Lymphoma risk in autoimmune diseases with multiple medication use: analysis from the LIFE Study

Autoimmune diseases (AIDs) are associated with an increased risk of lymphoma. Although treatment strategies have changed substantially in AIDs, recent evidence regarding this association is lacking. Particularly, the impact of novel immunosuppressive/immunomodulatory agents and the cumulative effect of multiple medication use on lymphoma risk have not been well investigated. To address these, we used the LIFE Study database, which contains health care claims data from 2014 to 2023 in 15 municipalities in Japan. Of 2,229,423 individuals, 211,592 had AIDs and 530 subsequently developed lymphoma. Overall, AID cases had a significantly higher incidence of lymphoma than non-AID cases (hazard ratio [HR] 1.9). Among 23 AIDs, lymphoma risk was significantly elevated in 14, including Takayasu arteritis (6.6) and adult-onset Still's disease (4.7). Among immunosuppressive/immunomodulatory agents, calcineurin inhibitors, iguratimod, or methotrexate were associated with higher lymphoma risks. Importantly, the use of two or more medications strongly increased lymphoma risk (HR 2.7) in AID cases. Lymphoma subtype-specific analysis revealed novel associations, including T/NK-cell lymphoma in systemic lupus erythematosus. Our large-scale cohort study reveals an increased risk of lymphoma in AID patients, particularly those receiving multiple immunosuppressants/immunomodulators, underscoring the need for careful monitoring in these patients.