From the Journals

One in five Crohn’s disease patients have major complications after infliximab withdrawal

Publish date: February 1, 2018
By
Amy Karon
MDedge News

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The option of stopping a biologic agent is an attractive prospect for most Crohn's disease (CD) patients in stable clinical remission. The STORI trial, published in 2012, was among the earliest and select few studies addressing withdrawal of biologic therapy in CD among patients in sustained clinical remission with combination therapy (infliximab and thiopurine/methotrexate) for at least 6 months. Almost 50% of patients experienced disease relapse within a year of stopping infliximab in the trial.

Reenaers et al. recently published long-term follow-up of the original STORI cohort. After a median follow-up time of 7 years; four out five patients previously in clinical remission with combination therapy experienced worsening disease activity following withdrawal of infliximab. While the majority (70%) were able to resume infliximab and recapture disease response without any untoward adverse effects; one in five patients experienced major disease-related complications such as complex perianal disease or need for abdominal surgery. Upper GI tract involvement, high white blood cell count, and low hemoglobin concentration were associated with increased likelihood of a major complication. Notably, median time to a major complication was almost 4 years.

These results are similar to long-term relapse rates reported in other studies of withdrawal of therapy in CD. While biomarkers such as C-reactive protein, fecal calprotectin, along with endoscopic disease activity are reliable predictors of short-term relapse; clinical factors such as family history of CD, disease extent, stricturing or penetrating disease, and cigarette smoking are more relevant predictors of long-term disease activity. It is important to consider both types of predictors when considering withdrawal of therapy in CD.

Lastly, while the majority of patients who relapse following withdrawal of a biologic agent will do so within a year or two, a subset may not experience disease-related complications for several years - underscoring the need for long-term follow-up.

Manreet Kaur, MD, is assistant professor in the division of gastroenterology and hepatology; medical director, Inflammatory Bowel Disease Center, and medical director, faculty group practice, Baylor College of Medicine, Houston.


 

FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY

About 20% of patients whose Crohn’s disease was stable and remitted on infliximab-antimetabolite combination therapy developed major complications within 7 years after infliximab withdrawal, according to research published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.09.061).

About 70% of patients remained free of both infliximab restart failure and major complications, said Catherine Reenaers, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium), and her associates. Significant predictors of major complications included upper gastrointestinal disease at the time of infliximab withdrawal, white blood cell count of at least 5.0 x 109 per L, and hemoglobin level under 12.5 g per dL. “Patients with at least two of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal,” the researchers reported.

Little is known about long-term outcomes after patients with Crohn’s disease withdraw from infliximab. Therefore, Dr. Reenaers and her associates retrospectively studied 102 patients with Crohn’s disease who had received infliximab and an antimetabolite (azathioprine, mercaptopurine, or methotrexate) for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and then withdrew from infliximab. Patients were recruited from 19 centers in Belgium and France and were originally part of a prospective cohort study of infliximab withdrawal in Crohn’s disease (Gastroenterology. 2012;142[1]:63-70.e5).

About half of patients relapsed and restarted infliximab within 12 months, which is in line with other studies, the researchers noted. Over a median follow-up of 83 months (interquartile range, 71-93 months), 21% (95% confidence interval, 13.1%-30.3%) of patients had no complications, did not restart infliximab, and started no other biologics. In all, 70.2% of patients (95% CI, 60.2%-80.1%) had no major complications and did not fail to respond after restarting infliximab.

Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: 14 who required surgery and 4 who developed new complex perianal lesions. In a multivariable model, the strongest independent predictor of major complications was leukocytosis (hazard ratio, 10.5; 95% CI, 1.3-83; P less than .002), followed by upper gastrointestinal disease (HR, 5.8; 95% CI, 1.5-22) and low hemoglobin level (HR, 4.1; 95% CI, 1.5-21.8; P less than .01). The 13 patients who lacked these risk factors had no major complications of infliximab withdrawal. Among 72 patients who had at least one risk factor, 16.3% (95% CI, 7%-25%) developed major complications over 7 years. Strikingly, among 17 with at least two risk factors, 43% (95% CI, 17%-69%) developed major complications over 7 years, the researchers noted.

Complications emerged a median of 50 months (interquartile range, 41-73 months) after patients received their last infliximab infusion, highlighting the need for close long-term monitoring even if patients show no signs of early clinical relapse after infliximab withdrawal, the investigators said. “One strength of this cohort was the homogeneity of the population,” they stressed. “Most studies of anti–tumor necrosis factor withdrawal after clinical remission were limited by heterogeneous populations, variable lengths of infliximab treatment before discontinuation, and variable use of immunomodulators and corticosteroids. In [our] cohort, the population was homogenous, infliximab withdrawal was standardized, and the disease characteristics at the time of stopping were collected prospectively.” Although follow-up times varied, less than 5% of patients were followed for less than 3 years, they noted.

The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.

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