TY - JOUR
AU - Peppercorn, Mark, A.
AB - Ulcerative proctosigmoiditis (also commonly referred to as distal ulcerative colitis) is defined as inflammation limited to the distal 30-50 cm of colonic mucosa, whereas ulcerative proctitis refers to disease confined to the rectum. The major recent breakthrough in the therapy of these conditions has been the advent of various topical anti-inflammatory agents. These agents directly contact the inflamed mucosa and have less systemic absorption than the oral medications. The first compounds used as rectal suspensions were corticosteroid enemas. Subsequently, sulfasalazine and 5-aminosalicylate (5-ASA) enemas were studied. Oral sulfasalazine and oral mesalamine also are being utilized, although there are very few studies assessing their efficacy specifically in disease limited to the distal colon. Immunomodulators have an increasingly important role in steroid dependent and steroid refractory distal colitis, situations in which physicians may be reluctant to send patients to surgery for disease that is so limited. This review discusses the various agents utilized in the therapy for conventional and refractory ulcerative proctitis and distal colitis. It will also outline our personal approach to treating patients with these conditions. Since there is very little data on Crohn's proctitis and proctosigmoiditis, we will not discuss these entities in our review. Review of Clinical Trials Aminosalicylates Topical 5-Aminosalicylates and Topical Sulfasalazine Although sulfasalazine became widely used in the therapy of both active and remitted ulcerative colitis (UC) following its introduction into clinical medicine in the 1940s, its pharmacology was not well studied until the early 1970s. These studies demonstrated that intestinal bacteria were solely responsible for the initial step of sulfasalazine's metabolism, cleavage of the azo bond linking its two components, sulfapyridine and 5-aminosalicylic acid (5-ASA). The sulfapyridine moiety is largely absorbed never reaching the distal colon while the 5-ASA portion remains within the lumen of the colon to be excreted with the feces. These investigations suggested that sulfasalazine may be serving merely as a vehicle for delivery of an active component (5-ASA) to distal disease sites and gave impetus to a series of investigations into the possible role of 5-aminosalicylate as a distinct therapeutic agent. A classic study by Azad Khan et al. (1) attempting to confirm the pharmacologic observations compared rectal suspensions of sulfasalazine (2 g), 5-ASA (0.7 g), and sulfapyridine (1.3 g) in active ulcerative colitis. Patients in both the sulfasalazine and 5-ASA enema groups had a significantly better clinical and sigmoidoscopic response than those on sulfapyridine (1). Although the study was flawed by the lack of a placebo group, it suggested that 5-ASA was the active moiety of sulfasalazine. The results were supported by Van Hees et al. (2) in a similar study that was placebo controlled. Subsequently, placebo-controlled trials demonstrated the efficacy of rectal instillations of both sulfasalazine (3,4) and 5-ASA in active ulcerative proctosigmoiditis (5,–7). Moreover, the success of topical 5-ASA therapy was not limited to new onset disease but extended to patients with proctosigmoiditis refractory to oral sulfasalazine and to both oral and topical corticosteroids (8,–12). Dose ranging studies have attempted to delineate the most effective dose and frequency of administration of these agents (7,13). In one placebo-controlled trial 1 g, 2 g, and 4 g 5-ASA daily enemas were found to be equally effective in attaining remission in active distal ulcerative colitis (7). In the United States only the 4 g enema is commercially available. 5-ASA liquid enemas also have been compared to 5-ASA foam preparations in the treatment of distal ulcerative colitis. In one study foam distributed more uniformly and persisted longer than the liquid suspensions in the descending and sigmoid colon (22). Whether these observations translate into superior efficacy of the foam remains to be determined. In the only study comparing the efficacy of both preparations, there was a greater tendency for patients with moderate colitis to attain clinical remission if they were taking the foam preparation (63%) as opposed to the liquid enemas (52%) after 3 weeks of therapy, although this was not statistically significant (23). Patients preferred the foam preparation in this study because it was easier to apply and to retain and did not warrant bedrest. Topical 5-aminosalicylates also have been compared to standard corticosteroid enemas in three clinical trials. Two studies demonstrated their equal efficacy (24,25) with prednisolone enemas. A third study suggested that 4 g 5-ASA enemas were superior to 100 mg hydrocortisone enemas (26). The usefulness of 5-ASA suppositories in active proctitis has also been assessed in five placebo-controlled trials (27,–31). Although the definition of proctitis differs slightly in these studies, it seems overall that suppositories are effective in disease limited to the distal 20 cm of the colon. One report found equal efficacy of 5-ASA suppositories and 5-ASA enemas in active proctitis (defined in this study as inflammation at <20 cm from the anal verge) (32). The only dose ranging trial demonstrates that 500 mg bid suppositories are equal to a 500 mg tid dosage in proctitis (31). 5-ASA suppositories are commercially available in the United States in a 500 mg dose. Radionuclide studies have been performed to assess the proximal migration of topical compounds in active ulcerative colitis. Results obtained from these studies do not always correlate with the clinical efficacy of these agents. For example, several studies indicate that 5-ASA enemas often migrate to the splenic flexure (14,–18); yet Sutherland et al. showed that the efficacy of these rectal suspensions did not extend beyond 40 cm (5). In contrast, radionuclide studies show that 5-ASA suppositories can migrate to the distal sigmoid colon (27), correlating with clinical trials supporting their efficacy in disease extending up to 15 or 20 cm from the anal verge (27,30,31). Topical 5-ASA agents are also associated with fewer side effects when compared to their oral counterparts. This is presumably due to their low systemic absorption (19,20,21). Studies have demonstrated the efficacy of topical 5-ASA compounds in prolonging remission for distal ulcerative colitis and proctitis. The duration of maintenance treatment, the optimal dose, and the dosing frequency remain somewhat in question. There are two placebo-controlled trials assessing the efficacy of 5-ASA enemas in remitted proctosigmoiditis. One trial reports significant reduction of relapse rates at one year with a nightly 1 g 5-ASA enema (33). Another report demonstrates the efficacy of a 4 g rectal suspension administered nightly or every other night but not every third night in maintaining remission for 24 weeks (34). A dose ranging study showed that 1 g 5-ASA enema was equally effective to 2 g 5-ASA enema in reducing relapse rates at 26 weeks (35). The dosage and dosing schedule for the use of 5-ASA suppositories in quiescent proctitis also require clarification. Suppositories at a dose of 400 mg bid were effective in maintaining remission at 1 year in one study (36). A 2-year multicenter trial supported the efficacy of nightly 500 mg mesalamine suppositories as maintenance agents in ulcerative proctitis (37). Oral 5-Aminosalicylates and Sulfasalazine Although the topical 5-aminosalicylic acids are indicated as first line treatment in proctosigmoiditis and proctitis, there are patients who are intolerant to or noncompliant with such therapy. In these patients clinicians will often use sulfasalazine or the oral 5-aminosalicylates as alternative medications. The latter agents were developed following the successful use of topical 5-ASA therapy and include slow release and pH dependent forms, encapsulated in ethylcellulose microspheres or coated with an acrylic resin and a dimer of 5-ASA that like sulfasalazine depends on bacterial azo bond cleavage. The evidence supporting the use of these agents as sole therapy for proctosigmoiditis is scant. In fact, there are no placebo-controlled studies that specifically assess the efficacy of these oral drugs in the treatment of active distal colitis. Most efficacy trials, for statistical power, report results of sulfasalazine and oral 5-ASA therapy in patients with ulcerative colitis who have been grouped together independent of disease extent. Despite this, when one reviews these studies and looks specifically at the therapeutic response of patients with proctosigmoiditis, there is a suggestion in some reports that sulfasalazine and oral 5-ASA agents show a benefit in this subset of patients (38,–40). Sulfasalazine at a dose of 2-4 g/day (41), mesalamine 2.4-4.8 g/day (42,43), and olsalazine 1-3 g/day (38,39,44,–47) are effective in attaining remission in active ulcerative colitis. Interestingly, there is a small study, not placebo-controlled, that has compared two types of oral 5-ASA agents in patients with acute proctosigmoiditis (48). In this study, olsalazine was found to be more effective than the pH-dependent delayed-release mesalamine, presumably because of greater colonic concentrations of 5-ASA attained with olsalazine. There are two studies that directly compare an oral 5-ASA agent to topical 5-ASA therapy in acute distal ulcerative colitis (49,49a). In one study patients with active proctosigmoiditis were treated with either oral sulfasalazine 4 g/day or a nightly mesalamine enema (4 g). After 6 weeks there was no statistical difference in therapeutic response between these two groups, although at 2 weeks there seemed to be a trend favoring the 5-ASA enemas. Furthermore, at termination of the trial more patients receiving the sulfasalazine reported blood in their stools when compared to those having received the enemas. Side effects also were more common in the sulfasalazine group. In a second study, 5-ASA enemas alone and the combination of 5-ASA enemas and oral mesalamine were more effective than oral mesalamine alone (49a). The only other published clinical trial comparing oral 5-ASA to some form of topical therapy in active proctosigmoiditis demonstrates the equal efficacy of 3.2 g/day of oral mesalamine and bid hydrocortisone enemas (50). However, in this 4-week trial there was a trend favoring the enemas for reduction of rectal bleeding. Oral agents also are effective in maintaining remission in ulcerative colitis. There are no placebo-controlled trials assessing efficacy of oral 5-ASA as remitting agents specifically in proctosigmoiditis or proctitis. Most studies report results for ulcerative colitis patients as a group without reporting efficacy rates in patients with different extents of disease. Consequently, it is difficult to make a statement on the role of these agents for maintenance of remission in distal ulcerative colitis. One placebo-controlled trial assessing sulfasalazine as a remitting agent does seem to suggest that it is beneficial in patients with proctosigmoiditis (51). However, a dose ranging study for sulfasalazine in remission reported higher relapse rates in patients with proctosigmoiditis as compared to other patient groups, although this was not statistically significant (52). Doses for long-term treatment include 2-3 g/day for sulfasalazine (51,–53), 1.2-2.4 g/day for mesalamine (54,–56), and 1-2 g/day for olsalazine (57,58). There have been three studies comparing oral 5-ASA agents with topical 5-ASA therapy in maintaining remission. One study found that a 4 g 5-ASA enema every third night was associated with a significantly lower relapse rate (26% at 2 years) than 1.5 g/day of oral mesalamine (68% at 2 years) (59). A second study demonstrated equal maintenance efficacy for a 4 g 5-ASA enema given the first 7 days of every month when compared to 2 g of oral sulfasalazine daily (60). Another study assessed the efficacy of oral sulfasalazine in maintaining remission in patients who had achieved remission with topical 5-ASA agents (61). In this study oral sul fasalazine 2 g/day was found to be equally effective as biweekly 4 g 5-ASA enemas in preventing relapse at 6 months in patients who had initially been treated with 5-ASA rectal enemas. Although it is common clinical practice to convert from rectal to oral maintenance medication because of compliance issues, this is the first controlled study supporting this practice. A recent open-label trial supports the efficacy of combination daily therapy, oral 1.6 g 5-ASA with biweekly 4 g 5-ASA enemas as maintenance in ulcerative colitis (62). Topical and Oral 4-Aminosalicylates (PAS) 4-Aminosalicylic acid has been used for many years as an antituberculous medication. Its safety profile and its relatively low cost make it an attractive alternative for treating ulcerative colitis. There are several placebo-controlled trials supporting its efficacy as a retention enema in proctosigmoiditis (63,–65). When compared to other topical agents, including 5-ASA enemas (66), sulfasalazine enemas (67), and prednisolone enemas (68), it has similar efficacy. Doses in all these studies were 1-2 g/day of 4-ASA enema. There are no trials assessing the use of topical 4-ASA as a maintenance agent. In a 12-week placebo-controlled trial, 4 g oral 4-ASA induced clinical and sigmoidoscopic improvement in patients with refractory ulcerative colitis. However, in this study, oral 4-ASA was less effective and slower to act in patients with distal ulcerative colitis (69). Corticosteroids Topical Steroids Topical corticosteroids for proctosigmoiditis were introduced in the late 1950s by Truelove (70) and Watkinson (71). These authors demonstrated the efficacy of 100 mg of hydrocortisone hemisuccinate enemas in placebo-controlled trials. Subsequently, preparations of hydrocortisone foams were compared to standard liquid enemas. Although hydrocortisone enema seems to migrate more proximally than hydrocortisone foam (72,73), both of these formulations are equally effective in treating active ulcerative proctosigmoiditis (74). Patients seem to prefer and better tolerate the foam formulation. An early open label study supported the beneficial use of hemisuccinate hydrocortisone or prednisolone suppositories in the treatment of ulcerative proctitis (75). A subsequent placebo-controlled trial demonstrated a 75% therapeutic response to prednisolone phosphate suppositories in patients with disease confined to the distal 25 cm (76). Because of the potential of systemic absorption and side effects associated with long-term steroid usage, new topical steroid preparations were devised that had lower systemic bioavailability. Tixocortol pivalate, a derivative of hydrocortisone, has anti-inflammatory properties with minimal adrenal suppression presumably due to its high “first pass’ metabolism in the liver. In an open label trial tixocortol rectal suspensions given for 2-4 weeks induced marked clinical and endoscopic improvement in patients with refractory proctosigmoidal colitis (77). One study suggested that tixocortol rectal instillations were superior and quicker acting than standard hydrocortisone enemas (78). A 3-week clinical trial compared 250 mg tixocortol pivalate enemas to 100 mg hydrocortisone enemas in patients with active left-sided ulcerative colitis and demonstrated similar efficacy with little glucocorticoid or mineralocorticoid effects (79). Beclomethasone dipropionate (BDP) is another steroid with rapid first pass liver metabolism. Topical BDP in small open trials was found to be as effective as betamethasone (80,81) and prednisolone enemas (82) for distal ulcerative colitis with less adrenal suppression. However, another study found 1 mg BDP enemas to be less efficacious than 30 mg prednisolone enemas (83). Beclomethasone dipropionate (BDP) 3 mg enemas alone also have been compared to the combination of BDP enemas and 1 g 5-ASA enemas in a 4-week clinical trial (84). This study demonstrated superior efficacy of the combination therapy over the single agent treatment. Prednisolone metasulfobenzoate (PMSB), a poorly absorbed steroid, also has been assessed in preliminary clinical trials. These studies report that PMSB when given in 20 mg enema form has low systemic absorption and may be as effective as prednisolone phosphate enemas (85,86) and superior to 7.5 mg of oral prednisolone (87). Recently, budesonide, a potent anti-inflammatory steroid without endocrine side effects, has been assessed as topical therapy in the treatment of distal ulcerative colitis. Budesonide enemas have been shown to be superior to placebo in attaining remission in distal ulcerative colitis (88). In addition, an early study demonstrated the superiority of nightly budesonide enemas (2 mg/100 ml) over nightly prednisolone enemas (31.25 mg/100 ml) (89). A subsequent study, however, showed equal efficacy of both rectal steroid preparations (90). Budesonide enemas (2 mg/100 ml) have also been shown to be as efficacious as hydrocortisone foam (125 mg/100 ml) (91). The only dose ranging study found 2 and 4 mg/100 ml budesonide rectal suspensions to be of equal therapeutic value (92). All clinical trials have demonstrated significantly less adrenal suppression with budesonide when compared to other steroid formulations. Topical budesonide (2 mg/100 ml) also has been compared to and found to be as effective as 4 g 5-ASA enemas in patients with active proctitis and proctosigmoiditis (93). There are no data on the use of topical corticosteroids in maintenance of remission of distal ulcerative colitis or proctitis. Oral Steroids The landmark study by Truelove and Witt introduced the use of oral cortisone in the treatment of active ulcerative colitis of varying severity (94). In this study oral cortisone 100 mg/day was compared to placebo. The clinical response was 71% for the steroid group versus 41% for the controls. A subsequent placebo-controlled study supported the use of prednisone 40-60 mg per day in the treatment of active ulcerative colitis (95). Although those studies included patients with left-sided colitis and proctosigmoiditis, no specific data are given on the therapeutic response of patients with proctosigmoiditis. Two placebo-controlled trials do not support the use of oral steroids for long-term maintenance therapy (96,97). In one of these studies extent of disease was defined radiologically, and there was a suggestion that steroids were ineffective in maintaining remission at 6 months in most patients, including those with proctosigmoiditis (97). Oral fluticasone, a steroid with decreased systemic absorption, was found to be ineffective at a dose of 20 mg/day in active distal ulcerative colitis (98). ACTH ACTH has been used parenterally in severe ulcerative colitis. There is some anecdotal experience suggesting that ACTH may be more effective and easier to withdraw than prednisone in the treatment of outpatient moderate proctosigmoiditis. (D. Present, personal communication). Patients who have not been on prednisone within the last month are given initially 40 U ACTH gel IM/day tapered over a 4-5-week period. Compliance may be a limiting factor in the use of this agent. Immunomodulators Azathioprine and 6-Mercaptopurine The immunomodulators have emerged as potent agents in the treatment of resistant inflammatory bowel disease. Although patients with distal ulcerative colitis may have been included, none of the published clinical trials on immunomodulators assess specifically the therapeutic response of patients with proctosigmoiditis. Ironically, it seems that the most suitable role for these agents is in those individuals with proctosigmoiditis, particularly when they are refractory to standard therapy. These are the patients in whom it is often difficult to justify total colectomy for disease that is limited in extent. Despite the lack of studies assessing the role of immunomodulators in distal colitis, the weight of the evidence supports their efficacy in chronic active ulcerative colitis independent of disease extent. Azathioprine and its metabolite 6-mercaptopurine (6-MP) are the immunomodulators that have been best studied in ulcerative colitis. There are no trials comparing these agents to each other. Early trials demonstrated no added benefit of one month of azathioprine to steroids (99) and equal efficacy of azathioprine to sulfasalazine (100). These studies were flawed by the short duration of treatment. Subsequent controlled trials demonstrated the efficacy of azathioprine 1.5-2.5 mg/kg in steroid refractory and steroid-dependent ulcerative colitis. (100,–103). Data for 6-MP in ulcerative colitis are uncontrolled, but there is no reason to believe that this medication is less effective than azathioprine. One retrospective analysis supports the benefit of 6-MP in symptomatic patients refractory to corticosteroids (104). A second retrospective study supports its efficacy as a steroid sparing agent in proctosigmoiditis (105). The experience with methotrexate is more limited. Two open-labeled trials demonstrated clinical improvement but not complete remission in refractory cases (106,107) of UC. These trials did not separate the patients with proctosigmoiditis from those with extensive disease. A retrospective review assessing long-term benefit of methotrexate reported that only 40% (12/30) of patients with UC patients who initially improved and remained on methotrexate sustained this response for a mean follow-up time of 59 weeks (108). Although these data suggests poor long-term response to methotrexate, it does not address the specific response of patients with distal ulcerative colitis. Several preliminary open-labeled reports assessing the efficacy of topical cyclosporine for distal and left-sided colitis were encouraging (109,–112). However, a more recent placebo-controlled trial did not demonstrate efficacy of nightly 350 mg cyclosporine enemas in treating mild to moderate left-sided colitis (113). To date, the major indication for cyclosporine use in ulcerative colitis is its parenter al administration in hospitalized patients with fulminant colitis not responsive to conventional medical therapy. Antibiotics Unlike Crohn's disease there is little evidence supporting the use of antibiotics as primary therapy in active ulcerative colitis. Furthermore, there are virtually no data on their therapeutic use in patients specifically with proctitis or proctosigmoiditis. One placebo-controlled trial that attempted to assess the efficacy of metronidazole suppositories in chronic proctitis found this antibiotic to be ineffective (114). In another study, oral metronidazole was compared to sulfasalazine in mild to moderate ulcerative colitis and was found to be of no efficacy (115). No data on the therapeutic response of patients with disease confined to the distal colon were given. One trial did show the short-term benefit of oral tobramycin in acute ulcerative colitis (116), but once again we are not told about the fate of patients with ulcerative proctitis or proctosigmoiditis. Recently, ciprofloxacin 1-1.5 g/day has been shown to be helpful as an adjunct to standard therapy in patients with ulcerative colitis, including those with steroid resistent UC, but no information is given on the extent of disease in these individuals (117). There are two trials assessing the role of antibiotics in maintaining remission in ulcerative colitis. In one study metronidazole 0.6 g/day was as effective as sulfasalazine 2 g/day in maintaining remission (188). However, most of the patients relapsing in the group on metronidazole had disease confined to the distal 20 cm of colon (seven of nine relapses in the metronidazole group), suggesting metronidazole may not be effective in this particular situation. Another study reported that oral tobramycin was not effective as a remitting agent (119). Although there are few reports suggesting the usefulness of antibiotics in active ulcerative colitis, their potential for exacerbating inflammatory bowel disease (120) or precipitating C. difficile infection warrants caution in their use in this disorder. Miscellaneous Short Chain Fatty Acids Short chain fatty acids (SCFA) produced from bacterial fermentation of carbohydrates are an important nutrient for the colonic epithelium. Colitis in a rectal stump after a proximal colonic diversion is thought to result from short chain fatty acid deficiency and responds to topical therapy with these compounds (121). The possibility that SCFA deficiency may have a role in the pathogenesis of ulcerative colitis has led to their use in therapeutic trials. An open trial supported the efficacy of a mixture of SCFAs in ulcerative colitis (122). Another open study suggested their benefit in refractory distal ulcerative colitis (123). When compared to nightly 100 mg hydrocortisone enemas and to nightly 4 g 5-ASA enemas, 40 mmol butyrate enemas were found to be equally effective with the added advantage of significant cost savings (124). A small placebo-controlled crossover study (10 patients) suggested that 100 mmol bid SCFA enemas were more effective than placebo in patients unresponsive or intolerant to standard therapy (125). Although the aforementioned studies were encouraging, a recent, as yet unpublished, placebo-controlled trial showed that nightly 60 ml butyrate enemas were not superior to placebo in treating left-sided ulcerative colitis (126). 5-Lipoxygenase Pathway Inhibitors Eicosapentanoic acid (EPA) is an omega-3-fatty acid found in fish oil. It inhibits the synthesis of leukotrienes, which are felt to have a role in the inflammatory response. One open-labeled (127) and two placebo-controlled trials support its role as an adjunct to standard therapy in active ulcerative colitis (128,129). In particular, one of these studies showed a decrease in disease activity index and an ability to lower the steroid dose much better than placebo (129). One placebo-controlled trial reported improvement in histology and reduction in rectal dialysate leukotrienes; however, and of greater importance to clinicians, this study did not show any superiority over placebo when assessing clinical response (130). None of the above studies address the specific issue of fish oil therapy in distal ulcerative colitis. There is no role for fish oil as long-term maintenance treatment (131). Zileuton, another 5-lipoxygenase inhibitor, has been assessed as possible therapy in ulcerative colitis. An initial open trial suggested a benefit of this agent in active ulcerative colitis (132). A placebo-controlled trial showed zileuton 800 mg bid to be superior to placebo in improving symptomatic and histologic scores but not sigmoidoscopic parameters (133). A recent study found zileuton 600 mg qid for 8 weeks superior to placebo (134). However, a parallel unpublished study showed no efficacy of zileuton. On this basis the pharmaceutical industry has abandoned any further studies of this particular agent in IBD. There is one study that found zileuton 600 mg qid to be better than placebo but less effective than 1.6 g 5-ASA/day in maintaining 6 month remissions (135). None of the zileuton studies assess its use in colitis limited to the distal colon. Bismuth The therapeutic effect of bismuth compounds may be related to their toxic effects on bacteria (136). An initial open-labeled 8-week trial supported the efficacy of bismuth subsalicylate enemas (700- 800 mg bid) in patients with ulcerative colitis refractory to conventional therapy including oral steroids (137). Another open trial also suggested efficacy of bismuth compounds in active proctitis and proctosigmoiditis (138). Recently, in a 4-week trial bismuth citrate rectal suspensions (450 mg) were compared to single 2 g 5-ASA enemas in the treatment of active distal ulcerative colitis (139). Bismuth appeared to be as effective in inducing clinical remission (12/31 patients) as 5-ASA enemas (18/32 patients). Sodium Cromoglycate Sodium cromoglycate is a mast cell inhibitor that has also been studied in ulcerative colitis. Initial trials found the oral form to be ineffective (140,141). Given in low (160 mg/day) or higher doses (2 g/day), it was clearly inferior to sulfasalazine (141). Furthermore, when given to patients resistant to conventional sulfasalazine or steroid enemas, it offered no additional benefit (140). These studies did not offer any data on patients with proctitis and proctosigmoiditis. One crossover therapeutic study did suggest the benefit of combination oral and topical disodium cromoglycate in the treatment of chronic proctitis (142). Cromoglycate 600 mg enemas were not found to be superior to placebo in another clinical trial (143). One controlled trial comparing high dosages of topical cromoglycate (600 mg/enema) to prednisolone enemas did find this compound to be safe and beneficial in patients with distal ulcerative colitis, although the improvement in rectal bleeding was less than that seen with prednisolone (144). Sucralfate Sucralfate is a mucopolysaccharide with cytoprotective properties used in peptic ulcer disease. An initial small open clinical trial in distal colitis suggested its efficacy (145). However, subsequent controlled trials found sucralfate rectal suspensions to be equal to placebo (146) and inferior to 5-ASA (146) and prednisolone metasulfobenzoate enemas (147) in the treatment of active proctosigmoiditis. Lidocaine Lidocaine, a local anesthetic that may inhibit neuroimmune interactions, has been suggested as possible therapy in ulcerative colitis. An open clinical assessment suggested symptomatic benefit with the nightly topical administration of 800 mg lidocaine gel in patients with proctitis, distal left-sided and universal colitis (148). Other Agents Several newer therapies may have a potential role in the treatment of ulcerative colitis. Studies assessing these possible novel therapies unfortunately do not specifically address the response in proctosigmoiditis or proctitis. In preliminary studies, intravenous immunoglobulins have induced clinical and colonoscopic improvement in patients with refractory ulcerative colitis (149,150). However, when immunoglobulin G enemas were used in a small open trial in patients with active distal ulcerative colitis, they did not seem to be beneficial (151). Anti-CD4 monoclonal antibodies are another potential new therapy in ulcerative colitis (152,153). In an open trial heparin seemed to be effective in a small group of patients who were refractory to conventional therapy (154). A recent placebo-controlled trial supported the efficacy of transdermal nicotine in the treatment of ulcerative colitis (155). Nicotine may be effective in colitis by acting on the colonic surface mucus or on mucosal eicasonoids (156). An open study suggested clinical improvement with the oxygen-derived free radical scavengers allopurinol and dimethyl sulfoxide (157). Ridogrel, a thromboxane synthetase inhibitor, was evaluated in a pilot study and seemed to be beneficial in patients with active UC (158). Finally, hydroxychloroquine, an antimalarial agent, also showed promise in the therapy of ulcerative colitis in an open trial (159). Although a subsequent 6-week controlled study found 400 mg/day of hydroxychloroquine to be comparable to placebo (160), further studies assessing higher dosages and longer treatment periods are necessary to support or disprove the efficacy of this agent. Recommended Therapeutic Approach to Proctitis and Proctosigmoiditis Active Disease Proctitis and proctosigmoiditis can present with urgency bloody mucousy diarrhea and tenesmus. In addition, proctitis may present with constipation. Topical agents are our first line of therapy in mild to moderate distal colitis. For proctitis, hydrocortisone foam or 500 mg 5-ASA suppositories bid can be initiated. For proctosigmoiditis, a nightly 100 mg hydrocortisone enema or 4 g 5-ASA enema is an effective means of therapy. Most often we prefer beginning treatment with the 5-ASA topical compounds because these have proven efficacy in both active and remitted proctitis and proctosigmoiditis. In the patient with distal colitis who remains symptomatic after 2-3 weeks of enema therapy, one can increase the 5-ASA rectal suspensions to a bid dosage or one can add a morning hydrocortisone enema to the nightly 5-ASA one. Similarly, persistent proctitis may respond to an increase of 5-ASA suppositories to a tid regimen or to prescribing a daily combination of hydrocortisone and 5-ASA suppositories. An acceptable alternative practiced by many gastroenterologists but that has not been as efficacious in our experience is initiating treatment with the oral 5-aminosalicylates. We favor utilizing the oral agents in combination with topical compound in patients who have initially failed to respond to the latter. Oral agents become the treatment of choice in patients who do not want or cannot tolerate rectal suspensions because of anal discomfort or irritation. Oral therapy can be initiated with sulfasalazine 1 g/day, mesalamine 1-1.2 g/day, and olsalazine 500 mg/day, and if tolerated these medications can be increased every 2-3 days until a therapeutic response is obtained or until maximal recommended dosages are reached. Maximal dosages are 4-6 g/day for sulfasalazine, 4.8 g/day for mesalamine, and 3 g/day for olsalazine. One common error in the management of patients with ulcerative colitis is accepting a therapeutic failure without having increased the 5-ASA agents to their maximal tolerated dosages. At these higher levels dose-related side effects such as headaches and nausea are seen more commonly with sulfasalazine. Because of the remote possibility of nephrotoxicity secondary to the new oral 5-ASA agents a periodic urine analysis, serum BUN and creatinine should be ordered when patients are taking high dosages of these agents. In the patient with ulcerative proctitis and proctosigmoiditis who remains symptomatic despite maximal oral 5-ASA and topical 5-ASA/corticosteroid therapy and who has no constitutional symptoms, there remain few options prior to considering oral corticosteroids. These include the use of fish oil or the quinolone antibiotic ciprofloxacin. Fish oil can be added to the regimen as MAXEPA capsules at a dose of 15-18 capsules per day. The large number of tablets to be ingested may decrease compliance. Some patients may also complain of a fish odor in their breath. Ciprofloxacin at a dose of 1-1.5 g/day may also prove to be beneficial. Fish oil and ciprofloxacin are usually used as adjunctive therapy and should not be utilized as sole therapy for distal ulcerative colitis. Oral corticosteroids are reserved for the nontoxic patient who presents with some constitutional symptoms or those who remain symptomatic despite maximizing the therapies discussed above. In general, we will treat a patient with a dose of prednisone that has successfully controlled a previous exacerbation. Otherwise we tend to be aggressive initially with higher dosages of prednisone such as 60 mg/day. We usually prescribe this dose for 10 days and gradually begin to taper the steroid with the goal of complete withdrawal of steroid treatment within 8-12 weeks. Disease Refractory to Conventional Therapy The patients who do not attain clinical remission with oral steroids may benefit from a hospital admission and parenteral corticosteroid therapy. Although intravenous steroid treatment may induce clinical remission in refractory patients, these individuals when discharged from hospital will still be faced with the problem of remaining on steroids. The alternatives for the patient who remains symptomatic despite oral steroids (steroid refractory) or who cannot be weaned off the prednisone (steroid dependent) are surgery or the immunomodulators. The major advantage of surgery is that it is curative and the new ileo-anal pouch operation precludes the need for a permanent ileostomy. However, we tend to favor therapy with the immunosuppressants in such patients prior to considering the surgical option. Patients with medically resistant ulcerative proctitis or proctosigmoiditis are probably the most suitable candidates for immunomodulator treatment because it is often difficult to justify total colectomy in individuals who have disease confined to a limited portion of the colon and who often have mild albeit troubling symptoms. Immunomodulator therapy can be initiated with azathioprine or its metabolite, 6-mercaptopurine (6-MP). Although higher dosages of azathioprine are theoretically required because of its different molecular weight and because it is only partially metabolized to 6-MP, in clinical practice we use these agents interchangeably and their ultimate dose will be based on patient clinical response and their effects on blood counts (i.e., leukopenia). We begin therapy with 50 mg po per day. Given that these medications can take up to 3-6 months to exert their maximal therapeutic effect, patients are initially maintained on prednisone and care is taken not to reduce the steroid dose too quickly in order to avoid precipitating a flare-up. The immunomodulators can be gradually increased as needed to a maximal dose of 2 mg/kg/day for 6-MP or 2.5 mg/kg/day for azathioprine. Blood counts, to detect hematologic toxicity, are monitored regularly with a greater frequency at the initiation of treatment. We usually attempt to taper and discontinue the immunomodulators after two years of clinical remission on these agents. Interestingly, a recent trial suggested that patients with Crohn's disease who remained in remission on 6-MP or azathioprine for >4 years had a more reduced risk of disease relapse than those who stopped the medication earlier (161). Whether this is applicable to patients with ulcerative colitis remains to be determined. What are the options for patients with distal ulcerative colitis who do not improve or who remain on high dosages of corticosteroids after 6 months of azathioprine or 6-MP? For most patients who reach this point surgery becomes a major consideration. However, for the individual who is firmly opposed to surgery and wants to avoid colectomy or for the patient who is not a surgical candidate, methotrexate is an alternative. This antiinflammatory agent can be administered orally or by the intramuscular route. Oral methotrexate can be initiated at a dose of 2.5 mg per week and increased in weekly 2.5 mg increments until a maximal weekly oral dose of 15 mg is reached. If the parenteral route is chosen methotrexate can be administered in weekly dosages of 25 mg IM. Although the duration of therapy and chronic dosage regimen for the use of methotrexate remain somewhat in question, we attempt to reduce and discontinue this agent in responders within one year. This is to avoid complications such as hepatotoxicity associated with long-term usage. A liver biopsy should be considered in individuals who remain on the medication for prolonged periods of time and have had a cumulative dose of 1-1.5 g. Maintenance of Remission Once clinical remission is attained with topical 5-ASA or topical steroids or oral 5-ASA agents, consideration must be given to long-term maintenance therapy. We feel that maintenance treatment should be reserved for patients with proctitis and proctosigmoiditis who have had an early recurrence of their disease or who have had an initial attack characterized by a protracted clinical course. We do not advocate long-term therapy in patients who have had a single episode of distal colitis that has responded promptly to standard therapy. In our experience, these individuals often may remain asymptomatic for long periods of time and if they do relapse they usually respond promptly to conventional treatment. If the decision to place a patient on remission therapy has been made, then the 5-ASA enemas/suppositories are gradually tapered and can be given every second or every third night. Alternatively, therapy with sulfasalazine, olsalazine, or oral mesalamine may be initiated or continued at doses discussed above. 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TI - Medical Therapy of Ulcerative Proctitis and Proctosigmoiditis, Including Refractory Disease
JO - Inflammatory Bowel Diseases
DO - 10.1097/00054725-199509000-00007
DA - 1995-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/medical-therapy-of-ulcerative-proctitis-and-proctosigmoiditis-XSn5Al0iir
SP - 207
EP - 219
VL - 1
IS - 3
DP - DeepDyve
ER -