New UC Guidelines Preferentially Rank Biologics

Diana Phillips

February 04, 2020

Changes in step therapy and the preferential use of specific biologics are among the key recommendations included in new guidance for the medical management of moderate to severe ulcerative colitis (UC) produced by the American Gastroenterological Association (AGA).

According to the clinical practice guideline published online January 13 in Gastroenterology, the anti-tumor necrosis factor (TNF) inhibitors infliximab, adalimumab, and golimumab as well as the anti-integrin agent vedolizumab, the interleukin inhibitor ustekinumab, and the janus kinase inhibitor tofacitinib are all recommended treatment options for inducing and maintaining remission in adult outpatients with moderate to severe disease.

Of these, the evidence suggests infliximab and vedolizumab are both preferred over standard-dose adalimumab or golimumab as first-line options for patients with no previous exposure to biologic agents, the authors write.

"The guideline moves away from typical insurance-based recommendations that prioritize one drug over another and instead bases recommendations on the current evidence that patients with moderate to severe ulcerative colitis who are naïve to biologics be treated with infliximab or vedolizumab as an initial therapy," Joseph D. Feuerstein, MD, guideline co-author and chair of the AGA Institute Clinical Guidelines Committee told Medscape Medical News.

"This recommendation is also contrary to other practices that have historically used mesalamine and other anti-inflammatory agents, which should not be started in patients with moderate to severe ulcerative colitis," said Feuerstein, who is from the Division of Gastroenterology and Center for Inflammatory Bowel Diseases at Beth Israel Deaconess Medical Center in Boston. "Instead, drugs that are efficacious in moderate to severe disease should be used as first-line therapy in these patients regardless of prior medications."

The authors developed the guideline from an unbiased assessment of the current evidence supporting the management of moderate to severe UC, focusing specifically on evidence supporting individual drug use and a network meta-analysis to better assess efficacy between drugs, Feuerstein explained. Using the PICO format, which frames a clinical question by defining a specific patient population (P), intervention (I), comparator (C), and outcome(s) (O), the guideline developers outlined a total of 11 questions — seven of which are focused on the medical management of adult outpatients with moderate to severe UC and four that focus on adult patients hospitalized with acute severe ulcerative colitis (ASUC).

Recommendations

In addition to the preferential ranking of biologics noted above, the guidance document also specifically recommends against gradual step up to biologic therapy after failure of 5-aminosalicylate (5-ASA) therapy. Instead, they prioritize early use of biologics with or without immunomodulator therapy.

"Importantly, 5-ASAs have not been specifically studied in patients with moderate-severe disease activity, and their use is limited to patients with mild-moderate disease activity," the guideline authors write. "Delaying effective treatment to induce remission in patients with moderate-severe UC at high risk of colectomy may be harmful due to ongoing untreated active disease, increasing risk of UC-related complications, hospitalization, colectomy and overall inferior quality of life."

Additional guidance for the medical management of outpatients with moderate to severe disease includes the following.

  • Recommendation against the use of the JAK inhibitor tofacitinib as a first-line treatment in biologic-naïve patients other than in the setting of a clinical trial or registry study, based on updated FDA recommendations that it only be used after failure or intolerance to an anti-TNFa agent.

  • Recommendation against the use of thiopurine monotherapy for induction of remission if the moderate-severe UC is active, although thiopurine monotherapy can be used for maintenance if the disease is in remission.

  • Recommendation against methotrexate monotherapy for induction or maintenance of remission.

  • Recommendation for combining TNFα antagonists, vedolizumab, or ustekinumab with thiopurines or methotrexate over biologic monotherapy or thiopurine monotherapy.

  • Recommendation against continuation of 5-ASA therapy in patients who have previously failed it and who subsequently achieved remission with biologics, immunomodulators, or tofacitinib.

The conditional recommendations for managing adult patients hospitalized with ASUC include the use of intravenous methylprednisolone dose equivalent to 40 to 60 mg/d rather than higher-dose intravenous corticosteroids and treatment with infliximab or cyclosporine in patients who do not respond to intravenous corticosteroids. Regarding the latter recommendation, "more research is needed to determine the optimal dosing of infliximab in this setting," Feuerstein stressed.

The guidelines also recommend against the use of adjunctive antibiotics in hospitalized patients without infections.

The authors note that there are multiple knowledge gaps that warrant future research, including whether patients in remission should use biologic monotherapy vs thiopurine monotherapy for maintenance of remission and whether patients with acute severe disease that is refractory to intravenous corticosteroids who are being treated with infliximab, should routinely be treated with intensive or standard infliximab dosing.

"With the increasing number of different drug classes available to treat UC, there is a clear need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal positioning of therapies," the authors write. In addition, risk-benefit profiles should be personalized based on key treatment attributes, including efficacy, safety, speed of onset of action, co-interventions, and convenience "to optimally inform shared decision making," they note.

Comparison With ACG Guidelines

Unlike the updated American College of Gastroenterology (ACG) ulcerative colitis guidelines released in 2019, as reported by Medscape Medical News, the AGA clinical practice guidelines are not intended to cover all aspects of UC. Rather, explains Feuerstein, "the [AGA] guidelines are focused on providing the most thorough evidence-based answers to specific PICO questions based only on the GRADE assessment of the evidence."

The ACG guidelines, on the other hand, include recommendations for the diagnosis, medical management of the disease at all levels of severity, and quality of life, according to David T. Rubin, MD, FACG, from the University of Chicago, Illinois, who was lead author on the ACG guidelines. The two guidelines overlap around the use of biologic therapies and the choice of severity-based maintenance therapies in patients with moderate to severe disease to reduce the likelihood of future complications, he told Medscape Medical News. And although the ACG guidance does not specifically recommend early use of biologic agents over gradual step up after failure of 5-ASA therapy, Rubin acknowledges that "large gaps in care with 5-ASA therapies indicate a clear need for better therapies."

AGA Clinical Guidelines Committee Member Isaacs reported relationships with Abbvie, Takeda, UCB, Janssen, and Hoffman-Laroche. Rubin reported relationships with AbbVie, Abgenomics, Allergan, Ferring, Genentech/Roche, Janssen, Merck, Medtronic, Napo Pharmaceuticals, Pfizer, Shire, Takeda, and Target Pharma Solutions.The remaining authors have disclosed no relevant financial relationships.

Gastroenterology. Published online January 13, 2020. Full text

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