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Background Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late‐stage development for adult patients with moderate‐to‐severe AD. Objective To report pooled safety data for baricitinib in patients with moderate‐to‐severe AD in the clinical development program including long‐term extension (LTE) studies. Methods This analysis included patient‐level safety data from six double‐blinded, randomized, placebo‐controlled studies (one phase 2 and five phase 3), one double‐blinded, randomized, LTE study and one open‐label LTE study, reported in three data sets: placebo‐controlled, 2‐mg – 4‐mg extended and All‐bari AD. Safety outcomes include treatment‐emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. Results Data were collected for 2531 patients who were given baricitinib for 2247 patient‐years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo‐controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo‐controlled period in baricitinib‐treated patients. Frequency of herpes simplex was higher in the 4‐mg group (6.1%) vs. the 2‐mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2‐mg IR = 9.6; 4‐mg IR = 14.5) were lower vs. the placebo‐controlled data set (2‐mg IR = 12.4; 4‐mg IR = 21.3). In the All‐bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2‐mg group): two venous thrombosis events (4‐mg group) and one death. Conclusion This integrated safety analysis in patients with moderate‐to‐severe AD confirms the established safety profile of baricitinib.

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 alpha-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18(-/-) mice, suggesting an impaired myofibroblast differentiation. TGF-beta signalling was clearly involved since TGF-beta1 and TGF-beta receptor type-II protein levels were decreased, while TGF-beta(1) 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-beta1. Indeed, in neutrophil-macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-beta1 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.

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Background: There are no treatments approved by the Food and Drug Administration for alopecia areata.Objective: To evaluate the efficacy and safety of baricitinib in patients with $50% scalp hair loss in a phase 2 study of adults with alopecia areata (BRAVE-AA1).Methods: Patients were randomized 1:1:1:1 to receive placebo or baricitinib 1 mg, 2 mg, or 4 mg once daily. Two consecutive interim analyses were performed after all patients completed weeks 12 and 36 or had discontinued treatment prior to these time points. The primary endpoint was the proportion of patients achieving a Severity of Alopecia Tool (SALT) score #20 at week 36. Logistic regression was used with nonresponder imputation for missing data.Results: A total of 110 patients were randomized (placebo, 28; baricitinib 1-mg, 28; 2-mg, 27; 4-mg, 27). The baricitinib 1-mg dose was dropped after the first interim analysis based on lower SALT 30 response rate. At week 36, the proportion of patients achieving a SALT score of #20 was significantly greater in baricitinib 2-mg (33.3%, P = .016) and 4-mg (51.9%, P = .001) groups versus placebo (3.6%). Baricitinib was well tolerated with no new safety findings.Limitations: Small sample size limits generalizability of results. Conclusion:These results support the efficacy and safety of baricitinib in patients with $50% scalp hair loss.