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Objective: To assess markers of neutrophil activation such as calprotectin and N-formyl methionine (fMET) in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and large-vessel vasculitis (LVV)., Methods: Levels of fMET, and calprotectin, were measured in the plasma of healthy controls (n=30) and patients with AAV (granulomatosis with polyangiitis (GPA, n=123), microscopic polyangiitis (MPA, n=61)), and LVV (Takayasu's arteritis (TAK, n=58), giant cell arteritis (GCA, n=68)), at times of remission or flare. Disease activity was assessed by physician global assessment. In vitro neutrophil activation assays were performed in the presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H., Results: Levels of calprotectin, and fMET were elevated in patients with vasculitis as compared to healthy individuals. Levels of fMET correlated with markers of systemic inflammation: C-reactive protein (r=0.82, p<0.0001), and erythrocyte sedimentation rate (r=0.235, p<0.0001). The neutrophil activation marker, calprotectin was not associated with disease activity. Circulating levels of fMET were associated with neutrophil activation (p<0.01) and were able to induce de novo neutrophil activation via FPR1-mediated signaling., Conclusion: Circulating fMET appears to propagate neutrophil activation in AAV and LVV. Inhibition of fMET-mediated FPR1 signaling could be a novel therapeutic intervention for systemic vasculitides., (© 2022. The Author(s).)

Background: Skin-limited forms of vasculitis, while lacking systemic manifestations, can persist or recur indefinitely, cause pain, itch, or ulceration, and be complicated by infection or scarring. High-quality evidence on how to treat these conditions is lacking. The aim of this comparative effectiveness study is to determine the optimal management of patients with chronic skin-limited vasculitis., Methods: ARAMIS is a multicenter, sequential, multiple assignment randomized trial with an enrichment design (SMARTER) aimed at comparing the efficacy of three drugs-azathioprine, colchicine, and dapsone-commonly used to treat various forms of isolated skin vasculitis. ARAMIS will enroll patients with isolated cutaneous small or medium vessel vasculitis, including cutaneous small vessel vasculitis, immunoglobulin A (IgA) vasculitis (skin-limited Henoch-Schönlein purpura), and cutaneous polyarteritis nodosa. Patients not responding to the initial assigned therapy will be re-randomized to one of the remaining two study drugs (Stage 2). Those with intolerance or contraindication to a study drug can be randomized directly into Stage 2. Target enrollment is 90 participants, recruited from international centers affiliated with the Vasculitis Clinical Research Consortium. The number of patients enrolled directly into Stage 2 of the study will be capped at 10% of the total recruitment target. The primary study endpoint is the proportion of participants from the pooled study stages with a response to therapy at month 6, according to the study definition., Discussion: ARAMIS will help identify effective agents for skin-limited forms of vasculitis, an understudied group of diseases. The SMARTER design may serve as an example for future trials in rare diseases., Trial Registration: ClinicalTrials.gov: NCT02939573. Registered on 18 October 2016.

Background: The effect of IL-1 blocking therapy on mucocutaneous manifestations of Behçet's disease is incompletely understood., Methods: Six patients with Behçet's disease and ongoing oral/genital ulcers for ≥1 month were enrolled into an adaptive, two-phase clinical trial and included in the analysis. Study duration was 6 months with extension up to 16 months. All were treated non-blinded with anakinra 100 mg subcutaneous daily with the option to escalate the dose to 200 mg in partial responders after 1 month and 300 mg after 6 months. Patients recorded the number and severity of ulcers in daily diaries. The primary outcome was remission defined as no ulcers on physical exam for two consecutive monthly visits between months 3 and 6. Secondary outcomes included the number and severity of patient-reported ulcers, patient/physician global scores, and standardized disease activity scores., Results: Two of six patients achieved the primary outcome. Five of six patients had improvement in the number and severity of ulcers. Non-statistically significant improvements were seen in secondary outcomes. Over the entire study, patients reported ≥1 oral and ≥1 genital ulcer on 665 (66%) and 139 (14%) days, respectively. On anakinra 200 mg vs 100 mg, patients reported fewer days with oral ulcers (65% vs 74% of days, p = 0.01) and genital ulcers (10% vs 22% of days, p < 0.001) and milder oral ulcer severity (p < 0.001). Increase of anakinra to 300 mg did not result in further improvements. Adverse events were notable for mild infections., Conclusion: Anakinra at an optimal dose of 200 mg daily had an acceptable safety profile and was partially effective in the treatment of resistant oral and genital ulcers in Behçet's disease., Trial Registration: Clinicaltrials.gov. NCT01441076 . Registered on 24 September 2011.