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.

However,  the maintenance data were better with 39 % of vedolizumab patients and 21 % of placebo patients in remission at week 52. Among patients with previous anti-TNF treatment,  there was no statistically significant difference in clinical remission at 6 weeks, but there was a statistical benefit at 10 weeks,  suggesting that vedolizumab has a slower onset of effect than anti-TNF agents, but is effective in patients with prior anti-TNF failure.

The only adverse effect that occurred more frequently in the vedolizumab group was nasopharyngitis, but the long- term safety of this novel therapy is not yet established. Additionally, the benefit of vedolizumab for treatment of fistulizing disease,  extra- intestinal manifestations or prevention of post-operative recurrence remain to be determined. 

### R. A. Fausel , MD
T. L. Zisman , MD, MPH
Division of Gastroenterology, University of Washington Medical Center , 1959 NE Pacific Street, Box 356424 , Seattle , WA 98195 , USA

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