Maintenance Therapy in Crohn’s Disease: Does the Drug Matter?

I read with interest the results reported by Calabrese et al.1Calabrese E. et al.Clin Gastroenterol Hepatol. 2021; https://doi.org/10.1016/j.cgh.2021.03.030PubMed Google Scholar The authors reported the efficacy of bowel ultrasonography in monitoring treatment responses in patients with Crohn’s disease (CD). However, there are questions regarding how the choice of biologic therapy can influence the improvement of sonographic parameters during follow-up. Such issues have not been adequately addressed by the authors. Relative to infliximab, other biologics were unable to elicit better sonographic findings at different time-points, especially ustekinumab. First, ustekinumab was significantly associated with lower incidence of transmural healing at 12 months than infliximab in the univariate analysis (odds ratio, 0.24; 95% confidence interval, 0.06–0.97; P = .04). The same pattern could be seen in the multivariate analysis, although the association was rendered statistically nonsignificant. Second, interesting patterns can be observed in vedolizumab use. Vedolizumab was the only biologic where transmural healing at 3 months was less likely to occur than infliximab use. This was true in univariate and multivariate analyses, although the associations were not statistically significant. Third, all 3 biologics presented with greater likelihood of unchanged/worsened lesions than infliximab at all time-points (3, 12 months) in both univariate and multivariate analyses. Correlations concerning ustekinumab here were statistically significant and stronger than adalimumab and vedolizumab, at all time-points in the univariate analysis. An inference can be made from these results: all 3 biologics, especially ustekinumab, are of lower efficacy than infliximab in CD maintenance therapy. An alternative view is that they do not exhibit superior effects to infliximab. These views do not entirely correspond with the literature. In a real-word study,2Patel H. et al.Crohns Colitis. 2019; 360: 1Google Scholar vedolizumab had consistently better clinical outcomes than infliximab in patients with inflammatory bowel disease in general when patients were monitored post maintenance therapy for up to 24 months. These correlations were statistically significant (P < .0001). Similar trends were observed in patients with CD. A composite outcome (health care resource use) was used, which comprised: (1) inflammatory bowel disease–related hospitalization, (2) inflammatory bowel disease–related surgery, and (3) the administration of intravenous corticosteroids in an inpatient/outpatient setting. In a small retrospective study (predominantly patients with CD; n = 14/15),3Kwapisz L. et al.Clin Gastroenterol Hepatol. 2021; 19: 616-617Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar more patients taking tumor necrosis factor (TNF)-α inhibitor-free combination therapy showed clinical response (80% [n = 4/5] vs 70% [n = 7/10]). Fewer of which had infections (0% [n = 0/5] vs 40% [n = 4/10]). In an observational cohort study,4Doecke J. et al.Aliment Pharmacol Ther. 2016; 45: 542-552Crossref PubMed Scopus (33) Google Scholar infliximab and adalimumab had similar rates of response, and maintenance of response when used in CD maintenance therapy (P = .972). Therefore, the assertion by Calabrese et al1Calabrese E. et al.Clin Gastroenterol Hepatol. 2021; https://doi.org/10.1016/j.cgh.2021.03.030PubMed Google Scholar that adalimumab use was associated with inferior sonographic improvement to infliximab, although statistically nonsignificant, could not be supported. To the author’s knowledge, there are no studies directly comparing the long-term efficacies of ustekinumab and infliximab when used as CD maintenance therapy. Two counterarguments should be addressed. First, sonographic interpretation incurs wide interrater variability. There is an inherently steep learning curve. Also, bowel ultrasound has lower sensitivity and specificity than magnetic resonance enterography in detecting CD presence and extent.5Taylor S. et al.Lancet Gastroenterol Hepatol. 2018; 3: 548-558Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Second, a major feature of the study is the use of imaging to monitor CD treatment responses. This is different from other studies that have used clinical correlates instead. However, the difference in monitoring method alone is unlikely to account for the observations stated before. Also, according to the methodology of this study, all sonographers were experienced and unblinded to clinical parameters. Interpretation errors are therefore minimized. An alternative explanation for the observations is that different biologics have different mechanisms of action (where infliximab and adalimumab are TNF-α inhibitors, vedolizumab inhibits the α4β7 integrin, and ustekinumab inhibits both interleukin-12 and -23) and pharmacokinetics. Therefore, they might achieve normalization of all predefined ultrasound outcomes at different paces. This is evidenced by the data presented in Figure 2D. Infliximab was the only biologic that exhibited a continuous increase in the proportion of patients with transmural healing and improved lesions throughout the 12-month follow-up period. Infliximab and adalimumab, both being TNF-α inhibitors, showed slower increases from months 6 to 12. It can thus be inferred that TNF-α inhibitors act faster than other biologics. However, as shown by Patel et al,2Patel H. et al.Crohns Colitis. 2019; 360: 1Google Scholar the difference between vedolizumab and infliximab in clinical outcomes remained static during the entire follow-up period (range, 12.0%–13.0%). More importantly, in patients with CD, the difference in health care resource use between the 2 biologics rose dramatically from months 12 to 24 (13.0% [P = .0003] vs 16.3% [P = .0001]). More studies using sonographic techniques are required to confirm such correlations, possibly involving other biologics, such as golimumab. Shorter time to radiologic improvement may result in greater improvement in quality of life and reduction in symptom severity. Therefore, understanding the behaviors of different classes of biologics carries significant clinical implications. Ultrasonography Tight Control and Monitoring in Crohn’s Disease During Different Biological Therapies: A Multicenter StudyClinical Gastroenterology and HepatologyVol. 20Issue 4PreviewBowel ultrasonography (BUS) is a noninvasive tool for evaluating bowel activity in Crohn’s disease (CD) patients. Aim of our multicenter study was to assess whether BUS helps to monitor intestinal activity improvement/resolution following different biological therapies. Full-Text PDF Open AccessReplyClinical Gastroenterology and HepatologyVol. 20Issue 2PreviewWe thank Dr Ng for his comments about our article1 and thereby giving us the opportunity to discuss this topic again. Full-Text PDF