Can Subcutaneous Infliximab Replace Dose-Intensified Intravenous Administration in Inflammatory Bowel Disease?

We read with interest the recently published REMSWITCH study by Buisson et al.1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar The authors report a large, multicenter cohort study evaluating clinical and pharmacologic outcomes following the switch from a range of maintenance intravenous (IV) infliximab regimens to subcutaneous (SC) CT-P13.1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar Relapse was defined as clinical relapse or an increase in fecal calprotectin (FCP) ≥150 μg/g and data were collected at 3 visits up to 24 weeks. All 133 patients were in clinical remission and a quarter received concomitant immunomodulation. Seventy-four out of 133 patients (55.6%) were receiving dose-intensified infliximab at the time of switching (30.8% 10 mg/kg 8-weekly, 13.5% 10 mg/kg 6-weekly, 11.3% 10 mg/kg 4-weekly). At the time of the third visit (16–24 weeks), there were comparable trough drug levels and similar proportions of relapse across the prior 5 mg/kg 8-weekly (10.2%), 10 mg/kg 8-weekly (7.3%), and 10 mg/kg 6-weekly (16.7%) groups. In contrast, two-thirds of patients previously requiring 10 mg/kg 4-weekly IV infliximab relapsed and trough drug levels failed to increment at any time point after switching. A significant discrepancy in relapse rate was observed as early as visit 1 (4–8 weeks). The authors report that either receiving 10 mg/kg 4-weekly IV infliximab or having a FCP >250 μg/g at baseline, in addition to no increase in drug level between baseline and visit 1, were associated with disease relapse post-switch.Although underpowered, there are growing trial and real-world data to support comparable efficacy and safety outcomes between SC CT-P13 and IV infliximab formulations in both Crohn’s disease and ulcerative colitis.2Schreiber S. et al.Gastroenterology. 2021; 160: 2340-2353Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3Smith P.J. et al.J Crohns Colitis. 2022; 16: 1436-1446Crossref PubMed Scopus (4) Google Scholar, 4Roblin X. et al.Aliment Pharmacol Ther. 2022; 56: 77-83Crossref PubMed Scopus (3) Google Scholar, 5Schreiber S. et al.Gastroenterology. 2018; 154 (S-1371)Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar More data are required to evaluate the efficacy and safety of SC CT-P13 in patients dependent on dose-intensified IV infliximab. The favorable outcomes in patients previously receiving low to moderate dose-intensified IV infliximab regimens in REMSWITCH complement existing reassuring outcomes in a subgroup of 50 patients previously receiving intensified IV infliximab in a post-switch cohort by Smith et al.3Smith P.J. et al.J Crohns Colitis. 2022; 16: 1436-1446Crossref PubMed Scopus (4) Google Scholar Buisson et al1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar also evaluated clinical and biochemical variables associated with disease relapse following switch - a useful strategy to aid patient selection in clinical practice. However, the reported associations between disease relapse and receiving a 10 mg/kg 4-weekly dose, an FCP >250 μg/g at baseline, and failure to increment drug levels by visit 1 would benefit from further clarification. Although attention to multicollinearity during logistic regression is mentioned in the Methods section, data from Supplementary Table 1 demonstrate that all 3 variables may be closely related. Indeed, the group previously receiving 10 mg/kg 4-weekly was the only group to have decreased median drug levels at all 3 visits and the only group with a significantly elevated baseline FCP (median 327 vs 16–53 μg/g in the lower regimens). The possibility that elevated baseline FCP is not independently associated with relapse is supported by the similar relapse rate in all 4 groups when analyzing only the 89 patients with FCP <250 μg/g. Clarifying efficacy in active disease is relevant to inform appropriate patient selection for SC CT-P13. Furthermore, the elevated FCP in the 10 mg/kg 4-weekly group despite high baseline median drug levels of 18.5 μg/mL may have suggested an impending clinical relapse regardless of any change in drug administration method.REMSWITCH contributes the largest published cohort of patients with perianal Crohn’s disease on SC CT-P13. Interestingly, Buisson et al1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar found no association between perianal lesions and relapse on a categorical univariable analysis. To integrate this into clinical practice, it would be useful to know the baseline severity of perianal disease and the progress post-switch in this complex subgroup of 40 patients. In contrast to data from IV infliximab,6Colombel J.F. et al.Clin Gastroenterol Hepatol. 2019; 17: 1525-1532Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 7Kennedy N.A. et al.Lancet Gastroenterol Hepatol. 2019; 4: 341-353Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 8Colombel J.F. et al.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2391) Google Scholar immunomodulator use was also not associated with relapse post-switch. This observation supports a post hoc analysis of the pivotal Part 2 CT-P13 trial2Schreiber S. et al.Gastroenterology. 2021; 160: 2340-2353Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar and data from Smith’s real-world cohort3Smith P.J. et al.J Crohns Colitis. 2022; 16: 1436-1446Crossref PubMed Scopus (4) Google Scholar showing immunomodulator use was not associated with response or infliximab trough levels, respectively. REMSWITCH also highlights the utility of SC dose-intensification to 240 mg 2-weekly to recapture response. Of the 22 patients who relapsed during the study period, 15 were escalated to 240 mg 2-weekly CT-P13 with recapture of clinical and combined clinicobiochemical remission in 93% and 80%, respectively. Information on which IV regimen these patients previously received, the trend in their drug levels on each SC dose regimen, why only two-thirds underwent dose-escalation, and how the remaining relapsers were managed would be useful to guide decision making in clinical practice. We congratulate Buisson et al1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar on reporting clinically relevant data from a practical real-world study. However, there is a need for prospective, controlled trials with longer follow-up to confirm Buisson’s observations that SC CT-P13 is an efficacious and safe alternative to most dose-intensified regimens for IBD. We read with interest the recently published REMSWITCH study by Buisson et al.1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar The authors report a large, multicenter cohort study evaluating clinical and pharmacologic outcomes following the switch from a range of maintenance intravenous (IV) infliximab regimens to subcutaneous (SC) CT-P13.1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar Relapse was defined as clinical relapse or an increase in fecal calprotectin (FCP) ≥150 μg/g and data were collected at 3 visits up to 24 weeks. All 133 patients were in clinical remission and a quarter received concomitant immunomodulation. Seventy-four out of 133 patients (55.6%) were receiving dose-intensified infliximab at the time of switching (30.8% 10 mg/kg 8-weekly, 13.5% 10 mg/kg 6-weekly, 11.3% 10 mg/kg 4-weekly). At the time of the third visit (16–24 weeks), there were comparable trough drug levels and similar proportions of relapse across the prior 5 mg/kg 8-weekly (10.2%), 10 mg/kg 8-weekly (7.3%), and 10 mg/kg 6-weekly (16.7%) groups. In contrast, two-thirds of patients previously requiring 10 mg/kg 4-weekly IV infliximab relapsed and trough drug levels failed to increment at any time point after switching. A significant discrepancy in relapse rate was observed as early as visit 1 (4–8 weeks). The authors report that either receiving 10 mg/kg 4-weekly IV infliximab or having a FCP >250 μg/g at baseline, in addition to no increase in drug level between baseline and visit 1, were associated with disease relapse post-switch. Although underpowered, there are growing trial and real-world data to support comparable efficacy and safety outcomes between SC CT-P13 and IV infliximab formulations in both Crohn’s disease and ulcerative colitis.2Schreiber S. et al.Gastroenterology. 2021; 160: 2340-2353Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3Smith P.J. et al.J Crohns Colitis. 2022; 16: 1436-1446Crossref PubMed Scopus (4) Google Scholar, 4Roblin X. et al.Aliment Pharmacol Ther. 2022; 56: 77-83Crossref PubMed Scopus (3) Google Scholar, 5Schreiber S. et al.Gastroenterology. 2018; 154 (S-1371)Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar More data are required to evaluate the efficacy and safety of SC CT-P13 in patients dependent on dose-intensified IV infliximab. The favorable outcomes in patients previously receiving low to moderate dose-intensified IV infliximab regimens in REMSWITCH complement existing reassuring outcomes in a subgroup of 50 patients previously receiving intensified IV infliximab in a post-switch cohort by Smith et al.3Smith P.J. et al.J Crohns Colitis. 2022; 16: 1436-1446Crossref PubMed Scopus (4) Google Scholar Buisson et al1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar also evaluated clinical and biochemical variables associated with disease relapse following switch - a useful strategy to aid patient selection in clinical practice. However, the reported associations between disease relapse and receiving a 10 mg/kg 4-weekly dose, an FCP >250 μg/g at baseline, and failure to increment drug levels by visit 1 would benefit from further clarification. Although attention to multicollinearity during logistic regression is mentioned in the Methods section, data from Supplementary Table 1 demonstrate that all 3 variables may be closely related. Indeed, the group previously receiving 10 mg/kg 4-weekly was the only group to have decreased median drug levels at all 3 visits and the only group with a significantly elevated baseline FCP (median 327 vs 16–53 μg/g in the lower regimens). The possibility that elevated baseline FCP is not independently associated with relapse is supported by the similar relapse rate in all 4 groups when analyzing only the 89 patients with FCP <250 μg/g. Clarifying efficacy in active disease is relevant to inform appropriate patient selection for SC CT-P13. Furthermore, the elevated FCP in the 10 mg/kg 4-weekly group despite high baseline median drug levels of 18.5 μg/mL may have suggested an impending clinical relapse regardless of any change in drug administration method. REMSWITCH contributes the largest published cohort of patients with perianal Crohn’s disease on SC CT-P13. Interestingly, Buisson et al1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar found no association between perianal lesions and relapse on a categorical univariable analysis. To integrate this into clinical practice, it would be useful to know the baseline severity of perianal disease and the progress post-switch in this complex subgroup of 40 patients. In contrast to data from IV infliximab,6Colombel J.F. et al.Clin Gastroenterol Hepatol. 2019; 17: 1525-1532Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 7Kennedy N.A. et al.Lancet Gastroenterol Hepatol. 2019; 4: 341-353Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 8Colombel J.F. et al.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2391) Google Scholar immunomodulator use was also not associated with relapse post-switch. This observation supports a post hoc analysis of the pivotal Part 2 CT-P13 trial2Schreiber S. et al.Gastroenterology. 2021; 160: 2340-2353Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar and data from Smith’s real-world cohort3Smith P.J. et al.J Crohns Colitis. 2022; 16: 1436-1446Crossref PubMed Scopus (4) Google Scholar showing immunomodulator use was not associated with response or infliximab trough levels, respectively. REMSWITCH also highlights the utility of SC dose-intensification to 240 mg 2-weekly to recapture response. Of the 22 patients who relapsed during the study period, 15 were escalated to 240 mg 2-weekly CT-P13 with recapture of clinical and combined clinicobiochemical remission in 93% and 80%, respectively. Information on which IV regimen these patients previously received, the trend in their drug levels on each SC dose regimen, why only two-thirds underwent dose-escalation, and how the remaining relapsers were managed would be useful to guide decision making in clinical practice. We congratulate Buisson et al1Buisson A. et al.Clin Gastroenterol Hepatol. 2022; 17 (S1542-3565(22)00776-5)Google Scholar on reporting clinically relevant data from a practical real-world study. However, there is a need for prospective, controlled trials with longer follow-up to confirm Buisson’s observations that SC CT-P13 is an efficacious and safe alternative to most dose-intensified regimens for IBD.