Autoimmune diseases (AIDs) are associated with an increased risk of lymphoma. The risk is influenced not only by the nature and severity of the underlying diseases, but also by the type, extent, and duration of immunosuppressive/immunomodulatory therapies. With the advent of novel immunosuppressive/immunomodulatory agents, treatment strategies have changed substantially in AIDs. However, recent evidence regarding this association is lacking. Particularly, the impact of novel agents as well as the cumulative effect of multiple medication use on lymphoma risk have not been well investigated.

To address these, we conducted a retrospective population-based cohort study using the Longevity Improvement & Fair Evidence (LIFE) Study database, which contains health care claims data with full details of medical prescriptions from 2014 to 2023 in 15 municipalities in Japan. In this study, 23 AIDs and 12 lymphoma subtypes were defined according to International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes, and 21 immunosuppressive/immunomodulatory agents were analyzed. Hazard ratios (HRs) for lymphoma risk were assessed using the Cox proportional-hazards regression model adjusted for sex and age. The primary outcome was the impact of the extent of immunosuppressive/immunomodulatory agents on lymphoma risk. The secondary outcomes included the impact of the type of these agents, overall and subtype-specific lymphoma risk across AIDs, and the bidirectional prognostic impact between lymphoma and AIDs.

Among 2,229,423 individuals included in the analysis, 211,592 had AIDs while 2,017,831 had never been diagnosed with AIDs (non-AID group). During a median follow-up of 4.2 years, 530 and 2,406 cases in the AID and non-AID groups developed lymphoma, respectively. AID-associated lymphoma accounted for 18.1% of all lymphoma cases, suggesting that a substantial proportion of lymphoma cases have various AIDs as underlying diseases. Overall, the AID group had a significantly higher incidence of lymphoma than the non-AID group (HR 1.9, 95% confidence interval [CI] 1.8–2.1). Among 23 AIDs, lymphoma risk was significantly elevated in 14, including Takayasu arteritis (6.6, 2.5–17.7), adult-onset Still's disease (4.7, 1.2–18.8), systemic lupus erythematosus (4.6, 3.4–6.1), systemic sclerosis (4.0, 2.6–6.0), and Sjögren's syndrome (2.9, 2.4–3.6). Lymphoma subtype-specific analysis confirmed well-known associations, such as diffuse large B-cell lymphoma in various AIDs, MALT lymphoma in Hashimoto thyroiditis and Sjögren's syndrome, and cutaneous T-cell lymphoma in psoriasis. This analysis also revealed novel associations, including T/NK-cell lymphoma in Sjögren's syndrome and systemic lupus erythematosus as well as Waldenström macroglobulinemia in psoriasis.

Among immunosuppressive/immunomodulatory agents used for AIDs, the use of calcineurin inhibitors (HR 3.6, 95% CI 1.9–6.9), iguratimod (3.4, 1.7–6.9), or methotrexate (2.2, 1.4–3.6) was associated with a higher risk of lymphoma compared to non-users of the respective agents. Importantly, lymphoma risk was significantly higher in AID cases using two or more (≥ 2) agents than in those using no agent (2.7, 1.8–4.1) or a single agent (2.2, 1.4–3.5). The elevated risk of the use of multiple (≥ 2) agents was observed regardless of methotrexate use. These results suggest that an increased number of immunosuppressive/immunomodulatory agents used strongly augments lymphoma risk.

Finally, we assessed the impact of AIDs on lymphoma survival. The 2-year overall survival was comparable between the AID group (76.9%, 95% CI 72.8%–81.3%) and the non-AID group (79.4%, 77.6%–81.2%) (HR 1.1, 95% CI 0.9–1.4). We also assessed the impact of lymphoma development on AID survival, which revealed increased mortality in AID cases with lymphoma compared to those without lymphoma (HR 3.2, 95% CI 2.7–3.8).

In conclusion, our study represents the largest investigation to date evaluating lymphoma risk and its association with immunosuppressive/immunomodulatory agent use across multiple AIDs in the era of modern treatment strategies. Our key finding suggests that patients receiving multiple agents have a particularly elevated risk of lymphoma, demonstrating the number of agents used as a simpler and more reliable indicator for lymphoma risk in AIDs. In addition, these observations underscore the need for careful monitoring in patients receiving multiple agents.

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2025
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