The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment with biologic therapies is discontinued, according to a new prospective study.
Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.
“Applying strict criteria for endoscopic healing, and mesalamine treatment…may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.
De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.
However, withdrawal of the drugs increases the risk of relapse by 30%–45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.
Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
Study Details
To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.
The study was limited to adult patients with IBD, with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.
The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months, and to perform endoscopy at 12 months.
Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient-Harvey Bradshaw Index for patients with Crohn’s disease and the patient-Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.
Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.
All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.
After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.
Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases, and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD, and between those discontinuing adalimumab and those stopping infliximab.
Better Healing, Better Outcomes
However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio vs complete endoscopic healing of 3.28.
At 12 months, 70% of patients with partial endoscopic healing had relapsed vs 35% of those with complete endoscopic healing.
Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.
Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal, and a median of 24 days since the onset of relapse.
Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
Reluctance Remains
Commenting for Medscape Medical News, Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine in Chicago, Illinois, said the findings “reinforce the benefits of the maintenance vs the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.
The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Hanauer said.
“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.
Nevertheless, Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”
The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, Cleveland, Ohio, told Medscape Medical News.
“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.
Although the study didn’t clear up that question for Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.
Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.
“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.
“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Regueiro added.
The study received support from the Dutch Health Insurance Innovation Fund.
Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article.
Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation (GiHF), Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.
Clin Gastroenterol Hepatol. Published online August 30, 2022. Full text
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