2018-02-22 06:07:29 UTC

What Happens When Patients With Crohn’s Disease in Remission Stop Taking Infliximab?

When patients with Crohn’s disease in sustained remission stopped taking infliximab for a median 7 years, almost one fifth did not require retreatment or have a major complication, researchers report in the February issue of Clinical Gastroenterology and Hepatology. Fewer than one fifth of patients required surgery or developed a complex perianal fistula.

Kaplan–Meier curve of survival without major complication. The proportions of patients surviving without major complications were 99.0% (95% CI, 97.3–99.8) after 1 year, 97.0% (95% CI, 93.6–99.6) after 3 years, and 88.2% (95% CI, 81.6–94.8), 5 years after infliximab withdrawal.

Increasing numbers of patients with Crohn’s disease are exposed to higher levels of immunosuppressants early in their disease course—usually tumor necrosis factor (TNF) antagonists in monotherapy or combination therapies. However, there are safety issues associated with these strategies, and there have been debates over how to select patients for treatment reduction or discontinuation.

The infliximab discontinuation in Crohn’s disease patients in stable remission on combined therapy with immunosuppressors (STORI) study found in 2012 that 50% of patients who were treated for at least 1 year with infliximab and an anti-metabolite had a relapse within 1 year after infliximab discontinuation. However, the authors identified patients at low risk for relapse based on a combination of clinical and biologic markers. The study also found that re-induction with infliximab was effective and well tolerated by most patients.

A systematic review concluded that approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission at 24 months, although longer-term studies are needed.

Catherine Reenaers et al therefore evaluated the long-term outcomes of 102 participants in the STORI trial. They aimed to identify factors associated with surgeries, major complications, and need to restart therapy with infliximab or another biologic agent. The de-escalation strategy was considered to have failed when a major complication or infliximab restart failure occurred.

Reenaers et al found that 21% of the patients did not restart treatment with infliximab or another biologic agent and did not have a major complication 7 years after infliximab withdrawal.

Among patients who restarted infliximab, treatment failed for 30.1% within 6 years. Overall, at 7 years after stopping infliximab therapy, major complications occurred in 18.5% of patients, but 70.2% of patients had no failure of the de-escalation strategy.

Factors independently associated with major complications were upper-gastrointestinal location of disease, white blood cell counts of  5.0 × 109/L or more, and hemoglobin levels of 12.5 g/dL or less at the time of infliximab withdrawal. Patients with at least 2 of these factors had a more than 40% risk of major complications in the 7 years following infliximab withdrawal.

Reenaers et al state that only a few studies have investigated the long-term effects of infliximab withdrawal for patients with Crohn’s disease in clinical remission. In previous studies, treatment was heterogenous, patients had less-severe disease, or long-term complications were not reported.

In the study of Reenaers et al, the patient population was homogenous and major complications occurred relatively late (median 45 months) after infliximab withdrawal. This indicates that long-term close monitoring of patients is required, even for patients without early relapse.

The authors state that the factors they associated with major complications after infliximab withdrawal support the concept that upper gastrointestinal involvement associates with progression toward strictures or penetrating disease and surgery.

Low blood concentrations of hemoglobin have been associated with short-term relapse in previous studies.

Reenaers et al conclude that 10%–15% of this cohort fell into a low-risk group, defined by the absence of any risk factor (hemoglobin level above 12.5 g/dL, white blood cell count below 5.0 109/L; or upper gastrointestinal tract involvement). These patients can be reasonably considered for infliximab withdrawal.

Patients at high risk for relapse or complications within 7 years after infliximab withdrawal (15% to 20% of the cohort) have at least 2 of these factors and should continue their treatment.

An intermediate-risk group, defined by the presence of 1 risk factor (70% of the cohort), have an estimated rate of major complications of 16.3%. Treatment withdrawal should be discussed with each individual patient, taking into account the risk of surgical resection or complex perianal lesions.

Prospective controlled trials are needed to assess the benefits and risks of transient and prolonged biologic therapy for patients with Crohn’s disease and to validate these reported risk factors.

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