Maarten Cozijnsen

127 Chapter 6 Benefits and risks of combination therapy in children with IBD (44%) used concomitant IMs and these patients had higher risk of NMSC and other malignancies than those onmonotherapy (adjusted relative risks: NMSC: 2.82 (1.07-7.44); other malignancies: 3.46 (1.08-11.06)). Similar AE rates were found by the aforementioned post-hoc analysis of ADA RCTs by Kopylov et al, but only few trials had addressed adverse events.(26) Within the TREAT registry (47), a prospective cohort in which 6,273 CD patients have been enrolledwith an average follow-up duration of 5.2 years, 3,420 received IFX treatment, of whom 1,780 also received IM. In total 252malignancies occurred, slightlymore in patients receiving IM or combination therapy, but this did not reach statistical significance (IFX+IM: 119/3,517 (3.4%), OR 3.33 (0.46-24); IFX mono: 5/247 (2.0%), OR 1.96 (0.23-17); IM mono: 102/2,413 (4.2), OR4.19 (0.58-30)). Using multivariate Cox regression analysis, neither combination therapy nor IFX monotherapywere associatedwith time tomalignancy (HR=1.22 (0.81-1.86), P=0.34 andHR=0.59 (0.28-1.22), P=0.16). Two other case-control studies were published comparing the risk of malignancy in combination vs. monotherapy. Within a cancer registry, Herrinton et al (48) analyzed the risk of lymphoma in IBD patients compared to non IBD patients. A total of 16,023 IBD patients with 89,064 recorded patient years (PY), both anti-TNF use, thiopurine use, and treatment with both drugs resulted in increased risk of lymphoma, the latter resulted in the highest risk (SIR: anti-TNF: 5.2 (3.5-6.8); thiopurine: 1.4 (1.2-1.7); combination 6.6 (4.4-8.8)). Anti-TNF monotherapy was associated with malignancy more often than with thiopurine monotherapy but it is noteworthy that all patients treated with anti-TNF monotherapy had previously received thiopurine treatment. Deepak et al (49) performed a case-control study to assess the risk of T-cell non-Hodgkin lymphomas (NHLs) and hepatosplenic T-cell lymphoma (HSTCL) in IBD patients using anti-TNF therapy (with or without thiopurines) compared to other IBD therapies. The American Food and Drug Administration (FDA) adverse events database and Medline were searched to identify patients. A total of 45 IBD patients with NHL were identified. Compared to other therapies, anti-TNF combined with thiopurines resulted in higher risk of T-cell NHL (OR 4.98–354.09; P<0.0001), whereas anti-TNF monotherapy did not result in higher risk (OR 0.13–10.61; P=1.00). The same was true for the sub-analysis of the risk for HSTCL (IFX+IM vs. control: OR 2.99– 993.04; P<0.0001; IFX vs. control: OR 0.02–15.70; P=1.00). Both the risk of NHL and HSTCL was also increased in thiopurines monotherapy (NHL: OR 8.32–945.38; P<0.0001; HSTCL: OR 6.90–3045.2; P<0.0001) Taken together, it seems that most evidence from children and adults indicate a minor but significant increase in malignancy rate using combination therapy with thiopurines compared with monotherapy. In contrast, no consistent findings indicate increased AE and SAE rates with combination therapy, including infections or serious infections.