Risk of New IBD Rises for Patients Treated With Etanercept

While anti—tumor necrosis factor (anti-TNF) drugs are effective at treating a range of inflammatory diseases, some limited data suggest that they may, paradoxically, result in a higher risk of developing other de novo inflammatory conditions.

Recently, Danish researchers sought to assess whether there is a link between anti-TNF therapy and development of inflammatory bowel disease (IBD).¹ Using nationwide Danish registries, the group examined data for all patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, pemphigus, alopecia areata, and vitiligo who were enrolled between 1994 and 2017. Anti-TNF agents were introduced in Denmark in 2004, and there were 17,018 individuals who had been exposed to anti-TNF drugs and 63,308 who had not been exposed.

Overall, 7344 patients were treated with infliximab, 9072 were treated with etanercept, and 8355 were treated with adalimumab. Fewer patients were treated with golimumab (n = 1973) or certolizumab pegol (n = 2503). Overall, 34.1% of patients were exposed to 2 anti-TNF drugs, and 16.7% were exposed to 3 or more.

The researchers found that patients treated with etanercept had a significant increase in the risk of developing new Crohn disease (CD), with an adjusted hazard ratio (HR) of 2.0 (95% CI, 0.8-2.2). The adjusted HRs for developing CD were 1.3 (95% CI, 0.8-2.22) for infliximab and 1.2 (95% CI, 0.8-1.8) for adalimumab. There was no statistically significant increased risk for new CD with golimumab or certolizumab pegol.

Additionally, patients treated with etanercept had a significant increase in the risk for developing new ulcerative colitis (UC), with an adjusted HR of 2.0 (95% CI, 1.5-2.8). The adjusted HRs for developing new UC were 1.0 (95% CI, 0.6-1.6) for infliximab and 0.6 (95% CI, 0.3-1.0) for adalimumab. Again, there was no statistically significant increased risk for new UC with golimumab or certolizumab pegol.

According to the authors, “This study firmly establishes the risk of developing de novo IBD while on anti‐TNFα agents, particularly with etanercept.”

In a letter linked to the publication, a separate group of authors from the centers in China noted that a different TNF binding pattern may be responsible for the increased risk of new IBD with etanercept versus other anti-TNFs.²

Etanercept binds to 2 of 3 sites of the TNF molecule, while infliximab binds to all 3, they explain. Additionally, unlike infliximab or adalimumab, etanercept does not bind to peripheral blood cells and lamina propria mononuclear cells derived from patients with IBD. Infliximab and etanercept also have different effects on cytokine production of T lymphocytes, “possibly inducing IBD in genetically predisposed patients,” say the authors, adding that more research into IBD-triggering pathways is warranted.

References

1. Korzenik J, Larsen MD, Nielsen J, Kjeldsen J, Norgard BM. Increased risk of developing Crohn’s disease or ulcerative colitis in 17,018 patients while under treatment with anti‐TNFα agents, particularly etanercept, for autoimmune diseases other than inflammatory bowel disease. Aliment Pharmacol Ther. 2019;50(3):289-294. doi: 10.1111/apt.15370.

2. Dai C, Jian M, Sun MJ. Letter: increased risk of developing Crohn's disease or ulcerative colitis in 17 018 patients while under treatment with anti‐TNFα agents, particularly etanercept, for autoimmune diseases other than IBD. Aliment Pharmacol Ther. 2019;50(7):834-835. doi: 10.1111/apt.15460.