From the AGA Journals

Studies support vedolizumab-calcineurin inhibitor combinations but not accelerated infliximab therapy for refractory UC

 

Key clinical point: For patients with treatment-refractory ulcerative colitis, an accelerated schedule of infliximab did not appear to reduce the likelihood of colectomy, compared with a standard induction schedule; induction with vedolizumab plus a calcineurin inhibitor (cyclosporine or tacrolimus) induced clinical remission in nearly half of such patients.

Major finding: Rates of colectomy were similar whether patients received induction immunotherapy with infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82). In a separate study, rates of steroid-free clinical remission were 55% at week 14 and 45% at week 52.

Study details: A retrospective study of 213 patients with acute severe steroid-refractory ulcerative colitis; a prospective observational study of 20 patients with ulcerative colitis or Crohn’s disease who received vedolizumab and a calcineurin inhibitor (cyclosporine or tacrolimus).

Disclosures: Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

Sources: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23; Christensen B, et al. Clin Gastroenterol Hepatol. 2018 May 8.

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Bold approaches to a difficult problem

We physicians are not known for our humility. However, acute severe ulcerative colitis (UC) can humble even the most confident inflammatory bowel disease specialist. The study by Nalagatla et al. did not show a difference of colectomy outcomes between accelerated versus standard infliximab induction. However, as the authors point out, their methodology was unable to address confounding by severity. Review of the baseline characteristics implies presence of confounding with numerically higher markers of inflammation in the accelerated infliximab group. The signal of lower, although not statistically significant, odds of colectomy in subgroup analyses of 10 mg/kg versus standard induction should encourage further investigation in 10-mg/kg induction dosing for acute severe UC.

Dr. Jason K. Hou

Christensen et al. described the novel use of coinduction of combination calcineurin inhibitors with vedolizumab in 11 UC patients, observing calcineurin inhibitor–free remission in 45% at week 52. Adverse events occurred as would be expected in severe UC; however, no additional major safety signals were observed with combination therapy. One should consider that the study was performed at a facility with standardized protocols and great experience in calcineurin inhibitors – prior studies at facilities with less experience have resulted in significant morbidity with calcineurin inhibitor monotherapy in this population. While this study is too small to change clinical practice, it highlights the opportunity to further study combination therapy of vedolizumab with calcineurin inhibitors or other more accessible immunosuppressive agents, such as tumor necrosis factor antagonists or tofacitinib in this population.

These two studies continue to expand possibilities to manage acute severe UC and direct areas to focus future research.

Jason Ken Hou, MD, MS, is assistant professor of medicine-gastroenterology, director of the GI & Hepatology Fellowship Program, and director of research–IBD at Baylor College of Medicine, Houston, and staff physician of gastroenterology at Michael E. DeBakey VA Medical Center, Houston. He has financial ties to Janssen, AbbVie, and Pfizer.


 

FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

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