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Natalizumabfor induction of remission in Crohn's disease. Macdonald J, McDonald J. CochraneDatabase Syst Rev. 2007 Jan 24;(1):CD006097.
BACKGROUND:The pathogenesis of Crohn's disease involves migration of leukocytes into guttissue and subsequent inflammation. Natalizumab (Tysabri(R), ElanPharmaceuticals and Biogen Idec) a recombinant humanized IgG4 monoclonal antibodythat blocks adhesion and subsequent migration of leukocytes into the gut bybinding the alpha4 integrin is a member of a new class of molecules known asselective adhesion molecule (SAM) inhibitors. The results of animal studiessuggest that alpha4 integrin blockade could be a useful therapy forinflammatory bowel disease. The results of randomized controlled trials suggestthat natalizumab may be an effective therapy for active Crohn's disease. Thissystematic review summarizes the current evidence on the use of natalizumab forthe induction of remission in Crohn's disease. OBJECTIVES: To determine theefficacy and safety of natalizumab for induction of remission in Crohn'sdisease. SEARCH STRATEGY: A computer assisted search of the Cochrane CentralRegister of Controlled Trials, the Cochrane Inflammatory Bowel Disease andFunctional Bowel Disorders Review Group Specialized Trials Register, MEDLINEand EMBASE was performed to identify relevant publications between 1966 andSeptember 2006. The medical subject heading (MeSH) terms "Crohndisease" or "inflammatory bowel disease","Natalizumab" or "Antegren" or "Tysabri" and"Antibodies, Monoclonal" were used to perform key word searches ofeach database. Manual searches of reference lists from potentially relevantpapers were performed in order to identify additional studies that may havebeen missed using the computer-assisted search strategy. Abstracts from majorgastroenterological meetings were searched to identify research submitted inabstract form only. Personal contacts, leaders in the field, and themanufacturers were contacted to identify other studies which may not bepublished. SELECTION CRITERIA: We included only randomized controlled trialscomparing natalizumab to a placebo or control therapy for the induction ofremission in Crohn's disease. DATA COLLECTION AND ANALYSIS: Data were analyzedusing Review Manager (RevMan 4.2.8). All data were analyzed on anintention-to-treat basis. For pooled data, summary test statistics were derivedusing the relative risk and 95% confidence intervals. Fixed and random effectsmodels were used where appropriate. The definitions of treatment success,remission and clinical improvement were set by the authors of each paper, andthe data were combined for analysis only if these definitions were sufficientlysimilar. MAIN RESULTS: Pooled data from the four included studies suggest thatnatalizumab (300 mg or 3 to 4 mg/kg) is effective for induction of clinicalresponse and remission in patients with moderately to severely active Crohn'sdisease. This benefit is statistically significant for one, two and threeinfusion treatments. There was a trend toward increased benefit with additionalinfusions of natalizumab. Natalizumab appears to provide greater benefit for patientsubgroups characterized by objective confirmation of active inflammation orchronically active disease despite conventional therapies. These subgroupanalyses demonstrated significantly greater clinical response and remissionrates for natalizumab compared with placebo in patients with elevatedC-reactive protein levels, active disease despite the use ofimmunosuppressants, or prior anti-tumor necrosis factor therapy. These benefitswere apparent for both short term (one infusion) and longer term treatment (twoor three infusions). Natalizumab was generally well tolerated and the safetyprofile observed in the four included studies was similar. Adverse eventsoccurred infrequently and were experienced by a similar proportion ofnatalizumab and placebo treated patients. There were no statisticallysignificant differences between natalizumab and placebo treated patients in theproportions of patients who withdrew due to adverse events or those whoexperienced serious adverse events. The included trials lacked adequate powerto detect serious adverse events that occur infrequently. Recently, twopatients with multiple sclerosis treated with natalizumab in combination withinterferon beta-1a and one patient with Crohn's disease treated withnatalizumab in combination with azathioprine developed progressive multifocalleukoencephalopathy (PML) resulting in two patient deaths. A retrospectiveinvestigation was conducted to assess the risk of PML in natalizumab treatedpatients and no new cases were identified. AUTHORS' CONCLUSIONS: Pooled datasuggest that natalizumab is effective for induction of clinical response andremission in some patients with moderately to severely active Crohn's disease.The clinical benefit of induction therapy with natalizumab in Crohn's diseaseshould be weighed against the potential risk of serious adverse events.Preliminary data from the retrospective investigation of adverse eventsassociated with natalizumab suggest that it may be possible to identifypatients at risk for PML by testing for the appearance of JC virus in plasma. Leggil'articolo