Infection risk in sarcoidosis patients treated with methotrexate compared to azathioprine: A retrospective 'target trial' emulated with Swedish real-world data.

Background And Objective: No clinical trial has examined the risk of infection associated methotrexate and azathioprine, two advocated treatments for sarcoidosis. We aimed to compare the 6-month risk of infection after the initiation of methotrexate or azathioprine.

Methods: We conducted a retrospective target trial emulation using Swedish pre-existing data. We searched for eligible participants who were dispensed methotrexate or azathioprine in the Prescribed Drug Register (PDR) every day between January 2007 and June 2013. Adults were eligible if they had ≥2 ICD-coded visits for sarcoidosis in the National Patient Register (NPR) and were dispensed ≥1 systemic corticosteroid but no methotrexate or azathioprine in the past 6 months (PDR). Within 6 months of methotrexate or azathioprine initiation, diagnosis of infectious disease was identified (visit in the NPR where infectious disease was the primary diagnosis). We estimated RR and risk differences comparing methotrexate (n = 667) to azathioprine initiations (n = 259) using targeted maximum likelihood estimation (TMLE) adjusting for demographic factors, comorbidity and sarcoidosis severity proxies.

Results: There were 43 infections in the methotrexate group (adjusted 6-month risk 6.8%) and 29 infections in the azathioprine group (12.0%). The RR for infectious disease at 6 months associated with methotrexate compared to azathioprine initiation was 0.57 (95% CI: 0.39, 0.82) and the risk difference was -5.2% (95% CI: -8.5%, -1.8%). The RR at 9 months was attenuated to 0.77 (95% CI: 0.52, 1.14).

Conclusion: Methotrexate appears to be associated with a lower risk of infection in sarcoidosis than azathioprine, but randomized trials should confirm this finding.