Vedolizumab: Action, Use and Notes on Inflammatory Bowel Disease

Vedolizumab is a humanised monoclonal antibody from the class of integrin antagonists used to treat chronic inflammatory bowel diseases (IBD). Under the brand name Entyvio, vedolizumab has been approved in the European Union since 2014. It targets alpha-4-beta-7 integrin on the surface of immune cells and thereby specifically inhibits their migration into intestinal tissue.

Vedolizumab is the first gut-selective biologic in IBD therapy. This gut selectivity fundamentally distinguishes it from systemically acting biologics such as TNF-alpha inhibitors or the integrin antagonist natalizumab, which is also active in the central nervous system. The favourable systemic safety profile makes vedolizumab an attractive option for many patients.

Mechanism of Action

Chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease arise in part through uncontrolled migration of immune cells, particularly T lymphocytes, into the intestinal mucosa. These cells carry the integrin alpha-4-beta-7 (alpha4beta7) on their surface, which acts as a docking molecule to MAdCAM-1 (mucosal addressin cell adhesion molecule 1) expressed on intestinal vascular endothelium. This binding enables the influx of immune cells from the blood into the intestinal tissue.

Vedolizumab binds highly specifically and with high affinity to alpha4beta7 integrin on activated lymphocytes, thereby blocking the interaction with MAdCAM-1. The migration of pro-inflammatory immune cells into the intestinal mucosa is inhibited without significantly impairing systemic immune functions. Selectivity for the gut arises from the fact that MAdCAM-1 is expressed almost exclusively in the gastrointestinal tract.

Unlike natalizumab, another integrin antagonist, vedolizumab does not block alpha-4-beta-1 integrin, which is responsible for the migration of lymphocytes into the central nervous system. This eliminates the risk of progressive multifocal leukoencephalopathy (PML) described with natalizumab.

Full effect does not occur immediately: vedolizumab typically requires several weeks to months to reduce inflammatory activity in the gut. This reflects the time the intestinal tissue needs to reduce the inflammatory response after reduced lymphocyte migration.

Indications

Vedolizumab is approved for the treatment of adult patients with moderately to severely active ulcerative colitis or active Crohn's disease who have had an inadequate response to, no longer respond to, or are intolerant of conventional therapies (e.g. aminosalicylates, corticosteroids, immunosuppressants) or a TNF-alpha inhibitor.

• Ulcerative colitis: moderately to severely active disease, including steroid-refractory and steroid-dependent courses
• Crohn's disease: moderately to severely active disease after failure of conventional therapies or TNF-alpha inhibitors
• Use in patients with increased infection risk in whom systemically acting biologics are of concern
• Maintenance therapy in patients who have responded to induction therapy

Vedolizumab may also be considered as a first-line biologic when a particular clinical situation (e.g. high infection risk, certain comorbidities) argues against TNF-alpha inhibitors. The therapy decision is always made individually in the context of a gastroenterological consultation.

Dosage and Administration

Vedolizumab is prescription-only and is administered exclusively under medical supervision.

The standard dose is 300 mg vedolizumab as an intravenous infusion over 30 minutes. The induction regimen consists of infusions at weeks 0, 2 and 6. Patients who respond to induction therapy receive maintenance therapy with an infusion every 8 weeks.

Since 2020, a subcutaneous dosage form has also been available for patients in maintenance therapy who have received at least two intravenous infusions. Vedolizumab as a pre-filled syringe (108 mg) can be self-injected subcutaneously every two weeks by the patient or a caregiver after training. This approach improves quality of life as clinic visits for infusions are eliminated.

Dose adjustment for elderly patients, in renal or hepatic insufficiency, is not recommended in current product information, as vedolizumab as an antibody is not renally or hepatically eliminated. In the case of inadequate response, the physician can reconsider the therapy or adjust dosing intervals.

Side Effects

Due to its gut selectivity, vedolizumab shows a more favourable safety profile compared to systemically acting biologics. Severe systemic and opportunistic infections occur less frequently than with TNF-alpha inhibitors.

Common side effects (1 to 10 in 100 patients):

• Nasopharyngitis and other respiratory tract infections
• Headaches and dizziness
• Joint pain (arthralgia)
• Fatigue
• Reactions at the infusion site (swelling, redness, burning)

Infusion reactions: Reactions such as nausea, chills, fever, headache, flushing or blood pressure fluctuations can occur during or shortly after the infusion. Severe anaphylactic reactions are rare. Patients are therefore observed during the infusion.

Infections: Even though systemic infection risk is lower than with TNF-alpha inhibitors, infections can occur. Upper respiratory tract diseases, bronchitis and sinusitis have been reported in particular. If signs of severe infections are present, vedolizumab should be temporarily paused.

PML risk: No confirmed PML cases have been reported to date with vedolizumab. The theoretical risk is considered very low since vedolizumab does not act on the central nervous system. Neurological symptoms should nevertheless be reported.

Drug Interactions

Vedolizumab can be combined with other immunosuppressants (e.g. azathioprine, 6-mercaptopurine, methotrexate) or corticosteroids. Concurrent use of these agents can increase infection risk and requires close clinical monitoring.

Combination with other biologics, particularly with other integrin antagonists or TNF-alpha inhibitors, is not recommended, as no adequate safety data are available and the risk of immunosuppression and infection may increase.

Live vaccines should not be administered during treatment. Inactivated vaccines can be used but should if possible be updated before the start of therapy, as the immune response under immunosuppression may be attenuated.

Special Notes

Infections: Active severe infections must be excluded before starting therapy. Patients with active tuberculosis must not receive vedolizumab. Tuberculosis screening is mandatory. Careful benefit-risk assessment is required in chronic infections or immunodeficiency.

Vaccination status: Before starting therapy, vaccination status should be reviewed and missing vaccinations given. Live vaccines must be completed at least six weeks before starting treatment.

Pregnancy and breastfeeding: Vedolizumab crosses the placenta, particularly in the third trimester. Animal data have shown no harmful effect on the foetus. The decision on use in pregnancy is weighed individually. During breastfeeding, vedolizumab may pass into breast milk in small amounts; the treating physician should give an individual recommendation.

Malignancies: Post-marketing data show no evidence of increased malignancy risk under vedolizumab compared to the general population with chronic inflammatory bowel diseases. Regular cancer screening is nevertheless recommended.

Frequently Asked Questions

How long does it take for vedolizumab to work?

Vedolizumab works more slowly than TNF-alpha inhibitors. First clinical improvements are often not noticed until 6 to 14 weeks. Full effect, including endoscopic healing, may take months. Therapy should not be discontinued prematurely.

Can I be vaccinated during vedolizumab therapy?

Inactivated vaccines (e.g. influenza, pneumococcal, SARS-CoV-2) can be administered. Live vaccines are contraindicated. The treating physician and a vaccination specialist should jointly determine the optimal vaccination plan.

Is vedolizumab also available as an injection?

Yes, since 2020 a subcutaneous pre-filled syringe has been available for patients in maintenance therapy. After training, patients can self-inject every two weeks, saving frequent hospital visits.

References

• European Medicines Agency (EMA): Entyvio Summary of Product Characteristics (current version)
• Feagan BG et al.: Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710
• Sandborn WJ et al.: Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013;369(8):711-721
• German Society for Gastroenterology: S3 Guideline Ulcerative Colitis (current version)
• German Society for Gastroenterology: S3 Guideline Crohn's Disease (current version)