Efficacy, Safety and Tolerability of Rectal Therapies in Ulcerative Proctitis and Ulcerative Proctosigmoiditis A Special Supplement

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Ulcerative colitis (UC) is a chronic condition in which inflammation extends proximally from the rectum along the colonic mucosa. Most patients experience alternating periods of active disease and clinical remission. In patients with ulcerative proctitis or ulcerative proctosigmoiditis, inflammation is limited to the rectum, or rectum and sigmoid colon, respectively. Induction of clinical remission is the primary goal of treatment for patients with active UC, whereas maintenance therapy is recommended for patients with UC in remission.

Ulcerative colitis (UC) is a heterogeneous disease that varies in the extent of affected colon and the severity of symptoms. Studies have suggested that at the time of diagnosis, approximately 46% of patients have inflammation limited to the rectum (ulcerative proctitis) or limited to the rectum and the sigmoid colon (ulcerative proctosigmoiditis). For distal forms of UC, a number of treatment options are available, including rectal and oral formulations. Rectal therapies (i.e., suppositories, foams, enemas) may be recommended for the management of patients with distal forms of UC, either as monotherapy, or in combination with oral therapies. First-line treatment for patients with distal UC is often 5-aminosalicylic acid rectal therapies, and is supported by a history of safety and efficacy in this patient population. However, second-generation corticosteroid (i.e., budesonide, beclomethasone dipropionate) rectal therapies have also been developed to treat active distal forms of UC. Despite the demonstrated safety and efficacy of rectal therapies for the induction and maintenance of remission of UC, rectally administered agents are widely underused and associated with nonadherence to treatment. However, decreased dosing frequency and the introduction of formulations of rectal agents that improve retention may increase use of rectal therapies and help to overcome barriers associated with nonadherence. Data support the use of rectal therapies for the induction and maintenance of remission of distal forms of UC.

Elisa McEachern, BS and Brian P. Bosworth, MD; Jill Roberts Center for Inflammatory Bowel Disease, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY. Elisa McEachern reports no conflicts. Brian Bosworth has received research grants from Pfizer Inc., Salix Pharmaceuticals, Inc., and Takeda Pharmaceutical Company Limited. Acknowledgments: Technical editorial and medical writing assistance was provided under the direction of the authors by Sophie Bolick, PhD, Synchrony Medical Communications, LLC, West Chester, PA. Funding for this support was provided by Salix Pharmaceuticals, Inc., Raleigh, NC.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, characterized in most patients by alternating periods of active disease and clinical remission.1 Common clinical symptoms of active UC include diarrhea, rectal bleeding, urgency, abdominal pain, and tenesmus. In one study, diarrhea was the most common symptom observed in patients with active UC, affecting approximately 65% of patients, with abdominal pain reported in approximately 34% of patients.2 The majority of patients with active distal UC had rectal bleeding (i.e., 70% of patients with ulcerative proctitis [UP] vs. 33 to 37% of patients with more extensive disease). In another study, 96% of patients with active UC passed blood and mucus in their stool.3 Thus, management of symptoms of active UC, which may cause concern for patients, is one of the goals of treatment.4,5

The prevalence of UC has been estimated between 206 and 263 per 100,000 persons in the United States, thus UC affects approximately 600,000 individuals.6-8 While diagnosis of UC can occur anytime, age at diagnosis typically has a bimodal distribution, with the first peak observed during the 20s and 30s, and a second, smaller, peak occurring during the 60s and 70s.9 Although it is not clear whether differences in incidence based on sex are apparent, some studies have suggested that males have slightly greater incidence of UC versus females.9,10 In general, patients with UC have the potential for a relatively long and variable disease course, associated with a substantial economic burden. Overall total costs for UC were estimated to be $390 to $920 million in the United States (in 2010 US dollars), with mean annual direct expenditures (health insurance and patient out-of-pocket costs) estimated at $8700 per patient.11

Whereas the etiology of UC remains to be elucidated, both genetic and environmental factors are thought to play a role in the development of the disease. A number of susceptibility loci associated with genes involved in barrier function and inflammatory and immune responses have been implicated as potential genetic risk factors for UC.12-18 Further, environmental exposures (e.g., hormone therapy, smoking status) have been associated with both increased and decreased risk of UC.19-22

Ulcerative colitis is a heterogeneous disease that varies in severity (i.e., mild to fulminant) and extent of the colon affected.23 Inflammation typically extends proximally from the rectum along the colonic mucosa.1 At the time of diagnosis, approximately 46% of patients had inflammation limited to the rectum (UP) or to the rectum and the sigmoid colon (ulcerative proctosigmoiditis [UPS]).2,23,24 Disease extent is not static, as approximately 45% of patients with an initial diagnosis of UP or UPS progressed to left-sided colitis or pancolitis after 5 years,2 and approximately 20% and 54% of patients with an initial diagnosis of UP experienced proximal extension of disease after 5 and 10 years, respectively.25

Most patients begin an intermittent disease course after resolution of symptoms associated with an initial disease flare.26,27 Approximately 40 to 50% of patients with UC are in clinical remission at any given point in time, and 90% of patients experienced relapsing disease within 25 years of diagnosis.26 However, 83% of patients with UC experienced disease relapse within 10 years; 54, 71, and 57% of patients with UP relapsed within 1 year, between 1 and 5 years, or between 5 and 10 years after diagnosis, respectively.27 Treatment choice affects the disease course of patients with UC, both during active disease and during disease in remission.26

Rectal Therapies for Treatment of Ulcerative Colitis

For patients with UC, the goal of treatment is multifaceted and includes symptom resolution, mucosal healing, induction and maintenance of remission, improvement in quality of life, and prevention of infirmity, surgery, and hospitalization.1,4,28-32 Approaches to treatment depend on the extent and severity of disease, but the initial goal of treatment is induction of clinical remission.4,5 Mild to moderate active distal colitis is typically treated with oral 5-aminosalicylic acid (5-ASA), rectal 5-ASA or steroids, or a combination of oral and rectal therapies.4,5 Maintenance therapy is recommended for patients with UC in remission, to reduce the risk of symptomatic relapse.5 Rectal 5-ASA is recommended as first-line therapy for the maintenance of remission of UP, and recommended as an option for patients with left-sided colitis.5 Oral 5-ASAs are also effective at maintaining remission as monotherapy and in combination with rectal 5-ASA.5 Rectal therapies differ in their proximal distribution: suppositories are limited to the rectum,33,34 whereas foams and enemas have been shown to reach to the proximal sigmoid colon and splenic flexure, respectively.34-38 In patients with UP, suppositories may be the most effective method for targeting the rectum.5 For the sigmoid or descending colon, enema and foams may be considered, with the greatest distribution of drug in these locations occurring within 2 hours of administration of enema or foam in patients with UPS or left-sided colitis.35


Sulfasalazine, a combination of the antibiotic sulfapyridine with the anti-inflammatory salicylate, was developed in the 1930s as a potential treatment for rheumatoid arthritis.39 Whereas the efficacy of sulfasalazine in rheumatoid arthritis was limited, sulfasalazine was subsequently found to have efficacy in UC.40,41 Sulfasalazine was widely prescribed for the treatment of UC in subsequent decades, but its use was associated with some toxicity (e.g., nausea, vomiting, anorexia, headache).42 A seminal study by Azad Khan et al43 demonstrated that 5-ASA was the active moiety of sulfasalazine. Sulfasalazine is not well absorbed in the small intestine and passes through to the colon, where colonic bacteria cleave the diazo bond, releasing 5-ASA and sulfapyridine.44-47 Ingesting a pure 5-ASA moiety administered orally does not reach the colon intact,42,48 and thus oral 5-ASAs have been developed with pH- dependent and delayed-release mechanisms to facilitate colonic delivery of active drug.42-44 The advantage of these agents is a reduction in adverse effects compared with sulfasalazine.49,50 However, unmodified 5-ASA can be administered rectally; for distal forms of UC, this allows direct delivery to the site of inflamed mucosa, while minimizing systemic absorption.51

Overall, the safety and efficacy of rectal 5-ASA for the induction and maintenance of remission of distal UC have been well established.52,53 In randomized, double-blind, placebo-controlled studies, clinical and endoscopic remission were achieved by a greater percentage of patients with UP, UPS, left-sided UC, pancolitis, or distal UC receiving 5-ASA suppositories compared with placebo after 4 weeks (Table 1).54-68 In addition, a once-daily dosing regimen had comparable efficacy with 2- or 3-times daily dosing of 5-ASA suppositories after 6 weeks in patients with active UP.57-59 However, patients preferred once-daily administration compared with 3-times daily administration of suppository.57 Furthermore, a greater percentage of patients with UP, UPS, or left-sided UC maintained remission for at least 1 year, and up to 2 years, with 5-ASA suppositories.60-62

In randomized, double-blind studies, 5-ASA enemas had greater efficacy than placebo in patients with active UP, UPS, or distal UC after 6 weeks.63,64 Remission or improvement (clinical, endoscopic, or histologic) was achieved by a greater percentage of patients on 5-ASA enema therapy for 4 weeks compared with placebo.65 Patients receiving 5-ASA enemas demonstrated improvement in the physician’s global assessment score and a decrease from baseline in the mean disease activity index (DAI) score after 6 or 8 weeks.63,64,66 In a study of patients with mild to moderate active UP and UPS receiving either 5-ASA enema or foam for 4 weeks, the majority of patients achieved clinical remission, and there was no apparent difference in the efficacy of 5-ASA enema or foam.67 5-ASA enemas were also efficacious for the maintenance of remission for at least 46 weeks compared with placebo in a clinical study of patients with left-sided UC.68 Finally, in addition to demonstrated efficacy, 5-ASA suppositories and enemas had a favorable safety profile in a number of clinical studies.54,55,57-64,66-68


Truelove first described the efficacy of rectal corticosteroids (i.e., hydrocortisone) for the induction of remission of UC in 1956.69 In this study, 67% of patients with mild to moderate UC receiving hydrocortisone enemas nightly for up to 3 weeks achieved clinical remission, usually within days of initiating treatment. Corticosteroids are efficiently absorbed across the colonic mucosa, with an estimated 30 to 50% of administered hydrocortisone enema absorbed through the rectal mucosa.70,71 Thus, the potential for serious adverse effects (e.g., diminished adrenal function, hypothalamic-pituitary-adrenal [HPA] axis suppression, metabolic bone disease, ophthalmologic impairment, cushingoid features, metabolic issues) associated with long-term corticosteroid treatment must be considered.4,72 Second-generation rectal corticosteroid therapies, including budesonide and beclomethasone dipropionate (BDP), with high first-pass hepatic metabolism (∼90% for budesonide)73 and limited systemic toxicity,74 have since been developed.


Patients with active UP, UPS, left-sided UC, or distal UC achieved remission, and endoscopic and histologic improvement, following treatment with budesonide enema for 4, 6, or 8 weeks (Table 2).75-83 However, a greater percentage of patients treated with 5-ASA enema compared with budesonide enema achieved clinical remission after 4 and 8 weeks.77 A similar percentage of patients with active UP or UPS achieved clinical remission with budesonide foam and budesonide enema after 4 weeks.81 However, the majority of patients preferred the foam to enema (83.6 vs. 6.2%, respectively). A significantly greater percentage of patients receiving budesonide foam achieved remission, a Mayo rectal bleeding subscore of 0, and endoscopic improvement (Mayo endoscopy subscore ≤ 1) after 6 weeks compared with placebo.80 Further, a greater percentage of patients with distal UC or UP maintained remission with twice-weekly administration of budesonide enema compared with placebo for 6 months.76 However, it is unknown what effect increased frequency of dosing will have on the percentage of patients maintaining remission of UC. Once- or twice-daily administration of budesonide foam or enema 2 mg or 8 mg for 4, 6, or 8 weeks was safe and, notably, did not adversely affect the HPA axis in most patients with active distal UC.75,78-80,82,83 However, in one study, twice-daily dosing with rectally administered budesonide for 8 weeks significantly increased the incidence of impaired adrenal function compared with once-daily dosing.76 It should be noted that studies have not explored the safety profile of these agents beyond 1 year.

Several baseline factors associated with response to treatment with budesonide enemas or foams have been identified.80-82 Less severe disease at baseline was associated with improved response to treatment, as patients with mild disease (not defined) at baseline had significantly greater odds of achieving clinical remission after 8 weeks of treatment than patients with more severe disease (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.72-10.48).82 Further, a second study demonstrated that a greater percentage of patients with less severe disease at baseline (i.e., clinical activity index [CAI] ≤ 8) achieved clinical remission (defined as CAI ≤ 4) following treatment with budesonide foam or budesonide enema for 4 weeks compared with patients with more severe disease (i.e., CAI >8; foam, 59 vs. 49%, respectively; enema, 71 vs. 47%, respectively; OR, 1.4; 95% CI, 1.01-2).81 However, extent of disease (i.e., UP or UPS) and disease duration (i.e., ≤5 years or >5 years) had no significant association with achievement of clinical response with budesonide foam or budesonide enema after 4 weeks.81 Finally, a significantly greater percentage of patients receiving budesonide foam achieved remission (i.e., Mayo endoscopy subscore ≤1, rectal bleeding subscore = 0, and improvement or no change in stool frequency subscore) compared with placebo when subgroup analyses of baseline disease (i.e., moderate disease, established disease, and extent of disease [UP, UPS]) and demographic (i.e., age, sex, white race, and smoking history) characteristics were conducted.80

The absence of exposure to previous therapeutic modalities was also associated with improved response to either budesonide foam or hydrocortisone foam, as patients who had not previously received treatment with rectal 5-ASA had significantly greater odds of achieving clinical remission compared with patients with prior exposure to rectal 5-ASA (OR, 2.97; 95% CI, 1.05-8.37).82 However, a second study reported that a greater percentage of patients with previous response (not defined) to oral or rectal 5-ASA achieved clinical remission (CAI =4) after 4 weeks of treatment with budesonide foam compared with patients with no previous response to oral or rectal 5-ASA, although the findings were not significant.81 Lastly, a randomized, double-blind, placebo-controlled study of budesonide foam found that remission was achieved with budesonide foam versus placebo regardless of a previous (baseline) 5-ASA use.80

Beclomethasone Dipropionate

Rectal formulations of BDP are safe and efficacious for the induction of remission of active UP, UPS, or distal UC, with improvement or induction of remission following treatment with BDP enema comparable with that of 5-ASA enema after 4 to 6 weeks (Table 3).84-92 A comparable percentage of patients with active, distal UC receiving BDP enema or foam, or 5-ASA enema or foam, achieved remission or response at 4 or 8 weeks.86 In both studies, patients in all groups achieved significant improvement from baseline in the DAI (total and subscale) scores and endoscopy scores after 4, 6, or 8 weeks of treatment.84,86 The safety profiles of BDP and 5-ASA were favorable in patients with UP or UPS.84,86

Whereas BDP enema and 5-ASA enema induced clinical and endoscopic improvement in the majority of patients with UP, and histologic improvement in approximately half of patients, after 28 days, the combination of BDP and 5-ASA resulted in greater efficacy than monotherapy, with all patients experiencing clinical, endoscopic, and histologic improvement.87 The efficacy of BDP enema was examined in patients with UC in 3 randomized, double-blind studies.88-90 Mulder et al89 found no differences in clinical, endoscopic, or histologic improvement between groups receiving BDP or prednisolone after 4 weeks, while van der Heide et al88 demonstrated improvement from baseline only in endoscopic scores in patients receiving prednisolone enema after 4 weeks. Further, a similar percentage of patients receiving BDP and prednisolone enemas achieved clinical and endoscopic remission after 4 weeks.90 However, in these studies, the safety profile of BDP was more favorable than that of prednisolone, with significant decreases from baseline in mean basal cortisol concentrations occurring after treatment with prednisolone, but not BDP.88-90

Clinical remission, clinical response, and endoscopic improvement were achieved by a comparable percentage of patients receiving either BDP enema or betamethasone (BMT) enema in 2 randomized, double- blind studies of patients with active, distal UC after 20 to 28 days.91,92 However, BDP had a more favorable safety profile compared with BMT, with steroid-related adverse events and suppression of adrenal function occurring with greater frequency following treatment with BMT.

Rectal and Oral Combination Therapy

Patients with more extensive active UC may benefit from a combination of oral and rectal 5-ASA therapies, as opposed to monotherapy with an oral or rectal 5-ASA (Table 4).93-98 Rectal therapies target sites of inflammation typically affected by distal forms of UC,24,33,35 but D’Incà et al.93 found that mucosal concentrations of 5-ASA following the administration of both oral and rectal drugs were greater in the sigmoid colons of patients with UC compared with when oral 5-ASA had been administered alone. Thus, in patients who are refractory to rectal therapies alone, a combination of oral and rectal therapies may be warranted.4,5

The addition of 5-ASA enema to oral 5-ASA therapy significantly increased the rate of remission compared with oral 5-ASA therapy alone after 8 weeks in patients with extensive mild to moderate active UC.94,95 However, the percentage of patients with extensive mild to moderate active UC achieving clinical or endoscopic remission after treatment with a combination of 5-ASA enemas plus oral 5-ASA for 6 weeks was similar to that of patients receiving 5-ASA enemas alone.96 The majority of patients receiving either 5-ASA combination therapy or oral 5-ASA alone achieved mucosal healing after 4 weeks.95 Resolution of rectal bleeding within 7 days of study initiation occurred in a greater percentage of patients receiving combination 5-ASA therapy versus oral 5-ASA monotherapy.

The combination of oral 5-ASA therapy and 5-ASA enemas had greater efficacy than oral 5-ASA monotherapy in 2 randomized, controlled studies of patients with UC in remission for up to 1 year.97,98 A greater percentage of patients with UC maintained remission following treatment with a combination of oral 5-ASA therapy and weekend 5-ASA enema compared with oral 5-ASA alone.97 Similarly, the combination of oral 5-ASAs with twice-weekly 5-ASA enemas was more efficacious for the maintenance of remission of UC after 12 months compared with oral 5-ASA monotherapy.98 Further, the results of a case- control study of patients receiving the combination of oral 5-ASA 1.6 g/day with twice-weekly 5-ASA 2 g/50 mL enemas for a median treatment period of 6 years demonstrated that patients receiving combination therapy had a significantly lower incidence of relapse (1.59 vs. 2.76, respectively; p = 0.034) and fewer hospitalizations.99 The safety profile of combination oral and rectal therapies for the induction and maintenance of remission of UC was favorable.94,96-98

Limitations Associated with the Use of Rectal Therapy

Rectal 5-ASAs are efficacious both for the induction and maintenance of remission in patients with mild to moderate distal UC, and rectal corticosteroids have demonstrated efficacy for the induction of remission in patients with active, distal UC. However, rectal therapies for UC are currently underused. A European study noted that a comparable percentage of patients with UP received oral or rectal therapy (29.5 vs. 25.6%, respectively); however, a greater percentage of patients with UPS received oral versus rectal treatment (42.8 vs. 6.9%, respectively).100 The percentage of patients with UP and UPS receiving combination oral and rectal therapy was 13.2% and 17.4%, respectively. Further, during 1992-2009, the number of prescriptions for all 5-ASAs increased 72%, yet those for rectally administered 5-ASAs remained generally at the same level, with a decline in the overall 5-ASA market share from 11% to 9%.101 Oral 5-ASAs accounted for ∼70% of 5-ASA prescriptions in 2009. Patients with UC, prescribed rectal therapies at time of diagnosis, have a high rate of discontinuation of therapy, often as soon as 1 month. Data from a US health insurance database demonstrated that patients with newly diagnosed UC, or UP and UPS were commonly prescribed oral 5-ASA (53%) or 5-ASA suppositories (42%), respectively.102 Within 1 month, approximately 40% of patients with UC discontinued treatment with oral 5-ASAs, and approximately 70% of patients with UP and UPS discontinued treatment with rectal therapy.

Underuse of rectal therapy may be related to a combination of patient preference for oral therapy and potential inconvenience and technical issues with administration of rectal agents.103,104 An important aspect of any treatment is patient adherence.101

Adherence to any treatment is particularly challenging during periods of remission in patients with UC, as demonstrated by prescription refill data that estimated that only approximately 40% of patients with UC were adherent to oral 5-ASAs.105 Other factors associated with a greater likelihood of nonadherence to treatment among patients with UC included less extensive disease and receiving >4 concomitant therapies (OR, 2.5; 95% CI, 1.4-5.7). Patients with UC receiving rectal therapy reported difficulty with use during work hours (OR, 4.4; 95% CI, 1.5-12.5; p = 0.003), pain and bloating (OR, 2.8; 95% CI, 1.20-6.54; p = 0.013), and difficulty with use (OR, 2.4; 95% CI, 1.00-5.73; p = 0.043) as reasons for nonadherence. Additional issues were associated with the use of rectal therapy, including retention of the medication (i.e., duration, position), leakage, and stained clothing with enemas,106 and difficulty with administration and with anal or rectal pain that occur in some patients using suppositories.61

Nonadherence to treatment has implications for the course of a patient’s disease, significantly increasing the risk of relapse compared with patients who are adherent to treatment (relative risk [RR], 1.4; 95% CI, 1.08-1.94; p = 0.014). Patient nonadherence to enemas was signif.icantly higher compared with oral therapies (68% vs. 40%, respectively; p = 0.001).107 However, in a clinical trial comparing enemas and foams, the majority of patients receiving enemas and foams reported no retention problems, unpleasant feeling, rectal or abdominal pain, or flatulence.81 Thus, although the issue of adherence to therapy is complex, providing patients with treatment options that include less frequent dosing and simplified administration may improve adherence and, ultimately, lead to more favorable outcomes for patients.104

Adherence is an ongoing issue in the overall management of UC.105,108,109 Common issues associated with nonadherence to treatment in patients with UC may be overcome by allowing for more flexible dosing regimens (i.e., weekend dosing) and addressing problems with insertion and retention with different formulations of rectal therapies. Rectal therapies (i.e., budesonide foam) have shown favorable safety profiles in clinical trials and are preferred by patients to enemas.81,83 These therapies have the potential to provide additional safe and efficacious options for healthcare providers treating UC. The most effective way to preserve adherence is to forge a therapeutic bond with the patient and discuss the duration of therapy. Additionally, seeing patients at least every 6 months may improve adherence to both oral and rectal treatment regimens.

In conclusion, this review of published data of rectal therapies, including 5-ASAs and corticosteroids, supports that these agents are well tolerated, safe, and efficacious for the induction and maintenance of remission of distal forms of UC. Furthermore, combination oral and rectal therapy is also well tolerated and efficacious for the induction of remission in patients with mild to moderate extensive UC compared with oral therapy alone, and should be considered in appropriate patient populations. Rectal therapies are an underused, yet valuable part of the management paradigm for patients with distal forms of UC. They may be appropriate as monotherapy or in combination with oral therapy for the induction or maintenance of remission of mild to moderate UC, depending on disease extent and patient considerations.

Funded by an unrestricted educational grant from Salix, a Division of Valeant Pharmaceuticals North America LLC.

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