Methotrexate better than azathioprine in reducing infection risk in sarcoidosis

Initiation of methotrexate appears to lower the risk of infection in patients with sarcoidosis at 6 months as compared to azathioprine, suggest the results from the emulation of a target trial with pre-existing data. However, the favourable effect of methotrexate is attenuated at 9 months.

“The observed lower risk of infection associated with methotrexate is in line with descriptive data suggesting that infectious diseases might be less common in patients with sarcoidosis treated with methotrexate than azathioprine,” the researchers said. [Chest 2013;144:805-812]

Swedish pre-existing data were used in this retrospective target trial emulation. Participants who were dispensed methotrexate or azathioprine in the Prescribed Drug Register daily between January 2007 and June 2013 were included. 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.

The researchers then identified diagnoses of infectious disease (visit in the NPR where infectious disease was the primary diagnosis) within 6 months of methotrexate or azathioprine initiation. They estimated relative risk (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.

Forty-three infections occurred in the methotrexate group (adjusted 6-month risk, 6.8 percent) and 29 in the azathioprine group (adjusted 6-month risk, 12.0 percent). [Respirology 2021;26:452-460]

At 6 months, the RR for infectious disease associated with methotrexate vs azathioprine initiation was 0.57 (95 percent confidence interval [CI], 0.39–0.82), and the risk difference was –5.2 percent (95 percent CI, –0.85 to –1.8 percent). At 9 months, however, the RR for infectious disease was less sustained at 0.77 (95 percent CI, 0.52–1.14).

“It remains unknown which pharmacodynamic mechanisms render methotrexate more advantageous regarding infection risk in sarcoidosis or other inflammatory diseases,” the researchers said. [Nat Rev Rheumatol 2020;16:167-178; Nat Rev Rheumatol 2020;16:145-154; Mol Biol Rep 2020;47:4699-4708]

“One may hypothesize that azathioprine is a more potent immunosuppressant and/or elicits its effect earlier than methotrexate does, which could explain the stronger association in favour of methotrexate at 3 months and the attenuation observed at 9 months after the initiation of treatment,” they added.

Although methotrexate was more commonly prescribed, both methotrexate and azathioprine were equally promoted as steroid-sparing treatment for sarcoidosis during the study period. Additionally, adjustments were made for proxies of sarcoidosis severity (eg, differences in corticosteroid dose) to improve the comparability of the two treatment arms. [Respir Med 2010;104:717-723; Expert Rev Clin Immunol 2012;8:95-103]

“Although our findings are in support of recent recommendations for the treatment of pulmonary sarcoidosis that endorse methotrexate as the primary steroid‐sparing alternative in the absence of specific contraindications, future prospective studies are warranted before developing informed guidelines for sarcoidosis treatment,” the researchers said. [Eur Respir Rev 2020;29:190146]