Rare but serious adverse effects of all anti-TNF agents also include severe hepatic reactions leading to acute hepatic failure, demyelinating disorders, hematologic reactions, and new or worsened congestive heart failure in patients with underlying heart disease. Anti-TNF agents may cause a variety of psoriatic skin rashes, which usually resolve after drug discontinuation.
Lymphoma appears to be increased in patients with untreated IBD. Anti-TNF agents may further increase the risk of lymphoma in this population, although the relative risk is uncertain. An increased number of cases of hepatosplenic T-cell lymphoma, a rare but usually fatal disease, have been noted in children and young adults, virtually all of whom have been on combined therapy with immunomodulators, anti-TNF agents, or corticosteroids. Anti-TNF agents may also be associated with an increased risk of nonmelanoma skin cancers.
Integrins are a family of adhesion molecules on the surface of leukocytes that may interact with another class of adhesion molecules on the surface of the vascular endothelium known as selectins, allowing circulating leukocytes to adhere to the vascular endothelium and subsequently move through the vessel wall into the tissue. Integrins consist of heterodimers that contain two subunits, alpha and beta. Two monoclonal antibodies directed against integrins are available for the treatment of inflammatory bowel disease: natalizumab and vedolizumab. Both are administered intravenously. Natalizumab is a humanized IgG4 monoclonal antibody targeted only against the α4 subunit; thus, it blocks several integrins on circulating inflammatory cells and prevents binding to the vascular adhesion molecules and subsequent migration into surrounding tissues, including the bowel and central nervous system. Unfortunately, patients treated with natalizumab may develop progressive multifocal leukoencephalopathy (PML) due to central nervous system reactivation of a human polyomavirus (JC virus), which is present in latent form in over 80% of adults. Patients who are positive for JC virus antibody have a mean risk of PML of 3.9 per 1000 patients; however, the risk is markedly increased in patients treated for more than 24 months or receiving other immunosuppressants.
Vedolizumab is a monoclonal antibody with activity directed specifically against the α4/β7 integrin, thereby blocking interaction of leukocytes with gut vascular endothelial cell adhesion molecules. Because lymphocytes trafficking to the brain are unaffected, the risk of reactivation of JC virus and PML is believed to be extremely low. With the advent of vedolizumab, natalizumab is almost never used for the treatment of IBD. Vedolizumab is increasingly used as a second-line treatment for patients with moderate to severe ulcerative colitis or Crohn’s disease who cannot take anti-TNF agents due to side effects, lack of efficacy, or loss of response. After intravenous induction therapy of 300 mg at 0, 2, and 6 weeks, patients with a clinical response are treated with intravenous maintenance therapy every 8 weeks. Vedolizumab appears to have a very low incidence of serious side effects. Neutralizing antibodies may develop in 2–10% of patients.