Risk perception, well-being, depression and anxiety in children and adolescents with rheumatic diseases during the COVID-19 pandemic - results from the prospective multicenter KICK-COVID study in Germany.

OBJECTIVE: To investigate the psychosocial burden in children and adolescents with juvenile rheumatic diseases during the COVID-19 pandemic. METHODS: As part of the multicentre observational KICK-COVID study linked to the National Pediatric Rheumatology Database, adolescents < 21 years and parents of children < 12 years with rheumatic diseases answered questions on perceptions of health risk (PHR) due to SARS-CoV2, stress, well-being (WHO-5) and symptoms of depression (PHQ-9) and anxiety (GAD-7). Data were collected at routine visits from June to December 2021 and assessed for association with demographic and clinical parameters, treatment and patient-reported outcomes by multivariable regression analyses. RESULTS: Data from 1356 individuals (69% female, 50% adolescents) were included. Median PHR on a numeric rating scale (NRS, 0-10) was 4 (IQR 2-6), median perceived stress was 3 (IQR 1-6). Adolescents reported a worse well-being with a significantly lower median WHO-5-score (60, IQR 40-76) than parents reported for their children < 12 years (80, IQR 68-84). Moderate to severe symptoms of depression and anxiety were reported by 14.3% and 12.3% of the adolescents, respectively. PHR was significantly higher in patients with systemic lupus erythematosus, methotrexate or biologic disease-modifying anti-rheumatic drug therapy than in patients without these characteristics, whereas lower WHO-5 or higher PHQ-9 or GAD-7 scores were only associated with poorer patient-reported health status and physical functioning. CONCLUSION: The perception of health risk due to SARS-CoV2 infection was not paralleled by an impairment of mental health, which were, however, significantly correlated with self-rated health status and functional capacity, highlighting the importance of patient-reported outcome assessment. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), no. DRKS00027974. Registered on 27th of January 2022.

Anxiety and depression symptoms in adolescents and young adults with juvenile idiopathic arthritis: results of an outpatient screening.

BACKGROUND: Previous studies have shown that growing up with rheumatic conditions can fuel dissatisfaction and psychological distress, which in turn affects disease self-management and treatment adherence. Primary objective of this study was to estimate the prevalence of anxiety and depression symptoms in adolescents and young adults (AYA) with juvenile idiopathic arthritis (JIA) and to identify correlates of conspicuous screening results. METHODS: Initiated as part of the COACH multicenter observational study, outpatients aged 12 to 21 years participating in the National Pediatric Rheumatological Database (NPRD) were prospectively screened for mental health using the Patient Health Questionnaire-9 (PHQ-9) and the Generalised Anxiety Disorder Scale-7 (GAD-7). RESULTS: Data from 1,150 adolescents with JIA (mean age 15.6 ± 2.2 years; mean disease duration 7.2 ± 4.9 years, 69% female, 43% oligoarthritis, 26% polyarthritis) were analysed. Overall, 32.7% (n = 316) of AYA showed conspicuous screening results, of whom 30.4% reported clinically relevant suicidal or self-harm thoughts. About 19% of screened patients showed moderate to severe depressive or anxious symptoms. AYA with conspicuous screening results were older (15.8 vs. 15.2 years; p < 0.0001), more often female (81% vs. 64%; p < 0.0001) and more often overweight (25% vs. 17%; p = 0.006). They had higher disease activity (physician global assessment on NRS 0-10; 1.7 vs. 1.2; p < 0.0001), more functional limitations (CHAQ; 0.44 vs. 0.14; <0.0001) and rated their health status worse (NRS 0-10; 3.5 vs. 1.8; p < 0.0001) than AYA with inconspicuous screening results. Females (OR 2.33 [CI 1.53-3.56]; p < 0.0001), older age (OR 1.09 [CI 1.01-1.18]; p = 0.026), patients with more functional limitations (OR 3.36 [CI 1.98-5.72]; p < 0.0001), and patients with worse subjective health status (OR 1.17 [CI 1.07-1.27]; p < 0.0001) were more likely to have a conspicuous screening result. Regular sports participation was associated with a lower likelihood of conspicuous screening result (OR 0.69 [CI 0.49-0.98]; p = 0.039). CONCLUSIONS: A large-scale outpatient screening of AYA with JIA in Germany shows a high prevalence of anxiety and depression symptoms. The need for routine screening for early detection of mental health problems became apparent.

Level and correlates of physical activity among children and adolescents with juvenile idiopathic arthritis compared to controls: results from a German nationwide prospective observational cohort study.

BACKGROUND: Physical active lifestyles are essential throughout growth and maturation and may offer potential preventive and therapeutic benefit in patients with juvenile idiopathic arthritis (JIA). Insufficient physical activity (PA), in contrast, can lead to aggravation of disease-related symptoms. This study aimed to i) examine PA levels in children and adolescents with JIA compared to general population controls and ii) investigate correlates of pronounced physical inactivity in order to identify risk groups for sedentary behaviour. METHODS: Data from children and adolescents with JIA and population controls aged 3 to 17 years documented in the National Pediatric Rheumatologic Database (NPRD) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were used. Self-reported PA was collected from parents/guardians of children up to 11 years of age or adolescents 12 years of age and older. To compare PA-related data, age- and sex-specific pairwise analyses were conducted considering NPRD/KiGGS participants' data from 2017. Correlates of physical inactivity among patients were identified using a linear regression model. RESULTS: Data of 6,297 matched-pairs (mean age 11.2 ± 4.2 years, female 67%, patients' disease duration 4.5 ± 3.7 years, persistent oligoarthritis 43%) were available for evaluation. Almost 36% of patients aged 3-17 years (vs. 20% of controls) achieved the WHO recommended amount of PA, while PA steadily decreased with age (18% of patients aged ≥ 12 years) and varied between JIA categories. Female adolescents and patients with enthesitis-related arthritis were least likely to achieve the minimum recommended level of PA. Physical inactivity was associated with female sex, higher age at disease onset, longer disease duration, more functional disability (C-HAQ) and higher disease activity (cJADAS-10). CONCLUSIONS: Depending on JIA category, children and adolescents with JIA were similarly or even more likely to achieve the WHO recommended minimum level of PA compared to general population controls. However, since a large proportion of young JIA patients appear to be insufficiently physically active, engagement in targeted efforts to promote PA is urgently needed.

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry.

OBJECTIVE: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). METHODS: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. RESULTS: At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. CONCLUSION: Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.

Adherence, helpfulness and barriers to treatment in juvenile idiopathic arthritis - data from a German Inception cohort.

OBJECTIVES: To develop and evaluate German versions of the Parent Adherence Report Questionnaire (PARQ) and Child Adherence Report Questionnaire (CARQ) and to evaluate adherence in patients with juvenile idiopathic arthritis (JIA). METHODS: The PARQ and CARQ were translated into German, cross-culturally adapted and administered to patients (age ≥ 8 years) and their parents enrolled in the Inception Cohort Study of newly diagnosed JIA patients (ICON). The psychometric issues were explored by analyzing their test-retest reliability and construct validity. RESULTS: Four hundred eighty-one parents and their children with JIA (n = 465) completed the PARQ and CARQ at the 4-year follow-up. Mean age and disease duration of patients were 10.1 ± 3.7 and 4.7 ± 0.8 years, respectively. The rate of missing values for PARQ/CARQ was generally satisfactory, test-retesting showed sufficient reliability. PARQ/CARQ mean child ability total scores (0-100, 100 = best) for medication were 73.1 ± 23.3/76.5 ± 24.2, for exercise: 85.6 ± 16.5/90.3 ± 15.0, for splints: 72.9 ± 24.2/82.9 ± 16.5. Construct validity was supported by PARQ and CARQ scores for medications, exercise and splints showing a fair to good correlation with the Global Adherence Assessment (GAA) and selected PedsQL scales. Adolescents showed poorer adherence than children. About one third of the parents and children reported medication errors. Perceived helpfulness was highest for medication, and adverse effects were reported the greatest barrier to treatment adherence. CONCLUSIONS: The German versions of the PARQ and CARQ appear to have a good reliability and sufficient construct validity. These questionnaires are valuable tools for measuring treatment adherence, identifying potential barriers and evaluating helpfulness of treatments in patients with JIA.

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.

Myositis-specific autoantibodies and their associated phenotypes in juvenile dermatomyositis: data from a German cohort.

OBJECTIVES: To describe a German cohort of patients with juvenile dermatomyositis (JDM) and to evaluate clinical manifestations, disease course and prognosis in JDM patients with a certain myositis-specific autoantibody. METHODS: Cross-sectional data on patients with JDM documented in the National Paediatric Rheumatologic Database in Germany between 2014 and 2016 were analysed. In a subgroup of the cohort, MSAs were determined with a commercial multiplex array, and a retrospective chart review was conducted to specify the clinical phenotype and patient outcome. RESULTS: The total cohort consisted of 196 patients with JDM (mean age 12.2±4.0 years, mean disease duration 5.1±3.8 years, 70% female). Apart from typical skin changes and muscle weakness, 41% of patients also had arthritis and/or contractures, 27% had calcinosis and approximately 10% had interstitial lung disease. Immunoblot testing was performed on the sera of 91 (46%) patients, detecting MSAs in 44% of patients. Patient groups with specific MSAs differed in clinical characteristics such as calcinosis, dysphagia, and lung and joint involvement. The extent of muscle weakness evaluated by the Childhood Myositis Assessment Scale was significantly associated with an increased level of creatine kinase. Patients with anti-MDA5 were particularly affected by polyarthritis of the small joints. After 5 years, 51 patients of the MSA cohort (56.0%) achieved an inactive disease state, 12/51 (23.5%) were off therapy. CONCLUSIONS: Patients with JDM in Germany show a broad spectrum of clinical manifestations that can be grouped into homogeneous groups using MSA, which also helps to predict the course and prognosis of the disease.

Consumer perspective on healthcare services for juvenile idiopathic arthritis: results of a multicentre JIA inception cohort study.

OBJECTIVES: To evaluate healthcare services for patients with juvenile idiopathic arthritis (JIA) from the parent-proxy perspective and to identify factors associated with perceived deficits in care. METHODS: Patients with JIA from 11 paediatric rheumatology units were enrolled in an inception cohort within the first 12 months after diagnosis. Healthcare services were assessed using The Child Healthcare Questionnaire on satisfaction, utilisation and needs. Factors associated with deficits in care were identified by logistic regression analysis. RESULTS: Data from parents of 835 JIA-patients were included in the analysis. At the assessment (4.7 months after diagnosis), 85% of the patients received drug treatment, and 50% had received multi-professional care. The most frequently used services were physiotherapy (84%), occupational therapy (23%), and telephone counselling (17%). Almost one-third of families reported that they had not received the services that they needed, with health education being the most frequently reported need. Most parents (93%) were satisfied with the overall healthcare provided for their children, especially regarding doctors' behaviour. However, approximately 1 in 3 consumers were dissatisfied with the time to JIA diagnosis and the school services. The lower the child's quality of life, the higher the chance was that the child and the family received multi-professional care, perceived unmet needs, and were dissatisfied with care. CONCLUSIONS: According to parents' experience and satisfaction with their child's care, performance at the system level can be further improved by diagnosing JIA earlier, providing additional information at disease onset, and ensuring that the child's social environment is taken into account.

Experiences with IL-1 blockade in systemic juvenile idiopathic arthritis - data from the German AID-registry.

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with dysregulation of the innate immune system driven by cytokines. A major role is ascribed to interleukin-1ß (IL-1ß), supporting the autoinflammatory character of the disease and offering an effective blocking mechanism for treatment. Here we present clinical practice data from the German AID-registry for patients treated with IL-1 inhibition (IL-1i). METHODS: In 2009 a clinical and research consortium (AID-Net) was established, including an online AID-registry. Patients with documented sJIA diagnosis were identified. Data for this retrospective IL-1i study were recorded by 17 centers. Response to treatment was evaluated according to Wallace criteria and additionally by an own classifying clinical response system. RESULTS: In 6 years, 202 patients with confirmed sJIA were recorded in the AID-registry. Out of these, 111 children received therapy with Anakinra (ANA) (n = 84, 39 f) and/or Canakinumab (CANA) (n = 27, 15 f) at a median age of 8.7 y (range 0.6-19.1). During the first 12 months 75/111 (ANA 55, CANA 20) patients were evaluated according to Wallace criteria (achievement of inactive disease 28/55 and 17/20, remission over 6 months under medication 13/55 and 7/20 cases). Over the whole period of time, clinical response was preserved in the majority of patients (ANA 54/80, CANA 20/27). Arthritis mostly persisted in polyarticular (PA) courses. During treatment with IL-1i concomitant medication could be tapered in about 15%. IL-1i was discontinued in 59/111 patients. 45 (15) adverse events (AE)s in ANA (CANA) treated patients (19.7 (26.6) AE/100 ANA (CANA) exposure years, 95%CI: 14.4-26.4 (14.9-43.9)) were reported. CONCLUSION: In a large cohort of sJIA patients from Germany, we can confirm an overall favorable clinical response to both available IL-1 blocking agents. IL-1i was well tolerated with acceptable safety and effectiveness in a real-life clinical setting.

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.

Vitamin D deficiency is associated with higher disease activity and the risk for uveitis in juvenile idiopathic arthritis - data from a German inception cohort.

OBJECTIVE: The objective was to evaluate the 25(OH) vitamin D (25(OH)D) status of patients with juvenile idiopathic arthritis (JIA) and determine whether the 25(OH)D level is associated with disease activity and the course of JIA. METHODS: Patients ≤ 16 years of age with recently diagnosed JIA (< 12 months) were enrolled in the inception cohort of patients with newly diagnosed JIA (ICON), an ongoing prospective observational, controlled multicenter study started in 2010. Clinical and laboratory parameters were ascertained quarterly during the first year and half-yearly thereafter. Of the 954 enrolled patients, 360 patients with two blood samples taken during the first 2 years after inclusion and with follow up of 3 years were selected. The serum 25(OH)D levels were determined and compared with those of subjects from the general population after matching for age, sex, migration status and the month of blood-drawing. RESULTS: Nearly half of the patients had a deficient 25(OH)D level (< 20 ng/ml) in the first serum sample and a quarter had a deficient level in both samples. Disease activity and the risk of developing JIA-associated uveitis were inversely correlated with the 25(OH)D level (ß = - 0.20, 95% CI - 0.37; 0.03, hazard ratio 0.95, 95% CI 0.91; 0.99, respectively). CONCLUSION: In this study, 25(OH)D deficiency was common and associated with higher disease activity and risk of developing JIA-associated uveitis. Further studies are needed to substantiate these results and determine whether correcting 25(OH)D deficiency is beneficial in JIA.

Growth During Tocilizumab Therapy for Polyarticular-course Juvenile Idiopathic Arthritis: 2-year Data from a Phase III Clinical Trial.

OBJECTIVE: Evaluate growth in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ) for up to 2 years in a phase III trial. METHODS: Patients with pcJIA lasting at least 6 months and inadequate response to methotrexate received open-label TCZ intravenously every 4 weeks (randomly assigned to 8 or 10 mg/kg if they weighed < 30 kg; received 8 mg/kg if they weighed ≥ 30 kg) for 16 weeks. Patients with JIA American College of Rheumatology 30 response at Week 16 were randomly assigned to TCZ or placebo for 24 weeks, with an open-label extension through Week 104. Mean ± SD height velocity (cm/yr) and World Health Organization (WHO) height SD score (SDS) were measured in patients receiving ≥ 1 dose of TCZ who did not receive growth hormone and in patients whose baseline Tanner stage was ≤ 3. RESULTS: The study included 187 of 188 patients (99.5%) with mean WHO height SDS -0.5 ± 1.2, which was unrelated to age or disease duration (Spearman rank correlations r = 0.08 and r = -0.12, respectively). There were 123 patients at Tanner stage ≤ 3 at baseline, among whom 103 completed the study with 2 years of height SDS data. Mean height SDS increased from baseline to year 2 (+0.40, p < 0.0001). In 74 of 103 patients (72%), height SDS was greater than at baseline, and mean height velocity was 6.7 ± 2.0 cm/year. CONCLUSION: Among patients with pcJIA at Tanner stage ≤ 3 at baseline, 72% (74/103) had increased height SDS at the end of the study.

Development of practice and consensus-based strategies including a treat-to-target approach for the management of moderate and severe juvenile dermatomyositis in Germany and Austria.

BACKGROUND: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM. METHODS: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements. RESULTS: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease. CONCLUSION: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.

Comorbidity of Type 1 Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis.

OBJECTIVES: To determine the prevalence of type 1 diabetes mellitus (T1D) in patients with juvenile idiopathic arthritis (JIA) and to characterize patients having both. STUDY DESIGN: Diabetes comorbidity was recorded in the National Pediatric Rheumatologic Database since 2012. Data from the North Rhine-Westphalian diabetes registry served as the reference population for the prevalence of diabetes in the general population. The National Pediatric Rheumatologic Database data were indirectly standardized for age and sex for comparison with the general population. The diabetes prevalence ratio was calculated using the Poisson regression model. RESULTS: The analysis included 12 269 patients with JIA. A total of 58 patients had comorbid T1D, and the diabetes prevalence was 0.5%. The mean age was 11.6 years at the time of documentation, and the mean disease duration was 4.2 years. Compared with the general population, the prevalence of diabetes in patients with JIA was significantly increased (prevalence ratio 1.76 [95% CI 1.34; 2.28], P < .001). The onset of diabetes in patients with JIA was earlier than that reported in the reference data. Sixty-three percent of patients developed T1D before JIA. On average, diabetes onset was 56 months before the onset of JIA. Patients who first developed JIA developed T1D on average 40 months later. The majority of patients had not received disease-modifying antirheumatic drugs before diabetes onset. CONCLUSIONS: T1D occurs more frequently in patients with JIA than in the general population. The likelihood of T1D occurrence appears to be slightly higher before JIA manifestation and without disease-modifying antirheumatic drug therapy after JIA onset.

Experience with etanercept, tocilizumab and interleukin-1 inhibitors in systemic onset juvenile idiopathic arthritis patients from the BIKER registry.

BACKGROUND: Treatment of systemic onset juvenile idiopathic arthritis JIA (sJIA), although dramatically improved, remains a challenge. Experience from clinical practice will be presented using data from the German Biologics register (BiKeR) for evaluation of efficacy and safety of treatment with etanercept (ETA), tocilizumab (TOC) and the interleukin-1 inhibitors anakinra and canakinumab (IL-1i) in sJIA. METHODS: Patients with sJIA documented in the BIKeR register, who were exposed to ETA, TOC or IL-1i were identified. Baseline demographics, clinical characteristics and disease activity parameters have been documented. Efficacy was determined using the JIA-American College of Rheumatology (ACR) response criteria and the Juvenile Disease Activity Score 10 (JADAS10). An intention-to-treat analysis was performed and patients who discontinued due to inefficacy or intolerance were analysed as non-responders. Safety assessments were based on adverse events (AEs) reports. RESULTS: Since 2000, 245 sJIA patients (50.3% male) exposed to biologic agents have been identified: 143 patients treated with ETA, 71 with TOC and 60 with IL-1i (anakinra 38, canakinumab 22). All patients received systemic steroids for pre-treatment but less frequently with TOC and IL-1i than with ETA for concomitant treatment. At baseline, the ETA cohort had fewer systemic disease manifestations but more active joints. The JIA-ACR 30/50/70/90 response over a period of 24 months was reached more often in the IL-1i and TOC cohort than with ETA. ETA/TOC/IL1i JADAS-remission (JADAS ≤1) was reached in 20%/37%/52%, minimal disease activity (JADAS ≤3.8 in 35%/61%/68% and ACR inactive disease in 24%/33%/56%). As compared to ETA, rates of AEs were significantly higher in the TOC cohort (risk ratio (RR) 5.3/patient-year; p < 0.0001) and serious AE were observed more frequently with TOC (RR 2.5; p < 0.5) and IL1i (2.9; p < 0.01). CONCLUSIONS: A large proportion of patients gained significant response to treatment especially with TOC or IL-1is. After 6 months on treatment, JADAS remission was reached by up to half of patients while up to two thirds reached JADAS minimal disease activity. ETA has been used in the past but it is clearly less effective and its use in systemic JIA has markedly decreased in Germany.

Protocols on classification, monitoring and therapy in children's rheumatology (PRO-KIND): results of the working group Polyarticular juvenile idiopathic arthritis.

OBJECTIVE: Several effective pharmacologic treatment options for polyarticual juvenile idiopathic arthritis (JIA) have emerged but initial treatment is heterogeneous in Germany. Therefore, the German Society of Pediatric Rheumatolgy has established a commission to develop consensus "Protocols on classification, monitoring and therapy in children's rheumatology (PRO-KIND)" to harmonize diagnostic and treatment approaches for new-onset JIA in Germany. METHODS: A set of definitions for in- and exclusion, diagnostic workup, parameters for the evaluation of disease activity criteria, therapeutic options, medication dosing, monitoring recommendations, targets, definitions of a therapy failure and four therapeutic algorithms developed by a working group were agreed by web based survey to which all members of the GKJR have been invited. A final protocol with 4 consensus treatment plans (CTP) was agreed in a face-to-face consensus conferences employing modified nominal group technique. RESULTS: The initial 17 definitions and recommendations for new-onset polyarticular JIA agreed by the working group reached >80% agreement in a web survey in 68 German paediatric rheumatologist. Four CTPs were developed based on treatment strategies for the first 12 months of therapy, as well as definitions for clinical and laboratory monitoring. The CTPs include a step-up plan (nonbiologic Disease-modifying antirheumatic drug [DMARD] followed by a biologic), a combination plan (combination of nonbiologic and biologic after failure of initial DMARD), an intensive pulse corticosteroid scheme in parallel with a DMARD followed by combination therapy and a multiple corticosteroids joint injections strategy in a treat to target approach. Step up will be guided by a treat to target strategy to reach a JADAS-improvement at month 3, acceptable disease at month 6 or 9 and JADAS remission or at least JADAS minimal disease activity at month 12. CONCLUSION: Standardized baseline work-up, disease activity evaluation and a definition of a treat to target approach will result in better health outcomes for polyarticular JIA patients. Four CTPs were developed for new-onset polyarticular JIA, which coupled with data collection at defined intervals will be evaluated and improved to optimize management of polyarticular JIA. Harmonization of treatment will be the basis for future comparative effectiveness research.