The natural history of Crohn’s disease involves fiuctuating periods of disease quiescence punctuated by episodes of exacerbation.  Cumulative bowel injury occurs over time with chronic smoldering inflammation and is accelerated by disease flares such that there is a progression from inflammatory to   fibrostenotic or penetrating disease behavior .  This understanding of Crohn’s disease implies that there is a window of opportunity to treat with medical therapy before permanent structural intestinal damage has occurred, and that effective treatment early in the disease course is essential to mitigate the risks of strictures, abscesses, and fistulas. This conceptual model of Crohn’s disease is supported by empiric evidence demonstrating that patients with shorter disease duration have a greater likelihood of responding to medical therapy.

Currently the most effective treatment available for induction of remission in moderate to severe Crohn’s disease is the combination of a TNF antagonist and a thiopurine immunosuppressant. In the SONIC trial, a landmark study of induction therapy for active Crohn’s disease, the combination of infiiximab and azathioprine was more effective than either infiiximab alone or azathioprine alone in achieving remission.

There were no significant differences in serious infections among the 3 treatment groups.

A study looking at methotrexate in combination with infliximab did not show any benefit over infiiximab alone for maintenance of steroid-induced remission. This may be in part because both the combination therapy group and the infiiximab monotherapy group received steroids,  so the additional benefit of methotrexate may have been masked. Patients who received methotrexate did have higher infiiximab levels and were less likely to have anti-infiiximab antibodies,  indicating methotrexate may have had some beneficial effect in reducing the immunogenicity of infiiximab. Taken together these studies support a role for early introduction of effective therapy for moderate to severe Crohn’s disease, and highlight a role for combination therapy with a TNF antagonist partnered with a thiopurine or methotrexate.  Whether to continue combination therapy indefinitely or to discontinue one agent or the other in select patients remains a subject of ongoing investigation.  Unfortunately,  many patients who initially respond to TNF antagonist therapy will eventually lose response. In this setting, dose intensification of the TNF antagonist can often recapture clinical response.  Measuring drug levels and anti-drug antibodies can inform decisions about switching to a second TNF antagonist or changing to another drug class. Vedolizumab should be considered for patients with moderate to severe disease who have a primary nonresponse to dual therapy with a TNF antagonist,  or those with contraindications to anti-TNF therapy.

Treatment of penetrating Crohn’s disease first requires control of infection with antibiotics, and possibly bowel rest and percutaneous drainage of any accessible fluid collections.  Once source control of infection is achieved, immunosuppression can be initiated. TNF antagonists are the preferred option for treatment of fistulizing Crohn’s disease because of their superior efficacy and faster onset of action than other Crohn’s disease therapies in this setting.

The optimal management of mild Crohn’s disease remains uncertain. For patients with disease isolated to the colon, 5-aminosalicylates may be a reasonable treatment option.  Other available options include monotherapy with a thiopurine or methotrexate.  Steroids are useful for rapid disease control in the setting of exacerbation,  but long-term use is limited by lack of sustained effect and by an unfavorable side effect profile.

Consequently,  steroids are primarily used as a bridge while waiting for slower acting therapies to take effect. Vedolizumab offers the promise of a targeted-intestinal immune suppression with a better safety profile.  However,  clinical experience with both safety and efficacy of vedolizumab are limited at this time,  so the optimal positioning of vedolizumab in the treatment algorithm remains undefined. 
  Conclusion
Medical therapy for Crohn’s disease has seen substantial advancements over the past few decades. Aminosalicylates and corticosteroids which were once the mainstay of treatment are now used only in unique situations.  Thiopurines,  methotrexate, and TNF antagonists have become the preferred treatment because of their improved efficacy and safety over prior therapies. The success of these therapies in regulating disease activity has allowed gastroenterologists to expand our goals of care beyond simply short-term symptom control.  We now aim to induce and maintain durable steroidfree remission and to prevent long-term disease complications such as strictures,  fistulas,  and colorectal cancer. Anti-integrin therapies represent a novel therapeutic approach with selective blockade of intestinal lymphocytes and offer the promise of disease control without the adverse consequences of systemic immunosuppression.   

### 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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