and lecture fees. Athimalaipet V Ramanan reports a relationship with UCB Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Gabriele Simonini reports a relationship with AbbVie Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Gabriele Simonini reports a relationship with Sobi Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Gabriele Simonini reports a relationship with Novartis that includes: consulting or advisory, funding grants, and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose of Review: This review summarises the major novel treatment options for children with juvenile idiopathic arthritis (JIA) since the pandemic, reflecting not only on advancements in therapeutics but also approach to management and research., Recent Findings: Several recent international paediatric trials have been important in advancing understanding of JIA and furthering available treatment options. Biologic and small molecule agents were demonstrated to be effective and safe in recalcitrant or severe JIA (including extra-articular complications), mirroring the adult equivalent diseases., Summary: Although joint and overall health have vastly improved for young people with JIA, ongoing international collaboration, critical review of treatment strategies and high quality research are essential to optimize outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The aim of this study is to investigate the effect of anti-interleukin (IL)-1/-6 biologics on systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome (MAS)., Methods: Demographic, clinical and laboratory data of patients followed up with a diagnosis of sJIA-associated MAS assessed from sixteen paediatric rheumatology centres across the country. The clinical and laboratory features of MAS developing while on biological drugs were compared with those without this treatment., Results: One hundred and sixty-two patients were included in the study. Forty-five of the MAS events were detected under the effect of anti-IL-1/-6 biologics, while the patients experiencing the remaining 155 events have not received biological treatment in the last three months. Platelet count [128 (72-232) vs 199 (130-371) 109/l], ferritin level on admission [1107 (676-2050) vs 2863 (1193-9562) ng/ml], C-reactive protein level [15.4 (2.9-56) vs 90 (32-160) mg/l], erythrocyte sedimentation rate [13 (3-36) vs 43.5 (13-77) mm/h] and fever duration [5 (4-7.5) vs 10 (7-14.3) days] were found lower in the group under the impact of anti-IL-1/-6 biologics. Among patients treated with biologics, 26.6% did not meet the published 2016 MAS classification criteria at presentation. The rates of hepatomegaly and splenomegaly were relatively lower in the canakinumab-treated group when compared with those receiving other biologicals or to patients, not on biologicals., Conclusion: Anti-IL-1/-6 therapies can mask the clinical and laboratory features of MAS, and proposed guidelines for MAS classification criteria may not be met., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing 2005-2010 and 2017-2021 inception cohorts., Methods: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan-Meier survival analysis and multivariable Cox regression., Results: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for good health-related quality of life (≥9/10)., Conclusion: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient-reported outcomes were smaller than improvements in disease activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The genetic architecture of JIA remains only partially comprehended. There is a clear imperative for continued endeavours to uncover insights into the underlying causes of JIA., Methods: This study encompassed a comprehensive spectrum of endeavours, including conducting a JIA genome-wide association study (GWAS) meta-analysis that incorporated data from 4550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritizing target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA., Results: Fourteen genome-wide significant non-HLA loci were identified, including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and BMD traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for the affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized., Conclusions: Our identification of four novel JIA-associated genes, CD247, RHOH, COLEC10 and IRF8, broadens the novel potential drug repositioning opportunities. We established a new genetic link between COLEC10, TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In juvenile idiopathic arthritis we have seen remarkable progress in the number of available licensed biological and small molecule treatments in the past two decades, leading to improved outcomes for patients. Designing clinical trials for these therapeutics is fraught with ethical, legislative, and practical challenges. However, many aspects of current clinical trial design in juvenile idiopathic arthritis do not meet the needs of patients and clinicians. Commonly used withdrawal trial designs raise substantial ethical concerns for patients and families who believe that they do not enable evidence-based and patient-centred decisions around medication choices. In this Viewpoint, we present the personal views of a patient and parent network that is of the opinion that current trial design in juvenile idiopathic arthritis is failing children and young people with juvenile idiopathic arthritis and set out the need for change informed by lived experience., Competing Interests: Declaration of interests AVR has received consulting fees from Eli Lilly, UCB, AbbVie, Novartis, and Alimera Biosciences. AVR has also received payment or honoraria from Eli Lilly, AbbVie, Pfizer, Novartis, Roche, and Sobi. AVR has participated on a data safety monitoring board or advisory board for Eli Lilly. EE is a trustee for Children's Chronic Arthritis Association (charity number 1185378). All other authors declare no competing interests. Funding for the CLUSTER Project has been provided by generous grants from the Medical Research Council (grant number MR/R013926/1), Versus Arthritis (grant number 22084), Great Ormond Street Hospital Children's Charity (grant number VS0518), and Olivia's Vision. This work is supported by the National Institute for Health and Care Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre, the NIHR Manchester Biomedical Research Centre, the British Society for Rheumatology, and the UK's Experimental Arthritis Treatment Centre for Children, supported by Versus Arthritis (grant number 20621). The CLUSTER consortium has been provided with generous grants from AbbVie and Sobi, and in-kind contributions from GSK, Pfizer, and UCB. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNF-α inhibitors (TNFi) in JIA patients., Methods: This was a retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were immediately discontinued, spaced (increased treatment interval) or tapered (reduced subsequent doses). Costs of hospital-associated resource use (consultations, medication, radiology procedures, laboratory testing, procedures under general anaesthesia, hospitalization) and associated travel costs and productivity losses were quantified during clinically inactive disease until TNFi withdrawal (pre-withdrawal period) and compared with costs during the first and second year after withdrawal initiation (first and second year post-withdrawal)., Results: Fifty-six patients were included of whom 26 immediately discontinued TNFi, 30 spaced and zero tapered. Mean annual costs were €9165/patient on active treatment (pre-withdrawal) and decreased significantly to €5063/patient (-44.8%) and €6569/patient (-28.3%) in the first and second year post-withdrawal, respectively (P < 0.05). Of these total annual costs, travel costs plus productivity losses were €834/patient, €1180/patient, and €1320/patient in the three periods respectively. Medication comprised 80.7%, 61.5% and 72.4% of total annual costs in the pre-withdrawal, first and second year post-withdrawal period, respectively., Conclusion: In the first two years after initiating withdrawal, the total annual costs were decreased compared with the pre-withdrawal period. However, cost reductions were lower in the second year compared with the first year post-withdrawal, primarily due to restarting or intensifying biologics. To support biologic withdrawal decisions, future research should assess the full long-term societal cost impacts, and include all biologics., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Coronavirus disease 2019 (COVID-19) has influenced the world over the last 3 years. Although the risk of a severe course is low in children, it can be influenced by chronic rheumatic diseases or treatment with immunosuppressive drugs or immunomodulatory medication. The German register for biologics in pediatric rheumatology (BIKER) documented systematic data from 68 centers on the occurrence, presentation and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in children with rheumatic diseases. Between March 2020 and December 2022, a total of 927 SARS-CoV‑2 infections in 884 patients could be reported and analyzed in pediatric patients with rheumatic diseases. Juvenile idiopathic arthritis (JIA) was the most frequent diagnosis (716 infections) followed by genetic autoinflammation (103 infections), systemic autoimmune diseases (78 infections), idiopathic uveitis (25 infections) and vasculitis (5 infections). Only four patients were treated as inpatients. A 3.5-year-old female patient died during the first wave from encephalopathy and respiratory failure. The patient was treated with methotrexate (MTX) and steroids for systemic JIA. Genetic tests revealed a previously unknown congenital immune defect. No other patient had to be ventilated or treated on the intensive care unit. A case of uncomplicated pediatric inflammatory multisystem syndrome (PIMS) was registered in a patient with JIA treated with MTX. At the time of the infection over 60% of the patients were treated with standard disease modifying antirheumatic drugs (DMARD) and/or biologics. Although the patients treated with MTX showed a slightly longer duration of symptoms, the antirheumatic treatment did not appear to have a negative influence on the severity or outcome of the SARS-CoV‑2 infection., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: The aim of this study was to report the interim 5-year safety and effectiveness of abatacept in patients with JIA in the PRINTO/PRCSG registry., Methods: The Abatacept JIA Registry (NCT01357668) is an ongoing observational study of children with JIA receiving abatacept; enrolment started in January 2013. Clinical sites enrolled patients with JIA starting or currently receiving abatacept. Eligible patients were assessed for safety (primary end point) and effectiveness over 10 years. Effectiveness was measured by clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10) in patients with JIA over 5 years. As-observed analysis is presented according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines., Results: As of 31 March 2020, 587 patients were enrolled; 569 are included in this analysis (including 134 new users) with 1214.6 patient-years of safety data available. Over 5 years, the incidence rate (IR) per 100 patient-years of follow-up of serious adverse events was 5.52 (95% CI: 4.27, 7.01) and of events of special interest was 3.62 (95% CI: 2.63, 4.86), with 18 serious infections [IR 1.48 (95% CI: 0.88, 2.34)]. As early as month 3, 55.9% of patients achieved cJADAS10 low disease activity and inactive disease (20.3%, 72/354 and 35.6%, 126/354, respectively), sustained over 5 years. Disease activity measures improvement over 5 years across JIA categories., Conclusion: Abatacept was well tolerated in patients with JIA, with no new safety signals identified and with well-controlled disease activity, including some patients achieving inactive disease or remission., Trial Registration: Clinicaltrials.gov, NCT01357668., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: TNF inhibitors (TNFi) have dramatically changed the prognosis of juvenile idiopathic arthritis (JIA), but it is not clear how and when to stop therapy. We aim to describe a multicentric cohort of JIA treated with adalimumab or etanercept who discontinued the treatment for persistent inactivity and to identify factors associated with relapse., Methods: In a multicentric Italian retrospective cohort study, medical records of patients with oligoarticular and polyarticular JIA were evaluated if they stopped therapy for persistent inactivity after the first TNFi., Results: 136 patients were enrolled (102 female, median age at onset 3 years (range 1-15), of whom 55.9% had oligoarticular JIA, 40.4% uveitis and 72.8% ANA positivity. Adalimumab (59.3%) and etanercept (40.7%) were started at a median age of 6 years (range 1-16), TNFi were discontinued after a median time of 30 months (range 6-90), increasing the interval (76.5%), reducing the dose (18.4%) and abrupt discontinuation (16.9%). 79.4% of patients relapsed after a median time of 5 months (range 0.5-66). Patients with uveitis relapsed earlier (log rank χ² 16.4 p<0.0001), while patients who lengthened the interval of administration showed a later relapse (log rank χ² 6.95 p=0.008). Uveitis (HR 2.11 CI 1.34-3.31), age at onset (HR 0.909 CI 0.836-0.987), duration of tapering (HR 0.938 CI 0.893-0.985) and to have a persistent oligoarticular JIA (HR 0.597 CI 0.368-0.968) are significant predictors of disease relapse (Mantel-Cox χ² 34.23 p<0.001)., Conclusions: Younger age at onset, uveitis, duration of tapering, and non-persistent oligoarticular JIA seem to be independent risk factors for earlier relapse after the first TNFi withdrawal.

Objective: To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA)., Methods: Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight-based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE., Results: Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 μg/ml; sJIA, ∼75 μg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection)., Conclusion: Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile., Clinical Trial Registration: clinicaltrials.gov, NCT02165345., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Juvenile idiopathic arthritis is the most common rheumatic disorder in childhood and adolescence posing a significant threat of short-term and long-term disability if left untreated. Methotrexate is a folic acid analog with various immunomodulatory properties. It has demonstrated significant efficacy for the treatment of juvenile idiopathic arthritis, often considered the preferred first-line disease-modifying anti-rheumatic drug given as monotherapy or in combination with biological drugs. Despite this, there is a considerable risk for treatment disruptions owing to the high prevalence of methotrexate intolerance, with symptoms such as nausea, stomach ache, vomiting, and behavioral symptoms. Many different risk factors for the intolerance have been proposed including gender, age, disease activity, treatment duration, dosing and administration, and genetic and psychological factors. As the studies have shown contradictory results, many questions are left unanswered. Therefore, a consensus regarding outcome measures and reporting is crucial. In this review, we describe the identification and assessment of methotrexate intolerance and evaluate potential risk factors, genetic associations as well as management strategies., (© 2024. The Author(s).)

Introduction: The most frequent adverse events (AEs) of methotrexate (MTX) are gastrointestinal symptoms and hepatotoxicity, which can affect its adherence, leading to reduced effectiveness. The SLCO1B1 gene codes for a liver protein (OATP1B1) responsible for drug transportation. Genetic variations within the SLCO1B1 gene locus impact drug transport, leading to altered pharmacokinetic profiles, delayed MTX clearance, and increased risk of toxicity. This study aimed to determine the association between single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene (rs4149056, rs2306283) with the development of AEs in patients with juvenile idiopathic arthritis (JIA) treated with MTX., Method: We performed an observational retrospective study to analyze the relationship between SNPs in the SLCO1B1 gene and the development of AEs in pediatric patients treated with MTX for JIA., Results: Thirty patients with JIA were included, 22 females (73.3%), with a median age of 11 years (IQR 8.3-15). The most frequent JIA subtype was rheumatoid factor-positive polyarthritis (36.7%). Twenty patients (66.7%) reported AEs. The *1B haplotype was the most frequent in this group (53.3%) and conferred a higher risk of developing AEs (OR = 3.89, 95% CI = 1.23 -12.29, p = 0.03)., Conclusions: Patients with the allele *1B may benefit from lower doses of MTX. SLCO1B1 genotyping is a promising technique to identify patients at higher risk of AEs during treatment with MTX, thus requiring dose optimization., Competing Interests: Declarations. Disclosures: None., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Juvenile idiopathic arthritis (JIA) refers to various types of arthritis appearing before age 16, categorized into seven subtypes by ILAR. Treatments target disease control, growth support, and quality of life, utilizing NSAIDs, DMARDs, and intraarticular corticosteroid injections (IACIs). Despite IACIs' efficacy for oligoarticular JIA, their usage and techniques vary due to anecdotal evidence. This study compares IACI strategies among pediatric rheumatologists in Turkey and India as part of a PReS Sister Center activity. A cross-sectional survey via Google Forms gathered IACI practice data from pediatric rheumatologists in Turkey and India. The 33-item questionnaire covered demographics, JIA subtypes treated with IACIs, preferred agents/dosages, injection sites, follow-up, complications, anesthesia, and post-IACI treatments. Seventy clinicians' responses were analyzed, with ethical approval from Gazi University's Ethics Committee. Seventy participants, with a mean age of 39.75 (±8.80) years responded, mostly clinical fellows (38.6%) at university hospitals (58.6%). All utilized IACIs, primarily for oligoarticular JIA (100%), with 20% exclusively using them for this subtype. Triamcinolone hexacetonide (TH) was preferred (74.3%), mainly targeting knee joints (15.7%). Initial side effect follow-up was 1-2 weeks post-IACI (65.7%), with ultrasound guidance used by 17.1%. Common complications included cutaneous hypopigmentation (38.6%) and subcutaneous atrophy (38.6%). Ketamine was the favored anesthesia (44.2%). Post-IACI, 21.4% did not add treatment for new-onset oligoarticular JIA, while NSAIDs and methotrexate were common for polyarticular JIA (51.4%)., Conclusion: IACIs are widely utilized in pediatric rheumatology for oligoarticular JIA, yet practice variability exists. Standardized protocols through randomized studies can enhance IACI efficacy and patient outcomes., What Is Known: • Intraarticular corticosteroid injections (IACIs) are a widely utilized and effective treatment modality in managing oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), offering rapid symptom relief and the potential to prevent long-term joint deformities. • Despite their widespread use, there is significant variability in the indications, techniques, and anesthetic methods employed for IACI administration among pediatric rheumatologists, and much of the supporting evidence remains anecdotal., What Is New: • This study highlights the diverse clinical practices and preferences regarding IACI use in pediatric rheumatology across two different countries, revealing considerable variations in the use of ultrasound guidance, anesthetic approaches, and corticosteroid formulations. • The findings underscore the need for standardized treatment protocols and further research to optimize IACI procedures, aiming to reduce variability and improve outcomes in the management of JIA., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Juvenile idiopathic arthritis (JIA) is the most prevalent pediatric rheumatic disease. While disease-modifying antirheumatic drugs (DMARDs), especially biologics, have greatly transformed the management of JIA, there remain some unmet medical needs that require new treatment options. The objective of this work was to describe and apply a modeling and simulation approach to extrapolate upadacitinib efficacy from the adult diseases, rheumatoid arthritis (RA) and psoriatic arthritis (PsA), to their respective pediatric diseases, polyarticular course JIA (pcJIA), and juvenile PsA (JPsA). A population pharmacokinetic model characterized upadacitinib pharmacokinetics in pediatric patients using data from two phase I studies in pediatric patients with pcJIA (N = 51) or atopic dermatitis (N = 33). Efficacy simulations were conducted using previously developed exposure-response models in adults with RA and PsA. Real-world pcJIA and JPsA patient databases were leveraged to construct representative patient profiles for the targeted population. Following administration of the proposed weight-based dosing regimen, the model-predicted median upadacitinib plasma exposures in pediatric patients were within 20% of those in adult RA and PsA patients receiving the approved adult regimen. Simulations demonstrate that upadacitinib efficacy in pcJIA and JPsA is predicted to be non-inferior to that in adults with RA or PsA, respectively. The results of this work enabled recent approvals of upadacitinib for the treatment of polyarticular JIA and JPsA in the United States. Upadacitinib safety in pediatrics is being further evaluated in ongoing clinical trials., (© 2024 AbbVie Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Enthesitis-related arthritis (ERA) is a subtype of juvenile idiopathic arthritis with high disease burden. The objectives of this study were to explore the prevalence of HLA-B27, clinical characteristics, and treatment outcomes in children with ERA and compare the differences between HLA-B27 positive and negative patients., Methods: A retrospective cohort study at a pediatric rheumatology clinic in a tertiary referral hospital in Bangkok, Thailand, including ERA patients with at least 6 months of follow-up (July 2011-April 2022) was performed. Data were collected from medical records from diagnosis to recent follow-up, assessing disease activity and treatment outcomes, with an analysis comparing HLA-B27 positive and negative patients. Descriptive statistics were used for data analysis., Results: There were 59 ERA patients with mean age ± SD at diagnosis 11.2 ± 2.5 years, 53 males (89.8%), and positive HLA-B27 in 38 patients (64.4%). The HLA-B27 positive group had significantly higher levels of inflammatory markers at initial diagnosis (p = 0.001), lower baseline hemoglobin (p = 0.001) and hematocrit (p = 0.002), higher disease activity assessed by the Juvenile Spondyloarthritis Disease Activity score at 6 and 12 months of follow-up (p = 0.028 and 0.040, respectively), increased utilization of bridging systemic corticosteroids (60.5% vs. 14.3%, p = 0.001) and anti-TNF (39.5% vs. 9.5%, p = 0.018), and longer duration of methotrexate (median[IQR] 1.7[1.1-3.1] vs. 1.3[0.6-1.9] years, p = 0.040). The HLA-B27 negative group had more prevalent hip arthritis than the positive group at initial diagnosis (66.7% vs. 28.9%, p = 0.005) and during the course of the disease (71.4% vs. 36.8%, p = 0.011)., Conclusion: Most of the ERA patients tested positive for HLA-B27. Throughout the follow-up period, these patients demonstrated greater disease activity, greater use of corticosteroids and anti-TNF, and longer duration of methotrexate to control the disease., (© 2024. The Author(s).)

Objectives: Our study aimed to evaluate the relationship of small joint involvement with demographic, clinical, and laboratory findings and to determine its possible effects on prognosis., Methods: This retrospective observational study was conducted in patients diagnosed with oligoarticular juvenile idiopathic arthritis (oJIA) in the paediatric rheumatology department of Ankara City Hospital between April 2009 and September 2022. The relationship between small joint involvement and demographic, clinical, and laboratory findings and prognosis was investigated by statistical methods with the data recorded from the medical records of oJIA patients., Results: Of the 198 patients diagnosed with oJIA, small joint involvement was observed in a total of 20 (10%) patients, 11 (5.5%) at the time of diagnosis, and 9 (4.5%) during the follow-up period. The frequency of small joint involvement in extended oJIA was significantly higher than in persistent oJIA (P = .001). Patients with small joint involvement had significantly higher erythrocyte sedimentation rate and C-reactive protein values at admission (P = .047, P = .038) and Juvenile Arthritis Disease Activity Score at 3, 6, and 12 months (P = .001, P = .001, P = .018). The need for conventional disease-modifying antirheumatic drugs and biologic disease-modifying antirheumatic drugs was significantly higher in patients with small joint involvement (P = .001, P = .001)., Conclusions: oJIA patients with small joint involvement may have higher acute phase reactants at diagnosis, a more extended course and active disease in follow-up, and the need for treatment escalation., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objective: The aim of this study was to assess the efficacy and safety of etanercept (ETA) use in juvenile idiopathic arthritis (JIA)., Methods: The 24-month data of patients with JIA on etanercept in a single center were evaluated retrospectively. Response to treatment was assessed according to 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), and JIA-American College of Rheumatology (ACR) improvement criteria. Safety assessments were based on adverse event (AE) reports., Results: The study included 152 patients with JIA. The mean age at diagnosis of JIA was 8.5 ± 4.4 years, and treatment with ETA started at a mean age of 11.1 ± 4.4 years. The mean duration of ETA use was 16 ± 11.1 months. The mean JADAS10 score at baseline was 18.5 ± 5.9. By the third month, it had reduced to 8.6 ± 6.6 and by the sixth month to 5.7 ± 6. By the twelfth month, the JADAS10 score was 4.9 ± 6.7, and by the twenty-fourth month, it had worsened to 7.3 ± 7.8. ACR50 response was achieved in 79.6% of patients at 3 months, 67.1% at 6 months, 79.3% at twelfth months, 70.7% at the twenty-fourth month. During ETA treatment, 10 patients required hospitalization for serious infections., Conclusion: Etanercept is a safe and effective option for patients with JIA. However, variations in response between JIA subtypes highlight the need for individualized treatment strategies.

Objective: The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non-TNFi biologic following discontinuation of a TNFi for patients with polyarticular-course juvenile idiopathic arthritis (pJIA)., Methods: Using the Childhood Arthritis and Rheumatology Research Alliance Registry, patients with pJIA who started receiving a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on the index date and a visit six months after the index date. Outcome measures included Clinical Juvenile Arthritis Disease Activity Score with a maximum of 10 active joints (cJADAS10), cJADAS10 inactive disease (ID; ≤2.5) and cJADAS10 minimal disease activity (MiDA; ≤5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aORs) were calculated using propensity score quintiles to compare outcomes at six months following second biologic initiation., Results: There were 216 patients included, 84% initially received etanercept, and most patients stopped receiving it because of its ineffectiveness (74%). A total of 183 (85%) started receiving a second TNFi, and 33 (15%) started receiving a non-TNFi. Adalimumab was the most common second biologic received (71% overall, 84% of second TNFi), and tocilizumab was the most common non-TNFi second biologic received (9% overall, 58% of non-TNFi). There was no difference between receiving TNFi versus non-TNFi in cJADAS10 ID (29% vs 25%; aOR 1.23, 95% confidence interval [CI] 0.47-3.20) or at least MiDA (43% vs 39%; aOR 1.11, 95% CI 0.47-2.62) at six months., Conclusion: Most patients with pJIA started receiving TNFi rather than non-TNFi as their second biologic, and there were no differences in disease activity at six months., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1., Methods: Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs., Results: Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6., Conclusion: LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The spectrum of Juvenile Idiopathic Arthritis (JIA) in Africa is still largely unknown. We thus set out to illustrate how we set up the PAFLAR JIA registry and describe the clinical profile of Juvenile Idiopathic Arthritis across various regions in Africa., Methods: We carried out a retrospective observational cohort study where collaborators were trained on use of the existing PAFLAR REDCAP database to enter data for the JIA patients currently under their care capturing their epidemiological data, clinical features, laboratory investigations, diagnosis and therapy at initial diagnosis. Descriptive statistics including means, standard deviations, medians, interquartile ranges (IQR) for continuous variables and proportions for categorical variables were calculated as appropriate. Tests for difference between groups were performed between categorical variables using Pearson's chi-square or Fisher's exact tests. All analyses were performed using SPSS version 22 software., Results: We enrolled 302 patients, 58.6% (177 of 302) of whom were female. The median age of disease onset was 7 years (range 3-11 years) and the median age at diagnosis was 8.5 years (range 5-12 years). The median duration delay in diagnosis was 6 months (range 1-20.8 months). The JIA categories included Systemic JIA 18.9% (57), Oligoarticular JIA 19.2% (83), Polyarticular RF + ve 5% (15), Polyarticular RF-ve 17.9% (54), Enthesitis Related Arthritis (ERA) 18.2% (55), Psoriatic Arthritis 7% (21) and undifferentiated JIA 5.6% (17). As regards treatment the commonest therapies were NSAID therapy at 31.1%, synthetic DMARDs at 18.1%, synthetic DMARDs combined with NSAIDs at 17.5% and steroid therapy at 9.6%. Biological DMARDs accounted for 2.3% of therapies offered to our patients at diagnosis. The average JADAS score was 10.3 (range 4.8-18.2) and the average CHAQ score was 1.3 (range 0.7-2.0)., Conclusion: Our study highlights strategies involved in setting up a Pan-African paediatric rheumatology registry that embraces our broad diversity and the vast spectrum of JIA in Africa while comparing the various therapies available to our patients. The PAFLAR JIA registry strives to ensure a comprehensive representation of the diverse healthcare landscapes within the continent. Further longitudinal observation studies are required to ascertain the long-term outcomes of our patients and ultimately help inform policy to create a more favorable health ecosystem to support the healthcare needs of JIA patients in Africa., (© 2024. The Author(s).)

Background: Pediatric uveitis poses challenges in diagnosis and treatment due to asymptomatic or oligosymptomatic presentations and high rates of intraocular complications., Objectives: This study aimed to characterize clinical manifestations and treatment approaches of pediatric uveitis patients in a northern Portuguese tertiary hospital., Methodology: A retrospective study was conducted involving 41 patients diagnosed with uveitis between 2006 and 2021. All individuals identified by the Opthalmology department were referred to Pediatric Rheumatology outpatient clinic. Demographic, clinical, treatment, and intraocular complications data were collected., Results: Of the patients, 78% had anterior uveitis, 17% had panuveitis, and 5% had intermediate uveitis. Uveitis associated with juvenile idiopathic arthritis (JIA) was the most common cause (43.9%), predominantly in the oligoarticular, anti-nuclear antibody-positive subgroup. Complications were identified in 80.5% of the patients. Uveitis associated with JIA was diagnosed earlier [5.0 years (3.0-10.5) vs. 9.0 years (5.5-14.0), P = .036], more frequently in asymptomatic patients (71% vs. 23%, P = .010), had a more insidious installation (71% vs. 17%, P = .004), and required more tumor necrosis factor (TNF) inhibitor treatment (70% vs. 39%, P = .027)., Conclusion: The high rates of intraocular complications and systemic pathology association highlight the need for a combined approach of ophthalmology and pediatric rheumatology in the diagnosis and treatment of pediatric uveitis., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Intra-articular corticosteroid injection (IACI) is a safe first-line or adjunct therapy used in any subtype of juvenile idiopathic arthritis (JIA). Limited studies evaluated the effect of IACI on cartilage. Our study aimed to examine the femoral cartilage thickness of patients with JIA who received IACI to the knee joint using ultrasound., Methods: We randomly selected JIA patients who performed IACI in the knee joint. Baseline bilateral joint cartilage and tendon thicknesses were measured. The articular fluid was aspirated, and applied IACI at the same period. Six months after injection, the exact measurements were repeated. Distal femoral cartilage, quadriceps tendon, and distal and proximal patellar tendon thicknesses were compared at the baseline (before IACI) and 6 months after IACI., Results: Thirty patients with JIA were included, and 23 (76.7%) were female. The median age was 11 years (interquartile range, 6 to 14), and the median disease duration was 3.3 years (interquartile range, 5 months to 5 years). The subtypes of JIA were oligoarticular in 25 (83.3%), polyarticular in 2 (6.7%), enthesitis-related arthritis in 2 (6.7%), and juvenile psoriatic arthritis in 1 (3.3%). Distal femoral cartilage thickness was 2.96 ± 0.79 mm at baseline and 2.85 ± 0.70 mm at 6 months after IACI (P = .35). The tendon thicknesses were similar at 6 months after baseline measurements., Conclusions: Our findings reveal that knee IACI in patients with JIA did not significantly change cartilage and tendon thicknesses. This observation could indicate that IACIs have no detrimental effects on the cartilage and the tendons., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: This review summarizes latest developments in treatment of juvenile spondyloarthritis (JSpA), specifically enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA)., Recent Findings: There has been addition of biologic disease modifying antirheumatic drugs (bDMARDs) beyond tumor necrosis factor inhibitors (TNFi) for JSpA such as IL-17 blockers, IL-23 blockers, and janus activating kinase inhibitors with favorable safety profile. Conducting robust clinical trials for this subpopulation of JIA remains a challenge; extrapolation studies are being used to obtain approval from regulatory agencies., Summary: Newer drug therapies have expanded the scope of treatment for patients with JSpA. bDMARDs such as adalimumab, etanercept, infliximab, and secukinumab have demonstrated clinically significant treatment efficacy in ERA and JPsA. Based on extrapolation studies, intravenous golimumab, etanercept, abatacept, and ustekinumab have gained Food and Drug Administration (FDA) approval for JPsA. Long-term follow-up studies continue to demonstrate acceptable safety profiles. There is need for more real-world data on drug efficacy from Registry studies and research on effective de-escalation strategies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: - Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment., Methods: - We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology., Results: - 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment., Conclusion: - JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases., Competing Interests: Declaration of Competing Interest AB has received grant support from Boehringer Ingelheim, Merck Serono, and consultant fees from Novartis, RocheChugai, GSK., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability., Materials and Methods: Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates., Results: A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure., Conclusions: Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA., (© 2024. The Author(s).)

Background: For cost-saving purposes, children and young people with juvenile idiopathic arthritis (JIA) are being switched (for non-medical reasons) from biological originators to biosimilars. Here, we aimed to investigate those who switched from an anti-tumour necrosis factor (TNF) originator to a biosimilar, regarding drug survival and disease activity, compared with a matched cohort who continued the originator., Methods: This analysis included all patients in the UK JIA Biologics Register switching directly from an anti-TNF originator to a biosimilar of the same product. All patients were matched (age, sex, disease duration, calendar year of when patients started originator therapy, line of therapy, and International League of Associations for Rheumatology [ILAR] category) to patients continuing the originator. For those matched successfully, a Cox proportional hazard model assessed whether drug persistence differed between those who switched compared with those who continued the originator. Overall change in the 71-joint juvenile arthritis disease activity score and the proportion of patients with a clinically important worsening score (by ≥1·7 units) after 6 months was compared between cohorts. This analysis was designed to address a priority research area set by our patient partners., Findings: There were 224 children and young people with non-systemic JIA (139 [62%] were female, and 85 [38%] were male) identified as switching from a biological originator to a biosimilar of the same product from Jan 1, 2017, to July 7, 2023. 143 (64%) patients were originally on adalimumab, 56 (25%) on etanercept, and 25 (11%) on infliximab. Of these, 164 patients were matched successfully to those continuing the originator. There was no evidence that patients switching were more likely to stop treatment compared with those continuing the originator, with a hazard ratio of 1·46 (95% CI 0·93-2·30). Of the 51 patients in the biosimilar group who stopped treatment, 18 (35%) switched back to the originator (14 in the first year), 28 (55%) started a different biological drug, and five (10%) discontinued all treatment by the last follow-up. Of the 87 matched patients with available disease activity, there was no evidence that JADAS-71 worsened more after 6 months, with an odds ratio of 0·71 (95% CI 0·34-1·51; p=0·38)., Interpretation: In this matched comparative effectiveness analysis, children and young people with JIA switched from originators to biosimilars. Disease activity was similar between patients switching compared with those continuing the originator. Three quarters of patients were still receiving their biosimilar after 1 year, with switching back to originator uncommon, at only 9% after 1 year, suggesting good tolerability of non-medical switching in this patient population. This information is reassuring to clinicians and patients regarding the effect of non-medical biological switching., Funding: British Society for Rheumatology, Versus Arthritis, and National Institutes for Health Research Manchester Biomedical Research Centre., Competing Interests: Declaration of interests KLH reports honoraria from AbbVie and grants from Pfizer and Bristol Myers Squibb unrelated to this manuscript; and is supported by the National Institutes for Health Research (NIHR), Manchester Biomedical Research Centre (NIHR203308). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the dynamics of serum levels of TNF-α in patients with juvenile idiopathic arthritis (JIA) treated with anti-TNF-α biological drugs and investigate their association with the disease activity., Methods: We conducted a single-centre, observational cohort study in 98 patients with JIA (30 boys, 68 girls, mean age 11.3 years) treated with anti-TNF-α biological drugs. Clinical examinations and laboratory assessments of serum levels of TNF-α were performed before starting therapy with biological drug and at 6-month intervals afterwards up to 2.5 years., Results: The analysis of serum levels of TNF-α in relation to the disease activity states showed the highest mean serum levels of TNF-α in patients on etanercept who had low disease activity states and in patients on adalimumab who had inactive disease. The correlation analysis in patients with JIA treated with etanercept or adalimumab showed a weak negative correlation between the serum levels of TNF-α and JADAS10 scores (p = 0.007), (r =  - 0.177)., Conclusion: The assessment of serum levels of TNF-α in children with JIA during treatment with etanercept or adalimumab is not a reliable biomarker of disease activity or immunological remission. Longitudinal measurement of TNF-α has no added clinical value in patients with JIA treated with anti-TNF-α biological drugs. Key Points • There is limited evidence regarding the effect of anti-TNF therapy on serum concentrations of TNF-α in patients with juvenile idiopathic arthritis • Our study showed an increase in the serum level of TNF-α after the initiation of therapy with either etanercept or adalimumab, which was more significant in patients with inactive or low disease activity • Serum TNF-α is most likely not biologically active during therapy with TNF-α inhibitors and therefore not a reliable biomarker of disease activity or immunological remission in patients with juvenile idiopathic arthritis., (© 2024. The Author(s).)

Background: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA)., Methods: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months., Results: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders., Conclusion: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA., (© 2024. The Author(s).)

The purpose of this study was to compare the demographic and clinical characteristics of the groups with and without bDMARDs added to the treatment of persistent oligoarticular juvenile idiopathic arthritis (JIA) patients on methotrexate (MTX) and also to determine the predictors of adding bDMARDs to treatment. This study included 86 oligoarticular JIA patients on MTX. Patients were divided into two groups receiving MTX (n = 69) and MTX plus bDMARD (n = 17). Predictors of adding bDMARDs were investigated by comparing demographic, clinical features and laboratory findings. Gender, age at diagnosis, time elapsed from the onset of symptoms to diagnosis, and disease duration, the number and distribution of affected joint at the time of diagnosis were similar in both groups. The mean JADAS10 at the time of diagnosis were 18.8 ± 4.2 and 19.5 ± 6.4 in the MTX and MTX plus bDMARDs groups, respectively (p = 0.68). JADAS10 at 3rd and 6th month were significantly higher in patients on MTX plus bDMARDs (p = 0.001, p = 0.004, respectively). In multivariate analysis, the risk of adding bDMARD was shown to increase 1.24-fold (p = 0.004, 95% CI: 1.07-1.43) for each point increase on the JADAS 10 at 3rd months. The number (p = 0.64) or type (p = 0.18) of joint involvement at disease onset were not predictors of adding a bDMARD., Conclusion: JADAS10 indicating ongoing severe disease activity at 3rd and 6th months rather than baseline JADAS10 is associated with the addition of bDMARDs., What Is Known: • Oligoarticular JIA patients have the best outcomes among JIA categories and respond favorably to first-line therapies such as non-steroidal anti-inflammatory drugs and intraarticular corticosteroid injections. • Clinically inactive disease rates have increased with the widespread use of biological agents in oligoarticular JIA patients who have not responded to initial therapies., What Is New: • Approximately one-fifth of patients with persistent oligoarticular JIA on methotrexate may require the addition of a biological disease modifying anti-rheumatic drug during follow-up. • The JADAS10 calculated at 3 and 6 months is a valuable tool to identify patients who should be added biological disease modifying anti-rheumatic drugs in persistent oligoarticular JIA., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)