DENVER—If patients and their providers decide to de-escalate inflammatory bowel disease therapy, cutting out the immunomodulator but keeping the anti–tumor necrosis factor agent may be the best bet, according to accumulating evidence.

Research is showing more reasons for discontinuing immunomodulator therapy in patients who are in stable remission. Although combination therapy with an immunomodulator, such as azathioprine, and anti-TNF medication is one of the most effective IBD treatments, it’s also associated with an increased risk for serious infections and cancer. De-escalating combination therapy to anti-TNF monotherapy after one year may be a beneficial approach for patients with IBD, noted Ryan Ungaro, MD, an associate professor of gastroenterology at the Icahn School of Medicine at Mount Sinai, in New York City.

“The evidence supports de-escalating combination therapy ... which decreases the risk of infection and cancer and simplifies medication regimens for our patients, making their lives easier,” Dr. Ungaro said in a presentation at the 2023 Crohn’s and Colitis Congress.

Dr. Ungaro noted that results of the SONIC trial established the effectiveness of combination therapy with azathioprine and anti-TNF therapy in inducing corticosteroid-free clinical remission compared with azathioprine monotherapy (N Engl J Med 2010;362[15]:1383-1395).

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However, subsequent studies have identified safety concerns with this regimen. For example, a large French cohort study of over 190,000 patients with IBD found that combination therapy was associated with a higher risk for serious infections, opportunistic infections and viral/bacterial infections (Gastroenterology 2018;155[2]:337-346.e10). The hazard ratio for lymphoma was also significantly higher in combination therapy compared with monotherapy with a thiopurine drug or an anti-TNF agent.

Patients often “want to minimize their medication regimen and simplify their treatment plan,” Dr. Ungaro said. Thus, they may be open to de-escalation if their clinicians think it is appropriate. A survey of patients in the United States and France found that the majority were in favor of de-escalating combination therapy to monotherapy if their doctor suggested it (Clin Gastroenterol Hepatol 2020;18[6]:1261-1267).

Other patients, however, may be reluctant to change a regimen that is working. In a recent #MondayNightIBD poll on Twitter, the majority of patient responders voiced a preference to continue on their current medicines as long as their disease was in remission and “‘not rock the boat’” (Gastroenterology & Endoscopy News June 2023).

Stopping Anti-TNF Tx Is Associated With High Rates of Relapse

When it comes to stopping the immunomodulator versus the anti-TNF therapy, Dr. Ungaro said the evidence supports stopping the immunomodulator. Results of the STORI trial showed that rates of relapse were very high after stopping anti-TNF therapy, with over 50% of patients relapsing by two years and nearly 80% relapsing after seven years (Gastroenterology 2012;142[1]:63-70.e5).

In addition, this analysis demonstrated that the benefit from combination therapy is primarily due to improved infliximab levels. Leaving the patient on the dominant drug (infliximab in this case) is, thus, the preferred approach, Dr. Ungaro said. He also noted that a post hoc analysis of the SONIC trial found no difference in steroid-free clinical remission and mucosal healing across quartiles of anti-TNF levels (Aliment Pharmacol Ther 2015;41[8]:734-746).

Stopping Immunomodulators: Evidence Growing

Until recently, the data supporting the discontinuation of immunomodulators in patients receiving combination therapy were limited to small heterogeneous studies. In the largest retrospective analysis to date, conducted in two European hospitals, investigators discovered that discontinuing immunomodulators did not affect the loss of response, disease activity or flares in 500 IBD patients using an anti-TNF agent (adalimumab or infliximab) and an immunomodulator (thiopurine or methotrexate) during a two-year period (Clin Gastroenterol Hepatol 2022;20[11]:2577-2587.e6).

A prospective randomized study conducted in Europe (IMID study) also found no differences between continuation of combination therapy and cessation of immunomodulators in terms of the frequency of flares, the duration of therapy or endoscopic healing in patients whose disease had been under control for at least six months (Gastroenterology 2008;134[7]:1861-1868).

In addition, data from the DIAMOND 2 study—conducted in Asia with 50 patients with Crohn’s disease receiving adalimumab and thiopurines—showed no statistically significant differences in corticosteroid-free clinical remission and endoscopic remission between patients who stopped taking thiopurines and those who continued combination therapy (J Gastroenterol 2019;54[10]:860-870).

Finally, the recently completed SPARE trial—a large international, multicenter, prospective study—compared three scenarios: continuing combination therapy, stopping anti-TNF therapy or stopping the immunomodulator. The study found that both continuing combination therapy and stopping immunomodulator therapy performed better than stopping anti-TNF treatment, with a slight increase in relapse days (Lancet Gastroenterol Hepatol 2023;8[3]:215-227). The investigators concluded that stopping anti-TNF therapy was associated with a higher relapse rate and reduced time in remission compared with continuing combination therapy or stopping immunomodulator therapy. Young age and active disease state at the time of de-escalation were other factors that appeared to predict relapse.

“Based on these data, we should de-escalate combo therapy with immunomodulators to biological monotherapy after one year in all IBD patients,” Dr. Ungaro said. “My only caveat is to make sure that patients are in objective remission before you stop.”

Some Patients Should Remain On Combination Therapy

Ryan W. Stidham, MD, MSc, an associate professor of gastroenterology and computational medicine and bioinformatics at University of Michigan Health, in Ann Arbor, said combination therapy may be the appropriate strategy for certain patients with aggressive disease and a history of complications.

“TDM [therapeutic drug monitoring] testing of thiopurine metabolite levels could be used to decide which methods might work for individual patients,” Dr. Stidham said. “I agree with Dr. Ungaro’s caveat that patients should be both in clinical and endoscopic remission before stopping. I would also check the drug level of the biologic first,” he added. “If the level is close to the borderline, I would recommend bumping up the biologic before de-escalating the immunomodulator.”

Miguel Regueiro, MD, a professor of medicine and the chair of the Digestive Disease & Surgery Institute at Cleveland Clinic, in Cleveland, underscored the need for shared decision making in this setting. In general, “it’s advisable to continue the medications that are working,” he commented in a recent column in Gastroenterology & Endoscopy News (May 2023.Regueiro Report: De-escalating-IBD Therapies and-Shared Decision Making). “However, if we are to stop a medication, discontinuing the immunomodulator and continuing infliximab monotherapy is reasonable.”

—Chase Doyle


Dr. Stidham reported financial relationships with AbbVie, Blue Cross Blue Shield, Bristol Myers Squibb, CorEvitas, Evergreen, Exact Sciences, Gilead, Janssen, Lilly, Merck and Takeda. Dr. Stidham also reported that he owns intellectual property on several IBD-related technologies. Dr. Ungaro reported financial relationships with AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Lilly, Pfizer and Takeda.

This article is from the July 2023 print issue.