Inflammatory bowel disease and lymphoproliferative disorders: the dust is starting to settle

Abstract

The risk of lymphoproliferative disorders (LDs) has become a major concern for clinicians managing patients with inflammatory bowel disease (IBD). Yet it is difficult to distinguish the possible responsibility of immunosuppressive therapy from the background risk due to the inflammatory disorder itself. LDs are clonal B or T cell proliferation showing considerable heterogeneity and the incidence has increased since the 1970s. The strongest and best-established risk factors for LDs are primary and acquired immunodeficiency (HIV, immunosuppressant), notably via defective immune surveillance of Epstein-Barr virus. In many auto-immune diseases (eg, Sjögren's syndrome), inflammatory diseases (eg, rheumatoid arthritis) or chronic suppuration (chronic pyothorax), the risk of LD is increased. In IBD patients, in general, the risk of LD seems to be similar to or very slightly higher than in the general population. The role of immunosuppressants in lymphomagenesis is difficult to individualise because other factors potentially involved are inter-linked. Concordant data suggest that thiopurine therapy is associated with a moderately increased risk of LD. Data regarding methotrexate are scarce and come from diseases other than IBD but the risk seems low. Data regarding risk of LD in IBD patients receiving anti-tumour necrosis factor alpha (TNFalpha) agents are insufficient at this time, mainly because most of the patients are co-treated with thiopurines. The recently individualised risks of hepatosplenic T cell lymphoma and fatal post-mononucleosis LD, in young male patients with IBD who are co-treated with anti-TNFalpha and thiopurines, and EBV-seronegative IBD males, respectively, are probably low but remain to be better quantified.

ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease

“…Within a period of a decade aft er transplantation ~35% of heart transplant recipients will develop a skin with current users. Th e increased risk of NMSC in IBD patients who receive thiopurines was increased with a HR of 5.9 (95% CI, 2.1-16.4; P =0.0006) for ongoing treatment and 3.9 (95% CI, 1.3-12.1; P =0.02) for past exposure in the CESAME cohort study ( 147 ). When assessing the risk based on patient's age; these values were 2.59/1,000 and 1.96/1,000 patient-years for the age group of 50-65 years and 4.04/1,000 and 5.70/1,000 patient-years for patients older than 65 years.…”

Hepatosplenic T-cell lymphoma and TNF-α inhibitors

“…In a study by the investigators at Mayo Clinic, more than 500 patients with Crohn's disease were treated with infliximab, only two patients developed lymphoproliferative disease, and most patients (86%) were also receiving thiopurines (75%) and methotrexate (11%) [44,45]. In another study, PeyrinBiroulet et al performed a meta-ana lysis of 21 placebo-controlled trials designed to evaluate TNF-a inhibitors for Crohn's disease, they found no difference in frequency of malignancies between the TNF-a inhibitor-treated groups and the controls [46].…”

Evaluating Lymphoma Risk in Inflammatory Bowel Disease

“…It can be postulated that the dysregulation of these immune systems seen in the chronic inflammation associated with IBD may lead to antigendriven lymphocyte proliferation and a relatively unhindered risk of genetic and chromosomal deviations (Sokol and Beaugerie, 2009). Another possibility is that the combination of metabolites, cytokines and chemokines seen in the mucosa of IBD patients promotes mutagenesis in bystander cells.…”

“…Continuing thiopurines but discontinued or never anti-TNFs 13 6.53 3.48 to 11.2 Table 4. SIRs in patients treated with thiopurines and anti-TNF drugs (Beaugerie et al 2009) …”

“…The pathobiology of EBV and its role in lymphomagenesis is complex. The hostincorporated EBV genome encodes a number of proteins with similarities to a variety of cytokines, anti-apoptotic molecules and signal transducers that can immortalise and mutate infected cells (Sokol and Beaugerie, 2009). The risk of other oncogenic viruses such as HLTV1 is not well described in the IBD literature.…”