More on Lymphoproliferative Disorders Associated With Crohn Disease Treatments

See “Extraintestinal Hodgkin Disease in a Young Man With Crohn Disease Treated With Multiple Immunosuppressive Therapies” by Grossi et al on page 248. Grossi et al (1) describe the development of Hodgkin lymphoma in a 22-year-old man diagnosed as having Crohn disease at age 16 years, who had been treated for a total of 5 years with 6-mercaptopurine monotherapy and, most recently, for 18 months with regularly scheduled infliximab and concomitant low-dose methotrexate. Surveillance, Epidemiology and End Results data from the National Cancer Institute indicate that lymphomas comprise 15% of neoplasms occurring in all children and adolescents ages 19 years or younger living in the United States. Among older children and adolescents, Hodgkin lymphomas are more common than non-Hodgkin lymphomas. As acknowledged by the authors of the present report, it is impossible in an individual occurrence in a teenager (or young adult) to attribute blame to any specific exposure; however, the article does cause us to reflect on what is known about the risks of lymphoproliferative disorders with the immunomodulatory treatments we commonly use. As discussed by the authors, available data mostly indicate that inflammatory bowel disease (IBD) itself, that is, apart from immune-modifying treatments, is not associated with an increased risk of lymphoma (2). Criteria proposed long ago by Hill provide a framework within which to analyze evidence of putative causality (3). These criteria include consideration of the research design (ie, prospective studies with randomization to exposure vs cohort studies vs case-control studies), the strength of the association, the consistency of observations in different studies, the presence of gradient by dose or duration of exposure, and scientific plausibility. Using this framework, we can attempt to assemble data concerning the risk of lymphoma with immunomodulatory treatments administered to patients with IBD. The purine analogues azathioprine and 6-mercaptopurine interfere with endogenous purines, essential components of RNA and DNA, and have traditionally been the first-line immunomodulatory drugs used to treat adults and children with Crohn disease. The earliest convincing evidence that thiopurines increase the risk of a patient with IBD's developing lymphoma came from the meta-analysis of cohort studies by Kandiel et al (4). Previous observational data in single IBD cohort studies had failed to demonstrate an increased risk (5), perhaps lulling pediatric gastroenterologists into a false sense of complete safety with respect to neoplasia, because early institution of thiopurine maintenance therapy among children newly diagnosed as having Crohn disease became increasingly common (6) and dosing regimens gradually more aggressive. As well summarized by Subramaniam et al (2), data from prospective cohort studies consistently demonstrates a 4- to 6-fold increase in the risk of lymphoma in patients with IBD treated with thiopurines compared with age- and sex-matched unexposed patients. More important for pediatric gastroenterologists, because the baseline absolute risk of lymphoma increases markedly with age, the absolute risk in patients with IBD presently treated with thiopurines is also many times lower and the number needed to harm is therefore much higher in our young patients (2). Absolute risks, rather than relative risks, are more easily understood by families and should be used in pretreatment counseling. With thiopurine monotherapy among young adults (ages 20–29 years) with IBD, 1 in 4000 to 5000 absolute risks for any lymphoma is generally quoted (2), and for adolescents 1 in 10,000. Lymphoproliferative disorders developing in patients with IBD treated with thiopurines are reported to be of B-cell origin and positive for Epstein-Barr virus (EBV) encoded RNA in 60% to 70% of patients (2). The overall low absolute risk of any lymphoma, particularly in young patients with IBD receiving thiopurine therapy, argues against the utility monitoring of EBV viral load status. In the spectrum of lymphoproliferative disorders, Hodgkin lymphoma-type is rare, but when encountered, is usually EBV–encoded RNA positive, as was the Hodgkin lymphoma reported by Grossi et al (1). Although previously exposed to fairly long-term 6-mercaptopurine both pre- and postileal resection, this young adult male had replaced thiopurine therapy with infliximab and methotrexate 18 months before the development of Hodgkin lymphoma. Data from the CESAME adult cohort suggest, somewhat reassuringly, that the increased lymphoma risk associated with present thiopurine use does not persist following discontinuation (7). Use of thiopurines in pediatric Crohn disease has decreased in many centers during the last several years in favor of increased use of anti-tumor necrosis factor (anti-TNF) antibodies, based on consideration of efficacy/known risk balance. Methotrexate, rather than a thiopurine, has also increasingly been used as the primary immunomodulator either as maintenance monotherapy or as concomitant therapy with anti-TNF, as was the case in the reported patient. This change in clinical practice is attributable primarily to the uncommon but frightening occurrences of fatal hepatosplenic T-cell lymphoma in young men treated with thiopurines alone or in combination with anti-TNF (8). The risk of lymphoma and other neoplasms is thought to be lower with methotrexate than with thiopurines, but to date no studies have specifically investigated risk among children or adults with IBD. Inferences from available data about rheumatoid arthritis are compromised because of the inherently increased risk of lymphoma even apart from therapies. In a French prospective study of patients treated with methotrexate for 3 years, the incidence of Hodgkin lymphoma was higher compared with the French population, whereas the risk of non-Hodgkin lymphoma was not (9). In a prospective national registry comparable in size with the CESAME IBD cohort, standardized incidence ratio for lymphoma among patients with rheumatoid arthritis treated with methotrexate was similar to that observed among patients not receiving methotrexate (10). Interpretation of data concerning occurrences of lymphomas among patients with IBD receiving anti-TNF therapy is difficult because until recently few patients have been treated with anti-TNF without previous and/or concomitant thiopurines. Anti-TNF therapy combined with thiopurines appears to increase the risk compared with thiopurine monotherapy (11). As yet, no definite data indicate an increased risk of lymphoma with single-agent anti-TNF therapy (or anti-TNF plus concomitant methotrexate), but the paucity of patients so treated and monitored long term precludes dismissal of possible risk. Certainly, anti-TNF is immunosuppressive, and immunosuppression is the risk factor for lymphoproliferative disorders. It must always be remembered that the morbidity associated with undertreated pediatric Crohn disease can be considerable. Anti-TNF therapy constitutes a significant therapeutic advance and must be used appropriately and with attention to preserving responsiveness, given the long lives ahead of our young patients. Our responsibilities, in addition to treating optimally, include maintaining awareness of treatment-associated risks that often become clearer over time, counseling families rationally, and ensuring that adverse events potentially associated with therapy are made known via reporting and participation in safety registries.

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