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Background: Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan. Objectives: To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods. Methods: This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated. Results: Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported. Conclusions: This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA. Whatߣs already known about this topic? The safety profile of baricitinib has been established in rheumatoid arthritis and atopic dermatitis. Baricitinib is now also approved in the United States, European Union and Japan for the treatment of patients with severe alopecia areata. What does this study add? To further support the current understanding of the safety profile of baricitinib, we report here the pooled safety analysis of two placebo-controlled trials in patients with severe alopecia areata, representing 1303 patients who were given baricitinib, with a median exposure of 532.0 days. [ABSTRACT FROM AUTHOR]

We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18−/− mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers α-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18−/− mice, suggesting an impaired myofibroblast differentiation. TGF-β signalling was clearly involved since TGF-β1 and TGF-β receptor type-II protein levels were decreased, while TGF-β1 injections into wound margins fully re-established wound closure. Since, in CD18−/− mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18−/− neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-β1. Indeed, in neutrophil–macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-β1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing. [ABSTRACT FROM AUTHOR]