Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications.

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.

Dysphagia without endoscopically evident disease: to dilate or not?

OBJECTIVES: It is not known whether patients with symptoms of dysphagia but normal upper endoscopy benefit from empiric esophageal dilation. The aim of this prospective study was to determine whether patients with solid food dysphagia and normal upper endoscopy have symptomatic benefit from empiric dilation using a through-the-scope balloon. METHODS: Patients who were seen for complaints of solid food dysphagia and who had normal endoscopic examinations at our institution from 1998 through 1999 were identified. Those patients who had agreed before sedation to participate in the study, if eligible, were randomized to either sham or balloon dilation using an 18-mm through-the-scope balloon at the time of esophagogastroduodenoscopy. All potentially eligible patients who had given provisional consent completed a dysphagia questionnaire and a 10-cm visual analog dysphagia scale before endoscopy. Follow-up questionnaires were completed on day 1 and at 3 months and 6 months after the procedure. The primary endpoint of the study was the patient's self-assessment of difficulty swallowing, based on the questionnaires. RESULTS: A total of 83 patients met the study criteria and were randomized to balloon dilation (n = 43) or sham (n = 40). The two groups were comparable in age, sex, severity of baseline dysphagia. and use of antireflux medication. Improvement in dysphagia comparing sham to balloon on day 1 was 66% versus 67% (p = 0.99); at 3 months it was 82% versus 76% (p = 0.56); and at 6 months it was 84% versus 73% (p = 0.38). There were no reported complications in either group. CONCLUSION: The data from this prospective randomized, controlled study do not support the practice of empiric dilation in patients with symptoms of dysphagia without an endoscopically evident cause of dysphagia.

A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn's colitis and ileocolitis.

Oral mesalamine (Asacol) in a dose of 3.2 g/day was administered in a 16-week placebo-controlled trial in 38 patients for the treatment of mildly to moderately active Crohn's colitis or ileocolitis. Eighteen patients continued a stable dose of prednisone of no more than 20 mg/day and 20 patients did not take prednisone. Changes in the Crohn's Disease Activity Index (CDAI) were used as the primary measure of efficacy. Oral mesalamine was effective in achieving partial or complete remission in 60% of patients as compared with 22% of placebo-treated patients. However, only 20 of 38 patients completed the 17-week study. The others withdrew early because of worsening of symptoms or were dropouts counted as failures. The high percentage of early withdrawals prevented comparison of mean 17-week CDAI scores. Although the number of patients in this study was relatively small, Asacol 3.2 g/day appears to be safe and effective treatment for mildly to moderately active Crohn's colitis and ileocolitis as compared with placebo, and this regimen is an option for treatment of patients who fail or are intolerant of sulfasalazine.

A placebo-controlled trial of cyclosporine enemas for mildly to moderately active left-sided ulcerative colitis.

BACKGROUND/AIMS: Uncontrolled studies suggest that cyclosporine administered as an enema may be of benefit for left-sided ulcerative colitis and safer than intravenous or oral administration. The efficacy and safety of cyclosporine enemas for left-sided ulcerative colitis in a placebo-controlled trial was assessed. METHODS: Steroid and mesalamine enemas were withdrawn before the study. Forty patients were assigned to 1 of 4 strata: no concomitant therapy, oral steroids, oral salicylates, or oral steroids and salicylates. After stratification, patients were randomized to nightly treatment with 350 mg cyclosporine (n = 20) or placebo (n = 20) enemas. Clinical response was determined at baseline and 4 weeks by endoscopy, physician assessment, and a patient diary of daily symptoms. Trough blood cyclosporine levels were measured by high-performance liquid chromatography. RESULTS: At 4 weeks, 8 of 20 patients (40%) who received cyclosporine showed clinical improvement compared with 9 of 20 patients (45%) who received placebo. One patient receiving cyclosporine had reversible neutropenia attributable to sulfasalazine, and another patient receiving cyclosporine was unable to tolerate the enema vehicle. No other toxicity was noted during the trial. Blood cyclosporine levels were detectable in only two patients. CONCLUSIONS: Cyclosporine enemas administered in a dosage of 350 mg/day for 4 weeks are not efficacious in mildly to moderately active left-sided ulcerative colitis.

Cyclosporine enemas for treatment-resistant, mildly to moderately active, left-sided ulcerative colitis.

Ten patients with treatment-resistant left-sided ulcerative colitis were treated in an open protocol with 350 mg cyclosporine enemas nightly for 4 wk. A 12-point clinical disease activity index (DAI) score was calculated at baseline and after 4 wk. Whole blood and colonic tissue cyclosporine concentrations were determined by HPLC at the end of the study. Five of 10 patients responded to treatment, defined as a decrease in the clinical DAI score > or = 3 points. Responders retained the enemas longer than nonresponders (7.5 +/- 1.3 vs. 3.3 +/- 2.2 h, p = 0.01), and there was a positive correlation between decrease in the clinical DAI score and enema retention time (r = 0.64, p = 0.05). The mean colonic tissue cyclosporine concentration was not significantly higher in responders than in nonresponders (2884 +/- 1635 vs. 2359 +/- 576 ng/g, p = 0.52), and the correlation between decrease in the clinical DAI score index and colonic tissue cyclosporine was weak (r = 0.39, p = 0.26). Cyclosporine was undetectable in whole blood samples from all patients, and there were no apparent side effects with treatment. In conclusion, 50% of patients with treatment-resistant left-sided ulcerative colitis significantly improved during therapy with cyclosporine enemas for 4 wk. Patients with longer enema retention times were more likely to respond. A controlled trial is underway to investigate these findings further.

Dysplasia in chronic ulcerative colitis: implications for colonoscopic surveillance.

Mucosal dysplasia has been used as a marker for patients with chronic ulcerative colitis considered to be most at risk of developing cancer, and its identification is the basis for colonoscopic surveillance programs. To evaluate the reliability of this premise, colectomy specimens from two groups of patients who had undergone surgery for chronic ulcerative colitis (50 with cancer and 50 without) were retrieved. The groups were matched by age, sex, duration of disease, disease extent, and symptoms at the time of surgery. Using a standard technique of multiple random biopsies, we utilized the standard colonoscopic biopsy forceps to obtain four biopsies from mucosa that was not macroscopically suspicious for dysplasia or cancer in eight defined regions in each of the 100 colon specimens. This technique mimicked exactly the methods used in our clinical surveillance program. All 3,200 biopsies were evaluated blindly by one pathologist for presence and grade of dysplasia. Twenty-six percent of colons with an established cancer harbored no dysplasia in any biopsy from any region in the colon. While an overall association between the presence of cancer and high-grade dysplasia was detected (relative risk = 9.00; 95 percent CI of 2.73-29.67), the sensitivity and specificity of random colonic biopsies to detect concomitant carcinoma were 0.74 and 0.74, respectively. These findings prompt concern that reliance on random biopsies, obtained during colonoscopic surveillance, may be misplaced.

Lung disease associated with orally administered mesalamine for ulcerative colitis.

Pulmonary symptoms, bilateral interstitial infiltrates and gas exchange abnormalities developed in a patient with ulcerative colitis treated with orally administered mesalamine. Improvement of symptoms and objective findings occurred after drug discontinuation. To the best of our knowledge, this is the first report of lung toxicity associated with orally administered mesalamine.

Acute gastrointestinal bleeding. Experience of a specialized management team.

The initial experience of a specialized management team organized to provide expedient care for all acute major gastrointestinal bleeding in protocolized fashion at a large referral center is presented. Of the 417 patients, 56% developed bleeding while hospitalized. Upper gastrointestinal bleeding accounted for 82%. The five most common etiologies included gastric ulcers (83 patients), duodenal ulcers (67 patients), erosions (41 patients), varices (35 patients), and diverticulosis (29 patients). Nonsteroidal anti-inflammatory drugs were implicated in 53% of gastroduodenal ulcers. The incidence of nonbleeding visible vessels was 42% in gastric and 54% in duodenal ulcers. The rates of rebleeding were 24% (20 patients) in gastric ulcers and 28% (19 patients) in duodenal ulcers. Predictive factors for rebleeding included copious bright red blood, active arterial streaming, spurting, or a densely adherent clot. The rebleeding rate for esophagogastric varices was 57%. The mortality rate overall was 6% (27 patients), with rates varying from 3% (five patients) for gastroduodenal ulcers to 40% (14 patients) for esophagogastric varices. The morbidity rate for the entire patient population was 18% (77 patients), dominated by myocardial events (34 patients). The average length of hospitalization for gastroduodenal ulcers was 5 days, for diverticulosis 8 days, and for varices 10 days. The major efforts of a specialized Gastrointestinal Bleeding Team would be best directed at both reducing the morbidity associated with acute bleeding and reducing the overall cost of care.

Treatment of benign esophageal stricture by Eder-Puestow or balloon dilators: a comparison between randomized and prospective nonrandomized trials.

To determine whether the natural history of strictures is affected by the type of dilator used to treat newly diagnosed peptic strictures, we designed a prospective randomized trial to compare the results after Eder-Puestow or Medi-Tech balloon dilation. We entered 31 patients into the trial. We also prospectively followed up all 92 nonrandomized patients who underwent their first dilation for a benign stricture during the same period as the prospective randomized trial. The nonrandomized patients also underwent dilation with either the Eder-Puestow or the balloon technique at the discretion of the gastroenterologist performing the endoscopy. We found no statistically significant differences in the immediate or long-term results of the two methods among the randomized, nonrandomized, and overall combined groups. All but 1 of the 123 patients had immediate relief of dysphagia. Within each group of patients, the probability of remaining free of dysphagia 1 year after the initial dilation was approximately 20%, and the probability of not requiring a second dilation was approximately 65% with either technique. Major (esophageal rupture) and minor (bleeding or chest pain) complications occurred in 1% and 5% of the patients and 0.4% and 3% of the total dilation procedures, respectively. The esophageal rupture and four of six minor complications occurred after repeated dilations. Five of the six minor complications occurred with use of the Eder-Puestow dilators. We conclude that Eder-Puestow and balloon dilations of benign esophageal strictures are associated with similar outcomes, but repeated dilations and the Eder-Puestow technique may be associated with an increased risk of complications.

Distribution of mesalamine enemas in patients with active distal ulcerative colitis.

Mesalamine (5-aminosalicylic acid), a topically administered anti-inflammatory agent, is effective treatment by enema for distal ulcerative colitis; it lacks many of the side effects of orally administered sulfasalazine. In this study, we determined the colonic distribution of a 60-ml mesalamine enema in eight patients (five women and three men, 18 to 48 years old) with active distal ulcerative colitis that ranged from 12 to 40 cm proximal to the anal verge. On 3 consecutive days, each patient self-administered a 4-g (60-ml) 5-aminosalicylic acid enema that contained 3.7 MBq of [99mTc]technetium-sulfur colloid. Anterior and posterior images were obtained at 0, 30, 60, 120, and 240 minutes. During the 4-hour study period, all patients retained the enemas. The enemas spread to the sigmoid region in 24 of 24 studies, to the splenic flexure region in 22 of 24, and to the transverse colon in 1 of 24. Most of the enema was retained in the sigmoid colon. Therefore, we conclude that a 60-ml enema, when administered as recommended clinically, routinely flows retrograde as far as the splenic flexure but rarely spreads beyond this point. These results support the use of intrarectally administered 5-aminosalicylic acid for segmental colitis of the descending colon.

Small bowel enteroscopy: an early experience in gastrointestinal bleeding of unknown origin.

Peroral small intestinal enteroscopy was performed in 35 consecutive patients with gastrointestinal bleeding of unknown origin by using a prototypic Sonde-type enteroscope. The median value for patient age was 69 years; duration of bleeding, 2 years (range, 2 months to 9 years); and transfusion requirements, 9 units. Bleeding was occult in 54% of these patients. Placement and passage of the enteroscope was performed by a gastrointestinal endoscopy assistant. Mean passage time was 4.3 hours. Complete passage was obtained in 14% of the patients, passage into the mid-distal ileum in 69%, and passage only into the jejunum in 17%. The diagnostic yield was 26%, with the majority of lesions encountered being mucosal vascular malformations. Small intestinal enteroscopy is a reasonable diagnostic procedure before embarking on visceral angiography and surgical exploration when standard endoscopic and radiologic methods fail to disclose a diagnosis.

Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.

We assessed oral 5-aminosalicylic acid (5-ASA) prepared with a pH-sensitive polymer coating in 87 patients with mildly to moderately active ulcerative colitis in a double-blind, placebo-controlled trial. Patients were randomly assigned to receive 5-ASA at a dosage of either 4.8 or 1.6 g per day or placebo for six weeks. The outcome was monitored by flexible proctosigmoidoscopic examinations and physicians' assessments at three-week intervals and by patients' recordings of daily symptoms. Results showed 24 percent complete and 50 percent partial responses in those receiving 4.8 g of 5-ASA per day as compared with 5 percent complete and 13 percent partial responses in those receiving placebo (P less than 0.0001, rank-sum test). At a dosage of 1.6 g per day, the response was twice as good as with placebo, but the difference did not reach statistical significance (P = 0.51). Age, sex, duration of disease, duration of active symptoms, or extent of disease did not affect the clinical outcome. We conclude that oral 5-ASA administered in a dosage of 4.8 g per day is effective therapy, at least in the short term, for mildly to moderately active ulcerative colitis.

Antibiotic prophylaxis for percutaneous endoscopic gastrostomy. A prospective, randomized, double-blind clinical trial.

Study Objective. To determine if prophylactic use of cefazolin reduces peristomal wound infection associated with percutaneous endoscopic gastrostomy. Design. Prospective, randomized, double-blind, placebo-controlled clinical trial. Setting. Academic medical center, referral-based, gastroenterology service. Patients. One hundred thirty hospitalized patients, 23 of whom were excluded. Of the remaining 107 patients, 52 (group I) were already using antibiotics at the time of randomization for gastrostomy, whereas 55 (group II) were not. Interventions. Patients received either intravenous saline as a placebo or intravenous cefazolin (1 g) 30 minutes before gastrostomy. Measurements and Main Results. For 1 week after gastrostomy, the peristomal area was evaluated and a score assigned each day for erythema (0 to 4), induration (0 to 3), and exudate (0 to 4). A maximum combined score of 8 or more or the development of pus was a criterion for infection. None of the patients in group I developed a wound infection. Only 2 of 27 group II patients given prophylaxis developed a wound infection, compared with 9 of 28 patients not given prophylaxis, a difference of 25% (95% confidence interval, 4.8 to 44.6%; p less than 0.025). The number of patients who developed a wound infection was 0 of 52 in group I and 2 of 27 in group II patients who received cefazolin, a difference of 7.4% (95% confidence interval, -2.5 to 17.3%; p = 0.07). Conclusion. Cefazolin prophylaxis significantly reduces the risk for peristomal wound infection associated with percutaneous endoscopic gastrostomy. It is needed, however, only for patients not already receiving antibiotic treatment at the time of gastrostomy.

Collagenous colitis: a clinicopathologic correlation.

Collagenous colitis is an unusual cause of chronic, watery diarrhea. To characterize this disease, we reviewed biopsy specimens and the clinical records of 17 patients (9 women and 8 men) with this diagnosis. Intermittent diarrhea with symptom-free intervals lasting years was found in 7 of the 17 patients. Two patients had incapacitating arthralgias, and nine had a mild weight loss. Collagen deposition beneath the surface epithelium formed a continuous layer in 11 but was discontinuous in 5 of the 16 patients who had undergone rectal or colonic biopsies at our institution. The thickness of the collagen band was variable (maximum, 93 microns). The symptoms of the patients did not correlate with the thickness of the collagen layer. Variability in collagen thickness may be related to disease phase and increases the need to obtain multiple biopsy specimens from the sigmoid colon and rectum. The optimal treatment for collagenous colitis is difficult to determine because three of six patients treated only symptomatically in our study had resolution of their diarrhea.

Radiographic appearance of mucosal dysplasia associated with ulcerative colitis.

The radiographic appearance of dysplasia, a precancerous histologic change that is frequently present in colitic colons at high risk for cancer, was analyzed. Over a 5-year period, 170 patients with long-standing ulcerative colitis participated in a cancer surveillance program at our institution. On entry, all patients underwent radiography with a double-contrast barium enema and colonoscopy with multiple random biopsies. All radiographs were reviewed retrospectively and were correlated with the colonoscopic and histologic findings. Dysplasia, ranging from mild to severe, was found in the biopsy specimens from 26 (15%) of these patients (in 59 different regions). Thirteen of the 26 patients with dysplasia had colectomies, and the specimens were available for review. Most dysplasia is not radiographically visible, as was the case in 40 (68%) of the 59 regions found histologically to have dysplasia. In the 19 regions in which dysplasia was visible radiographically, it appeared as a solitary nodule or as several separate nodules in 11 (19%) of the 59 regions or as a close grouping of multiple adjacent nodules with apposed, flattened edges in 8 (14%) of the 59 regions. The radiographic finding of a nodule or of several separate nodules was not specific because these nodules were indistinguishable from the inflammatory nodules often present in colitic colons. On the other hand, the radiographic finding of a close grouping of adjacent nodules with apposed, flattened edges was associated with dysplasia 50% of the time. This radiographic appearance was seen in five of our 26 patients who had dysplasia. Our study shows that barium examinations are useful in some patients with chronic ulcerative colitis by suggesting the presence of dysplasia and directing the endoscopist to specific locations for biopsy.

Percutaneous endoscopic gastrostomy. Indications, success, complications, and mortality in 314 consecutive patients.

The aim of this study was to determine the indications, success rate, procedure-related mortality, and major and minor complication rates in 314 consecutive patients in whom we attempted a percutaneous endoscopic gastrostomy. The most common indications for placement of the gastrostomy tube were neurologic (n = 235, 75%) and oropharyngeal disorders (n = 42, 13%). We noted that the gastrostomy tube was successfully placed in 299 (95%) of the 314 patients. Ninety-three percent (n = 291) of the patients had the procedure performed in the hospital and 7% (n = 23) were outpatients when the procedure was performed. In those patients with stable underlying conditions, the procedure can safely be performed in the outpatient setting. A low rate of procedure-related mortality (1%), major complication (3%), and minor complication (13%) was noted. Our experience suggests that the percutaneous endoscopic gastrostomy is safe and has a low mortality rate even in patients who are medically debilitated secondary to their underlying disease.

Pulmonary infiltrates and eosinophilia associated with sulfasalazine.

Asymptomatic pulmonary infiltrates and eosinophilia developed in a patient with chronic ulcerative colitis 1 month after therapy with sulfasalazine had been instituted. The abnormalities resolved completely after use of the drug was discontinued. The sulfapyridine component of the sulfasalazine was the likely causative agent because 41 years earlier, the patient had experienced fever, myalgias, and eosinophilia after taking a sulfonamide. Ten previous cases of sulfasalazine pulmonary toxicity, including one fatality, have been reported.

Polymyositis associated with jejunoileal bypass.

We report a patient with polymyositis who had a functioning jejunoileal bypass. Although many connective tissue syndromes have been reported with small bowel bypass, the association of polymyositis is unusual even though similar pathogenetic mechanisms might be involved.

Percutaneous endoscopic gastrostomy. Simplified access for enteral nutrition.

The recently described technique of endoscopic placement of a permanent feeding gastrostomy is reviewed with several modifications. Our experience in 23 adults has led us to conclude that this nonsurgical technique is the procedure of choice in achieving long-term enteral nutrition in patients who have an intact, nonobstructed gut and in whom the stomach can be directly apposed to the anterior abdominal wall.

Quantitative investigations of idiotypic antibodies. V. Factors affecting the persistence and replacement of clones of antibody-producing cells.

The effect of challenge by antigen on persistence of clones of antibody-producing cells and on the induction of new clones was investigated through quantitative measurements of idiotypic specificities. In each of nine rabbits idiotypic specificities present in the earliest bleedings were completely replaced after a few months; subsequent changes occurred much more slowly. On a quantitative basis the population of molecules used as immunogen always reacted most effectively with the homologous anti-idiotypic antiserum. Little effect of increased antigen dose on the rate of change of idiotype was observed. Even large amounts of antigen administered every 2 wk caused only gradual changes in idiotypic specificities. This was attributed either to more effective capture of antigen by memory cells, as compared to precursor cells, or to the induction of tolerance in those clones that were not expressed. In two of three rabbits on a monthly injection schedule, the idiotypic specificities identified underwent very slow changes over a period as long as 17 months. Changes occurred more rapidly when antigen was administered every 2 wk. In each of four rabbits investigated, all idiotypic specificities identified before a 5 month rest period were still present afterwards, indicating the survival of essentially all clones of antibody-producing cells during that interval. Quantitative inhibition data indicated that some new clones of cells were initiated.