Background-Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.

Objective Fever of unknown origin (FUO) in children presents a diagnostic challenge. Differential diagnosis includes Systemic Onset Juvenile Idiopathic Arthritis (SJIA), an auto-inflammatory syndrome associated with activation of phagocytic cells which at presentation is difficult to differentiate from severe systemic infections. In this study, we investigated whether serum concentrations of the phagocytic pro-inflammatory protein S100A12 may help in the decision between antibiotic or immunosuppressive therapy in patients with FUO. Methods Serum samples were obtained from 45 healthy controls and 240 patients: 60 had SJIA, 17 Familial Mediterranean Fever (FMF), 18 Neonatal-Onset Multisystem Inflammatory Disease (NOMID), 17 Muckle Wells Syndrome (MWS), 40 Acute Lymphoblastic Leukemia (ALL), 5 Acute Myeloblastic Leukemia (AML), and 83 systemic infections. All samples were collected at presentation before initiation of anytreatment, and were analyzed for S100A12 by ELISA. Results In SJIA patients the mean S100A12 serum level was 7,190 ng/ml (95% confidence interval ±2,690), in FMF 6,720 ng/ml (±4,960), in NOMID 720 ng/ml (±450), in MWS 150 ng/ml (±60), in infections 470 ng/ml (±160), in ALL 130 ng/ml (±80), and in AML 45 (±60) compared to 50 ng/ml (±10) in healthy controls. Sensitivity and specificity of S100A12 to distinguish SJIA from infections were 66% and 94% respectively. Conclusions S100A12, a marker of granulocyte activation, is highly overexpressed in SJIA and FMF, which may point to so far unknown common inflammatory mechanisms in these diseases. The measurement of S100A12 serum levels may provide a valuable diagnostic tool in the evaluation of FUO.

Objective. Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1gene, leading to excessive secretion of interleukin-1␤ (IL-1␤), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS.Methods. Results. In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/ swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen.Conclusion. In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this ClinicalTrials.gov identifier: NCT00094900.

In two independent studies, serum IL-5, EDN, and ECP were modulated following benralizumab. Eosinophil depletion after benralizumab also resulted in significant reductions in EDN and ECP concentrations, suggesting that cytotoxic granule proteins were not released after eosinophil reduction.