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Anti-tumor Necrosis and Inflammatory Bowel Disease
Q: Is It Ever Appropriate to Stop Anti-tumor Necrosis Factor in a Stable Patient?
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A: The inflammatory bowel diseases are chronic, relapsing inflammatory disorders of the gastrointestinal tract with a propensity to develop tissue damage — including fibrosis and strictures — penetrating lesions and fistulas, and small bowel and colorectal cancer. Therefore, the aim of treatment is no longer a simple clinical response or even remission, but a state of biological and tissue remission ideally associated with the absence of disease progression. Any therapeutic decision in inflammatory bowel disease, either escalating or de-escalating the treatment, must be made by taking this into account.
Anti-tumor necrosis factors (TNFs), including infliximab, adalimumab and certolizumab pegol for Crohn’s disease (CD) and infliximab and adalimumab for ulcerative colitis (UC), have been used in clinical trials and routine practice for more than 10 years. These have been associated with long-term benefits, such as sustained clinical remission, mucosal healing, fistula healing, decreased number of hospitalizations, decreased number of surgeries, increased quality of life and the ability to work and perform activities of daily living. These have been associated with a reasonably good safety profile and, globally, a favorable benefit/risk ratio. The most striking risks are opportunistic infections, mainly tuberculosis (incidence of approximately one per 1,000 patients per year) and lymphomas (fewer than one per 1,000 treated patients).
Despite the favorable benefit/risk ratio, reasons exist to contemplate anti-TNF withdrawal in patients with inflammatory bowel disease (IBD). The main reasons are patient preference (often dominated by the fear of complications or mild chronic side effects), pregnancy and cost. Among mild chronic adverse events are skin lesions that can affect up to one-fifth of anti-TNF–treated patients. These are usually not severe enough to justify treatment arrest, but may impair quality of life. Despite that no increased risk of malformation has been described with anti-TNF, immunoglobulin G1 (IgG1) anti-TNFs (infliximab and adalimumab) are actively transported through the placenta from week 20 of pregnancy, and a significant amount of these anti-TNFs has been detected in the blood of newborns, sometimes remaining for several months after birth. In this context, one newborn died from disseminated mycobacterial infection after a Bacillus Calmette-Guerin vaccination. As far as cost, anti-TNFs have been shown to be potentially cost-effective for the treatment of IBD, but sensitivity analyses have highlighted that this cost-effectiveness was influenced by treatment duration and that treating beyond 4 years may not be cost-effective at classically admitted thresholds.
Overall, the decision to stop or continue anti-TNF therapy is a trade-off integrating all of the previously mentioned considerations. However, paramount in this trade-off is the risk of relapse upon anti-TNF withdrawal, as well as the possibility to retreat relapsing patients. No data are currently available on this in UC, making the decision for anti-TNF withdrawal difficult in this disease, where a flare may sometimes rapidly lead to fulminant colitis and colectomy. In CD, we may separately consider perianal fistulizing disease and luminal disease. For perianal disease, no prospective specific study of anti-TNF withdrawal has been performed. However, long-term assessment of perianal CD continuously treated with anti-TNF showed persisting inflammatory fistulous tracks in a large proportion of them. For luminal CD, a prospective study by the Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID) specifically focused on the risk of relapse after infliximab discontinuation in patients in stable remission without steroids and having been treated for at least 1 year by a combined therapy with an immunosuppressant. This study revealed a relapse rate for 1 year approaching 50%. Discontinuing anti-TNF is not a globally advisable strategy because the relapse rate in such patients continuing their anti-TNF is likely below 10% per year. Nevertheless, this study also showed patients could be stratified according to their risk of relapse and that a subgroup of patients representing 25% of the whole cohort experienced a more acceptable risk, approximately 10% per year. Among the factors associated with a low risk of relapse that may help to select patients for such a de-escalation strategy were mucosal healing, normalized C-reactive protein (CRP), low fecal calprotectin and high hemoglobin levels. Another important aspect of this study was that relapsing patients could be effectively and safely retreated by resuming infliximab-scheduled treatment. Approximately 90% were in remission 2 months to 4 months after resuming infliximab, and none developed infusion reaction or anti-infliximab antibodies. This remission was also sustained with time, and the secondary loss of response was approximately 6% per year, with a median follow-up of 2 years.
Overall, one can conclude that the benefit/risk ratio of anti-TNF in IBD seems to remain favorable with time. As most patients would experience early relapse upon anti-TNF discontinuation, this is not a globally advisable strategy. I am particularly reluctant to stop an anti-TNF in UC, where data are lacking about the risk of fulminant colitis and colectomy, and in complex perianal fistulizing CD due to the difficulty to fully heal these complex fistulas. However, due to cost constraints or specific reasons, such as pregnancy concerns or mild intolerance, it is important to determine the patient’s individual risk of relapse. It seems this risk can be assessed according to the degree of remission achieved, particularly in luminal CD; it will be lower if the patient has achieved some kind of deep remission, including not only clinical but also biological remission and tissue healing.
In my practice, I generally advise patients to continue their anti-TNF treatment when it is effective and well tolerated. If I am asked by the patient or payer to consider treatment withdrawal for the reasons previously mentioned, I propose to assess disease activity by measuring blood CRP and fecal calprotecin and by doing ileocolonoscopy and/or MRI. If these indicate persisting tissue inflammation, I advise not to stop the anti-TNF because the risk of early relapse is high. Otherwise, I accept trying to withdraw the anti-TNF, proposing close monitoring of the patient by the measurement of CRP and/or fecal calprotectin every 3 months. In case of a confirmed increase in these markers, I propose to either reassess the patient by endoscopy and/or imaging or simply to restart the anti-TNF treatment.
Excerpted from
Rubin DT, et al. Curbside Consultation in IBD: 49 Clinical Questions, Second Edition (pp 105-107). © 2015 SLACK Incorporated.
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