Combination therapy of ustekinumab and immunomodulator for inflammatory bowel disease: concerns about the different results observed between two meta‐analyses (2023)

To the Editor, We previously conducted a meta-analysis published in the Journal of Gastroenterology and Hepatology, reporting that ustekinumab (UST) and immunomodulator (IM) combination therapy was more effective than UST monotherapy as induction therapy for Crohn's disease (CD) (pooled odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.06–1.71).1 However, the effectiveness of combination therapy in inflammatory bowel disease (IBD) patients remains inconclusive2, 3 because the meta-analyses conducted by Yzet et al. indicated no benefit of UST/IM combination therapy compared with that of UST monotherapy (OR: 1.1, 95% CI: 0.87–1.38).4 In this letter, we aim to discuss the difference in results between the meta-analyses by Yzet et al. and our group. Possible reasons for this discrepancy involve differences in characteristics of the included studies, such as the targeted disease (IBD or CD) and the definition of the induction phase. Of importance is the difference in calculated ORs of the UNITI trials5 utilized in the meta-analyses of our previous study and that of Yzet et al. In the UNITI trials,5 patients with CD were administered a placebo, 130 mg UST, or 6 mg/kg UST as induction therapy. Patients who received 130 mg UST and 6 mg/kg UST were included in the study by Yzet et al. (table 2 in ref. [2]).2 However, our calculation suggested that patients in the 130 mg UST group (n = 454) were omitted by Yzet et al. The excluded patients represent a significant percentage (16.3%) of the sum of patients in the meta-analysis (n = 2786), raising concerns regarding the interpretation of results. Moreover, the study by Greenup et al.6 included in our meta-analysis was omitted in the meta-analysis of Yzet et al., although eligible for inclusion. To address this concern, we conducted a new meta-analysis determining the efficacy of UST/IM combination therapy in IBD patients. We investigated the overall phase (induction or maintenance phase) and induction phase using both the reports included and omitted by Yzet et al. (130 mg UST group in the UNITI trials and the study by Greenup et al.) (Table 1). The new meta-analysis demonstrated that UST/IM combination therapy for patients with IBD was significantly more effective than UST monotherapy (overall phase: pooled OR: 1.24; 95% CI: 1.04–1.49, induction phase: pooled OR: 1.30; 95% CI: 1.06–1.60) in the random-effects model (Fig. 1). Heterogeneity among studies was considered low (overall phase: Q = 14.22, P = 0.58, I2 = 0%, induction phase: Q = 6.33, P = 0.71, I2 = 0%). The funnel plot detected no significant publication bias (overall phase: P = 0.28, induction phase: P = 0.31, Egger's regression test, figure not shown) (Data S1). Although the present meta-analysis complements that of Yzet et al. and provides crucial evidence, several limitations exist. First, the studies included in the meta-analysis were conducted using various UST regimens (Table 1). Specifically, studies added to the new meta-analysis used low-dose UST regimens. Furthermore, patients who received UST/IM combination therapy could have had more severe symptoms than those who received UST monotherapy. Such selection bias could have affected the results. Finally, the mechanism of action of the combination therapy has not been studied in this analysis and needs further investigation. However, the new meta-analysis has enough weight to exhibit significant differences in the efficacy of UST/IM combination therapy. In conclusion, this new meta-analysis demonstrated the efficacy of UST/IM combination therapy in IBD patients, indicating that this is a valuable treatment option for IBD patients. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.