German BIKER Registry Research Articles

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

ObjectiveAnalysis of etanercept biosimilars in pediatric patients with juvenile idiopathic arthritis (JIA) in comparison with the etanercept originator in terms of efficacy and safety.MethodsPatients 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.ResultsAfter 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.ConclusionIn 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.

POS1202 EXPERIENCE WITH COVID-19 IN GERMAN PAEDIATRIC RHEUMATOLOGY CENTRES

Background:COVID-19 is a major challenge worldwide. Although the risk for a severe disease course is low among children with COVID-19, symptoms may be exacerbated by underlying disease and/or immunosuppressive medication. We analysed clinical data from COVID-19 cases in among pediatric patients with juvenile idiopathic arthritis (JIA) in Germany reported to the BIKER registry.Objectives:This is an analysis of clinical data for 56 COVID-19 cases reported to the German BIKER registry from 29 German pediatric rheumatology centers and clinics from February 2020 to January 2021.Methods:The major task of the German BIKER (Biologics in Paediatric Rheumatology) Registry is surveillance of biologics used in pediatric rheumatology patients. Following the start of the COVID-19 pandemic in Germany, a survey was established to proactively interview all participating centers regarding the occurrence, presentation and outcome of SARS-CoV-2-infected children with rheumatic diseases. Initially, the interviews were conducted in weekly intervals, later bi-weekly.A standardized Adverse Event of Special Interest form was developed requesting biographic data, pre-treatment, current medication, data on clinical presentation, course, treatment and outcome of COVID-19 pediatric rheumatology patients.Results:In all, 56 patients with JIA and SARS-CoV-2 infection were reported (Table 1). Of these patients, 71% were 12 or more years old.Table 1.Patient characteristics. COVID-19 positive patients.JIA patients, n=56n (%)Age 0-5 years / 6-11years / 12-18years3 (5.4) / 13 (23.2) / 40 (71.4)JIA category•Systemic JIA5 (8.9)•Oligoarthritis JIA9 (16)•Polyarticular JIA32 (57)•Enthesitis-related JIA2 (3.6)•Psoriatic JIA1 (1.8)•Unknown7 (12.5)Uveitis (concomitant)4 (7.1)Treatment•DMARD / MTX23/ 22 (41/39)•Biologics29 (52)•TNF inhibitors20 (36)•Tocilizumab5 (8.9)•Abatacept1 (1.8)•Anakinra1 (1.8)•Ustekinumab1 (1.8)•JAK inhibitors1 (1.8)•Steroids5 (8.9)Asymptomatic13 (23.2)Hospitalized/ICU/Ventilation/Death1/1/1/1 (1.8)At the time of infection, 41% of the patients received conventional DMARDs and 52% received biologics (Table 1). Forty-four patients (79%) received either a conventional DMARD or a biologic. Most patients had a polyarticular course of their JIA (57%).In 49 of the 56 cases (88%) COVID-19 was detected directly by PCR (n=46), by antigen test only (n=1) or an undisclosed method (n= 2). Six patients had detectable SARS-CoV2 antibodies and reported to have had typical symptoms. One patient tested negative but developed typical symptoms at approximately the same time a positive SARS-CoV-2 test was returned for a family member.Symptoms were reported in 43 of the 56 patients (77%): fever n=15, rhinitis n=14, cough n=12, headache n=10, loss of sense of taste and/or smell n=9, pharyngitis n=8, fatigue n=5, musculoskeletal pain n=5, GI symptoms n=2 (abdominal pain n=1, diarrhoea n=1), dizziness n=3, encephalitis/seizure/respiratory failure/death n=1. Thirteen patients (23%) were asymptomatic.A 3½ -year-old female patient initially diagnosed with systemic JIA developed intracranial oedema and respiratory failure. Her SARS-CoV2 PCR test was positive and pulmonary imaging displayed typical changes in lung texture. Before her SARS-CoV-2 infection, the patient was treated with methotrexate and low-dose steroids. Unfortunately, she died three days following hospital admission. Genetic testing revealed an inborn immunodeficiency. Except for this one patient, all other cases were treated as outpatients and no deaths were reported.Conclusion:Apart from one patient with an inborn immunodeficiency who died from her COVID-19 infection, no case of hospitalization or severe COVID-19 was reported in our cohort of JIA patients. At the time of COVID-19 diagnosis, nearly 80% of patients in our cohort had been treated with conventional DMARD and/or biologics. This seemed not to have a negative effect on severity or outcome of SARS-CoV2 infection.Acknowledgements:Thanks also for contributing Reports for this analysis to: Normi Brück, Frank Dressler, Ivan Foeldvari, Tilman Geikowski, Hermann Girschick, Johannes-Peter Haas, Tilmann Kallinich, Bernd-Ulrich Keck, Eggert Lilienthal, Anna-Hedrich Müller, Ulrich Neudorf, Nils Onken, Peggy Rühmer.Disclosure of Interests:None declared.

Outcome of children with oligoarticular juvenile idiopathic arthritis compared to polyarthritis on methotrexate- data of the German BIKER registry

BackgroundOligoarticular juvenile idiopathic arthritis (oligoJIA) is the most commonly diagnosed category of chronic arthritis in children. Nevertheless, there are no evidence- based guidelines for its treatment, in particular for the use of methotrexate (MTX). The primary objective of this analysis is to evaluate the outcomes in patients with persistent oligoJIA compared to those with extended oligoJIA and rheumatoid factor (RF) negative polyarthritis treated with methotrexate.MethodsPatients with persistent or extended oligoJIA or RF negative PA recorded in the Biologics in Pediatric Rheumatology Registry (BiKeR), receiving methotrexate for the first time were included in the analyses. Efficacy was determined using the Juvenile Arthritis Disease Activity Score 10 (JADAS 10). Safety assessment included the documentation of adverse and serious adverse events.ResultsFrom 2005 through 2011, 1056 patients were included: 370 patients with persistent oligoJIA, 221 patients with extended oligoJIA and 467 patients with RF negative PA. Therapeutic efficacy was observed following the start of methotrexate.Over a period of 24 months JADAS-minimal disease activity (JADAS ≤2) was reached in 44% of patients with persistent oligoJIA, 38% with extended oligoJIA, 46% with RF negative PA, JADAS-remission defined as JADAS ≤1 was reached in 33% of patients with persistent oligoJIA, 29% with extended oligoJIA and 35% (RF negative PA). Patients with extended oligoJIA achieved JADAS remission significantly later and received additional biologic disease-modifying drugs significantly more often than patients with persistent oligoJIA or RF negative PA (p < 0.001). Tolerability was comparable. New onset uveitis occurred in 0.3 to 2.2 per 100 patient years.ConclusionsPatients with persistent oligoJIA taking methotrexate are at least as likely to enter remission as patients with extended oligo JIA or polyarticular JIA. Patients with extended oligoJIA achieved JADAS remission significantly later. Within 2 years, almost half of the patients with persistent oligoJIA achieved JADAS-minimal disease activity.

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.

Safety and efficacy of anakinra as first-line or second-line therapy for systemic onset juvenile idiopathic arthritis - data from the German BIKER registry

ABSTRACT Background: The IL-1 receptor-antagonist anakinra is recommended for the treatment of systemic juvenile idiopathic arthritis (sJIA) and was recently approved for first-line treatment. Long-term data from clinical practise are scarce. Methods: SJIA patients from the German biologics in pediatric rheumatology (BIKER) registry starting anakinra were grouped into two cohorts: Patients in the first-line cohort received no prior sJIA treatment except NSAID and a maximum of 3 days of steroids. Second-line cohort patients were pre-treated with steroids; DMARDs or biologics. Patient characteristics, disease-activity parameters, efficacy, and safety-parameters were compared. Results: Until December 2018, 51 anakinra patients were documented, representing 117.96 patient-years. Mean disease duration was 3.5 (± 3.8) years. At baseline, all anakinra first-line users had active systemic disease compared to 82% in the second-line users. Significant JADAS-10 improvement at last follow-up was observed in both cohorts (p = 0.02, p = 0.0014). Substantial numbers of patients in both groups reached JADAS-MDA/JADAS-remission/inactive disease (66.7%50%50% in first-liners and 60%45%70% in second-liners). Rates of serious adverse events were comparable and consistent with the overall AE profile of anakinra in patients. Conclusion: This analysis adds to the established safety profile of anakinra and demonstrates that anakinra is effective as first-line or second-line treatment.

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

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. 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. 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. 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.

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

ObjectiveBiologics 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.MethodsPatients 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.ResultsA 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.ConclusionSurveillance 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.

Adalimumab versus adalimumab and methotrexate for the treatment of juvenile idiopathic arthritis: long-term data from the German BIKER registry

Objective: Adalimumab (ADA) has become a valuable treatment option for juvenile idiopathic arthritis (JIA). The importance of combination with methotrexate (MTX) is unclear.Method: Data from the German Biologics in Paediatric Rheumatology (BIKER) registry are reported. Response to treatment was analysed using JIA American College of Rheumatology (ACR) scores, 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), and improvement of functional status and ACR inactive disease criteria. Compa-risons between rates of adverse events (AEs) and serious adverse events (SAEs) provided data for the safety assessment.Results: Overall, 584 patients with non-systemic JIA started ADA therapy, 61% of whom received concomitant MTX treatment at baseline. The latter patients were younger (p < 0.001), with shorter disease duration (p = 0.001), more frequently had antinuclear antibodies (p = 0.04), and had higher baseline JADAS10 scores (p = 0.03). In patients with ADA monotherapy, enthesitis-related arthritis (p = 0.004) and presence of human leucocyte antigen-B27 (p = 0.008) were documented more often. Mean treatment duration in both cohorts was 15 months. Comparable last follow-up rates for JIA ACR 30/50/70/90% response, JADAS minimal disease activity, JADAS remission, and ACR inactive disease were, respectively, 75/72/64/49%, 66%, 46%, and 58% for ADA monotherapy, and 77/72/61/45%, 64%, 48%, and 55%, for ADA + MTX. During 1082 patient-years (PY) of ADA exposure, 725 AEs (67/100 PY), including 57 SAEs (5.3/100 PY), were reported. Serious infections were reported in 10 patients (0.9/100 PY) and 11 (1.0/100 PY) had varicella infections/zoster reactivation. Rates of AEs, SAEs, infectious events, and serious infections did not differ between the cohorts. Elevated transaminases (p = 0.005) and gastrointestinal events (p < 0.0001) were reported more often in the combination cohort. Two pregnancies and no deaths were reported.Conclusion: ADA demonstrated an acceptable risk profile and high percentages of patients in both cohorts showed sufficient treatment response. No differences in treatment response or adherence to treatment were found.

OP0143 Serious Infections in Juvenile Idiopathic Arthritis Patients upon TNF Inhibitors Depend on Disease Activity

BackgroundSerious infections are a major concern in JIA patients treated with immunosuppressants and biologics. An increased risk has been described also for JIA patients without such treatments. An additional effect...

OP0183 Jadas Remission and Minimal Disease Activity upon First Biologic in Jia

BackgroundRemission and minimal disease activity have been proposed as treatment goal as both can be achieved. For both JADAS based definitions have been proposed.MethodsThis retrospective analysis used data of the...

FRI0345 Response to etanercept in juvenile idiopathic arthritis using the continuous measure juvenile arthritis disease activity score JADAS

BackgroundThe ACR paediatric criteria used in clinical trials are validated to analyse the response to a treatment in comparison to baseline but does not indicate the absolute disease activity nor...

FRI0344 Safety and efficacy of etanercept in juvenile idiopathic arthritis patients under two years of age

BackgroundIn Juvenile Idiopathic Arthritis (JIA) patients Etanercept is an effective therapeutic agent with an excellent safety profile. Currently it is licensed for treatment in polyarticular JIA patients over the age...

THU0311 What happens when etanercept is discontinued in “remission” in patients with juvenile idiopathic arthritis?

BackgroundEtanercept turned out to be highly effective in juvenile idiopathic arthritis. The aim of this study was to use the German Biker Registry data base to analyse the performance after...

THU0312 Reduction of concomitant treatment upon therapy with etanercept in juvenile idiopathic arthritis

BackgroundCombination treatment of Etanercept with corticosteroids and/or Methotrexate has been shown to have an impact on the occurrence of adverse events. (1)MethodsThe data base of the German BIKER registry documenting...

THU0310 Performance of the juvenile arthritis disease activity score JADAS compared to the acr pediatric measures of response in 1470 juvenile idiopathic arthritis patients

BackgroundThe pedACR criteria are validated to analyse the response to a treatment but do not indicate the absolute disease activity nor the absolute improvement. This study correlates the JADAS 71...