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Background Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Clinical trials.gov until Nov 3, 2020, including studies with two or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Results Of the 3,688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on seven different combinations were included. Median number of prior biologics ranged from 0-4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-Tumor Necrosis Factor (aTNF, n=56) or tofacitinib (Tofa, n=57), respectively. Pooled rates of SAE for these were 9.6% (95% CI, 1.5–21.4) for VDZ-aTNF and 1.0% (95% CI, 0.0–7.6) for Tofa-VDZ. The overall certainty of evidence was very low due to the observational nature of the studies, and very serious imprecision and inconsistency. Conclusions DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain.

Patients with HCC were mainly older men diagnosed at an advanced stage. Treatment was associated with better overall survival, but few patients survived to be treated.