everal studies have suggested that there is an increased risk of lymphoma in IBD patients both on thiopurine alone and in combination with anti-TNF.[72,73] Beaugerie et al. studied a large prospective cohort of adults with IBD with median follow-up of 35 months.[74] The three groups included: thiopurine continued (5867) with 9% also on anti-TNF; thiopurine discontinued (2809) with 12% also on anti-TNF; and never on thiopurines (10,810) with <1% on anti-TNF. Duration of disease ranged from 7.5 to 10.5 years among the three groups. Twenty three lymphomas were reported (14 non-Hodgkin's lymphoma [NHL] and one Hodgkin's lymphoma) on continued thiopurines compared with two NHL in discontinued thiopurines and six NHL in never thiopurines. The youngest case was in a 20-year-old male. The multivariate adjusted hazard ratio was 5.26 (2.2–12.6) in those continuing thiopurines compared with others. Furthermore, ten out of 15 lymphoma cases in the continuing thiopurine group exhibited post-transplant lymphoproliferative disorder with EBV positivity. Only two out of eight cases were EBV positive in the naive thiopurine group. The authors concluded that the thiopurines increased the risk of developing lymphoproliferative disease with risk factors including EBV presence, older age, male gender and longer duration of IBD.[74]
Dayharsh et al. described a similar association between EBV and the risk of lymphoma.[75] In a retrospective review of adults at the Mayo clinic, 18 patients with lymphoma were identified: EBV infection was found in five out of six patients on thiopurine for a median of 3.5 years, versus two out of 12 patients never receiving thiopurines. The authors hypothesized that post-transplant lymphoproliferative disorder probably occurs because of reduced cell-mediated immune surveillance allowing EBV-infected lymphocytes (especially B cells) to proliferate.[75]
In the pediatric literature, Ashworth et al. performed a retrospective review at a single pediatric hospital to examine the relationship between IBD and lymphoma.[76] Among the 1374 patients, 58% had CD, 34% had UC and 3% were IBD undetermined. Two lymphoma cases were observed among 2574 patient-years of taking thiopurine (2 per 4441 past years of ever taking thiopurine). Both patients were male, aged 12 and 18 years old, with CD and UC, respectively. Both patients had been taking thiopurines (22 and 28 months thiopurine use) but were EBV negative. A third patient had hemophagocytic lymphohistiocytosis on thiopurines. Compared with the Surveillance Epidemiology and End Results Program data (0.58 per 10,000 patient-years) the rate of lymphoma was three out of 10,000 patient-years in total and 4.5 lymphoma per 10,000 patient-years on thiopurines. Interestingly, no malignancies were observed in 1140 patient-years of combination anti-TNF and thiopurine therapy or 694 patient-years of MTX therapy
