Examples of Medical Writing & Editing

Mesalamine Induces Mucosal Healing In Ulcerative Colitis

David T. Rubin, MD
Assistant Professor of Medicine
Section of Gastroenterology
The University of Chicago


Abstract: Whereas treatment of ulcerative colitis (UC) largely focuses on relieving the symptoms of rectal bleeding and frequent stools, many pathologists and gastroenterologists believe that mucosal healing is an important aspect of the treatment process. There is evidence that the degree of mucosal inflammation may have relevance for future disease risk, and may correlate with disease remission rates and long-term outcomes. Numerous studies suggest that treatment with mesalamine can induce mucosal healing, possibly resulting in durable remission of UC. Recent data demonstrate that mesalamine therapy results in endoscopically measured mucosal healing as early as 3 weeks, with mucosal healing evident throughout the colon, while also improving rectal bleeding and stool frequency regardless of the location or extent of UC. Those findings suggest the predictive value of mucosal healing in treatment outcomes, a concept that may facilitate the optimization of therapy and improve the prognosis of patients with UC.

Ulcerative colitis (UC) is an inflammatory disease of the colon that affects roughly 500,000 Americans. [1] The disease is characterized by mucosal changes such as loss of vascular pattern, granularity, friability (brittleness) and ulceration, producing symptoms such as rectal bleeding and frequent stools. Such mucosal pathology typically involves the distal rectum and extends proximally to affect all or part of the colon. [2] Current treatment goals for patients with UC are often based on surrogates of mucosal improvement or healing rather than on confirmation of actual mucosal healing. The American College of Gastroenterology (ACG) practice guidelines [2] suggests that treatment of UC should induce and maintain remission of symptoms and mucosal inflammation to improve quality of life. Those treatment goals have engendered measurement of outcomes such as symptom improvement, stool frequency or cessation of rectal bleeding as assessments of treatment efficacy. While those outcomes are clinically important, they paint an incomplete picture in the absence of actual mucosal healing, which is increasingly understood as a vital aspect of the treatment process in UC.

A lack of uniform standards for detecting mucosal healing has limited its utility and acceptance as a measure of treatment outcomes in UC. Interpretation of clinical findings is complicated by the use of varying outcomes and definitions of mucosal healing, as well as by the multifaceted nature of inflammatory bowel disease, which encompasses both UC and Crohn’s disease. Histology and endoscopy are two methods currently in use for assessing mucosal healing, and each method has advantages and disadvantages. Histologic definitions of UC are probably less subjective than endoscopic definitions, and provide a better indication of the extent of inflammation in the mucosa. The endoscopic definition of mucosal healing is often used in clinical trials, and endoscopy has the advantage of not requiring a biopsy, but it provides a highly subjective assessment. Clinical trials use varying endoscopic definitions, with some studies calling an endoscopic subscore of 0 or 1 (on a scale of 0-3) an acceptable level of healing, and others using a more rigorous score of 0 to define healing. Moreover, the utility of endoscopy is limited by the reported lag between improvement in histology or symptoms and endoscopic improvement. In many cases, patients with mucosal injury exhibit symptomatic improvement in the absence of complete healing of the mucosa. In other cases, an endoscopy score may indicate mucosal healing without symptomatic improvement. The disparity between endoscopic findings and the disease state at a microscopic or clinical level may complicate a patient’s assessment. Such a discordance was recently illustrated in the Active Ulcerative Colitis Trials (ACT) 1 and 2 [3], in which the percentages of patients achieving mucosal healing, as assessed by endoscopy, were greater than the proportion of patients achieving clinical remission of UC.

Clinical significance of mucosal healing

The importance of mucosal healing in the UC treatment process is underscored by emerging evidence suggesting that the degree of inflammation at a histologic level, and possibly at an endoscopic level, has relevance for future disease risk. If, for example, patients experiencing symptomatic improvement without mucosal healing are at higher risk of worsening disease than patients with both mucosal healing and symptomatic improvement, healing becomes a treatment goal in and of itself. Similarly, if achievement of mucosal healing results in durable remission of disease and/or a reduced need for surgery, the clinician has a compelling reason to adopt mucosal healing as a goal of therapy. In fact, research suggests that quiescent disease, marked by complete mucosal healing, predicts the amount of active disease likely to occur over the subsequent year, and that patients achieving mucosal healing are more likely to attain remission and may have more durable and positive outcomes. [4]

Treatment -- Achieving mucosal healing with mesalamine

For mild-to-moderate distal colitis, the ACG guidelines [2] recommend treatment with oral aminosalicylates (5-ASAs/mesalamine), rectally administered mesalamine, and/or rectally administered steroids. Oral mesalamine, in doses up to 4.8 g/day, with or without rectal 5-ASA, is recommended as initial therapy in mild-to-moderate extensive UC.

Mesalamine (Asacol®) is indicated for the treatment of mildly to moderately active UC (the usual dosage in adults is two 400-mg tablets tid for 6 weeks) and for the maintenance of remission of UC (recommended dosage is 1.6 g/day, in divided doses). Each tablet contains 400 mg of mesalamine coated with a pH-sensitive, acrylic-based resin, which dissolves in the terminal ileum or colon, thereby delivering effective drug concentrations to the colon, with low systemic absorption. [5]

Recent data from two prospective 6-week, double-blind, randomized, multi-site, active-control studies demonstrate that mesalamine induces mucosal healing throughout the colon. In the ASCEND I and II (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) trials [6,7], 349 patients with mildly to moderately active UC received a 2.4-g/day dose (in 400-mg tablets) of delayed release oral mesalamine. The investigators defined mucosal healing as an endoscopy score of 0 or 1. [3] 

Endoscopically measured mucosal healing was observed in mesalamine-treated patients as early as 3 weeks, by which time 62% of patients had achieved mucosal healing; this proportion increased to 71% after 6 weeks of therapy. Whereas all patients had an endoscopy score of 2 or greater at baseline, 27% had an endoscopy score of 0 at 6 weeks, and 44% had a score of 1 at this time point. [6,7]

Mesalamine induced mucosal healing regardless of the location or extent of UC. In the subgroup of patients with pancolitis, the appearance of mucosal tissue showed improvement in 65% of patients at 3 weeks; 71% of patients in this subgroup achieved mucosal healing at 6 weeks. In the subgroup of patients with left-sided disease (including patients with proctosigmoiditis and left-sided colitis), 60% attained mucosal healing after 3 weeks of therapy, and 70% achieved this end point at 6 weeks. Among patients with proctitis, 64% had mucosal healing at 3 weeks, and 75% showed healing of the mucosa at 6 weeks. [6,7]

The subgroup analysis also showed improvement in rectal bleeding in at least 76% of patients at 6 weeks, as well as a reduction in stool frequency in at least 57% of patients at this time point. [6,7]

Adverse events and safety information

In pivotal clinical trials involving patients with mildly to moderately active UC, the most frequent adverse events reported for mesalamine and placebo, respectively, were headache (35% vs. 36%), abdominal pain (18% vs. 14%), and eructation (16% vs. 15%). In trials for the maintenance of remission of UC, the most frequently reported adverse events were headache (50% vs. 50%), rhinitis (42% and 36%), and diarrhea (35% vs. 50%). [5]

Mesalamine is contraindicated in patients with a hypersensitivity to salicylates. Caution should be exercised when using mesalamine in patients with known renal dysfunction or a history of renal disease. It is recommended that all patients have an evaluation of renal function prior to initiation of mesalamine treatment and periodically while on mesalamine therapy. [5]

Discussion

The extent of mucosal healing with mesalamine in patients with mildly to moderately active UC, as observed in ASCEND I and II, has practical implications for clinicians, as this study population is representative of the type of patients typically seen in daily clinical practice, especially in gastroenterology. As mucosal healing is generally accompanied by clinical improvement, the ASCEND I and II results support what clinicians have long suspected but, until now, have not been able to prove.

The evidence of mucosal healing throughout the colon with mesalamine may run counter to what many physicians believe about this agent. Since mesalamine is a pH-dependent product, many would expect to observe its effects in the right colon. Yet the data show efficacy in all areas of the colon.

The results in the subgroup of patients with proctitis are particularly notable, as proctitis can be highly resistant to therapy, making these patients especially difficult to treat. The proctitis mucosal healing rate of 75% at 6 weeks – an effect achieved without rectal therapy – is a result that many clinicians might not have believed was possible.

Additionally, because patients tend to prefer oral 5-ASA therapy over rectal therapy [8], the substantial degree of mucosal healing with mesalamine may enhance adherence to therapy – a key consideration in light of the importance of treatment persistence. With mucosal healing response rates continuing to increase between 3 and 6 weeks of the mesalamine treatment regimen, the ASCEND I and II data suggest that repairing a damaged bowel requires full-dose therapy over a 6-week period, and that patients should be encouraged to “stay the course.”

In summary, the data from ASCEND I and II demonstrate that for patients with mildly to moderately active UC, mesalamine (2.4 g/day) induces endoscopically measured mucosal healing as early as 3 weeks, with mucosal healing evident throughout the colon. Mesalamine also improves symptoms of rectal bleeding and stool frequency regardless of the location or extent of UC. Mucosal healing therefore appears to be an important predictor of treatment outcomes, a concept that may facilitate the optimization of therapy and improve the prognosis of patients with UC.

References

1. Loftus EV, Silverstein MD, Sandborn WJ, et al. Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: Incidence, prevalence, and survival. Gut, 2000;46:336-343.

2. Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of  Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American  College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol, 2004;99:1371-1385.

3. Rutgeerts P, Sandborn WJ,  Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med, 2005;353:2462-2476.

4. Bitton A, Peppercorn MA, Antonioli DA, et al. Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology, 2001;120:13-20.

5. Asacol® (mesalamine) Delayed-Release Tablets product information. Procter & Gamble Pharmaceuticals. Revised September 2006. Available at: http://www.pgpharma.com/pi/US-Asacol.pdf. Accessed June 2007.

6. Rubin DT, Yacyshyn BR, Ramsey D, Lichtenstein GR. Endoscopically measured mucosal healing correlated with response to therapy in moderately active UC. Presented at the Annual Scientific Meeting of the American College of Gastroenterology. October 24, 2006, Las Vegas, Nevada. Abstract 1133.

7. Lichtenstein GR, Rubin D, Regalli G, et al. Endoscopically measured mucosal healing of delayed-release oral mesalamine 4.8 g/day versus 2.4 g/day. Presented at the Annual Scientific Meeting of the American College of Gastroenterology. October 24, 2006, Las Vegas, Nevada. Abstract.

8. Data on file, Procter & Gamble Pharmaceuticals.