Curbing Crohn’s for the Long Term?

Most people with Crohn’s disease receive surgery, yet the disease comes back a short time later. A study in the July issue of Clinical Gastroenterology and Hepatology reports that giving patients low doses of infliximab immediately after surgery prevents disease recurrence over long time periods.

Dario Sorrentino et al. began giving 12 patients with Crohn’s disease 5 mg/Kg infliximab (an inhibitor of tumor necrosis factor (TNF)-a within 2 weeks after surgery—they found no clinical or endoscopic evidence of disease recurrence after 3 years of treatment. However, when therapy with infliximab was discontinued, the disease recurred in 10 patients within 4 months. Sorrentino et al. then gave these patients 3 mg/Kg infliximab every 8 weeks and their symptoms disappeared again for an entire year (1 or 2 mg/Kg were not effective).

Appearance of the mucosal anastomosis at different infliximab doses: (A) 5 mg/kg bw on an 8-week dosing interval for 3 years after surgery; (B) 1 mg/kg bw, 4 weeks after 3 infusions on an 8-week dosing interval; (C) 2 mg/kg bw, 4 weeks after 3 infusions on an 8-week dosing interval; (D) 3 mg/kg bw, 4 weeks after 3 infusions on an 8-week dosing interval; and (E) 3 mg/kg bw on an 8-week dosing interval for 1 year. The progressive increase in infliximab dose re-established mucosal integrity, which was maintained at 1 year.

So should all patients who undergo surgery for Crohn’s disease immediately receive infliximab? The disease does not recur in 20%–30% of patients after surgery and infliximab increases risks for infections and lymphoma. This study did not include a placebo group, so it is not clear how many of the patients would have remained disease free without the drug. Nonetheless, 7 of the patients in this study were considered to be at high risk of relapsing—3 had previous surgeries and 4 had penetrating disease. Better markers are needed to identify patients at greatest risk for Crohn’s recurrence; Sorrentino et al. observed that levels of fecal calprotectin correlated with mucosal healing.

There might be simpler, less expensive alternatives to anti-TNF therapy to reduce post-operative recurrence. 5-ASA, metronidazole, azathioprine, and ornidazole have shown different levels of efficacy against Crohn’s disease. Different dosing schedules than those tested in this study might also be more safe and effective for long-term maintenance of recovery. Additional clinical trials are required to determine the best way to prevent recurrence of this autoimmune disorder.

What do you think? Leave your reply below using the “Leave a Comment” link.

Sorrentino D, Paviotti A, Terrosu G, et al. Low-dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn’s disease. Clin Gastroenterol and Hepatol 2010; 8: 591–599.

Watch Dr. Sorrentino discuss this study in his video abstract.


Read the article online at CGH.

Read the accompanying free editorial.
Bernstein CN. Anti–tumor necrosis factor therapy in Crohn’s disease: more information and more questions about the long term. Clin Gastroenterol and Hepatol 2010; 8:556–558.

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About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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2 Responses to Curbing Crohn’s for the Long Term?

  1. Dear Kristine,

    thank you for choosing our paper for your blog!
    You have clearly read very carefully our study as well as
    Dr. Bernstein editorial. I agree with many of your comments. However I believe there are a few issues which may need clarification.

    1. We did base our dose-finding study on endoscopic recurrence – not on clinical recurrence. Endoscopic recurrence is an objective parameter and a forerunner of clinical symptoms. Standard (5 mg/Kg) infliximab therapy after 3 years prevented clinical and endoscopic recurrence in all patients. When we stopped it, after 4 months, we observed endoscopic recurrence (> 2 Rutgeerts score) in 10/12 patients. None of them became symptomatic during the study. We re-started therapy in these 10 patients at low infliximab doses and found that 3 mg/Kg (not 1 or 2) were sufficient to heal the mucosa in all of them. Such q8wk low dose mantained mucosal integrity for a full year. As a matter of fact, as of today, these patients have been treated with 3 mg/Kg for over 2 years and the mucosa is still intact.

    2. You say that it is not clear how many of the patients would have remained disease free without the drug.
    We know exactly how many: 17%. Which is the proportion who did not have
    endoscopic recurrence upon stopping the medication (2/12). Thus, 83% (10/12) would have had recurrence. Whether they would all become symptomatic we don’t know – however they had serious endoscopic recurrence (see above) which has already been proven to lead to symptomatic recurrence in time.

    3. You say that other strategies – with other medications (such as
    azathioprine) – could work for prevention of post-op recurrence. This is highly unlikely because they have never been proven to work in several studies. At most, they have shown a modest benefit (25%) over placebo. In addition side effects are extremely frequent with immunosuppressives.
    We don’t know whether different infliximab dosing schedules could work to prevent recurrence. In theory, a period of time longer than 6 months with 1 o 2 mg/Kg could be as effective as 3 mg/Kg. Or, 2.5 mg/Kg could also be effective. The only way to know is to perform additional studies but such studies may be very demanding since they would require very frequent colonoscopies. Alternatively, if validated, calprotectin levels could play a role in the design of future trials.

    Finally, there is an additional point which, I think, should be
    stressed here. This study shows, for the first time, that
    infliximab should be given long term to mantain biologic remission.
    Baert et al (Gastroenterology 2010) have stopped
    infliximab (and/or other medications) after reaching mucosal healing and the large majority of those patients remained asymptomatic for up to 2 years. However that study (by the way, an excellent one) did not check mucosal healing after stopping infliximab. They only checked symptoms. We show here that as soon as you stop infliximab mucosal inflammation comes back.
    Therefore it is likely that symptoms will also come back as soon as
    significant damage returns at the mucosal level. Stopping infliximab for a year or two does not seem a suitable long term solution – symptomatic disease will come back sooner or later and you may loose anti TNF response for ever. If the disease does not come back then we have to assume that infliximab has re-set the immune system – something never proven as of today.
    That’s all I wanted to say for the moment.
    Thanks again Kristine.
    And looking forward to discuss this work with other colleagues as well.

    All the best,

    Dario

  2. Krisitne Novak says:

    Thanks for the comments and clarifications Dario!
    Kris

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