Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab

Background Treatment response, remission rates and compliance in patients with polyarticular juvenile idiopathic arthritis (polyJIA) treated with adalimumab, etanercept, or tocilizumab were analyzed in clinical practice. Methods Data collected in the German BIKER registry were analyzed in patients with polyJIA who started treatment with approved biologics, adalimumab, etanercept or tocilizumab, from 2011 to 2015. Baseline patient characteristics, treatment response, safety and drug survival were compared. Results Two hundred thirty- six patient started adalimumab, 419 etanercept and 74 tocilizumab, with differences in baseline patient characteristics. Baseline Juvenile Disease Activity Score (JADAS)10 (mean ± SD) in the adalimumab/etanercept/tocilizumab cohorts was 12.1+/−7.6, 13.8 ± 7.1 and 15.1 ± 7.4, respectively (adalimumab vs etanercept, p = 0.01), and Childhood Health Assessment Questionnaire (CHAQ)-disability index scores was 0.43 ± 0.58, 0.59 ± 0.6 and 0.63 ± 0.55, respectively (adalimumab vs etanercept, p < 0.001). Uveitis history was more frequent in the adalimumab cohort (OR 5.73; p < 0.001). Balanced patients’ samples were obtained by a generalized propensity score to adjust for baseline differences. Pediatric ACR30/50/70/90 criterion improvement after 3 months treatment was achieved by 68%/60%/42%/24% in the etanercept cohort, 67%/59%/43%/27% in the adalimumab cohort and 61%/52%/35%/26% in the tocilizumab cohort. At 24 months, JADAS minimal disease activity was achieved in 52.4%/61.3%/52.4% and JADAS remission in 27.9%/34.8%/27.9% patients in the adalimumab/etanercept/tocilizumab cohorts, respectively. Etanercept was used in 95.5% of patients as a first biologic, adalimumab in 50.8% and tocilizumab in 20.2%. There were no important differences in efficacy between first-line and second-line use of biologics. In total 60.4%/49.4%/31.1% patients discontinued adalimumab/etanercept/tocilizumab, respectively (HR for adalimumab 1.67; p < 0.001; HR for tocilizumab 0.35; p = 0.001). Drug survival rates did not differ significantly in patients on biologic monotherapy compared with combination therapy with methotrexate. Over 4 years observation under etanercept/adalimumab/tocilizumab, 996/386/103 adverse events, and 148/119/26 serious adverse events, respectively, were reported. Conclusions In clinical practice, etanercept is most frequently used as first-line biologic. Adalimumab/etanercept/tocilizumab showed comparable efficacy toward polyJIA. Overall, tolerance was acceptable. Interestingly, compliance was highest with tocilizumab and lowest with adalimumab. This study provides the first indication for the comparison of different biologic agents in polyarticular JIA based on observational study data with all their weaknesses and demonstrates the need for well-controlled head-to-head studies for confirmation

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

BackgroundTo describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN.MethodsSurvey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN.ResultsFifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria.ConclusionThe majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists

Practice and consensus-based strategies in diagnosing and managing systemic juvenile idiopathic arthritis in Germany

Background: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany. Methods: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements. Results: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy. Conclusions: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany

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

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 alpha (TNF alpha)-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 TNF alpha- (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 TNF alpha-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 TNF alpha 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

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

Paediatric Cogan´s syndrome - review of literature, case report and practical approach to diagnosis and management

Abstract Background Cogan´s syndrome is a rare, presumed autoimmune vasculitis of various vessels characterized by interstitial keratitis and vestibular impairment accompanied by sensorineural hearing loss. Due to the rarity of Cogan´s syndrome in children, therapeutic decision making may be challenging. Therefore, a literature search was performed to collect all published paediatric Cogan´s syndrome cases with their clinical characteristics, disease course, treatment modalities used and their outcome. The cohort was supplemented with our own patient. Main text Altogether, 55 paediatric Cogan´s syndrome patients aged median 12 years have been reported so far. These were identified in PubMed with the keywords “Cogan´s syndrome” and “children” or “childhood”. All patients suffered from inflammatory ocular and vestibulo-auditory symptoms. In addition, 32/55 (58%) manifested systemic symptoms with musculoskeletal involvement being the most common with a prevalence of 45%, followed by neurological and skin manifestations. Aortitis was detected in 9/55 (16%). Regarding prognosis, remission in ocular symptoms was attained in 69%, whereas only 32% achieved a significant improvement in auditory function. Mortality was 2/55. Our patient was an 8 year old girl who presented with bilateral uveitis and a history of long standing hearing deficit. She also complained of intermittent vertigo, subfebrile temperatures, abdominal pain with diarrhoea, fatigue and recurrent epistaxis. The diagnosis was supported by bilateral labyrinthitis seen on contrast-enhanced magnetic resonance imaging. Treatment with topical and systemic steroids was started immediately. As the effect on auditory function was only transient, infliximab was added early in the disease course. This led to a remission of ocular and systemic symptoms and a normalization of hearing in the right ear. Her left ear remained deaf and the girl is currently evaluated for a unilateral cochlear implantation. Conclusions This study presents an analysis of the largest cohort of paediatric Cogan´s syndrome patients. Based on the collected data, the first practical guide to a diagnostic work-up and treatment in children with Cogan´s syndrome is provided

First-year follow-up of children with chronic nonbacterial osteomyelitis—an analysis of the German National Pediatric Rheumatologic Database from 2009 to 2018

Objective!#!To assess the first-year features of patients with chronic nonbacterial osteomyelitis (CNO).!##!Methods!#!Patients with a diagnosis of CNO, disease duration of under 13 months, and first registration in the German National Pediatric Rheumatologic Database (NPRD) between 2009 and 2018 were included in this cross-sectional analysis.!##!Results!#!Of 774 documented patients, 62.8% were female, and all patients had a median age of 11 years. The most affected clinical sites were the tibia (29.7%), pelvis (28.0%), and femur (27.8%). HLA-B27 was positive in 48 of 314 analyzed patients (15.3%). In 406 patients, an X-ray was performed at the first visit; X-ray results showed osteosclerosis/-lysis in 34.0% and hyperostosis in 14.5% of the patients. MRI scans (focal and whole-body scans) were performed in 648 patients, and 81.5% showed a positive TIRM/STIR signal. A total of 84.7% of the patients were administered nonsteroidal anti-inflammatory drugs, 9.6% were administered oral glucocorticoids, 10.8% were administered disease-modifying anti-rheumatic drugs (DMARDs), and 6.1% were administered bisphosphonates. An evaluation of the patient's questionnaire showed an overall well-being (NRS 0-10) of 2.0. The PedCNO disease 'activity' score revealed a 70% improvement in variables in 43% of patients in the initial 1-year follow-up. Copresentation with diagnostic criteria of pediatric enthesitis-related arthritis was rare.!##!Conclusion!#!To our knowledge, the NPRD cohort seemed to be the largest cohort of children and adolescents suffering from CNO worldwide. Most patients were treated effectively with NSAIDs, and only a small group of patients was administered additional medication. The patient-defined measures of disease activity had a moderate impact on patients' daily lives.!##!Trial registration!#!Not applicable

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

Abstract 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