Effectiveness and Safety of Advanced Combination Treatment (ACT) in patients with refractory inflammatory bowel disease or concomitant immune mediated disease or extra-intestinal manifestations: A Multi-Center Canadian Study

INTRODUCTION: Due to the therapeutic ceiling associated with inflammatory bowel disease (IBD) therapies, some patients may require two advanced therapeutic agents, known as advanced combination treatment (ACT) to control disease or treat associated extraintestinal manifestations (EIMs). METHODS: We included adult IBD patients from 9 Canadian centers treated with either two biological therapies, a biological plus an oral small molecule, or two small molecules. Indications for ACT were: 1) refractory IBD; 2) uncontrolled immune mediated diseases (IMIDs); 3) uncontrolled EIMs. Primary outcomes were cumulative rates of clinical and endoscopic response and remission at 6 and 12 months. Secondary outcomes included serious adverse events and infections. Cox-proportional hazard analyses identified independent predictors of treatment effectiveness. RESULTS: We included 105 IBD patients (76 CD, 29 UC) with median age 35 (IQR 35.4-40.8). At baseline, 39% had perianal involvement, 58% had failed at least 3 advanced therapies and 40% had prior surgery. The primary reason for ACT was refractory IBD (63.8%), with the add-on approach used in 97.1% cases. The most frequent combination was anti-TNF + anti-integrin. At 12 months, cumulative rates of clinical and endoscopic response were 60.0% and 32.4%, respectively, and remission rates were 29.5% and 28.6%. Perianal disease was associated with reduced clinical remission (hazard ratio [HR] = 0.33, 95% confidence interval [CI]: 0.17-0.65, p = 0.001) and endoscopic response (HR = 0.42, 95% CI: 0.12-0.50, p=0.001). Longer disease duration (HR = 0.96, 95% CI: 0.92-0.99, p = 0.035) and baseline steroid use (HR = 0.39, p = 0.006) was associated with reduced clinical remission. Serious adverse events and infections occurred in 12.4% and 7.6% of patients, respectively. DISCUSSION: ACT was effective in achieving clinical and endoscopic outcomes in patients with refractory IBD or concomitant IMIDs/EIMs, with favorable safety profile.