Combination Biological or Small Molecule Therapy in Refractory Crohn's Disease: A Multicenter Brazilian Experience

Background: Refractory Crohn’s disease (CD) is a major challenge for physicians and patients, today. The number of patients that have failed to all available therapies in Brazil is significantly rising. The combination of advanced therapies seems to be a new opportunity for them. This preliminary study describes the Brazilian experience on dual biologic therapy or small molecule combined with a biologic therapy in patients with CD refractory to multiple biologics. Methods: We identified CD patients from 5 IBD centers in Brazil between July 2021 and September 2022 who received treatment with a combination of 2 biologics or a biologic and a small molecule drug due to persistent disease activity or concomitant immunomediated condition. The primary end-point was effectiveness, based on improvements in inflammatory markers and Harvey-Bradshaw Index (HBI). The secondary end-point was safety. Any missing data were removed from the analysis. Results: Fourteen patients were identified (50% woman, mean age 44.5 years old [SD = ± 14.0 years]). Colonic and ileocolonic location were the most common (6/14 patients each) and 64.2% (9 patients) had penetrating disease. All patients have failed to, at least, 2 advanced therapies, the most common was anti-TNF therapy (n = 10, 71.4%). Only 1 patient had indication of combotherapy for concomitant disease (ankylosing spondylitis). The most common combination used was UST+ADA (n = 7, 50.0%), followed by UST+VEDO (n = 4, 28,5%), UST+TOFA (n = 2, colonic CD, 14.3%) and VEDO+TOFA (n = 1, 7.1%). Mean treatment time was 42.8 weeks (SD = 25.8 weeks, CI 95% = [25–59.2]). Mean HBI score at baseline was 10 (SD = ± 3.7 points; CI 95% [8.0- 12.2]), decreasing to a mean of 5.4 at week 16 (SD = ± 2.9 points; CI 95% [3.8 - 7.0]) and stabilizing in a mean of 3.9 at week 24 (SD = ±1.4 CI 95% [3.2- 4.6]). There was a notable decrease in HBI at week 16 (P = 0.05) and a significant decrease at week 24 (P < 0.01) compared to baseline. The mean CRP at week 16 was numerically lower than baseline CRP (6.7mg/dL vs 10.2 mg/dL, p>0.05 CI 95% [6.6-13.7]). Ten patients (71.4%) achieved clinical remission (ie, HBI <5) at week 16. There were no adverse events related to therapy during follow up. Conclusion(s): Despite combination of advanced therapies in CD is not yet recommended by Brazilian treatment guidelines, this strategy seems to be a promising option for patients with refractory CD or concomitant autoimmune disease. Larger prospective studies are needed for confirming the long-term effectiveness and safety of this therapeutic approach.