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Objectives: To investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA)., Methods: This multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patients reached the intervention phase in which the decision whether to continue or stop treatment was based on S100A12 and hsCRP levels. Patients were monitored for 12 months after stopping medication for flares of disease. Results were compared with withdrawal of therapy without biomarker-based stratification in patients from the German Biologika in der Kinderrheumatologie (BiKeR) pharmacovigilance registry., Results: In the PREVENT-JIA group, 49 patients had a flare, and 45% of patients stopping medication showed flares within the following 12 months. All patients (n=8) continuing therapy due to permanently elevated S100A12/hsCRP at more than one visit flared during the observation phase. In the BiKeR control group, the total flare rate was 62%, with 60% flaring after stopping medication. The primary outcome, time from therapy withdrawal to first flare (cumulative flare rate after therapy withdrawal), showed a significant difference in favour of the PREVENT-JIA group (p=0.046; HR 0.62, 95% CI 0.38 to 0.99). As additional finding, patients in the PREVENT-JIA trial stopped therapy significantly earlier., Conclusion: Biomarker-guided strategies of therapy withdrawal are feasible in clinical practice. This study demonstrates that using predictive markers of subclinical inflammation is a promising tool in the decision-making process of therapy withdrawal, which translates into direct benefit for patients., Trial Registration Number: ISRCTN69963079., Competing Interests: Competing interests: JG has received honoraria from TESARO, QUIRIS Healthcare, Ecker+Ecker, Dr August Wolff, Roche, University Clinics Schleswig‐Holstein and RWTH Aachen University, Germany; GH has received research grants from Pfizer, Merck Sharp Dome, Novartis and Roche and honoraria from Bayer, Chugai, Janssen, Pfizer, Sanofi, Sobi Swedish Orphan and Novartis; CK has received honararia from Novartis and SOBI and research support from Novartis; JFS has received consultancy fees from Amgen; HIB has received speaking fees from Novartis, Pfizer and GlaxoSmithKline and consultancy fees/honoraria from AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol Myers Squibb, Celgene, Eli Lilly, EMD Serono, Idorsia, Cerocor, Janssen, GlaxoSmithKline, F Hoffmann-La Roche, Merck, Novartis, R-Pharm and Sanofi, while The Cincinnati Children’s Hospital, where HIB works as a full-time public employee, has received contributions from Bristol Myers Squibb, F Hoffmann-La Roche, Janssen, Novartis and Pfizer; DF has received research grants from Pfizer, Sobi Swedish Orphan and Novartis, and he has received speaking fees from Sobi Swedish Orphan, Novartis and Werfen as well as consultancy fees/honoraria from Boehringer; The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To observe if capillary patterns in childhood-onset SLE (cSLE) change over time and find associations between a capillary scleroderma pattern with disease activity, damage or scleroderma-like features., Methods: Clinical and (yearly) capillaroscopy data from a longitudinal cohort of patients with cSLE (minimum of four Systemic Lupus International Collaborating Clinics (SLICC) criteria, onset <18 years) were analysed. Disease activity was measured by Systemic Lupus Erythematosus Activity Index (SLEDAI) and disease damage by SLICC Damage Index. A scleroderma pattern was defined according to the 'fast track algorithm' from the European League Against Rheumatism Study Group on Microcirculation in Rheumatic Diseases. An abnormal capillary pattern, not matching a scleroderma pattern, was defined as 'microangiopathy'., Results: Our cohort consisted of 53 patients with cSLE with a median disease onset of 14 years (IQR 12.5-15.5 years), median SLEDAI score at diagnosis was 11 (IQR 8-16), median SLEDAI at follow-up was 2 (IQR 1-6). A scleroderma pattern (ever) was seen in 18.9%, while only 13.2% of patients had a normal capillary pattern. Thirty-three patients had follow-up capillaroscopy of which 21.2% showed changes in type of capillary pattern over time. Type of capillary pattern was not associated with disease activity. Raynaud's phenomenon (ever) was equally distributed among patients with different capillaroscopy patterns (p=0.26). Anti-ribonucleoprotein antibodies (ever) were significantly more detected (Χ 2 , p=0.016) in the scleroderma pattern subgroup (n=7 of 10, 70%). Already 5 years after disease onset, more than 50% of patients with a scleroderma pattern had SLE-related disease damage (HR 4.5, 95% CI 1.1 to 18.8, p=0.034), but they did not develop clinical features of systemic sclerosis at follow-up. Number of detected fingers with a scleroderma pattern was similar between cSLE, juvenile systemic sclerosis and juvenile undifferentiated connective tissue disease., Conclusion: This longitudinal study shows that the majority of capillary patterns in cSLE are abnormal and they can change over time. Irrespective of disease activity, a capillary scleroderma pattern in cSLE may be associated with higher risk of SLE-related disease damage., Competing Interests: Competing interests: VS is a Senior Clinical Investigator of the Research Foundation–Flanders (Belgium) (FWO) (1.8.029.20N). VS is supported by an unrestricted educational chair on systemic sclerosis of Janssen-Cilag NV., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA., Competing Interests: Competing interests: AR has received grant support and/or speaking or consultant fees from AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche and Johnson & Johnson; AC reports personal fees from AbbVie and non-financial support from Pfizer; GH has received research funds, advisory board membership and honorary fees from AbbVie, Pfizer and Roche; RML has been consultant and/or participated in advisory boards for AbbVie, Eli Lilly, Novartis, Sanofi and Sobi; DJL reports grants/research support from the National Institutes of Health, NIAMS, and received consultancy fees from AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene and Janssen, and speaker bureaus from Genentech; NMW reports research grants and/or consultant fees from AbbVie and Novartis; JDA has received consultant fees from Pfizer; SMA-M does not report competing interests; JA reports grant support and/or personal fees from AbbVie, Gebro, Pfizer, Novartis, Roche and Sobi; TA has received speaking and/or consultant fees from AbbVie, Boehringer Ingelheim and Pfizer; RAB does not report competing interests; MWB does not report competing interests; RB-V does not report competing interests; RC has received consultant fees from AbbVie, Alfa Wassermann and Novartis; FDB reports grants from Hoffmann-La Roche, Bristol-Myers Squibb, Novimmune, Novartis, Abbott, Pfizer and Sobi; ED does not report competing interests; DF reports grant support and/or personal fees from Pfizer, Novartis, Roche and Sobi; YI does not report competing interests; PL has received grant support from AbbVie; EMM does not report competing interests; PQ has received speakers' fees from AbbVie, Novartis, Pfizer, Roche and Sobi, grants from AbbVie, Pfizer and Novartis, and personal fees for consultancy from AbbVie, Novartis, Novimmune and Sanofi; NR reports personal fees from AbbVie, Amgen, Biogen Idec, Alter, AstraZeneca, Baxalta Biosimilars, Boehringer, Bristol-Myers Squibb, Celgene, CrescendoBio, EMD Serono, Hoffmann-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi-Aventis, Servier, Takeda and UCB Biosciences, and other financial relationships from Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Pfizer, Sanofi-Aventis, Schwarz Biosciences, Abbott, Francesco Angelini SPA, Sobi and Merck Serono; RR does not report competing interests; CS-M does not report competing interests; SSa does not report competing interests; CS does not report competing interests; SSh has received speaking and advisory board fees from Novartis; JFS does not report competing interests; YU reports grant support and/or personal fees and/or non-financial support from AbbVie, Janssen, Novartis, Pfizer and Roche; SJV reports grant support from Sobi; JSS has received grant support from and/or provided expert advice to AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Celltrion, Gilead, Glaxo, Janssen, Lilly, Pfizer, MSD, Roche, Samsung, Novartis-Sandoz and UCB., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX)., Methods: Monocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated., Results: Physicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%-75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate., Conclusions: The cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biological agents in 1999., Objective: To evaluate trends in prescription patterns of biological agents and the subsequent outcome of JIA., Methods: The Arthritis and Biologics in Children register (multicentre prospective observational study) aimed to include all consecutive patients with JIA in the Netherlands who had started biological agents since 1999. Patients were divided according to year of introduction of first biological agent. Patient characteristics at introduction of the first biological agent and its effectiveness were analysed over 12 years., Results: 335 patients with non-systemic JIA and 86 patients with systemic JIA started a biological agent between 1999 and 2010. Etanercept remained the most often prescribed biological agent for non-systemic JIA; anakinra became first choice for systemic JIA. The use of systemic glucocorticoids and synthetic disease-modifying antirheumatic drugs before biological agents decreased. During these 12 years of observation, biological agents were prescribed earlier in the disease course and to patients with lower baseline JADAS (Juvenile Arthritis Disease Activity Score) disease activity. All baseline disease activity parameters were lowered in patients with non-systemic JIA. In systemic JIA, prescription patterns changed towards very early introduction of biological agents (median 0.4 years of disease duration) in patients with a low number of joints with active arthritis and high erythrocyte sedimentation rates. These changes for both systemic and non-systemic JIA resulted in more patients with inactive disease after 3 and 15 months of treatment., Conclusions: Biological agents are increasingly prescribed, earlier in the disease and in patients with JIA with lower disease activity. These changes are accompanied by better short-term disease outcomes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: To explore the immunosuppressive effect and mechanism of action of intraperitoneal (ip) and intra-articular (ia) mesenchymal stem cell (MSC) injection in proteoglycan induced arthritis (PGIA)., Methods: MSC were administered ip or ia after establishment of arthritis. We used serial bioluminescence imaging (BLI) to trace luciferase-transfected MSC. Mice were sacrificed at different time points to examine immunomodulatory changes in blood and secondary lymphoid organs., Results: Both ip and local ia MSC injection resulted in a beneficial clinical and histological effect on established PGIA. BLI showed that MSC ip and ia in arthritic mice are largely retained for several weeks in the peritoneal cavity or injected joint respectively, without signs of migration. Following MSC treatment pathogenic PG-specific IgG2a antibodies in serum decreased. The Th2 cytokine IL-4 was only upregulated in PG-stimulated lymphocytes from spleens in ip treated mice and in lymphocytes from draining lymph nodes in ia treated mice. An increase in production of IL-10 was seen with equal distribution. Although IFN-γ was also elevated, the IFN-γ/IL-4 ratio in MSC treated mice was opposite to the ratio in (untreated) active PGIA., Conclusions: MSC treatment, both ip and ia, suppresses PGIA, a non-collagen induced arthritis model. MSC are largely retained for weeks in the injection region. MSC treatment induced at the region of injection a deviation of PG-specific immune responses, suggesting a more regulatory phenotype with production of IL-4 and IL-10, but also of IFN-γ, and a systemic decrease of pathogenic PG-specific IgG2a antibodies. These findings underpin the potential of MSC treatment in resistant arthritis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To evaluate the effectiveness and safety of switching to a second or third biological agent in juvenile idiopathic arthritis (JIA) after etanercept failure., Methods: The Arthritis and Biologicals in Children Register aims to include all Dutch JIA patients who have used biological agents. Data on the disease course were used to estimate drug survival with Kaplan-Meier and calculate adverse event (AE) rates., Results: Of 307 biologically naive JIA patients who started etanercept, 80 (26%) switched to a second and 22 (7%) to a third biological agent. During 1030 patient-years of follow-up after the introduction of etanercept, 49 switches to adalimumab, 28 infliximab, 17 anakinra, four abatacept and four trial drugs were evaluated. 84% (95% CI 80% to 88%) of patients who started etanercept as a first biological agent were, after 12 months, still on the drug, compared with 47% (95% CI 35% to 60%) who started a second and 51% (95% CI 26% to 76%) who started a third biological agent. Patients who switched because of primary ineffectiveness continued the second agent less often (32%, 95% CI 12% to 53%). After etanercept failure, drug continuation of adalimumab was similar to infliximab for patients with non-systemic JIA; anakinra was superior to a second TNF-blocker for systemic JIA. AE rates within first 12 months after initiation were comparable for each course and each biological agent., Conclusions: Switching to another biological agent is common, especially for systemic JIA patients. A second (and third) agent was less effective than the first. The choice of second biological agent by the physician mainly depends on availability and JIA category.