Time‐dependent effect of prophylactic trimethoprim‐sulfamethoxazole on the incidence of serious infections in ANCA‐associated vasculitis: A target trial emulation study

Objectives To investigate the effect of prophylactic trimethoprim‐sulfamethoxazole (TMP‐SMX) on the incidence of serious infections in patients with anti‐neutrophil cytoplasmic antibody‐associated vasculitis (AAV). Methods This multicenter cohort study designed to emulate a target trial studied 296 patients with AAV treated with rituximab or cyclophosphamide as induction therapy. Patients were grouped based on the administration of TMP‐SMX within 14 days following induction therapy (n=240 and 56 patients in prophylaxis and control groups, respectively) (intention‐to‐treat) and also as a time‐dependent exposure (time‐varying). Inverse probability weighting was applied to minimize the baseline imbalance between the two groups. Primary outcome was 1‐year incidence of serious infection. Results During the 252.1 person‐years of observation, 77 cases of serious infections were recorded in 65 patients, with a fatality rate of 18.5%. Most serious infections (n=66, 85.7%) occurred within the first 180 days of observation. The prophylaxis group showed a significantly lower incidence of serious infections than the control group (HR 0.48 [0.32–0.72]). However, this beneficial effect of TMP‐SMX was only significant during the first 180 days (HR 0.41 [0.22–0.76]) and not thereafter (HR 3.76 [0.46–29.43]) (interaction p=0.044). This result was also consistent with the time‐varying analysis result. Based on one case of severe adverse drug reaction related to TMP‐SMX, the number needed to harm was 127.4 whereas the number needed to treat to prevent one serious infection was 8.0. Conclusion Prophylactic TMP‐SMX significantly reduced the risk of serious infections in patients with AAV, particularly during the first 6 months of induction therapy with rituximab or cyclophosphamide.