Anti-Integrin Therapies

Integrins are glycoproteins expressed on the surface of circulating leukocytes and mediate their adhesion to the vascular endothelium and their subsequent migration into adjacent tissue.

Anti- integrin therapies have been developed to selectively block this critical step in the recruitment of leukocytes to the gut in patients with inflammatory bowel disease. Natalizumab, the first anti- integrin therapy studied in Crohn's disease is a humanized IgG4 monoclonal antibody that leads to inhibition of both α4β7 integrin (responsible for leukocyte trafficking to the GI tract) and α4β1 (responsible for leukocyte trafficking to the central nervous system). As a result, natalizumab induces a selective immunosuppression of both the GI tract and the brain and has demonstrated benefit in treating both Crohn's disease and multiple sclerosis. Results of the pivotal ENCORE and ENACT studies showed that natalizumab was superior to placebo for induction 43and maintenance of response and remission in patients with moderately to severely active Crohn's disease. The benefit of natalizumab was most pronounced for patients with an elevated CRP at baseline and in those previously treated with anti-TNF therapy.

Unfortunately, use of natalizumab has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease of the CNS caused by reactivation of the JC polyomavirus. PML usually presents with sub-acute neurologic deficits, including cognitive deficits (48 %), motor deficits (37 %), language disturbances (31 %), and visual difficulties (26 %). Although JC virus infection is quite common (affecting up to 86 % of the general population) PML is only seen in immunosuppressed individuals, suggesting that depletion of CNS lymphocytes is responsible for the increased risk in natalizumab-treated patients. Among patients receiving natalizumab, concomitant immunosuppression, longer duration of natalizumab therapy, and a positive JC virus antibody test at baseline or during treatment are all associated with a higher risk of PML . In recognition of the risk of PML, patients receiving natalizumab must be enrolled in a safety monitoring program that involves periodic testing for JC virus antibody, avoidance of adjunctive immunosuppression, and consideration of drug holidays for patients on long-term therapy.

Vedolizumab is a humanized monoclonal IgG1 antibody specific for the α4β7 integrin that does not cross-react with α4β1, and does not interfere with leukocyte migration to the CNS.

This is supported by studies showing no alteration of the lymphocyte composition in the cerebrospinal fluid of patients treated with vedolizumab. Additionally, no cases of PML have been observed among the 3,000 patients who received vedolizumab in clinical trials, including nearly 1,000 patients with 2 years or more of continuous exposure. The efficacy of vedolizumab for inducing remission in active Crohn's disease was modest with 14.5 % of patients achieving remission at week 6, compared to 6.8 % of patients receiving placebo.