[Course of the COVID-19 pandemic in pediatric rheumatological patients in Germany during the first 3 years (2020-2022)]. / Verlauf der COVID-19-Pandemie bei pädiatrisch-rheumatologischen Patienten in Deutschland über die ersten 3 Jahre (2020 bis 2022).

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-CoV­2 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-CoV­2 infection.

Incident psoriasis under treatment with tumor necrosis factor-α inhibitors in juvenile idiopathic arthritis patients-analysis of the BiKeR registry.

The efficacy of tumor necrosis factor inhibitors (TNFi) for the treatment of psoriasis is well established, but patients may develop psoriasis for the first time while on TNFi as a paradoxical effect. Limited data on this association in patients with juvenile idiopathic arthritis (JIA) are available. Safety data from patients registered to the German Biologics registry (BiKeR) were analyzed. Patients were grouped by treatment regime: single TNFi, multiple TNFi, non-TNFi biologics or bDMARD-naïve control group receiving methotrexate. TNFi-associated psoriasis was defined as incident diagnosis of psoriasis after starting TNFi treatment. Patients with a history of psoriasis or psoriasis arthritis prior to TNFi therapy were excluded. Event rates using AEs reported after first dose were compared by Wald's test. A total of 4149 patients were treated with a TNFi (etanercept, adalimumab, golimumab, infliximab), 676 with a non-TNFi biologic (tocilizumab, abatacept, anakinra, canakinumab) and 1692 with methotrexate only. A total of 31 patients were diagnosed with incident psoriasis while on one of the above treatments. Compared with methotrexate, psoriasis was more frequent in the TNFi cohorts (RR 10.8, p = 0.019), specifically in the subgroup of TNF antibodies (RR 29.8, p = 0.0009), whereas no significant signal was observed with etanercept. Also, non-TNFi-treated patients presented high incident psoriasis rates (RR 25.0, p = 0.003). Our findings indicate a higher rate of incident psoriasis in JIA patients treated with TNFi monoclonal antibodies or non-TNFi biologic treatment. JIA patients receiving monoclonal antibody TNFi or non-TNFi bDMARD should be monitored for incident psoriasis. Medication change, if topical skin treatment remains insufficient, may be considered.

Prevalence and risk factors of depressive symptoms in children and adolescents with juvenile idiopathic arthritis.

Depression is a serious disorder disproportionately affecting people with chronic diseases, yet, to date is rarely recognized comorbidity in pediatric rheumatology clinical routine care. The aim of this study was to investigate the prevalence of depressive symptoms and depression in children with Juvenile idiopathic arthritis (JIA) and to identify associations to risk factors. Depressive symptoms were assessed using the Beck's Depression Inventory (BDI)-Fast Screen Questionnaire validated for ages 13 and older and confirmed by the BDI or Hamilton Depression Scale. A cross-sectional analysis of 148 patients attending the rheumatology outpatient clinic of the Asklepios Children's Hospital Sankt Augustin between January 2018 and May 2019 was performed. Possible associations between routinely assessed parameters of disease activity and treatment were analysed. 148 JIA patients (71.5% female), median age 14.7 years, were included. The prevalence for depressive symptoms was 13% and for depression 9.5%, of which 71.4% were newly identified with depression. Significant associations with depressive symptoms included rheumatoid factor negative polyarthritis, higher pain scores, functional limitations, higher disease activity, decreased general well-being, higher number of medications taken and not being in remission. In addition, poor treatment response (persistent pain despite therapy) and failure to achieve minimal activity/remission of disease despite intensified therapy with biologics correlated significantly with depressive symptoms. Depressive symptoms are an important comorbidity in JIA. Early recognition and treatment of psychological distress is essential to prevent deterioration in quality of life and long-term prognosis. Consequently, treat-to-target principles should include mental health as a therapeutic goal.

Development of Inflammatory Bowel Disease in Children With Juvenile Idiopathic Arthritis Treated With Biologics.

OBJECTIVE: The aim of our study was to describe the distinct features of inflammatory bowel disease (IBD) in juvenile idiopathic arthritis (JIA) patients and to identify risk factors for its development. METHODS: Data from the German biologics in pediatric rheumatology registry (Biologika in der Kinderrheumatologie) collected between 2001 and 2021 were analyzed retrospectively. RESULTS: In 5009 JIA patients, 28 developed confirmed IBD before the age of 18 years: 23 (82.1%) with Crohn disease (CD), 4 (14.3%) with ulcerative colitis (UC), and 1 (3.6%) with IBD-unclassified (IBD-U). The incident rate of IBD during 20 years of observation was 0.56% (0.46% for CD, 0.08% for UC, and 0.02% for IBD-U), of whom 20.3% were HLA-B27 positive, 25% had enthesitis-related arthritis, and 14.3% psoriatic arthritis. Within 90 days before IBD diagnosis, 82.1% (n = 23) received treatment with etanercept (ETA), 39.3% (n = 11) non-steroidal anti-inflammatory drugs, 17.9% (n = 5) systemic corticosteroids, 8 (28.6%) methotrexate (MTX), 14.3% (n = 4) sulfasalazine, 10.7% (n = 3) leflunomide, and 3.6% (n = 1) adalimumab and infliximab, respectively. The incidence of IBD was lower in patients treated with MTX, but higher in patients treated with ETA except if ETA was combined with MTX. Also in patients on leflunomide or sulfasalazine, the IBD incidence was higher. CONCLUSIONS: In our JIA cohort, an increased IBD incidence is observed compared to the general population, and the ratio of CD to UC is markedly higher hinting at a distinct phenotype of IBD. Pretreatment with MTX seems to be protective. Treatment with ETA does not prevent IBD development and JIA patients treated with leflunomide and sulfasalazine may be at an increased risk for IBD development.

Biologics with or without methotrexate in treatment of polyarticular juvenile idiopathic arthritis: effectiveness, safety and drug survival.

OBJECTIVE: To investigate the impact of additionally given MTX on biologic treatment of polyarticular JIA in terms of effectiveness, safety and drug survival. METHODS: Patients suffering from polyarticular JIA and treated with either monotherapy with a first biologic or a combination of a biologic and MTX were selected from the BIKER registry. The TNF-α inhibitors (TNFi) adalimumab, etanercept and golimumab and the IL-6 inhibitor tocilizumab were considered. Upon a non-randomized study design, we adjusted the different cohorts using propensity score matching to improve comparability. RESULTS: A total of 2148 patients entered the analysis, who were treated by either combination therapy (n = 1464) or monotherapy (n = 684). Disease activity declined significantly more in patients upon combination therapy than upon biologic monotherapy. Comparison of adjusted cohorts revealed that patients who received TNFi gained more benefit from additionally given MTX than patients treated with tocilizumab. Median survival time of therapy with biologics was significantly longer upon combination therapy (3.1 years) than with monotherapy (2.7 years), as demonstrated by a Kaplan-Meier analysis (log rank test: P = 0.002). The safety profile was moderately affected by additional MTX due to increased incidence of gastrointestinal and hepatic adverse events. Serious adverse events occurred at an equal rate of 3.6 events per 100 patient-years in both cohorts. CONCLUSION: Additionally given MTX improves the effectiveness of biologic treatment in polyarticular JIA without seriously compromising treatment safety. Especially TNFi benefit from combination, while no improvement in outcome has been observed by combining tocilizumab with MTX.

Outcome of adult patients with JIA treated with the biosimilar Benepali®: results of the biologic register JuMBO.

BACKGROUND: To analyze therapy adherence, safety, and outcome in adult patients with juvenile idiopathic arthritis (JIA) treated with the etanercept biosimilar Benepali® (Biogen Inc, Cambridge, USA). METHODS: Data from the prospective registry, JuMBO (Juvenile arthritis MTX/Biologics long-term Observation), were used for the analysis. JuMBO is a long-term observational cohort study. It follows adult patients with JIA who were formerly included in the national JIA biologic register (BiKeR Registry). Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in JIA patients treated with disease-modifying anti-rheumatic drugs (DMARDs). RESULTS: Eighty-three patients from the German JuMBO registry were treated with Benepali®. Of these, 74% had switched from Enbrel® (Pfizer Inc., NYC, USA) the originator of etanercept to Benepali® for cost reasons. Therapy survival of patients treated with Benepali® in comparison to Enbrel® in patients matched by significant parameters was comparable. Adverse events (AE) were reported in 25.3% and serious adverse events (SAE) in 9.6% of patients. Physicians rated no SAE causative related to Benepali®. The majority of SAEs were surgical/medical procedures and there was only one infection. All efficacy parameters (cJADAS-10, Physician Global Assessment, number of joints with active arthritis, patients' overall well-being, pain, and HAQ) demonstrated improvement over 24 months (p-values were not significant). 9.6% of patients permanently discontinued Benepali® because of an AE. CONCLUSIONS: Tolerability and effectiveness of the biosimilar Benepali® were satisfactory and therapy survival was comparable to the originator. Further data on therapy with biologics and biosimilars such as Benepali® must be collected by registries such as BiKeR and JuMBO in order to optimize therapy and patient outcomes and to reduce costs in the health system in the long term.

Medication burden in young adults with juvenile idiopathic arthritis: data from a multicentre observational study.

OBJECTIVE: To assess the medication and disease burden of young adults with juvenile idiopathic arthritis (JIA). METHODS: Young adults with JIA prospectively followed in the Juvenile Arthritis Methotrexate/Biologics long-term Observation reported on their health status and medication use. All medications taken (disease-modifying antirheumatic drugs (DMARDs)/prescription/over-the-counter drugs, but excluding most local therapies) classified according to the Anatomical Therapeutic Chemical Classification System were included in this analysis. Medication use at last follow-up was evaluated by sex, JIA category and time from symptom onset to the first biological DMARD (bDMARD) start. RESULTS: A total of 1306 young adults (68% female) with JIA and a mean disease duration of 13.6±6 years were included in the study. Patients reported using on average 2.4±2.1 medicines and 1.5±1.7 non-DMARD medicines, respectively, at the last follow-up. Almost a quarter of the patients reported polypharmacy. The higher the number of medications used was, the higher the disease activity, pain and fatigue, and the lower the quality of life of patients. Medication usage differed significantly between sexes and JIA categories, being highest in patients with rheumatoid factor-positive polyarthritis and systemic JIA. The number of medications used was significantly associated with the time from symptom onset to bDMARD start. Patients taking opioids or antidepressants had a particularly high disease burden and had received bDMARDs an average of 2 years later than patients not taking these medications. CONCLUSION: Medication use in adults with JIA varies depending on sex, JIA category, and the time between symptom onset and initiation of treatment with bDMARD.

Update of evidence- and consensus-based guidelines for the treatment of juvenile idiopathic arthritis (JIA) by the German Society of Pediatric and Juvenile Rheumatic Diseases (GKJR): New perspectives on interdisciplinary care.

BACKGROUND: New therapeutic strategies for juvenile idiopathic arthritis (JIA) have evolved within the past ten years, and as a result, an update of the 2011 recommendations of the German management guidelines was initiated. METHODS: A systemic literature review was performed, overarching principles were proposed and pre-selected via an online survey followed by two multidisciplinary consensus conferences. Pharmacological and non-pharmacological treatments were discussed, statements were proposed and ultimately agreed upon by nominal group technique (NGT). RESULTS: 12 overarching therapeutic principles, as well as 9 recommendations on pharmacological and 5 on non-pharmacological treatments for JIA were agreed upon. CONCLUSION: This report summarizes the recent update of the interdisciplinary, consensus-based German guidelines on the management of JIA. The multi- and interdisciplinary participation of all caregivers was central for this patient-focused update. With these guidelines, physicians can choose an evidence-based approach, which allows better tailored treatment in this vulnerable cohort of children and adolescents.

Prevention of disease flares by risk-adapted stratification of therapy withdrawal in juvenile idiopathic arthritis: results from the PREVENT-JIA trial.

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.

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

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

Efficacy and Safety of Etanercept Biosimilars Compared With the Originator for Treatment of Juvenile Arthritis: A Prospective Observational Study.

OBJECTIVE: Analysis of etanercept biosimilars in pediatric patients with juvenile idiopathic arthritis (JIA) in comparison with the etanercept originator in terms of efficacy and safety. METHODS: Patients diagnosed with JIA who started treatment with either the etanercept originator or a biosimilar after January 1, 2017, were selected from the German BIKER registry (Biologics in Paediatric Rheumatology Registry). Furthermore, patients who started therapy with the originator and switched to a biosimilar during the course of therapy were identified. For both patient groups, disease activity and safety were examined and compared separately. RESULTS: After January 1, 2017, 348 patients started treatment with the etanercept originator (n = 293) or a biosimilar (n = 55). Another 57 patients switched to a biosimilar during the course of therapy. A significant decrease or a stable remission of disease activity was observed in both patient groups. The safety profiles were comparable, and frequencies and types of adverse events (AEs) and serious AEs were similar in patients starting therapy with the originator or a biosimilar. Only injection site reactions occurred slightly more frequently under biosimilar therapy, without having an impact on therapy adherence. In patients who switched therapy, the AE rate per 100 patient-years was comparable before (26.4) and after (32.1) the switch. CONCLUSION: In patients with JIA who require treatment with etanercept, the originator is still used much more frequently. However, our study highlights the equivalence of etanercept biosimilars for therapy for JIA. Increased use of these biosimilars in pediatric patients can therefore be recommended without hesitation.

Clinical manifestations and outcome of SARS-CoV-2 infections in children and adolescents with rheumatic musculoskeletal diseases: data from the National Paediatric Rheumatology Database in Germany.

OBJECTIVES: This study aimed to investigate the clinical manifestations, course and outcome of SARS-CoV-2 infection among children and adolescents with rheumatic and musculoskeletal diseases (RMD). Due to their underlying disease as well due to therapeutic immunosuppression, these patients may be at risk for a severe course of COVID-19 or for a flare of the underlying disease triggered by SARS-CoV-2 infection. METHODS: Demographic, clinical and treatment data from juvenile patients with RMD as well as data about SARS-CoV-2 infection like test date and method, clinical characteristics, disease course, outcome and impact on the disease activity of the RMD were documented on a specific SARS-CoV-2 questionnaire implemented in the National Paediatric Rheumatology Database (NPRD) in Germany. The survey data were analysed descriptively. RESULTS: From 17 April 2020 to 16 February 2021, data were collected from 76 patients (52% female) with RMD and laboratory-proven SARS-CoV-2 infection with median age of 14 years, diagnosed with juvenile idiopathic arthritis (58%), autoinflammatory (24%) and connective tissue disease (8%). Fifty-eight patients (76%) received disease-modifying antirheumatic drugs (DMARDs), 41% biological DMARDs and 11% systemic glucocorticoids. Fifty-eight (76%) had symptoms of COVID-19. Disease course of SARS-CoV-2 infection (classified as asymptomatic, mild, moderate, severe, life-threatening) was mild and outcome of COVID-19 (classified as recovered, not yet recovered, permanent damage or deceased) was good (recovered) in the majority of patients. Two patients were hospitalised, one of whom required intensive care and died of cardiorespiratory failure. In 84% of SARS-CoV-2-positive patients, no relevant increase in disease activity of the RMD was observed. CONCLUSIONS: In our cohort, SARS-CoV-2 infection in juvenile patients with RMD under various medications was mild with good outcome in the majority of cases and does not appear to have a relevant impact on disease activity of the underlying condition.

Re-treatment with etanercept is as effective as the initial firstline treatment in patients with juvenile idiopathic arthritis.

OBJECTIVES: To determine (i) correlates for etanercept (ETA) discontinuation after achieving an inactive disease and for the subsequent risk of flare and (ii) to analyze the effectiveness of ETA in the re-treatment after a disease flare. METHODS: Data from two ongoing prospective registries, BiKeR and JuMBO, were used for the analysis. Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in juvenile idiopathic arthritis (JIA) patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) and conventional synthetic DMARDs (csDMARDs). RESULTS: A total of 1724 patients were treated first with ETA treatment course (338 with second, 54 with third ETA course). Similar rates of discontinuation due to ineffectiveness and adverse events could be observed for the first (19.4%/6.2%), second (18.6%/5.9%), and third (14.8%/5.6%) ETA course. A total of 332 patients (+/-methotrexate, 19.3%) discontinued ETA after achieving remission with the first ETA course. Younger age (hazard ratio (HR) 1.08, p < 0.001), persistent oligoarthritis (HR 1.89, p = 0.004), and shorter duration between JIA onset and ETA start (HR 1.10, p < 0.001), as well as good response to therapy within the first 6 months of treatment (HR 1.11, p < 0.001) significantly correlated to discontinuation with inactive disease. Reoccurrence of active disease was reported for 77% of patients with mean time to flare of 12.1 months. We could not identify any factor correlating to flare risk. The majority of patients were re-treated with ETA (n = 117 of 161; 72.7%) after the flare. One in five patients (n = 23, 19.7%) discontinued ETA again after achieving an inactive disease and about 70% of the patients achieved an inactive disease 12 months after restarting ETA. CONCLUSION: The study confirms the effectiveness of ETA even for re-treatment of patients with JIA. Our data highlight the association of an early bDMARD treatment with a higher rate of inactive disease indicating a window of opportunity.

Comparative risk of infections among real-world users of biologics for juvenile idiopathic arthritis: data from the German BIKER registry.

To examine whether treatment with interleukin (IL)-1-, IL-6-, tumour necrosis factor α (TNFα)-inhibitors or Abatacept is associated with an increased risk of common infections, infections requiring hospitalization (SAE) or opportunistic infections among real-world juvenile idiopathic arthritis (JIA) patients. Furthermore, the influence of other patient-related covariates on the occurrence of infections was investigated. Patients diagnosed with JIA and treated with biologics were selected from the German BIKER registry. Incidence rates (IR) of infections per 100 person years were calculated and compared between the different cohorts. Using multivariate logistic regression, odds ratios with 95% confidence intervals (CI) were determined for the influence of patient-related covariates (age, diagnosis, laboratory data, concomitant medication, JIA activity, comorbidities, and premedication) on the occurrence of infections. 3258 patients entered the analysis. A total of 3654 treatment episodes were distributed among TNFα- (Etanercept, Adalimumab, Golimumab, Infliximab, n = 3044), IL-1- (Anakinra, Canakinumab, n = 105), IL-6- (Tocilizumab, n = 400) and T-cell activation inhibitors (Abatacept, n = 105). 813 (22.2%) patients had at least one infection, 103 (2.8%) patients suffered from an SAE infection. Both common and SAE infections were significantly more frequent in IL-1 (IR 17.3, 95% CI 12.5/24 and IR 4.3, 95% CI 2.3/8.3) and IL-6 cohort (IR 16.7, 95% CI 13.9/20 and IR 2.8, 95% CI 1.8/4.4) compared to TNFα-inhibitor cohort (IR 8.7, 95% CI 8.1/9.4 and IR 1, 95% CI 0.8/1.3). When comparing the influencing factors for various infectious diseases, the use of corticosteroids, younger age, cardiac comorbidities and higher JIA-activity are the most striking risk factors. Relative to TNFα inhibitors and Abatacept, IL-1 and IL-6 inhibitors were associated with an increased risk of common and SAE infections. The influencing covariates identified may be helpful for the choice of a suitable biologic to treat JIA.

Long-term safety and effectiveness of etanercept in JIA: an 18-year experience from the BiKeR registry.

BACKGROUND: At present, etanercept represents the most commonly prescribed biologic agent for juvenile idiopathic arthritis (JIA) treatment. Children and adolescents with JIA are often treated with etanercept over long periods, sometimes even into adulthood. The objectives of this analysis were to determine the long-term safety of etanercept compared to a biologic-naïve cohort and to assess the long-term treatment response upon continuous etanercept exposure using data from the German biologics registry (BiKeR). METHODS: JIA patients newly exposed to etanercept were documented in the BiKeR registry from January 2001 to March 2019, and baseline characteristics, effectiveness, and safety parameters were analysed. Response to treatment was assessed according to 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), JADAS-defined minimal disease activity and remission, JIA-American College of Rheumatology (ACR) improvement criteria, and ACR-inactive disease definition. Safety assessments were based on adverse event (AE) reports. RESULTS: A total of 2725 new etanercept users with a diagnosis of JIA were registered. Of these, etanercept was received as a first-line biologic by 95.8% and as monotherapy without concomitant methotrexate by 31.5%. After nine years on continuous treatment, 68.1% of patients presented minimal disease activity, 43.1% JADAS-defined remission on drug, and 36.6% ACR-inactive disease. JIA-ACR30/50/70/90 response rates were still 82/79/71/54% after nine years of treatment. Overall, 2053 AEs (34.3/100PY), including 226 serious AEs (SAE, 3.8/100PY), were observed upon etanercept, compared to 1345 AEs [35.6/100PY; p = 0.3] and 52 SAEs (1.4/100PY; p = 0.0001) in the biologic-naïve cohort. Respective exposure-adjusted rates for etanercept and biologic-naïve patients were 0.9/100PY and 0.2/100PY (p = 0.0001) for serious infections, 0.4/100PY and 0.1/100PY (p = 0.01) for zoster reactivation, 0.3/100PY and 0.03/100PY (p = 0.015) for inflammatory bowel disease, and 1.9/100PY and 1.4/100PY (p = 0.09) for uveitis. Three and two malignancies were documented in the etanercept and biologic-naïve groups, as well as three and one deaths, respectively. CONCLUSIONS: No new safety signal was observed, especially no increased risk for malignancies or autoimmune disorders other than inflammatory bowel disease. However, SAEs and serious infections, though infrequent, were more often reported on etanercept than in biologic-naïve patients. In addition, etanercept demonstrated a long-term maintenance of clinical benefits up to nine years of continuous treatment.

Treat-to-target study for improved outcome in polyarticular juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis is one of the most prevalent chronic inflammatory diseases in children. Evidence suggests that early effective treatment minimises the burden of disease during childhood and in further life. We hypothesise that a guided treat-to-target (T2T) approach is superior to routine care in polyarticular juvenile idiopathic arthritis (pJIA) in terms of reaching a clinical remission after 12 months of treatment. METHODS: Patients with early and active pJIA were enrolled. Targets for treatment were the following: Recognisable Juvenile Arthritis Disease Activity Score (JADAS) improvement after 3 months, acceptable disease at 6 months, minimal disease activity at 9 months and as primary endpoint remission after 12 months. Initially, patients received methotrexate. Failure to meet a defined target required treatment modification at the specified intervals. The choice of biologics was not influenced by the protocol. Finally, T2T patients were compared with a cohort of matched controls of patients with pJIA with unguided therapy documented by BIKER. RESULTS: Sixty-three patients were enrolled. Treatment targets after 3/6/9 and 12 months were reached by 73%/75%/77% and 48% of patients. Fifty-four patients completed the protocol. Compared with matched controls, on T2T guidance significantly more patients reached JADAS remission (48% vs 32%; OR 1.96 (1.1-3.7); p=0.033) and JADAS minimal disease activity (JADAS-MDA) (76% vs 59%; OR 2.2 (1.1-4.4); p=0.028). Patients from the T2T cohort received a biologic significantly more frequent (50% vs 9% after 12 months; OR 9.8 (4.6-20.8); p<0.0001). CONCLUSION: The T2T concept was feasible and superior to unguided treatment. High rates of patients reached JADAS-MDA and JADA remission after 12 months. Approximately half of the patients achieved their therapy goals without a biologic.

Biologic Therapies in Polyarticular Juvenile Idiopathic Arthritis. Comparison of Long-Term Safety Data from the German BIKER Registry.

OBJECTIVE: Biologics have an important role in the treatment of juvenile idiopathic arthritis (JIA). Long-term safety data are limited. Direct comparison of different agents regarding occurrence of adverse events (AEs), especially of rare events, requires large quantities of patient years. In this analysis, long-term safety with regard to AE of special interest (AESI) was compared between different biologics. METHODS: Patients with nonsystemic JIA were selected from the German BIKER registry. Safety assessments were based on AE reports. Number of AEs, serious AEs, and 25 predefined AESIs, including medically important infection, uveitis, inflammatory bowel disease, cytopenia, hepatic events, anaphylaxis, depression, pregnancy, malignancy, and death, were analyzed. Event rates and relative risks were calculated using AEs reported after first dose through 70 days after last dose. RESULTS: A total of 3873 patients entered the analysis with 7467 years of exposure to biologics. The most common AESIs were uveitis (n = 231) and medically important infections (n = 101). Cytopenia and elevation of transaminases were more frequent with tocilizumab (risk ratio [RR] 8.0, 95% confidence interval [CI] 4.2-15, and RR 4.7, 95% CI 1.8-12.2, respectively). Anaphylactic events were associated with intravenous route of administration. In patients ever exposed to biologics, eight malignancies were reported. Six pregnancies have been documented in patients with tumor necrosis factor inhibitors. No death occurred in this patient cohort during observation. CONCLUSION: Surveillance of pharmacotherapy as provided by the BIKER registry is an import approach, especially for long-term treatment of children. Overall, tolerance was acceptable. Differences between biologics were noted and should be considered in daily patient care.

Long-term surveillance of biologic therapies in systemic-onset juvenile idiopathic arthritis: data from the German BIKER registry.

OBJECTIVE: Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed. METHODS: Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model. RESULTS: Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept. CONCLUSION: Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care.

[Biologics in the treatment of juvenile idiopathic arthritis : A comparison of mono- and combination therapy with synthetic DMARDs]. / Biologikabehandlung bei der juvenilen idiopathischen Arthritis : Vergleich von Mono- und Kombinationstherapie mit synthetischen DMARDs.

In polyarticular juvenile idiopathic arthritis, methotrexate (MTX) is still used as first-line treatment. In case of insufficient response or intolerance, a number of biologics are now available. This faces physicians with challenging choices. Biologics are often combined with MTX, although in JIA there is little evidence and inconsistent results from various studies. In rheumatoid arthritis, combination therapy with tumor necrosis factor (TNF) inhibitors has been associated with higher efficacy. Tocilizumab appears to be highly effective as a monotherapy. MTX has a protective effect on the formation of anti-drug antibodies, which is particularly important for the use of anti-TNF antibodies. This could also be observed in children. For golimumab, combination with MTX is mandatory according to its approval, as is the cause for abatacept. With regard to tolerability, apart from the classic side effects of MTX, there are no other significant differences concerning the combination of MTX and biologics. In case of MTX intolerance, leflunomide may be considered as an (unapproved) alternative.

Time of Disease-Modifying Antirheumatic Drug Start in Juvenile Idiopathic Arthritis and the Likelihood of a Drug-Free Remission in Young Adulthood.

OBJECTIVE: To study juvenile idiopathic arthritis (JIA) long-term outcomes in relation to the time of initiation of biologic disease-modifying antirheumatic drug (bDMARD). METHODS: Outcomes of JIA patients prospectively followed by the Biologika in der Kinderrheumatologie (BiKeR) and Juvenile Arthritis Methotrexate/Biologics Long-Term Observation (JuMBO) registers were analyzed with regard to drug-free remission and inactive disease, functional status and quality of life, and surgery. To analyze the influence of early bDMARD therapy on outcomes, patients were assigned to 3 groups based on the time from symptom onset to bDMARD start (G1: ≤2 years, G2: >2 to ≤5 years, and G3: >5 years). Propensity score-adjusted outcome differences were analyzed by multinomial logistic regression analyses among the groups. RESULTS: A total of 701 JIA patients were observed for mean ± SD 9.1 ± 3.7 years. At the last follow-up (disease duration mean ± SD 14.3 ± 6.1 years), 11.7% of patients were in drug-free remission, and 40.0% had inactive disease. More than half of the patients reported no functional limitation, while 5% had undergone arthroplasty, and 3% had eye surgery. At the 10-year time point, patients in G1 (n = 108) were significantly more likely to be in drug-free remission than those patients who began treatment later (G2, n = 199; G3, n = 259), with 18.5%, 10.1%, and 4.9%, respectively. Patients in G1 had significantly lower disease activity (clinical Juvenile Arthritis Disease Activity Score in 10 joints = 4.9), a better overall well-being (18.2% patient global assessment score = 0), and higher functional status (59.2% Health Assessment Questionnaire score = 0), compared to patients in G3 (7.1, 8.4%, and 43.7%, respectively). G1 patients required arthroplasty significantly less frequently than G3 patients and had significantly lower disease activity over time than patients in both G2 and G3. CONCLUSION: Early DMARD treatment is associated with better disease control and outcomes, which supports the concept of a "window of opportunity" for JIA.