Early Combined Immunosuppression for Crohn’s Disease

EBM Focus - Volume 10, Issue 44

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Reference - REACT trial (Lancet 2015 Nov 7;386(10006):1825) (level 2 [mid-level] evidence)

  • Early aggressive therapy with the TNF inhibitor infliximab plus azathioprine has been shown to increase remission compared to conventional step therapy in patients with recently diagnosed or moderate-to-severe Crohn’s disease.
  • In this trial, combined immunosuppressive therapy and conventional step therapy had similar rates of remission in patients with Crohn’s disease of varying duration and severity.
  • Combined immunosuppressive therapy was associated with decreased Crohn’s disease-related surgery and serious disease-related adverse events.

    Treatment for Crohn’s disease is often dictated by illness severity as well as the risk of rapid disease progression. In low-risk patients with minimal symptoms, recommendations suggest initiating treatment with corticosteroids and progressively adjusting therapy to include TNF inhibitors and antimetabolites until remission is achieved (step therapy) (Am J Gastroenterol 2011 Apr;106 Suppl 1:S2). High-risk patients with moderate-to-severe disease may begin treatment with immunosuppressive medications. While treatment escalation prevents unnecessary exposure to immunosuppressive medication for some patients, it may prolong achievement of remission for others. Early aggressive therapy with the TNF inhibitor infliximab plus azathioprine has been shown to increase 6-month and 1-year remission rates compared to conventional management in patients with recently diagnosed Crohn’s disease (Lancet 2008 Feb 23;371(9613):660). This drug combination has also been found to increase remission compared to either medication alone (N Engl J Med 2010 Apr 15;362(15):1383). To further investigate the potential benefit of early aggressive therapy, a recent cluster randomized trial compared an early combined immunosuppression therapy algorithm vs. conventional management in 41 community gastroenterology practices. Each randomized practice enrolled up to 60 adults with confirmed Crohn’s disease and 1,982 patients were treated overall. The mean duration of Crohn’s disease was 12.75 years.

    Disease remission was defined as a Harvey-Bradshaw Index (HBI) score ≤ 4. The early combined immunosuppression algorithm initiated treatment with corticosteroid therapy for 4-12 weeks. If corticosteroid therapy did not achieve remission or patients relapsed on corticosteroid tapering, a TNF inhibitor (generally adalimumab) plus an antimetabolite were added. Patients were then assessed for remission every 12 weeks and combination therapy was progressively modified according to the algorithm until remission was achieved or surgery recommended. Practices randomized to conventional management did not receive the early combined immunosuppression algorithm and treated patients according to their usual practice. Patients were followed for up to 2 years with 87.1% completing 1-year follow-up and 70.8% completing 2-year follow-up.

    Comparing early combined immunosuppression vs. conventional management, remission was achieved by 66% vs. 61.9% at 1 year (not significant) and 73.1% vs. 65.1% at 2 years (p = 0.083). Major adverse events were defined as hospitalization, surgery, or serious Crohn’s disease-related complications. Early combined immunosuppression was associated with reduced major adverse events at 2 years (27.4% vs. 34.7%, p = 0.0003, NNT 14). The individual outcomes of surgery and serious disease-related adverse events were also significantly lower in the early combined immunosuppression group. There were no significant differences in rates of hospitalization, mean HBI scores, serious drug-related adverse events, or mortality.

    While this trial did not prove that early combined therapy was better at inducing remission than step therapy, there are a number of limitations that need to be considered. Previous trials evaluating early combined immunosuppressive therapy have included patients with recently diagnosed Crohn’s disease or without prior biologic treatment, but this trial included patients of all disease durations, severities, and prior therapies. At baseline, approximately 30% of patients were receiving antimetabolites without TNF inhibitors, 20% were receiving TNF inhibitors without antimetabolites, and 13% were taking combined therapy. The exposure of most patients to at least one of the treatment components prior to the study may have seriously limited the ability to evaluate the intervention. Over 50% of patients were also in remission at baseline, further limiting the ability to evaluate early immunosuppressive therapy. This trial did find that early combined immunosuppression therapy reduced major adverse events compared to conventional management, suggesting that this more aggressive treatment not only appears safe, but may prevent harm to some patients. Overall, early combined immunosuppression algorithm may be a safe and effective treatment strategy to consider for patients with Crohn’s disease.

    For more information, see the Crohn’s disease in adults topic in DynaMed Plus. DynaMed users click here.