Sunday, December 22, 2013

5-ASA Drugs and Inflammatory Bowel Disease

Mesalamine and IBD

Mesalamine (or mesalazine), also known as 5-aminosalicylic acid, has been a staple of the treatment for Crohn’s disease and Ulcerative Colitis for decades.  Sold as Canasa, Rowasa, and Pentasa under various formulations and delivery mechanisms, it has been known to have very low side effects, and was a traditional first-line favorite treatment.  What does the evidence tell us about its actual efficacy, though?

With mesalamine, the evidence for efficacy in Crohn’s disease and Ulcerative Colitis must be viewed separately.  Introduced in the 1970’s when it was discovered to be the active component of sulphasalazine,(1) it was touted as a low-risk treatment for inducing and maintaining remission in Crohn’s disease.  Initial clinical trials (many not using a placebo control) looked positive, and the drug was prescribed widely as a core treatment for the disease. In the late 1990’s and early 2000’s, larger, better controlled trials were performed when absorption of the drug and its impact on full thickness diseases like Crohn’s was questioned. 

When through meta-analyses were performed based on the larger studies, they found that there was no statistically significant difference between the mesalamine drugs and placebo in either inducing or maintaining remission.  A 2011 Cochrane summary concluded that “Mesalazine and mesalamine formulations are not effective for inducing remission in active Crohn's disease...Aminosalicylates are safe for patients with Crohn's disease. Side effects are generally mild in nature and typically include nausea, vomiting, diarrhea, abdominal pain and dyspepsia (upset stomach or indigestion). [T]he existing data show little benefit for mesalamine.”(2)  Similarly, another review in the American Journal of Gastroenterology found that there was “no definite benefit of mesalamine over placebo”, despite a benefit over sulfasalazine over placebo. (3)

The story is a bit different for UC patients.  Mesalamine can be delivered to the colon either through some form of controlled release pill or through enemas and suppositories.   When compared to placebo in maintaining remission, the mesalamine was more effective, with a relative risk of 0.65.  Similarly, in inducing remission the relative risk was 0.79 when compared to placebo.  These results come in a 2011 meta-analysis of the strongest clinical trials, showing that mesalamine has efficacy against UC (astute readers will note this was the same team that found no efficacy in Crohn’s using the same methodology).(4) 

Because of the different delivery mechanisms, there have been additional studies with UC to determine the efficacy of different formulations.  A review looking at sustained release pills, delayed release pills, and pro-drug variants all taken orally found no efficacy difference.(5)  Further review showed that once daily dosing orally had the same efficacy as 2-3 times a day dosing.(6)  Finally, a review looking at the efficacy of oral v. suppository/enema (topical) delivery found that both were effective, but that combined oral/topical and just topical were both superior to oral in inducing and maintaining remission.(7)

The mesalamine story is a great learning lesson for evidence-based medicine.  Based on the efficacy of sulfasalazine, these drugs should have worked in Crohn's disease, and were enthusiastically prescribed due to the low side effect factor.  Unfortunately, they were increasingly shown to be ineffective, but the evidence won out.  The medical establishment eventually came around, and they are now not part of general treatment protocols for Crohn's (with the possible exception of terminal ileum-only disease).  On the other hand, they performed as projected for UC and are now a low-risk, staple treatment for the disease.

Bottom Line

·         Although still being prescribed, the evidence does not show that 5-ASA drugs are effective treatments for Crohn’s Disease.
·         Both oral and topical 5-ASA drugs are effective at treating Ulcerative Colitis.  Once-a-day oral is as effective as multi-dosing oral.
·         Suppository and enema-based delivery are more effective either alone or combined with oral than just oral dosing.

1.       Khan, A. K., Juan Piris, and S. C. Truelove. "An experiment to determine the active therapeutic moiety of sulphasalazine." The Lancet 310, no. 8044 (1977): 892-895.
2.       Lim, W. C., and S. Hanauer. "Aminosalicylates for treatment of active Crohn's disease." (2011).
3.       Ford, Alexander C., Sunanda V. Kane, Khurram J. Khan, Jean-Paul Achkar, Nicholas J. Talley, John K. Marshall, and Paul Moayyedi. "Efficacy of 5-aminosalicylates in Crohn's disease: systematic review and meta-analysis."The American journal of gastroenterology 106, no. 4 (2011): 617-629.
4.       Ford, Alexander C., Jean-Paul Achkar, Khurram J. Khan, Sunanda V. Kane, Nicholas J. Talley, John K. Marshall, and Paul Moayyedi. "Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis."The American journal of gastroenterology 106, no. 4 (2011): 601-616.
5.       Feagan, Brian G., Nilesh Chande, and John K. MacDonald. "Are There Any Differences in the Efficacy and Safety of Different Formulations of Oral 5-ASA Used for Induction and Maintenance of Remission in Ulcerative Colitis? Evidence from Cochrane Reviews." Inflammatory bowel diseases (2013).
6.       Feagan, Brian G., and John K. MacDonald. "Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: A systematic review and metaanalysis." Inflammatory Bowel Diseases 18, no. 9 (2012): 1785-1794.
7.       Ford, Alexander C., Khurram J. Khan, Jean-Paul Achkar, and Paul Moayyedi. "Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis." The American journal of gastroenterology 107, no. 2 (2011): 167-176.

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