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International audience; Ustekinumab, a monoclonal antibody that targets interleukin (IL)-12/23, is used to treat psoriasis, psoriatic arthritis and Crohn disease. In 2011, a meta-analysis of randomized trials alerted on a potential risk of major adverse cardiovascular events (MACE) within the first months after the initiation of anti-IL-12/23 antibodies. Our objective was to assess if ustekinumab initiation may trigger MACE. Using the French National Health Insurance database, covering 66 million subjects, we included all patients exposed to ustekinumab between 2010 and 2016, classified according to their cardiovascular risk level (high vs. low risk). We conducted a case-time-control study. We defined the ‘risk’ period as the 6 months before MACE, defined as myocardial infarctions and strokes, and the ‘reference’ period as the 6 months before the risk period. The initiation of ustekinumab was screened in both periods, enabling to assess the odds-ratio (OR) between the initiation of ustekinumab and MACE. Among the 9290 patients exposed to ustekinumab, 179 displayed MACE: 65 myocardial infarctions, 68 unstable anginas and 46 strokes. Among patients at high-level cardiovascular risk, a significant association between ustekinumab initiation and MACE occurrence was identified (OR, 4.17; 95% CI, 1.19-14.59). Conversely, no association was found in patients at low-level cardiovascular risk (OR, 0.30; 95% CI, 0.03-3.13). From real-world data, we suggest that ustekinumab initiation could trigger MACE in patients at high cardiovascular risk, in line with current immunologic models of atherosclerotic disease. These results should call for caution regarding the prescription of ustekinumab in patients at high cardiovascular risk.

PAR2 activation in basal keratinocytes stimulates inflammation via the Ca2+-dependent production of mediators such as IL-1β, TNF-α, and TSLP. In this study, we investigated PAR2 calcium signaling and the consequent production of inflammatory mediators in differentiated human primary keratinocytes (DhPKs). Stimulation with the PAR2-activating peptide SLIGKV promoted Ca2+ store depletion in both undifferentiated human primary keratinocytes and DhPKs. SLIGKV-evoked Ca2+ store depletion did not trigger the store-operated Ca2+ entry (i.e., SOCE) through ORAI1 in DhPKs compared with undifferentiated human primary keratinocytes. The inhibition of phospholipase C and the concomitant inhibition of TRPV1 and inositol triphosphate receptor in DhPKs abrogated the SLIGKV-evoked Ca2+ store depletion; NF-κB activity; and the production of inflammatory mediators such as IL-1β, TNF-α, and TSLP. Taken together, these results indicate a key role for both InsP3R and TRPV1 in Ca2+ internal stores in the PAR2-evoked Ca2+ release and consequent skin inflammation in DhPKs. These findings may provide clues to understanding the pathological role of DhPKs in skin disorders in which PAR2 is known to be involved, such as atopic dermatitis, Netherton syndrome, and psoriasis.

National audience; Background - In cases of immunodeficiency, a systemic infection may be revealed by atypical symptoms, particularly those involving the skin. Patients and methods - The present case describes a 19-year-old male with X-linked hypogammaglobulinemia, or Bruton agammaglobulinemia, treated with intravenous immunoglobulin G antibodies. Over a 6-week period, the patient developed recurrent plaques in both legs, first on one and then on the other, without fever. Blood cultures were repeated and the fifth pair proved positive for Campylobacter jejuni. An abdominal scan showed appendicitis without intestinal signs. The patient was treated with azithromycin for 2 weeks, which resulted in full recovery from the skin lesions. Discussion - Campylobacter bacteremia infections are severe and carry a 15% mortality rate at 30 days. The majority of affected patients present humoral immunodeficiency. The literature contains reports of 10 patients with C. jejuni-associated cellulitis, of whom 6 presented hypogammaglobulinemia. We postulate that the cutaneous manifestations were caused by septic metastases. The immunoglobulin replacement therapy mainly comprised IgG antibodies; IgA and IgM antibodies appear to play a key role in the response to C. jejuni infection, which could explain the susceptibility observed. The American guidelines recommend blood and skin cultures in patients with cellular immune defects. We suggest that this recommendation be extended to patients with humoral immunodeficiency.