Abstract
Background: There is increasing interest in using ≥2 advanced therapies in inflammatory bowel disease (IBD), including, for refractory disease, multi-organ manifestations and multiple concurrent autoimmune diseases. However, there are extremely limited data on prescribing practices, and comparative efficacy and safety outcomes remain relatively unknown.
Methods: We collected a comprehensive binational registry (Australia and Taiwan) of any patient with IBD on combined advanced therapies (ATs)/combined immunosuppressives outside of regular prescribing practice ≥1 month.
Results: There were 307 combinations in 257 patients, via patient: median age 37 years, 146/257 (56.8%) Crohn's disease (CD) and 110/257 (42.8%) with ulcerative colitis, and 111/257 (43.2%) female from Australia (220/257, 85.6%) and Taiwan (37/257, 14.4%). The commonest combinations were Vedolizumab (VED)+ Janus kinase inhibitor (JAKi) (n= 57, 18.6%), JAK + ustekinumab (UST) (n=52, 16.9%), VED + tumour necrosis factor inhibitor (TNFi) (n=44, 14.3%). Overall, via 5-point Likert scale, the combinations were rated as effective by the clinician in 66.8%. p19 inhibitors (p19i) + JAK, UST + JAK, UST + TNF had the greatest clinician-deemed efficacy rates (effective ≥70%) whereas UST + tacrolimus (TAC), JAK + TAC, & TNFi + JAK were deemed the poorest (<60%) (P=0.032). Clinical remission was achieved in 174/307 (56.7%), and in 198/307 (65%), there was confirmed objective improvement (biochemically, endoscopically, or radiologically). The commonest adverse events were from uncontrolled disease (n=17, 5.5%), though there were 5/307 (1.6%) serious infection rate and 11/307 (3.6%) opportunistic infection rate. Two combinations were associated with life-threatening adverse events (Common Terminology Criteria for Adverse Events (CTCAE: 4), both associated with uncontrolled IBD activity. The commonest serious adverse event (CTCAE 3) was from uncontrolled IBD activity (4/307, 1.3%). There were three deaths, two from uncontrolled IBD activity, one from myeloma progression in a patient with liver cirrhosis. Combinations containing JAKi and tacrolimus were associated with more frequent adverse events (21/87 (24.1%) and 17/63 (27.0%) respectively), and least frequent with Th17 inhibition (p19i & UST) (16/118 (13.6%)) (P=0.03).
Conclusion: This largest binational registry to date of combined advanced therapies in IBD, show that combination use in treatment-resistant IBD effective in the majority. However, despite combination, medication inefficacy remains a key area of concern. We demonstrate signals for greater efficacy and safety using several combinations that require further investigation.