Background: Immunosuppressants and biologic agents are commonly used in the treatment of autoimmune and inflammatory conditions. Antimetabolites in combination with anti-tumor necrosis factor (anti-TNF) therapies are often used to enhance therapeutic efficacy. This combination, however, has been reported in the literature to carry an increased risk of developing lymphoma. To further investigate this risk, we conducted a pharmacovigilance analysis using the U.S. FDA's Adverse Event Reporting System (FAERS) database. Our study compared combinations of antimetabolites—such as methotrexate (MTX), mercaptopurine (6-MP), and azathioprine (AZA)—with anti-TNF agents including infliximab, adalimumab, certolizumab, and golimumab, to determine which regimens were most strongly associated with lymphoma.

Methods: The FAERS database is a collection of voluntarily reported adverse drug reactions (ADRs), used for post-marketing surveillance of medications. A total of 30,668,520 FAERS reports from January 1968 to March 2025 were reviewed. Of these, ADRs for MTX, 6-MP, AZA, infliximab, adalimumab, certolizumab, and golimumab accounted for 462,467; 16,199; 81,882; 226,911; 692,389; 102,909; 77,469; and 93,715 cases, respectively. Both monotherapy and combination regimens involving antimetabolites with anti-TNF agents and reports of lymphoma were analyzed for this study using the OpenVigil FDA program. The Reporting Odds Ratio (ROR) was used as the main metric to determine if these reports represented a significant signal in the FAERS database. The 95% confidence intervals (CI), and p-values were also calculated to assess the strength and significance of the association between each drug or combination and reports of lymphoma. P-values were significant (≤ 0.05), unless stated otherwise.

Results: Among the antimetabolite agent monotherapies, MTX had the strongest association with lymphoma with an ROR of 3.64 (95% CI: 3.52-3.96). AZA had an ROR of 3.38 (95% CI: 2.95-3.88), and 6-MP demonstrated the lowest risk of lymphoma with an ROR of 2.29 (95% CI: 1.58-3.32).

Among the biologic agent monotherapies, infliximab demonstrated the strongest association with lymphoma, with an ROR of 6.61 (95% CI: 6.22–7.02), the highest among both biologic and antimetabolite monotherapies. Golimumab and adalimumab followed, with RORs of 3.03 (95% CI: 2.62–3.52) and 2.36 (95% CI: 2.23–2.50), respectively. Certolizumab exhibited the lowest association with lymphoma among all monotherapies and combination regimens, with an ROR of 1.65 (95% CI: 1.39–1.97).

The combination therapies overall revealed stronger associations with lymphoma in comparison to most of the monotherapies. Infliximab and MTX, with an ROR of 7.85 (95% CI: 7.05-8.74), had the strongest association with lymphoma among both combination and monotherapies. Infliximab and 6-MP closely followed with an ROR of 7.54 (95% CI: 3.61-5.73), followed by infliximab and AZA with an ROR of 4.55 (95% CI: 3.61-5.73). Combinations of adalimumab and the antimetabolites showed statistically significant risks of lymphoma as well, though none of these regimens were as strong as the regimens with infliximab. The risks are as follows: adalimumab with MTX (ROR 4.04, 95% CI: 3.63-4.49); with 6-MP (ROR 3.72, 95% CI: 1.86-7.45); and with AZA (ROR 2.56, 95% CI: 1.86-3.52). Certolizumab combinations only revealed a statistically significant association with MTX (ROR 4.38, 95% CI: 3.22-5.95), while the combination with AZA was not (ROR 0.31, 95% CI: 0.04–2.20, p = 0.2415), and no lymphoma cases were reported with certolizumab and 6-MP. Finally, golimumab combinations showed some of the lowest associations with lymphoma overall, with MTX (ROR 1.92, 95% CI: 1.42-2.61). However, golimumab with AZA was not statistically significant (ROR 1.10, 95% CI: 0.36–3.42, p = 0.867), and no lymphoma cases were reported with golimumab and 6-MP.

Several drug combinations demonstrated higher RORs for lymphoma compared to individual agents, suggesting potential synergy. Infliximab with MTX (ROR 7.85) and infliximab with 6-MP (ROR 7.54) both exceeded the RORs of their respective monotherapies. No protective effects were observed from the dataset.

Conclusion: Clinicians should carefully weigh the risks and benefits of combination immunosuppressive therapy, especially when prescribing infliximab with MTX or 6-MP, given the observed synergistic increase in risk for lymphoma.

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2025
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