Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma.

OBJECTIVES: Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis. METHODS: IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFß, and the fibrotic reaction measured by histology and ELISA of plasma. RESULTS: IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFß, which supressed IL-31RA. CONCLUSION: IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients.

Immediate cephalosporin allergy.

BACKGROUND: Patients who suffer from acute IgE-mediated allergy to a cephalosporin antibiotic are frequently assumed to be at high risk of allergy to other cephalosporins and penicillins. AIM: To define cross-reactivity patterns in patients with confirmed allergy to a cephalosporin. METHODS: Subjects presenting with a history of immediate allergy to a cephalosporin-family antibiotic between March 2009 and July 2017 were investigated with specific IgE testing to penicillin, amoxycillin and cefaclor, followed by skin prick testing, intradermal testing and drug provocation testing with a panel of penicillins and cephalosporins. RESULTS: Out of 564 subjects with a reported beta-lactam allergy, 90 identified a cephalosporin as their index drug. Fifty-five (61.1%) of the 90 subjects tested had a history consistent with an IgE-mediated reaction, of whom 24 (43.6%) were proven to be allergic to their index cephalosporin. Twenty (83.3%) of the 24 were allergic only to their index cephalosporin. Of the four remaining subjects, two were co-sensitised to another beta-lactam with a similar side chain, while the other two had no specific cross-reactivity pattern. Major and minor penicillin determinants were negative for all cephalosporin-allergic individuals. CONCLUSION: In our cohort, cephalosporin allergy does not appear to be a class effect, with most cases found allergic only to their index cephalosporin. Co-sensitisation to other cephalosporins or penicillins was uncommon, and when it occurred, was usually consistent with side chain cross-reactivity.

The effect of calcium channel blockers on digital ulcers in systemic sclerosis: data from a prospective cohort study.

Digital ulcers (DU) are a common, severe vascular manifestation of systemic sclerosis (SSc) with few effective treatment options. Using data from the Australian Scleroderma Cohort Study (ASCS), we sought to evaluate the effect of calcium channel blockers (CCB) on the treatment and prevention of DU.Using data from 1953 participants, with a median of 4.34 years of follow-up, we used generalised estimating equations to evaluate the clinical characteristics associated with CCB use and ascertain the risk factors for the presence of DU at subsequent study visits. A time-dependent Cox-proportional hazard model was applied to evaluate the risk of future occurrence of DU with CCB use.Sixty-six percent of participants received CCB and patients with a history of DU were more likely to be prescribed a CCB (76.76% vs 53.70%, p < 0.01). CCB use was more frequent in patients with severe complications of DU including chronic DU (OR 1.47, p = 0.02), need for hospitalisation for iloprost (OR 1.30, p = 0.01) or antibiotics (OR 1.36, p = 0.04) and digital amputation (OR 1.48, p < 0.01). Use of CCB was more likely in patients who experienced DU at subsequent study visits (OR 1.32, p < 0.01) and was not associated with a decreased risk of the development of a first DU (HR 0.94, p = 0.65).CCB are frequently used in the management of SSc in the ASCS and their use is associated with severe peripheral vascular manifestations of SSc. However, our results suggest that CCB may not be effective in the healing or prevention of DU.