November 4, 2011 (National Harbor/Washington, DC) — Combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment for inflammatory bowel disease (IBD), according to a study presented here at the American College of Gastroenterology 2011 Annual Scientific Meeting and Postgraduate Course.
This combination therapy gives another treatment option for patients with IBD who fail conventional thiopurine therapy, lead author Frank Hoentjen, MD, PhD, told Medscape Medical News. He is assistant professor of medicine at Raboud University Medical Center in Nijmegen, the Netherlands.
The researchers wanted to see whether they could lower the discontinuation rate for thiopurine by optimizing therapy before increasing the dosage.
"In patients with a skewed thiopurine metabolism who have either adverse reactions or an inability to achieve remission, allopurinol plus low-dose thiopurines should be considered before escalating maintenance therapy," Dr. Hoentjen said.
The "long-term effectiveness and tolerability of allopurinol and thiopurine combination therapy in inflammatory bowel disease patients" confirm previous small studies, which have shown the benefit of combination therapy, he said. The cohort size and follow-up time in this study were double those of the largest previous study.
Physicians have puzzled over the problems associated with thiopurines for a few decades, but only in the past 10 years have they learned that levels of metabolites correlate with efficacy and adverse effects, Dr. Hoentjen explained. Some of the adverse reactions that have caused patients to discontinue thiopurine therapy are nausea, vomiting, headaches, muscle aches, leucopenia, transaminitis, and pancreatitis.
The study looked at 85 patients with an average follow-up time of 20.4 months. Most of the patients were diagnosed with Crohn's disease or ulcerative colitis. Patients started combination therapy because of previous thiopurine refractoriness (54%), an inability to achieve or maintain remission despite optimized thiopurine therapy, hepatotoxicity (47%), nonhepatic adverse reactions (8%), or for other reasons (5%).
Participants were adults with IBD from 2 tertiary referral IBD centers who failed monotherapy with thiopurines; they were subsequently treated with allopurinol plus low-dose thiopurine. Therapeutic effectiveness was assessed by calculating the cumulative number of patients still using combination therapy at 6, 12, 24, and 60 months and who were still in clinical remission, based on Physician's Global Assessment and on laboratory, radiologic, and/or endoscopic findings.
The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 88%, 84%, 76%, and 73%, respectively.
The genetic background in this subgroup of patients might be an area for future research, Dr. Hoentjen said. If researchers can genetically identify patients who will develop a skewed thiopurine metabolism (and possibly the consequences, like hepatotoxicity or lack of clinical remission), they will be able to start combination therapy without trying monotherapy with thiopurines first, he said. Although physicians already use thiopurine methyltransferase genotyping in clinical practice, it is not 100% predictive.
James Lewis, MD, MSCE, chair elect of the National Scientific Advisory Committee of the Crohn's and Colitis Foundation of America, told Medscape Medical News that he finds the study "very interesting."
Although thiopurines are commonly used to treat IBD, data on the use of allopurinol to modify thiopurine metabolism toward the production of 6-thioguanine nucleotides are limited, and long-term data on the combination are even harder to come by. "These data suggest that in selected patients who preferentially metabolize mercaptopurine to 6-methylmercaptopurine, this may be an effective long-term strategy," he said.
Dr. Lewis, who is also associate professor of medicine and epidemiology at the University of Pennsylvania in Philadelphia, offered up some warnings. Patients and physicians who consider using this combination need to be aware of the risks for bone marrow suppression and perhaps liver injury, he cautioned. Leukopenia occurred in 13% of these patients. We know that it is challenging to closely monitor patients treated with azathioprine or 6-mercaptopurine for bone marrow suppression, he said. "This combination raises the stakes even higher, and an optimal monitoring frequency has not been established."
Dr. Hoentjen has disclosed no relevant financial relationships. Dr. Lewis reports providing consulting/research support services to Roche, Amgen, Centocor, Dark Canyon Laboratories, Millennium Pharmaceuticals, Pfizer, Shire, Takeda, and United Biosource Corporation.
American College of Gastroenterology (ACG) 2011 Annual Scientific Meeting and Postgraduate Course. Abstract 27. Presented November 1, 2011.
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