This nationwide nested case-control study evaluated lymphoma risk associated with IBD treatments — thiopurines, methotrexate, anti-TNF agents, vedolizumab, ustekinumab, and JAK inhibitors — in 422,793 IBD patients from the French National Health Data System (SNDS) between 2009 and 2024, with 1,238 lymphoma cases matched to 52,565 controls.
Current thiopurine use nearly doubled lymphoma risk (aOR 2.36, 95% CI 2.00–2.79) and anti-TNF use raised it by 72% (aOR 1.72, 95% CI 1.45–2.05); their combination more than tripled risk (aOR 3.44, 95% CI 2.62–4.51). Vedolizumab, ustekinumab, and JAK inhibitors showed no increased lymphoma risk.
Methotrexate's association with lymphoma was inconsistent across sensitivity analyses, limiting firm conclusions. As a claims-based study, residual confounding by disease severity or unmeasured factors cannot be excluded. Exposure to newer agents (vedolizumab, ustekinumab, JAKi) may be underrepresented, limiting power for those comparisons.
When choosing maintenance therapy for IBD, clinicians should weigh the clear lymphoma risk of thiopurines and anti-TNF — especially in combination — against the reassuring safety profile of vedolizumab, ustekinumab, and JAK inhibitors. Elevated risk from thiopurines may persist up to 3 years after stopping, so post-discontinuation vigilance is warranted.
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