Natalizumab for induction of remission in Crohn's disease
Published Online: 24 JAN 2007
Assessed as up-to-date: 26 SEP 2006
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
MacDonald JK, McDonald JWD. Natalizumab for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD006097. DOI: 10.1002/14651858.CD006097.pub2.
- Publication Status: Edited (no change to conclusions)
- Published Online: 24 JAN 2007
The pathogenesis of Crohn's disease involves migration of leukocytes into gut tissue and subsequent inflammation. Natalizumab (Tysabri®, Elan Pharmaceuticals and Biogen Idec) a recombinant humanized IgG4 monoclonal antibody that blocks adhesion and subsequent migration of leukocytes into the gut by binding the α4 integrin is a member of a new class of molecules known as selective adhesion molecule (SAM) inhibitors. The results of animal studies suggest that α4 integrin blockade could be a useful therapy for inflammatory bowel disease. The results of randomized controlled trials suggest that natalizumab may be an effective therapy for active Crohn's disease. This systematic review summarizes the current evidence on the use of natalizumab for the induction of remission in Crohn's disease.
To determine the efficacy and safety of natalizumab for induction of remission in Crohn's disease.
A computer assisted search of the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group Specialized Trials Register, MEDLINE and EMBASE was performed to identify relevant publications between 1966 and September 2006. The medical subject heading (MeSH) terms "Crohn disease" or "inflammatory bowel disease", "Natalizumab" or "Antegren" or "Tysabri" and "Antibodies, Monoclonal" were used to perform key word searches of each database. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Personal contacts, leaders in the field, and the manufacturers were contacted to identify other studies which may not be published.
We included only randomized controlled trials comparing natalizumab to a placebo or control therapy for the induction of remission in Crohn's disease.
Data collection and analysis
Data were analyzed using Review Manager (RevMan 4.2.8). All data were analyzed on an intention-to-treat basis. For pooled data, summary test statistics were derived using the relative risk and 95% confidence intervals. Fixed and random effects models were used where appropriate. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar.
Pooled data from the four included studies suggest that natalizumab (300 mg or 3 to 4 mg/kg) is effective for induction of clinical response and remission in patients with moderately to severely active Crohn's disease. This benefit is statistically significant for one, two and three infusion treatments. There was a trend toward increased benefit with additional infusions of natalizumab. Natalizumab appears to provide greater benefit for patient subgroups characterized by objective confirmation of active inflammation or chronically active disease despite conventional therapies. These subgroup analyses demonstrated significantly greater clinical response and remission rates for natalizumab compared with placebo in patients with elevated C-reactive protein levels, active disease despite the use of immunosuppressants, or prior anti-tumor necrosis factor therapy. These benefits were apparent for both short term (one infusion) and longer term treatment (two or three infusions). Natalizumab was generally well tolerated and the safety profile observed in the four included studies was similar. Adverse events occurred infrequently and were experienced by a similar proportion of natalizumab and placebo treated patients. There were no statistically significant differences between natalizumab and placebo treated patients in the proportions of patients who withdrew due to adverse events or those who experienced serious adverse events. The included trials lacked adequate power to detect serious adverse events that occur infrequently. Recently, two patients with multiple sclerosis treated with natalizumab in combination with interferon beta-1a and one patient with Crohn's disease treated with natalizumab in combination with azathioprine developed progressive multifocal leukoencephalopathy (PML) resulting in two patient deaths. A retrospective investigation was conducted to assess the risk of PML in natalizumab treated patients and no new cases were identified.
Pooled data suggest that natalizumab is effective for induction of clinical response and remission in some patients with moderately to severely active Crohn's disease. The clinical benefit of induction therapy with natalizumab in Crohn's disease should be weighed against the potential risk of serious adverse events. Preliminary data from the retrospective investigation of adverse events associated with natalizumab suggest that it may be possible to identify patients at risk for PML by testing for the appearance of JC virus in plasma.
Plain language summary
Natalizumab for treatment of active Crohn's disease
Crohn's disease is a chronic inflammatory disease of the intestines. Crohn's disease frequently occurs in the lower part of the small intestine, called the ileum, but it can affect any part of the digestive tract, from the mouth to the anus. The most common symptoms of Crohn's disease are abdominal pain, often in the lower right area, and diarrhea. Natalizumab blocks the adhesion and migration of white blood cells into the gut reducing chronic inflammation associated with Crohn's disease. Four high quality studies were reviewed. The studies tested 1692 people over the age of eighteen who had moderate to severe Crohn's disease. The subjects received 1 to 3 infusions of natalizumab (at a dosage of 300 mg or weight based dosages of 3, 4 or 6 mg/kg) or placebo (fake infusions). The studies lasted for 12 weeks. The results of the studies indicate that natalizumab is effective therapy for some people with active Crohn's disease. People with active disease responded positively to even one treatment of the drug and the studies examined showed increased benefits with additional injections of natalizumab. More people improved through treatment using natalizumab than those using the fake treatments. The drug was generally well tolerated and side effects occurred infrequently. Serious side effects occurred rarely (range 7 to 11% for natalizumab and placebo patients). Few patients withdrew from the studies due to side effects (2 to 8% for natalizumab compared to 3 to 7% for placebo). Side effects that occurred during the trials included: headache, worsening of Crohn's disease, abdominal pain, arthralgia, colitis, influenza syndrome, infection, nausea, vomiting, fatigue, hypersensitivity-like reactions, and the development of antibodies against natalizumab. Recently, it was found that two patients who received natalizumab in combination with interferon beta-1 for multiple sclerosis and one patient who received natalizumab in combination with azathioprine for Crohn's disease developed a severe disease called progressive multifocal leukoencephalopathy (PML) resulting in two deaths. PML is a serious infection of the nervous system. However an investigation of more than 3500 patients who took natalizumab found no new cases of PML. It was discovered that PML is not always fatal and regular testing of patients could provide adequate safety and ensure the well-being of those taking natalizumab. However, the benefits of natalizumab for people with Crohn's disease should be carefully weighed against the potential risk of serious adverse events such as the possibility of infection of the nervous system.