BackgroundTreatment 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.MethodsPatients 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.ResultsSince 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).ConclusionsA 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1462-2) contains supplementary material, which is available to authorized users.
The observation of higher concordance rates for MZ compared to DZ twin pairs indicates that genetic factors contribute to isolated EA.
The VATER/VACTERL association is typically defined by the presence of at least three of the following congenital malformations: vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. The identification of 14 twin pairs with an initial diagnosis of VATER/VACTERL association at our clinical centers led to the performance of a classical twin study. This involved a thorough evaluation of these 14 twin pairs and a further 55 twin pairs identified from a systematic review of the literature. The zygosity, concordance, and malformation status of all 69 twin pairs were evaluated. Twenty-four twin pairs fulfilled the criteria for inclusion in a comparison of the concordance rates between monozygous (MZ) and dizygous (DZ) twin pairs. The pairwise concordance rates were 15% [95% confidence interval (CI) 4–42%] for MZ and 18% (95% CI 5–48%) for DZ twin pairs (P = 0.53). The probandwise concordance rates were 27% (95% CI 11–52%) for MZ and 31% (95% CI 13–58%) for DZ twin pairs (P= 0.40). Although based on a limited number of twin pairs, the findings of the present study are consistent with the low number of familial cases reported to date, and suggest that the role of inherited genetic factors in the majority of VATER/VACTERL cases is limited.
The etiology of gastroschisis remains elusive. A classic twin study was used to assess the relative contribution of environmental and genetic factors in its development. Screening of 4872 twin pregnancies identified three unreported twin pairs comprising two monozygous and one dizygous discordant pair of twins. Review of the literature identified an additional 21 twin pairs. We observed lower pair- and proband-wise concordance rates for monozygotic compared to dizygotic twin pairs, pair- and proband-wise concordance ratios below 1.0. Our results suggest environmental to play a greater role than genetic factors in the development of gastroschisis.
BackgroundSystemic juvenile idiopathic arthritis (sJIA) is characterised by arthritis accompanied or preceded by systemic autoinflammation. High-dose steroids has been the mainstay of therapy with proven effectiveness but also with side-effects. In many patients a chronic course with destructive arthritis long-term cannot be prevented.ObjectivesIn patients naïve for steroids, a steroid-free treatment may allow reconstitution of an impaired NK-cell function and probably remission of sJIA.MethodsFirst experience with first line Anakinra without steroids in 9 consecutive patients is reported.ResultsAll patients presented with ongoing spiking fever and rash and further features of sJIA, high CRP, S100 and IL18 (table 1). Daily sq. injections of Anakinra 2 mg/kg for 3 months resulted in complete remission in 4 and partial response in two children presenting with an oligoarticular involvement. One patient with typical sJIA and very high S100 (MRP8/9) levels did not respond to Anakinra nor to Canakinumab. Two patients presented with polyarthritis. One had no response, the other showed a minor response but improved on steroids and was later treated with tocilizumab. One of the oligoarticular patients with an initial partial response had a flare upon anakinra captured by increased dosing (4 mg/kg) but finally developed macrophage activation syndrome. Anakinra was discontinued after 3 months in 3 of the 4 responders. Two remained in drug free remission while the remainder flared several months later and retreatment was instituted. The patients with polyarticluar involvement first received corticosteroids and were later both treated successfully with the IL-6 inhibitor.ConclusionsExperience with first line steroid free treatment with Anakinra for sJIA is presented. A complete remission was reached in 4 cases with oligoarticular involvement. In 3 further cases improvement was observed and 2 had no response including one who also failed Canakinumab. A toddler with a particular response to Anakinra later on developed MAS. One patient did not respond to both IL-1 inhibitors. Thus, steroid free treatment regimen with Anakinra is feasible and resulted into remission in most but not all patients. Aside, unwarranted effects of long lasting steroid application were avoided.Disclosure of InterestNone declared
ZusammenfassungBiologika haben die Therapiemöglichkeiten der juvenilen idiopathischen Arthritis (JIA) in den letzten 15 Jahren erheblich erweitert. Trotz der hohen Wirksamkeit sind Sicherheitsaspekte, insbesondere Infektionen, von großem Interesse. Das Risiko für medizinisch bedeutsame bakterielle Infektionen scheint allein aufgrund der Erkrankung bei JIAPatienten erhöht und weiter durch die anti- rheumatische Behandlung anzusteigen. Insgesamt ist die Häufigkeit ernsthafter Infektionen niedrig. Die Kombination von Daten aus verschiedenen Quellen ergeben vergleichbare Raten ernsthafter Infektionen pro 100 Patientenjahre für Abatacept (1,1 [0,5–2,5]), Adalimumab (1,9 [1,4–2,6]), Etanercept (1,5 [1,4–1,8]) sowie Tocilizumab (2,06 [1,0–4,3] und gering-fügig höhere für Golimumab (3,0 [1,3–7,3]) und Infliximab (3,4 [1,7–6,8]). Der Vergleich von Patientenkohorten ohne eine Biologikatherapie (0,67 [0,48–0,93]) ergibt ein signifikant erhöhtes Risiko (p < 0,05) für ernsthafte Infektionen für alle Biologika mit Ausnahme von Tocilizumab und Abatacept aufgrund kleinerer Fallzahlen. Ein Herpes zoster ist die einzige häufiger auftretende spezifische Infektion. Opportunistische Infektionen einschließlich Tuberkulose sind sehr selten. Insgesamt sind die Sicherheitsprofile von für die JIA zugelassenen Biologika sehr akzeptabel.
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