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Patients with inflammatory bowel disease (IBD) who are in remission on combination therapy may withdraw one of their medications -- usually a tumor necrosis factor (TNF) inhibitor -- if they are at low risk and are followed closely, according to a researcher.

"The question all our patients have been asking is when they can stop or cut down on therapy if they're in remission," said Stephen Hanauer, MD, of Northwestern University Feinberg School of Medicine in Chicago, during an oral presentation at the Advances in Inflammatory Bowel Diseases virtual meeting.

"This is the huge elephant that many of us blind men have tried to tackle over the past years," he added.

Patients with IBD have typically relied on combination therapy, which can include steroids, salicylates, immunomodulators, and now biologics. Some of the advantages of combination therapy are the prevention of immunogenicity, increasing drug concentrations, and greater efficacy through multiple mechanisms of action, while the disadvantages include increased adverse events from each component of the regimen and complexity and cost. "Safety of course is a major concern with combination therapy, with patients having small increased risks for serious infections and lymphomas," Hanauer said.

Studies have shown that patients do tend to relapse even after being in the deepest remission if they stop treatment. For instance, in of 193 patients receiving infliximab (Remicade) for ulcerative colitis who had been in clinical remission for at least a year, more patients who stopped the TNF inhibitor flared (HR 3.70, 95% CI 2.02-6.77) compared with those who continued on infliximab. These patients were relatively spared from disease flare if they also were on a thiopurine, but there was still a greater risk of relapse.

Risk factors for disease relapse after withdrawal of infliximab in ulcerative colitis included having had a previous course of anti-TNF therapy, male sex, having elevated inflammatory markers or low hemoglobin, and elevated infliximab trough levels. "But being in deep remission was somewhat protective, meaning an absence of symptoms and biomarkers and the deepest endoscopic or histologic remission possible in that individual patient," Hanauer noted.

Another factor that possibly has contributed to disease flares after anti-TNF withdrawal is that, in general, the TNF inhibitors have been used relatively late in the course of disease. One recent report suggested that patients who received combination therapy early were relatively protected from hospitalization, surgery, and complications. "This probably related to lower exposure to steroids, which of course are our most dangerous drug," Hanauer said.

To the question of which agent to stop in combination therapy with a TNF inhibitor plus an immunomodulator, Hanauer noted that stopping one or the other has been explored in small trials and in real-world experiences. One suggested that patients remaining on infliximab might not need to continue with azathioprine, but with longer-term follow-up, an increasing number of patients relapsed or required higher doses of infliximab.

The possibility of stopping the TNF inhibitor was addressed in the , in which patients who were on a combination of infliximab and azathioprine had the infliximab withdrawn and were maintained on azathioprine alone. About 44% of patients relapsed after 1 year and 52.2% by 2 years.

"However, half stayed in remission -- this was a glass half empty or glass half full situation," Hanauer said. "But the investigators were smart. They looked at the risk factors of different groups for relapse after withdrawal."

The strongest factor that reduced the likelihood of relapse after withdrawal of infliximab was deep remission, with significantly elevated risk for relapse in patients with a Crohn's Disease Endoscopic Index of Severity above 2.3 (95% CI 1.1-4.9, P=0.04). Other factors associated with relapse included male sex, corticosteroid use before baseline, no previous surgical resection, and hemoglobin level below 145 g/L.

The STORI investigators also observed that many patients did ultimately flare and required the re-institution of the biologic. "The good news was that gave us some insight into whether we can rechallenge the patient after discontinuation of the biologic from combination therapy," Hanauer noted.

The vast majority of patients who lost their clinical response after stopping infliximab were able to successfully restart the treatment, with certain caveats. They had to have not previously developed antidrug antibodies, continued the immune modulator, be predosed with steroids, be observed for subtle signs of post-infusion allergic events, or have had a poor initial response, which may signal the development of antidrug antibodies. This most often occurred not after the first re-infusion, but after the second and sometimes the third re-infusion, Hanauer said.

In conclusion, the decision to stop the TNF inhibitor relies on choosing the right patient who is at low risk and in deep remission, possibly early in treatment rather than when the disease is refractory. It's necessary to confirm stable deep remission and adequate drug levels, and to reassess serum concentrations after several dosing cycles. Then the treat-to-target strategy should be continued with monitoring at 3 months, 6 months, and 1 year.

"So when patients ask me, 'how long do I need to stay on treatment,' I tell them 'until you're cured,' which at present does not occur. I give them the example of hypertension, where the goal is control rather than cure," Hanauer said.

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