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Should IBD Biologics Be Offered in Combination or as Monotherapy?

Adding or switching biologics is a common practice in the treatment of patients with inflammatory bowel disease (IBD), but there is a dearth of clinical data on whether patients should receive their first or second biologic as monotherapy or combined with immunomodulatory therapies. It’s a clinical conundrum made more difficult by the increasing number of biologics and drugs available to treat IBD, and the fact that some first-line biologics may fail because of immune responses.

The authors of a new review by Roni Aoun, MD, published in the Journal of Clinical Gastroenterology sought to provide some much-needed advice on these issues, surveying the literature that does exist in order to offer evidence-based recommendations for how and when biologics should be used.

A Confusing Array of Therapeutic Choices

The review arrives at a moment when IBD treatments have hit a therapeutic plateau, producing remission rates of only around 30%-35%, despite new treatments and mechanisms of action. “That’s just not where we want to be [so] there’s a lot of interest in how we can make our therapies better,” said David Rubin, MD, a professor of medicine and the codirector of the Digestive Diseases Center at the University of Chicago, and the chair of the scientific advisory committee for the Crohn’s & Colitis Foundation.

Rubin, who did not participate in authoring the review, added that the field also faces questions of what patients should receive after their first has either failed to work entirely or the initial response has waned.

“Understanding sequencing is important,” he said. “The best way to assess that right now has been through claims data, which are notoriously missing important information like [disease activity].”

The landmark SONIC and SUCCESS studies concluded that combining antibodies with immunomodulatory drugs was the best approach, but times have changed since these results were published. One recent study showed that the patient’s HLA subtype can be associated with anti–tumor necrosis factor (TNF) immune responses.

“We now know that you can be much more specific and precise about this. You can predict the likelihood someone’s going to have antidrug antibodies against an anti-TNF [agent],” said Rubin.

Factors that go into the decision of whether or not to prescribe an immunomodulator include the class of biologic, whether it is a first or second biologic, the presence or absence of antidrug antibodies, patient preference, and any comorbid conditions.

Anti-TNF agents often lose efficacy, with one study finding an average 41% loss of response to certolizumab, 33% to infliximab, and 30% to adalimumab. Another problem is posed by the intrinsic risk of immunogenicity with biologics, with rates reported to be as high as 65.3% for infliximab and 38% for adalimumab.

Immunogenicity to one anti-TNF agent often predicts immunogenicity to other anti-TNF biologics. Some data suggest that, in patients who produced antibodies to an initial anti-TNF agent, combination therapy can provide benefit with a second anti-TNF biologic. However, there are some scenarios that call for monotherapy, such as when a patient can’t take immunomodulators or when over-suppression could be risky. According to Aoun and colleagues, limited data and lessons from clinical practice suggest that monotherapy anti-TNF biologics with proactive therapeutic drug monitoring is a reasonable approach in these cases. Monitoring may also reduce the risk of immunogenicity.

What the Authors Recommended

For those reasons, if the first biologic is an anti-TNF agent, the authors recommend an immunomodulator combined with anti-TNF agents for induction or maintenance treatment of either ulcerative colitis or Crohn’s disease. If immunogenicity is present after a loss of response, they recommend a second anti-TNF agent with an immunomodulator. If there is no immunogenicity and the failure is mechanistic, they recommend switching to vedolizumab monotherapy or ustekinumab monotherapy. Immunomodulators can be prescribed on an individualized basis.

When vedolizumab or ustekinumab are the patient’s first biologic, they should be used as monotherapy. Both have very low rates of immunogenicity, and an immunomodulator is unlikely to confer a meaningful benefit, according to the review authors, who nonetheless called for prospective trials to explore these questions further. If there is a loss of response, they recommend anti-TNF agents combined with an immunomodulator, or monotherapy if the second agent is ustekinumab or vedolizumab.

In severe IBD cases, when combining agents with different mechanisms of action, or in patients who have immunogenicity to more than one class of biologic, the authors don’t provide general recommendations. Instead, they noted that the risks and benefits to individual patients should be weighed for combinations with immunomodulators.

The authors declare that they have nothing to disclose. Rubin has consulted for Janssen, AbbVie, and Takeda.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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