SYSTEMATIC REVIEW WITH META-ANALYSIS: SAFETY AND EFFICTIVENESS OF COMBINING BIOLOGICS AND SMALL MOLECULES IN INFLMAMMATORY BOWEL DISEASE
Authors: Osman Ali , Anderson Scott , Zamani Mohammad , Alayo Quazim , Sands Bruce , Rahier Jean-Francois , Colombel Jean-Frederic , Deepak Parakkal 
Published: January 2024

Abstract

BACKGROUND
Effectiveness and safety of Dual biologic therapy (DBT) or in combination with small molecules for treatment of refractory cases of inflammatory bowel diseases (IBD) has been studied previously. In this systematic review and meta-analysis (SRMA), our aim was to update prior SRMA by Alayo et al including newer studies and randomized clinical trials Explorer and VEGA and newer endpoints including corticosteroid free remission rates, need for surgeries, and effectiveness based on IBD subtype.

METHODS
We conducted a systematic literature search using Clinical trials.gov, Cochrane Library, Embase, Ovid Medline, PubMed Medline, Scopus and Web of Science, identifying additional relevant studies published until January 19, 2023. Random-effects inverse variance model was used to combine the proportions of patients who achieved response/remission or developed AEs to obtain pooled estimates (primary outcomes).

RESULTS
A total of 1184 citations were identified through the database searches, of which 360 duplicates and 755 unsuitable studies were excluded following title/abstract screening. Then, the full-texts of the remaining 69 articles were retrieved for further investigation. Of these, 59 were excluded, leaving 10 additional eligible studies since the prior systematic review. A total of 23 studies met the inclusion criteria including 13 in prior SRMA, published between 2007 and 2023. Final analysis included 531 patients who underwent 543 therapeutic trials (TTs) of 8 different combination therapies. Of these 264 (49.7%) were men men. Among combination therapies, Ustekinumab (UST) + anti-tumor necrosis factor-alpha antagonist (aTNF) had the highest pooled clinical response (81.6% [95% CI: 66.2-97.0], I2=52%, p=0.04; 9 studies, 44 TTs) and remission (Figure 1) (64.2% [95% CI: 45.2-83.1], I2=55%, p=0.03; 8 studies, 42 TTs) rates. In patients with CD, the highest pooled clinical response and remission rates pertained to UST + aTNF (91.6% [95% CI: 79.8-100.0], I2 = 19%, p=0.28; 8 studies, 29 TTs). In patients with UC, the highest pooled clinical response rate was seen with Vedolizumab (VDZ)+UST (100.0% [95% CI: 70.0-100.0], I2 = 0%, p=1.00; 4 studies, 4 TTs) and UST + aTNF (100.0% [95% CI: 73.2-100.0], I2 = 0%, p =1.00; 4 studies, 5 TTs). and while the highest pooled clinical remission rate was with VDZ + UST (75.0% [95% CI: 26.0-100.0], I2 = 63%, p=0.05; 4 studies, 4 TTs). The lowest pooled AEs rate (Figure 2) related to tofacitinib (Tofa) + VDZ (12.5% [95% CI: 2.9-22.0], I2 = 41%, p = 0.10; 8 studies, 76 TTs), followed by UST + aTNF (12.7% [95% CI: 0.0-25.8], I2=43%, p = 0.08; 9 studies, 43 TTs) and Tofa+aTNF (13.0% [95% CI: 0.8-25.3], I2=49%, p=0.08; 6 studies, 27 TTs) in patients with IBD.

CONCLUSION
Combining biologics or with small molecules in treatment of refractory IBD is promising and appeared to be generally safe with no major side effects.

Figure 1 Clinical remission

Figure 2 Adverse events