GAIN for Loss: Adalimumab for Infliximab-Refractory Crohn Disease

The much-anticipated revolution that anti–tumor necrosis factor-α (anti–TNF-α) antibodies brought to conventional treatment for Crohn disease nearly a decade ago remains unfulfilled. Current medical therapy for Crohn disease follows a “step-up” model proceeding from 5-aminosalicylate–based drugs and corticosteroids to immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) and anti–TNF-α antibodies for patients with corticosteroid-dependent or corticosteroid-refractory disease. Broadly speaking, we use 5-aminosalicylate–based drugs, corticosteroids, and anti–TNF-α antibodies for short-term symptom relief (days to weeks) and immunomodulators and anti–TNF-α antibodies to maintain these benefits for months to years.

Anti–TNF-α antibodies have important limitations in treating Crohn disease. Although the commercially available anti–TNF-α antibodies—infliximab and adalimimab—are effective when disease is refractory to other conventional therapies, up to 40% of patients with Crohn disease do not respond to the treatment initially (1, 2). In addition, whereas infliximab can significantly decrease rates of hospitalization and surgery in the short term (3, 4), its long-term effect is not clear (a result critical to the advocacy of anti–TNF-α as first-line therapy and perhaps its earlier use in children). Standard maintenance dosing of infliximab (5 mg/kg of body weight every 8 weeks) can sustain remissions for up to 1 year, but only for 20% of patients overall (60% of all patients with Crohn disease are primary responders, and only 30% of them achieve a 54-week remission) (1). Finally, “infliximab-refractory” has become a veritable category of Crohn disease status. Therefore, despite the anti–TNF-α antibody revolution, we still need new therapies and strategies to treat Crohn disease.

Infliximab maintenance therapy is a successful strategy for sustaining clinical improvement in patients who respond to initial therapy; however, up to 60% of patients worsen within a year either because the drug becomes less effective or because of intolerable side effects (1). To make progress, we must understand the biology of …