Objective. To evaluate the impact of early treatment and IL1RN genetic variants on the response to anakinra in systemic juvenile idiopathic arthritis (JIA).Methods. Response to anakinra was defined as achievement of clinically inactive disease (CID) at 6 months without glucocorticoid treatment. Demographic, clinical, and laboratory characteristics of 56 patients were evaluated in univariate and multivariate analyses as predictors of response to treatment. Six single-nucleotide polymorphisms (SNPs) in the IL1RN gene, previously demonstrated to be associated with a poor response to anakinra, were genotyped by quantitative polymerase chain reaction (qPCR) or Sanger sequencing. Haplotype mapping was performed with Haploview software. IL1RN messenger RNA (mRNA) expression in whole blood from patients, prior to anakinra treatment initiation, was assessed by qPCR.Results. After 6 months of anakinra treatment, 73.2% of patients met the criteria for CID without receiving glucocorticoids. In the univariate analysis, the variable most strongly related to the response was disease duration from onset to initiation of anakinra treatment, with an optimal cutoff at 3 months (area under the curve 84.1%). Patients who started anakinra treatment ≥3 months after disease onset had an 8-fold higher risk of nonresponse at 6 months of treatment. We confirmed that the 6 IL1RN SNPs were inherited as a common haplotype. We found that homozygosity for ≥1 high-expression SNP correlated with higher IL1RN mRNA levels and was associated with a 6fold higher risk of nonresponse, independent of disease duration. Conclusion.Our findings on patients with systemic JIA confirm the important role of early interleukin-1 inhibition and suggest that genetic IL1RN variants predict nonresponse to therapy with anakinra.

BackgroundSystemic juvenile idiopathic arthritis (sJIA) accounts for 10-20% of all patients with JIA. The prominent systemic clinical features, the marked elevation of inflammatory markers and the absence of autoantibodies make this disease different from other JIA forms. sJIA should be considered as a polygenic autoinflammatory disease. Interleukin 1 (IL-1) has been shown to be a major mediator of the inflammatory cascade that underlies sJIA. Treatment with anakinra has been reported to be effective in a sizable portion of patients with sJIA.ObjectivesTo assess clinical response rate and disease course in sJIA patients treated with anakinra. To evaluated whether the response to anakinra was related to baseline variables.MethodsWe reviewed 56 (28 F) consecutive patients with sJIA treated with anakinra for at least 6 months in our institution. The diagnosis of sJIA was established according to the International League of Associations for Rheumatology (ILAR) classification criteria. We analyzed the effect of anakinra on fever, rash, number of active joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cells count, platelets count and ferritin levels. Clinically inactive disease (CID) was defined according to Wallace criteria. Clinical and laboratory data were obtained using a standard data collection form.ResultsThe median age at the disease onset was 5.7 (IQR 2.9-10.2) years. The median time from onset to received anakinra was 1.9 (IQR 0.7-9.7) months. At baseline 52/56 (93%) of patients had fever and median number of active joints was 2 (IQR 1-4). After 6 months of treatment 39 patients (69.6%) met criteria for inactive disease. Among 56 patients 17 (30.3%) received anakinra in monotherapy and 39 (69.6%) received anakinra with glucocorticoids. There were no statistically significant differences between the two groups for demographic, clinical and laboratory features. 13/17 (76.4%) patients treated with anakinra alone and 26/39 (66.6%) patients treated with anakinra and glucocorticoids met criteria for CID off glucocorticoids at 6 months (p=0.54). Among the 56 patients, 29 (51.7%) received anakinra within 2 months from disease onset. There were no statistically significant differences for demographic, clinical and laboratory features among patients who started anakinra in the first 2 months from disease onset compared to those that started anakinra after 2 months. At 6 months after beginning of anakinra treatment, 27/29 patients (93.1%) who started anakinra within 2 months from disease onset and 12/27 (44.4%) who started anakinra after 2 months from disease onset reached clinical inactive disease off glucocorticoids (p=0.0001). Patients who started anakinra after the first 2 months from disease onset have a significantly higher risk of non-response (OR=8.06, 95% CI: 2.03-32.0).ConclusionAccording with several observations, anakinra is effective in a significant proportion of patients with sJIA. A possible approach to introduce IL-1 inhibitor, with or without concomitant glucocorticoid...

Non-syndromic primary ovarian insufficiency due to ovarian dysgenesis in 46,XX patients is an uncommon finding in the general population, even though several monogenic variants have been reported as causative factors. Here, we describe a 15-year-old patient diagnosed with gonadal dysgenesis possibly due to the interaction of three potentially pathogenic variants of genes involved in ovarian maturation, namely factor in the germline alpha (FIGLA), newborn ovary homeobox-encoding (NOBOX) and nuclear receptor subfamily 5 group A member 1 (NR5A1). We also describe a different degree of residual ovarian function within the proband's family, whose female members carry one to three demonstrated variations in the aforementioned genes in a clinical spectrum potentially dependent on the number of alleles involved. Our results support the hypothesis that the severity of the clinical picture of the proband, resulting in complete ovarian dysgenesis, may be due to a synergic detrimental effect of inherited genetic variants.