Combining Immunomodulator With Vedolizumab or Ustekinumab Does Not Improve IBD Outcomes

Loss of response to biological therapies for ulcerative colitis (UC) and Crohn's disease (CD) remains an important clinical concern. Most expert guidelines recommend that when a tumor necrosis factor-alpha inhibitor is started, the addition of an immunomodulating agent should be considered.

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In contrast, no adequately powered study has examined the potential benefit of adding an immunomodulator to the newer biologic agents for UC and CD, including vedolizumab and ustekinumab.

Anne Hu, MD, former Advanced IBD fellow at Massachusetts General Hospital, Ashwin N. Ananthakrishnan, MBBS, MPH, director of the Crohn's and Colitis Center, and colleagues recently conducted the largest multicenter prospective cohort study of this issue to date. According to their report in Clinical Gastroenterology and Hepatology, combining vedolizumab or ustekinumab with an immunomodulator was not associated with improved clinical or endoscopic remission or response in the first year.

Study Methods

The study was performed at Mass General and two other tertiary care centers, one in Canada and one in France. and it included 549 adults (263 with UC and 286 with CD) who received maintenance vedolizumab and 363 adults (four with UC and 359 with CD) who received maintenance ustekinumab between January 1, 2012, and July 1, 2019.

Combination therapy was at the clinician's discretion. At baseline, 131 patients starting vedolizumab (24%) were using azathioprine or 6-mercaptopurine (n=78), or methotrexate (n=53). 120 patients starting ustekinumab (33%) were using a thiopurine (n=57) or methotrexate (n=63).

The primary outcome was clinical remission or response at weeks 14, 30 and 52. Clinical remission was defined as Harvey–Bradshaw index (HBI) ≤4 or simple clinical colitis activity index (SCCAI)/Mayo score <3. Clinical response was defined as a ≥3-point decrease in HBI from baseline or a ≥2-point decrease in SCCAI/partial Mayo score.

Vedolizumab

Results using vedolizumab treatment were as follows:

• Clinical remission/response at week 14—68% with combination therapy vs. 74% with monotherapy (P=0.22)
• At week 30—74% vs. 76% (P=0.78)
• At week 54—78% vs. 73% (P=0.33)
• Endoscopic remission at 54 weeks—55% vs. 52% (P=0.80)
• Therapy failure during the first year—49% vs. 45% (P=0.44)

Ustekinumab

Researchers reported the following results with ustekinumab treatment:

• Clinical remission/response at week 14—55% with combination therapy vs. 66% with monotherapy (P=0.08)
• At week 30—72% vs. 77% (P=0.33)
• At week 54—62% vs. 67% (P=0.52)
• Endoscopic remission at 54 weeks—58% vs. 41% (P=0.14)
• Therapy failure during the first year—54% vs. 46% (P=0.15)

On multivariable analysis, baseline immunomodulator use did not predict clinical response/remission at weeks 14, 30 or 54 with either vedolizumab or ustekinumab.

Other Key Findings

The following were true in analyses of both vedolizumab- and ustekinumab-treated patients:

• Propensity score–adjusted models, used to account for the fact that assignment to combination therapy was nonrandom, showed no association between combination therapy and clinical remission/response at weeks 14, 30 and 54
• Combination therapy was not associated with any incremental benefit in subgroup analyses (UC vs. CD, biologic-naive vs. biologic-experienced status, and type of immunomodulator)
• At week 54, similar proportions of patients in the combination therapy and monotherapy groups remained on treatment

Overall, researchers concluded that combination therapy may not be warranted for all patients initiating vedolizumab or ustekinumab.

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