Combo Infliximab, Azathioprine More Effective Than Either Drug Alone in CD Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease

Background: Therapy of Crohn disease (CD) with anti-tumor necrosis factor biologics and/or immunomodulators has altered the disease natural history. The comparative efficacy and safety of these medications alone or in combination is unknown. Objective: To evaluate the efficacy and safety of infliximab (IFX) monotherapy, azathioprine (AZA) monotherapy, and combination therapy in patients with moderate to severe CD. Design: Randomized double-blind multicenter 30-week trial (SONIC-Study Of Biologic and Immunomodulator Naive Patients In CD). Participants: 508 adults with moderate to severe CD (Crohn Disease Activity Index [CDAI], 220 to 450) who had not previously been treated with either immunomodulator or biologic therapy were included. Patients had not responded to at least 4 weeks of mesalamine and most were steroid dependent. Patients with previous opportunistic infections or malignancy and those with thiopurine methyltransferase phenotypic heterozygous or homozygous mutations were excluded. Methods: Patients were randomized into 3 groups: IFX infusions 5 mg/kg at 0, 2, and 6 weeks and then every 8 weeks plus either oral daily AZA (2.5 mg/kg) (combination) or daily oral placebo tablets (IFX alone). The third group received placebo infusions and daily AZA. Primary end point was rate of steroid-free remission (CDAI <150) at week 26. Results: Of the 508 randomized patients, 170 received AZA monotherapy, 169 IFX monotherapy, and 170 combination therapy (COMB). Baseline disease characteristics were similar in the 3 groups. At week 26, 75 of 169 (44.4%) receiving IFX monotherapy and 51 of 170 (30%) receiving AZA monotherapy were in steroid-free remission (P =0.006). In total, 96 of 169 (56.8%) receiving COMB therapy were in steroid-free remission, which was significantly higher than IFX alone (P =0.02) and AZA alone (P =0.001). Mucosal healing was more likely after COMB (43.9%) than IFX monotherapy (30.1%) or AZA monotherapy (16.5%). Infusion reactions were 3 times more common after IFX monotherapy (16.6%) than after COMB treatment (5.0%). Antibodies to IFX (ATI) were more common after IFX monotherapy (14.6%) than COMB (0.9%). Conclusions: COMB therapy with IFX + AZA was more effective in producing steroid-free remission and mucosal healing than monotherapy with either IFX or AZA. Infusion reactions and ATI were less likely after COMB therapy. Reviewer's Comments: Steroid-free remission is more likely after COMB with IFX + AZA than after monotherapy with either drug in patients naïve to therapy with AZA and IFX. Standard practice adds treatment with IFX when AZA therapy fails. In most of these patients, AZA is continued in combination with IFX; however, it remains unknown whether the continuation of a drug that has already failed (AZA) is of therapeutic benefit. This question is not answered in this study. The finding that ATIs are less common in patients treated with IFX + AZA suggests that even after failure of AZA monotherapy, combination therapy may be beneficial by suppression of IFX immunogenicity. (Reviewer-Allen L. Ginsberg, MD).