BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity.

Activity of the NLRP3 inflammasome, a critical mediator of inflammation, is controlled by accessory proteins, posttranslational modifications, cellular localization, and oligomerization. How these factors relate is unclear. We show that a well-established drug target, Bruton's tyrosine kinase (BTK), affects several levels of NLRP3 regulation. BTK directly interacts with NLRP3 in immune cells and phosphorylates four conserved tyrosine residues upon inflammasome activation, in vitro and in vivo. Furthermore, BTK promotes NLRP3 relocalization, oligomerization, ASC polymerization, and full inflammasome assembly, probably by charge neutralization, upon modification of a polybasic linker known to direct NLRP3 Golgi association and inflammasome nucleation. As NLRP3 tyrosine modification by BTK also positively regulates IL-1ß release, we propose BTK as a multifunctional positive regulator of NLRP3 regulation and BTK phosphorylation of NLRP3 as a novel and therapeutically tractable step in the control of inflammation.

Efficacy and safety of etanercept in patients with the enthesitis-related arthritis category of juvenile idiopathic arthritis: results from a phase III randomized, double-blind study.

OBJECTIVE: To evaluate the efficacy and safety of etanercept in patients with enthesitis-related arthritis (ERA) in juvenile idiopathic arthritis (JIA). METHODS: This was a 2-phase study in JIA patients with active, refractory ERA. Phase I was an open-label, uncontrolled 24-week study period in which all patients were administered etanercept. Patients considered to be treatment responders at week 24 according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement in juvenile arthritis entered the second phase, a 24-week randomized, double-blind, placebo-controlled withdrawal study, for an additional 24 weeks, for evaluation of the primary end point, occurrence of a disease flare from week 24 to week 48, based on the ACR preliminary definition of disease flare in juvenile arthritis. RESULTS: Forty-one patients were enrolled. At week 24, treatment with etanercept resulted in response rates of 93%, 93%, 80%, 56%, and 54% based on the ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria, respectively. In addition, a marked decrease in all disease activity measures was observed. The mean number of tender joints, swollen joints, and joints with active arthritis decreased by 91%, 97%, and 94%, respectively. Physician's global assessment of disease activity, parent's assessment of patient's overall well-being, and the Childhood Health Assessment Questionnaire disability index improved by 91%, 80%, and 86%, respectively. The number of tender enthesis sites and total scores for back pain, nocturnal pain, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, and Juvenile Arthritis Disease Activity Score based on 10-joint counts (JADAS10) decreased by 75%, 72%, 81%, 72%, 85%, and 87%, respectively. In phase II, 38 patients were randomly assigned to receive placebo (n = 18) or to continue receiving etanercept (n = 20). Up to week 48, 12 disease flares occurred, in 9 patients receiving placebo and 3 patients receiving etanercept (odds ratio 6.0, P = 0.02). There were no serious infections, malignancies, or deaths. CONCLUSION: In this study of patients with the ERA category of JIA, etanercept proved effective, as indicated by high ACR Pedi response rates and JADAS10 response rates at week 24. Patients who continued treatment with etanercept had significantly fewer flares than those who received placebo, although 50% of patients in the placebo group did not experience a flare. Treatment suspension may be a consideration for patients with the ERA category of JIA who achieve remission.

Risk factors for severe Muckle-Wells syndrome.

OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease resulting in excessive interleukin-1 release. It is unknown whether demographic, clinical, or laboratory characteristics at the time of diagnosis may identify patients who are at high risk for severe disease activity. This study was undertaken to analyze clinical and laboratory features of MWS, compare genetically defined subcohorts, and identify risk factors for severe MWS. METHODS: A multicenter cohort study of consecutive MWS patients was performed. Parameters assessed included clinical features, MWS Disease Activity Score (MWS-DAS), inflammation markers, and cytokine levels. E311K mutation-positive patients were compared with E311K mutation-negative patients. Putative risk factors for severe MWS (defined as an MWS-DAS score of ≥10) were assessed in univariate analyses, and significant predictors were entered into a multivariate model. RESULTS: Thirty-two patients (15 male and 17 female) were studied. The most frequent organ manifestations were musculoskeletal symptoms and eye and skin disorders. Renal disease and hearing loss were seen in >50% of the patients. Genetically defined subcohorts had distinct phenotypes. Severe disease activity was documented in 19 patients (59%). Predictors of severe MWS identified at the time of diagnosis were female sex, hearing loss, musculoskeletal disease, increased erythrocyte sedimentation rate, and low hemoglobin level. Female sex and hearing loss remained significant after adjustment for age in a multivariate model (relative risk 1.8 and 2.6, respectively). CONCLUSION: MWS patients at high risk for severe disease can be identified at the time of diagnosis. Female patients presenting with hearing loss have the highest likelihood of manifesting severe MWS and should be considered a high-risk group.