Topical Therapy in Ulcerative Colitis: Always a Bridesmaid but Never a Bride?

Abstract

See “Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis,” by Sandborn WJ, Bosworth B, Zakko S, et al, on page 740. See “Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis,” by Sandborn WJ, Bosworth B, Zakko S, et al, on page 740. Proctitis, proctosigmoiditis, and left-sided ulcerative colitis define the anatomic extent in 70% of patients at inception in the population-based IBSEN (Inflammatory Bowel South-Eastern Norway) cohort from Scandinavia.1Solberg I.C. Lygren I. Jahnsen J. et al.Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN study).Scand J Gastroenterology. 2009; 44: 431-440Crossref PubMed Scopus (519) Google Scholar Despite rather limited affected area of the colon, these patients suffer from significant morbidity and poor quality of life, because active distal disease elicits symptoms such as urgency, tenesmus, blood loss per anum, and a feeling of incomplete evacuation. Limited extent of disease makes topical anti-inflammatory therapy appealing owing to safety and efficacy. Newer preparations of effective topical therapy that are relatively small in volume and well-tolerated may increase options for treatment of such patients. In addition, topical mesalamine combined with oral mesalamine may also provide additional benefits in terms of efficacy in more extensive ulcerative colitis, as well as in more limited disease.2Probert C.S.J. Dignass A.U. Lindgren S. et al.Combined oral and rectal mesalazine for the treatment of mild-to-moderately active ulcerative colitis: rapid symptom resolution and improvements in quality of life.J Crohn’s Colitis. 2014; 8: 200-207Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 3Safdi M. Demicco M. Sninsky C. et al.A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis.Am J Gastroenterol. 1997; 92: 1867-1871PubMed Google Scholar, 4Marteau P. Probert C.S. Lindgren S. et al.Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study.Gut. 2005; 54: 960-965Crossref PubMed Scopus (278) Google Scholar Mesalamine and corticosteroid preparations are available as topical therapy. Suppositories, foam, gel, and liquid enemas are preparations used for proctitis, proctosigmoiditis, and left-sided colitis, tailoring the therapy to extent of disease, tolerability, and patient preference. Suppositories are best used for proctitis, whereas foam enema, rectal gel, and liquid enema are used for proctosigmoiditis and left-sided colitis. The formulations have different physicochemical characteristics and different extent of spread shown by scintigraphic studies, but scintigraphic studies can sometimes be challenging to interpret, difficult to conduct in patients with inflammation, and very few research centers have the experience to conduct scintigraphic studies.5William C.N. Haber G. Aquino J.A. Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active proctitis and measurement of extent of spread using 99m-Tc labelled 5-ASA suppositories.Dig Dis Sci. 1987; 72: 71S-75SCrossref Scopus (96) Google Scholar Mesalamine suppositories can reach rectum and even distal sigmoid; foams, gels, and liquid enemas can be used to treat proctosigmoiditis and left-sided colitis. Foams and gels are well-retained and tolerated by patients and may provide a homogeneous coating of the mucosa. However, the volume of the topical therapy influences the extent of proximal spread and possible tolerability of the treatment. Larger volumes may reach more proximal colonic areas, but are also more likely not to be well-tolerated when acute inflammation reduces rectal compliance. Individuals may vary in their tolerance not simply based on the formulation and volume, but also the nature and ease of use of the delivery device and the shape of the nozzle. In addition, rare hypersensitivity reactions to topical mesalamine have been reported and these patients are appropriate for topical steroids.6Regueiro J.R. Loftus E.V. Steinhart A.H. et al.Medical management of left-sided ulcerative colitis and ulcerative proctitis: critical evaluation of therapeutic trials.Inflamm Bowel Dis. 2006; 12: 979-994Crossref PubMed Scopus (98) Google Scholar Some of the predominant symptoms of proctitis, such as urgency, tenesmus, and a feeling of incomplete evacuation, are not formally recorded and scored as part of clinical disease activity indices such as the Mayo score or the evolving Patient-Reported Outcome tools.7Kappelman M.D. Long M.D. Martin C. et al.Evaluation of the patient-reported outcomes measurement information system in a large cohort of patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2014; 12: 1315-1323Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 8Williet N. Sandborn W.J. Peyrin-Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease.Clin Gastroenterol Hepatol. 2014; 12: 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Patients with proctitis may have frequent bloody bowel movements, but not ‘true’ diarrhea. Many systemic therapy trials in ulcerative colitis exclude topical therapies and the effect of topical therapies on bowel frequency and consistency has not been studied rigorously. Rectal bleeding and endoscopic appearance seem to best reflect severity of proctitis and therapeutic response to topical therapies, but other patient reported parameters associated with proctitis need to be explored and incorporated into patient reported outcome tools specifically for proctitis. In a large Swiss Inflammatory Bowel Disease Cohort Study, it was clear that topical therapy is underused even in patients where the disease extent would make such therapy the optimal choice.9Siebold F. Fournier N. Beglinger C. et al.Topical therapy is underused in patients with ulcerative colitis.J Crohns Colitis. 2014; 8: 56-63Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Other studies have also expressed concern over the underuse of rectal therapies, even in distal ulcerative colitis.10Reddy S.I. Friedman S. Telford J.J. et al.Are patients with inflammatory bowel disease receiving optimum care?.Am J Gastroenterol. 2005; 100: 1357-1361Crossref PubMed Scopus (128) Google Scholar Physicians may anticipate poor acceptability of topical therapy in their patients, but the evidence supports good acceptance by >80% of patients in clinical studies such as the PINCE study.2Probert C.S.J. Dignass A.U. Lindgren S. et al.Combined oral and rectal mesalazine for the treatment of mild-to-moderately active ulcerative colitis: rapid symptom resolution and improvements in quality of life.J Crohn’s Colitis. 2014; 8: 200-207Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Topical therapy with mesalamine with or without oral mesalamine may lead to early cessation of rectal bleeding and possibly mucosal healing.2Probert C.S.J. Dignass A.U. Lindgren S. et al.Combined oral and rectal mesalazine for the treatment of mild-to-moderately active ulcerative colitis: rapid symptom resolution and improvements in quality of life.J Crohn’s Colitis. 2014; 8: 200-207Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Such topical therapy may continue to maintain remission once remission has been induced. In a previous double-blind, double-dummy, 4-week study, budesonide foam enema 2 mg/25 mL was compared with budesonide liquid enema 2 mg/100 mL in a noninferiority design study in patients with active ulcerative proctitis or proctosigmoiditis.11Gross V. Barr-Meir S. Lavy A. et al.Budesonide foam versus budesonide enema in active ulcerative proctitis and proctosigmoiditis.Aliment Pharmacol Ther. 2006; 23: 303-312Crossref PubMed Scopus (82) Google Scholar Of 541 patients, 449 were evaluable for per protocol analysis, and clinical remission rates were 60% for budesonide foam and 66% for budesonide enema within a predefined noninferiority margin of 15%. Of interest, 11% of the patients had retention problems after administration of the foam and 39% had retention problems after the enema. Overall, 84% of patients preferred the foam, 6% preferred the enema, and 10% had no preference. Budesonide foam enema and hydrocortisone foam enema have been shown to have comparable efficacy in inducing remission in patients with proctosigmoiditis; of interest, 52% of patients who did not respond to topical mesalamine responded to budesonide foam enema.12Bar-Meir S. Fidder H.H. Faszczyk M. et al.Budesonide foam vs. hydrocortisone acetate foam in the treatment of active ulcerative proctosigmoiditis.Dis Colon Rectum. 2003; 46: 929-936Crossref PubMed Scopus (66) Google Scholar Mesalamine enema, however, has been shown to induce remission in a significantly higher proportion of patients compared with budesonide liquid enema 2 mg/100 mL.13Hartman F. Stein J. Clinical trial: Controlled, open, randomized multicenter study comparing the effects of treatment on quality of life, safety and efficacy of budesonide or mesalazine enemas in active, left-sided ulcerative colitis.Aliment Pharmacol Ther. 2010; 32: 368-376Crossref PubMed Scopus (50) Google Scholar In the study published by Sandborn et al14Sandborn W.J. Bosworth B. Zakko S. et al.Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis.Gastroenterology. 2015; 148: 740-750Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar in this issue of Gastroenterology budesonide foam enema 2 mg/25 mL twice daily for 2 weeks followed by 2 mg/25 mL once daily for 4 weeks was compared with placebo in a double-blind design in patients with ulcerative proctitis or proctosigmoiditis. Concomitant oral mesalamine in a stable dose was permitted. Budesonide foam enema was effective and safe in 2 phase III studies—remission at week 6 was achieved in the active arm in 38.3% and 44% compared with 25.8% and 22.4% in the placebo arm. Cessation of rectal bleeding and mucosal healing was achieved in a significantly higher proportion of patients receiving budesonide foam enema compared with placebo enema. As mentioned, bowel frequency may not be a robust parameter to track in ulcerative proctitis on topical therapy and this is seen in the study too. At week 6, approximately 14% of patients on budesonide foam did not have normal response to adrenocorticotrophic hormone challenge, showing that a small proportion of patients do have subclinical suppression of the pituitary adrenal axis.14Sandborn W.J. Bosworth B. Zakko S. et al.Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis.Gastroenterology. 2015; 148: 740-750Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Overall, however, budesonide topical treatment demonstrated minimal effects on adrenal function. In these trials, administration of even twice daily 25 mL rectal foam formulation for the initial 2 weeks had extremely high adherence (>94%) and this was not different from when the drug was administered once daily for the latter 4 weeks. Faced with a choice from a number of formulations of topical therapy (Table 1), physicians have to make evidence based decisions while taking into account patient preferences. Gastroenterologists treating ulcerative proctitis, proctosigmoiditis, or left-sided colitis have the option of using topical mesalamine or corticosteroids, liquid enema, foam enema, rectal gel, or suppositories, and concomitant therapy with oral mesalamine.15Travis S.P.L. Stange E.F. Lemann M. et al.European evidence based consensus on the management of ulcerative colitis: current management.J Crohn’s Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Patients seem to tolerate foam enema better than liquid enema. Topical gel is also well-tolerated, although not available in many countries. In clinical practice, a 100-mL foam enema to reach splenic flexure may have unacceptable distension, especially during acute phase. The 25-mL volume used in these 2 trials may be the explanation for excellent tolerability (but perhaps the trade-off is a shorter retroprogression into the colon). Topical therapy with mesalamine is superior to topical therapy with corticosteroids16Dignass A. Lindsay J.O. Sturm A. Windsor A. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: current management.J Crohn’s Colitis. 2012; 6: 991-1030Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar; therefore, topical mesalamine would be a first-line choice for patients suffering from ulcerative proctitis, proctosigmoiditis, or left-sided colitis.16Dignass A. Lindsay J.O. Sturm A. Windsor A. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: current management.J Crohn’s Colitis. 2012; 6: 991-1030Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar For patients with proctitis, mesalamine suppository is the initial choice because it delivers the drug optimally to the rectum. An alternative would be mesalamine foam enema.15Travis S.P.L. Stange E.F. Lemann M. et al.European evidence based consensus on the management of ulcerative colitis: current management.J Crohn’s Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 16Dignass A. Lindsay J.O. Sturm A. Windsor A. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: current management.J Crohn’s Colitis. 2012; 6: 991-1030Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar Topical corticosteroid is the second-line option, and budesonide foam enema will have a place in the armamentarium owing to its efficacy, tolerability, and safety. For patients suffering from ulcerative proctosigmoiditis or left-sided colitis, a combination of topical and oral therapy may be the optimal choice with mesalamine being the preferred topical drug. A foam enema may deliver the drug over the same anatomic extent as a liquid enema and is generally better tolerated; however, tolerance also depends on volume and spread depends on viscosity. Figure 1 shows a suggested algorithm based on current evidence for treatment of proctitis, proctosigmoiditis, and left-sided colitis. A head-to-head comparison of budesonide foam with a mesalamine foam enema is necessary. Topical therapies are also useful as maintenance therapy either on their own or in combination with oral therapy with mesalamine.16Dignass A. Lindsay J.O. Sturm A. Windsor A. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: current management.J Crohn’s Colitis. 2012; 6: 991-1030Abstract Full Text Full Text PDF PubMed Scopus (750) Google ScholarTable 1Preparations Available for Topical Therapy in Ulcerative ColitisFormulationDrugSuppositoryMesalamineHydrocortisoneBeclomethasone dipropionateLiquid enemaMesalamineHydrocortisoneBudesonideBeclomethasone dipropionateFoam enemaMesalamineBudesonideHydrocortisoneBeclomethasone dipropionateRectal gelMesalamineNot all formulations are available in different countries and there are some country-specific variation in the exact formulation, volume, and coatings. Open table in a new tab Not all formulations are available in different countries and there are some country-specific variation in the exact formulation, volume, and coatings. It is important to emphasize education and training of patients in the proper use of topical therapy because the delivery systems are different and patients may prefer 1 preparation over another. Adherence to therapy may also be optimized by patient education, support, and reinforcement of appropriate technique for administration. In addition to physicians, inflammatory bowel disease nurse practitioners or pharmacists may be able to provide support, because patients may require some time to get used to initiation of topical therapy. A single daily (night-time) administration instead of 2 doses during the day should be further studied, because this may be a useful means to maximize adherence, if proven to be equally effective. Mesalamine topical therapy does not demonstrate a significant dose response. Most patients with mild or moderate ulcerative colitis may benefit from the use of effective topical therapy in their treatment regimen with or without oral mesalamine. However, currently these topical preparations are clearly underused.9Siebold F. Fournier N. Beglinger C. et al.Topical therapy is underused in patients with ulcerative colitis.J Crohns Colitis. 2014; 8: 56-63Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 10Reddy S.I. Friedman S. Telford J.J. et al.Are patients with inflammatory bowel disease receiving optimum care?.Am J Gastroenterol. 2005; 100: 1357-1361Crossref PubMed Scopus (128) Google Scholar It is possible, therefore, that a significant number of patients suffering from proctitis, proctosigmoiditis, and left-sided colitis are currently treated suboptimally. The precise reasons for the underuse of these effective therapies may require further studies to understand better. Apart from patient preference and cultural influences on beliefs, the influence of patient education as well as physician education may be important. Many of the opportunities for topical therapy use in ulcerative colitis are in primary care, where many mild ulcerative colitis patients are seen. The usefulness and utility of topical preparations for most patients with ulcerative colitis need to be emphasized further and we now have a variety of formulations, preparations, and dispensers to suit most patients, using a little trial and error and patience. Budesonide Foam Induces Remission in Patients With Mild to Moderate Ulcerative Proctitis and Ulcerative ProctosigmoiditisGastroenterologyVol. 148Issue 4PreviewBudesonide is a high-potency, second-generation corticosteroid designed to minimize systemic adverse consequences of conventional corticosteroids. We performed 2 randomized, phase 3 trials to evaluate the ability of budesonide rectal foam, formulated to optimize retention and provide uniform delivery of budesonide to the rectum and distal colon, to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis. Full-Text PDF Open AccessCovering the CoverGastroenterologyVol. 148Issue 4PreviewCurrent approaches to the treatment of ulcerative proctitis or proctosigmoiditis have largely consisted of topical applications of antiinflammatory compounds such as corticosteroids or mesalamine. These agents are administered usually as suppositories or liquid enemas. Budesonide is a corticosteroid that is applied topically to affected areas. Its major advantage is that 90% is metabolized on its first pass through the liver, which significantly lowers the incidence and severity of systemic adverse effects often associated with corticosteroids. Full-Text PDF