In further analyses adjusted for baseline factors and variables associated with IBD diagnosis and treatment, patients exposed to thiopurine monotherapy had more than 2.5 times increased risk for lymphoma compared with unexposed patients (adjusted hazard ratio [aHR], 2.60; 95% CI, 1.96 - 3.44; P < .001). Likewise, the risk for lymphoma was 2.4 times higher with anti-TNF monotherapy (aHR, 2.41; 95% CI, 1.60 - 3.64; P < .001). This risk was more than six times higher with combination therapy (aHR, 6.11; 95% CI, 3.46 - 10.8; P < .001).
Lymphoma risk did not differ between patients receiving thiopurine monotherapy and those receiving anti-TNF monotherapy (aHR, 0.93; 95% CI, 0.60 - 1.44; P = .93).
However, patients receiving combination therapy had about 2.3 times higher lymphoma risk compared with thiopurine monotherapy (aHR, 2.35; 95% CI, 1.31 - 4.22; P < .001) and about 2.5 times higher lymphoma risk compared with anti-TNF monotherapy (aHR, 2.53; 95% CI, 1.35 - 4.77; P < .001), suggesting that increased lymphoma risk with these drugs may be additive, the authors explain.
However, in various sensitivity analyses intended to weed out current from past drug exposures, the results remained unchanged. This suggests that the higher lymphoma risk with combination therapy may be due to the current regimen, rather than past exposure to thiopurines. Likewise, it suggests that current anti-TNF therapy may increase lymphoma risk regardless of past exposure to thiopurines.
Results were consistent regardless of age, sex, IBD type, and Hodgkin vs non-Hodgkin lymphoma.
The authors mentioned several limitations. Combination therapy is often used in severe IBD, so the link between increased lymphoma risk and combination therapy could reflect high levels of inflammation rather than treatment. Also, follow-up for combination therapy was short (8 months), during which time only 14 patients developed lymphoma. So the results carry some certainty and may require longer-term studies for confirmation.
"These findings may inform decisions regarding benefits and risks of treatment," the researchers conclude.
