Efficacy of S ~ aminosalicylic acid enemas in the treatment of distal ulcerative colitis

The efficacy of 4 g 5-aminosalicylic acid (5-ASA, mesalamine) enemas was assessed in 666 patients with distal ulcerative colitis. Patients were enrolled in an open-label compassionate use program. One 4 g 5-ASA enema was administered each night for a period of four weeks and the disease activity index was assessed at baseline and on days 14 and 28. On days 14 and 28, 78.0% and 88.1% of patients, respectively, demonstrated an improvement in disease activity index. The mean decline in disease activity index on day 14 was 40.7% (P=0.0001) and on day 28 it was 55.4% (P=0.0001). Efficacy was similar whether the disease was confined to or extended beyond 30 cm from the anus. There was no difference in efficacy in patients suffering their first episode of disease compared to patients suffering subsequent attacks. In conclusion, high dose 5-ASA enemas are a highly effective treatment for distal ulcerative colitis.

F OR THE PAST FOUR DECADES medical management of ulcerative colitis has generally required the use of corticosteroids or sulphasalazine.Although both treatment options have proved useful, each has its drawbacks.Corticosteroid treatment in enema form or orally admin istered has been associated with a wide variety of well known side effects such as fluid retention, muscle wasting, osteoporosis, moon facies and acne.Similarly, sulphasalazine has induced allergic reactions and been associated with dose, limiting side effects such as nausea, vomiting, headache and malaise.
Sulphasalazine is a conjugate of 5aminosal icyl ic acid (5-ASA, mesalamine) and sulfapyridine.These two components are linked by a diazo-bond that is cleaved by bacterial reductases in the colon.Studies by Azad Khan (I) and others (2,3) have shown that 5-ASA is the active moiety and that many of the side effects, which have limited the usefulness of sulphasalazine, can be attributed to the 'inac~ive' sulpha portion of the molecule.
Topical 5-ASA therapy offers benefits to patients with distal ulcerative colitis by delivering high concentrations of 5-ASA to that area of the colon which will benefit most while maintaining relatively low serum  4) documented homogeneous delivery of drug to the inflamed lower colon, often reaching the splenic flexure following low volume 5-ASA enema administration.Although there was some absorption across the inflamed mucosa, urinary excretion accounted for only 15% of the adm inistered dose (5,6).Various relatively small, controlled studies have supported the safety and efficacy of 5-ASA enemas in the treatment of distal ulcerative colitis and proctitis (7-10).The aim of the present study was to evaluate further the efficacy and tolerance of t he 5-ASA formulation, Rowasa (Reid-Rowell, Georgia) in a large patient population.The increased size of the study population also permitted a comparative assessment of drug efficacy in patients with disease boundaries less than 30 cm versus greater than 30 cm above the anal verge.Similarly, it was possible to assess the effectiveness of 5-ASA enemas for patients exhibiting their first episode versus those with a history of mu ltiple attacks of ulcerative colitis.

PATIENTS AND METHODS
Patients diagnosed with mild to moderate d istal ulcerative colitis were enrolled in a four week, open-label, compassionate use program.Participation required the administration of one 4 g 5-ASA enema ( 60 mL Rowasa retention enemas containing 4 g mesalamine in a buffered aqueous solution) each night for four weeks.
The study population was composed of outpatients older than 17 years of age, all of whom had disease involving a minimum of 5 cm to a max imum of 50 cm as measured from the anus and confirmed by sigmoidoscopy and biopsy.
Patients were seen at an initial visit and were thereafter assessed on days 14 and 28.At each of these assessments, the disease activity index was measured.The disease activity index (Table l) represents an attempt to provide objective criteria for assessment of drug efficacy and has been used in previous studies (9).Four variables arc assessed: stool frequency, rectal bleeding, sigmoidoscopic appearance of mucosa and physician's assessment of disease severity.Each variable has a range of values for severity with O representing no abnormality and 3 representing the most severe d isease involvement.As the variables have equal weighting, the overall disease activity index could range from O to 12.
A t test was used to determine if the mean percentage improvement at weeks 2 and 4 was different from baseline.AP value of less than 0.05 was required to indicate a statistically significant improvement.The total number of patients varied between analyses because of missing data for some patients.

RESULTS
Patient characteristics: Six hundred and eighty-four patients entered the study.Of this population 666 were analyzed, 39 of whom were included despite the fact that they did not meet th e selection criteria.Of these 39 patients, 20 exhibited disease extending beyond 50 cm, 15 were diagnosed with Crohn's disease and 14 suffered from colitis of other etiologies.An additional 12 patients were excluded from the analysis because they were younger than 17 years.
Patient population characteristics are presented in Table 2.The mean age Efficacy: Several parameters including stool frequency, rectal bleeding, sigmoidoscopic appearance of mucosa and the physician's assessment of d isease severity were used to provide a d isease activity index and thus assess each patient's response to therapy.In addition, two patient subsets were examined independently: patients with disease extension greater or less than 30 cm; and patients suffering t heir first episode of inflammatory bowel d isease.
The disease activity index was assessed at baseline and weeks 2 and 4. At week 2, the mean d isease activity index decreased from a baseline of 6.8 to 3.95, with 78% of patients demonstrating an improvement.A frequency distribution of change in d isease activity index/improvement of disease severity is presented in Figure 1.At week 4, 88.1 % of patients showed improvement, and the mean disease activity index decreased further to a value of 3.04.The patient disease activity index distribution at week 4 is presented in Figure 2. Overall, the mean improvement in disease activity index at weeks 2 and 4 was 40.7% and 55.4%, respectively (P<0.00 1).
A summary of the mean values for each of the evaluated parameters is presented in Table 3. Again, the total ,.Patients with disease less than or greater than 30 cm: A comparison of the responsiveness of patients with ulcerative colitis extending less than 30 cm from the anal verge to those with disease extendi ng beyond 30 cm revealed no significant difference between the percentage of colitis patients within these groups who responded to 5-ASA enemas.At week 2, 174 of 219 patients (79.5%) with disease confined to 30 cm showed an improvement in disease activity index.By week 4 this percentage had increased to 89. 7% (127 of 145 patients).For patients with disease extending beyond 30 cm, 102 of 137 (74.5%) showed an improvement after two weeks.At week 4, 12 7 of 14 5 (87.6%) showed improvement.
Although there was no difference in overall patient proportions responding to 5-ASA enemas, the magnitude of 470 response did seem to differ.Patients with disease less than 30 cm showed a significantly greater reduction in disease activity index (P<0.003)after two weeks (44%, n=219) compared to patients with disease beyond 30 cm (33.5%, n= 13 7).The statistical significance of these differences disappeared after four weeks, when the improvement increased to 56.8% and 51.2%, respectively.First episode versus multi-episode patients: The responsiveness of a small group of first episode patients was also evaluated and compared to that of patients who had experienced more than one episode of ulcerative coli tis.Sixty-seven per cent (16 of 24) offirst episode patients showed an improvement in disease activity index at week 2, while 78.7% (270 of 343) of multiepisode patients showed improvement.At week 4 the percentage of improved patients increased to 84.6% (22 of 26) and 88.3% (324 of 367), respectively, while the differences between groups were diminished.Similarly, there was TABLE 3 no statistically significant difference in mean percentage improvement in disease activity index fo r pati encssuffenng their first attack compared to patients with more than one episode.

DISCUSSION
Patients included in this study were enrolled on a compassionate use basis.Therefore che study was open-label and nonrandomized.However, an extreme, ly large patient population was assessed.These results clearly support 4 g 5-ASA enemas as effective treatment of distal ulcerative colitis and are consistent with results of smaller, placebo controlled, double-blind studies (7,9).
Patients improved in all four categories which comprise the disease activity index: stool frequency, rectal bleeding, sigmoidoscopic appearance of mucosa and physician's assessment of Mean improvement from baseline in disease activity Index These patients did not respond to 5-ASA e n emas in a significantly different manner than patients who have suffe red from multiple episodes.
In conclusion, 5-ASA enemas are a highly effective and well tolerated treatment for Jistal ulcerattve colitis.Excellent responses in acute left-sided colitts as well as chronic recurrent disease were observed.

TABLE 1
Disease activity index

TABLE 2 Patient characteristics
Change in disease activity index at week 2. A negative number indicates a decrease in disease activity index, ie, an rmprovemenc Figure 2) Change in disease activity index ai week 4. A negative number indicates a decrease in disease activity index, ie , an impr011ement