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Ulcerative Colitis

The importance of maintenance therapy and treatment adherence

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Ulcerative colitis (UC) is an inflammatory bowel disease affecting approximately 700,000 people in North America.1 It is characterized by relapsing and remitting symptoms including rectal bleeding, diarrhea and abdominal pain.1 Active UC symptoms can be disruptive, with many patients reporting embarrassment, depression and worry about disease complications.1 UC can therefore impose a significant emotional and psychological burden, negatively affecting quality of life. In the United States, the economic burden of UC exceeds $4 billion in annual direct medical costs.2

The cause of UC is unknown, but genetic susceptibility, host immunity and environmental factors have been implicated in its pathophysiology.3 Genetic studies indicate that multiple heterogeneous gene variants are linked to UC-related dysfunction of the epithelial barrier, defects in transcriptional regulation and apoptosis.3 Other pathological factors that may play a role in UC are alterations in the composition of gut microbiota, defects in mucosal immunity (humoral and cellular adaptive immunity) and autoimmunity.3 Therefore, treatment approaches targeting mucosal healing appear to be an important step toward therapeutic efficacy.

The goals of UC management are to induce and maintain disease remission in order to improve health and quality of life.2 Current therapy options for induction include 5-aminosalicylic acid (5-ASA), corticosteroids, thiopurines and infliximab. Oral 5-ASA is the standard first-line therapy for active mild to moderate UC, and some 5-ASA formulations are effective in inducing remission.2 The corticosteroids thiopurine and infliximab are associated with significant adverse events (AEs; discussed below), and they are recommended for severe UC or UC that is refractory to oral 5-ASAs.2

Although no standardized definition of UC remission has been determined, commonly used parameters include clinical remission, typically defined as normal stool frequency without rectal bleeding, and endoscopic remission, often defined as normal appearance of the mucosa by endoscopy. These parameters are typically measured by the Mayo Clinic Score and UC Disease Activity Index (UCDAI).2

UC is a chronic disease, thus its long-term management is a key issue in treatment. Although therapies that effectively induce and maintain remission are available, the high rate of treatment nonadherence is a challenge to remission maintenance.4 Good communication between patients and their health care providers is important for optimal disease management and may help support treatment adherence.4-6 Nurse practitioners, who often are the primary contact during healthcare visits, are well positioned to provide thorough patient education.5

 

Maintenance Therapy Options

Oral 5-ASA, available in several formulations, is the recommended first-line therapy for the maintenance of remission (see table).2 Sulfasalazine (SASP) has demonstrated efficacy in maintaining UC remission.7 In a study of UC patients on maintenance therapy for 1 year or longer, those on placebo had a significantly higher rate (54.8%) of relapse (defined as recurrence of symptoms with sigmoidoscopic and histologic evidence of intestinal inflammation) at 6 months versus those taking SASP (12.1%; P < 0.001).7 AEs associated with SASP included dyspepsia, headache, nausea, and allergy.2 Similarly, patients with inactive UC (defined as having formed stool without blood or mucus) who received the 5-ASA olsalazine 500 mg 4 times/day demonstrated significantly longer median time to relapse than patients who received placebo (P = 0.024).8

UC patients in remission who received controlled-release mesalamine 4 g/day (64%) also reported a higher rate of remission at 12 months versus those who received placebo (38%; P = 0.0004).9 In this study, remission was defined as less than 5 stools/day, no rectal bleeding, and a sigmoidoscopic index score less than 5 on a nonstandard endoscopy scoring scale (summed categories of erythema, friability, granularity/ulceration, mucopus and mucosal vascular pattern rated from 0 [normal] to 3 [severe]). However, controlled-release mesalamine is not approved in the United States for maintenance of remission. Similarly, significantly more patients who received delayed-release mesalamine 0.8 g/day or 1.6 g/day maintained endoscopic remission at 6 months (58.8% and 65.5%, respectively) versus placebo (39.7%; P < 0.05 for both).10

A once-daily oral mesalamine formulation, mfultimatrix mesalamine, has demonstrated effectiveness in maintaining UC remission/quiescence.11,12 A phase 3 trial11 of UC patients in clinical and endoscopic remission showed that 64.4% of those who received multimatrix mesalamine 2.4 g once daily maintained clinical and endoscopic remission at 12 months versus 68.5% of patients who received an equivalent daily dose twice a day (1.2 g twice daily; P = 0.351).

Similarly, a phase 4 trial12 in UC patients with quiescent disease showed that after 6 and 12 months, respectively, 76.5% and 64.4% of patients who received multimatrix mesalamine 2.4 g once daily were recurrence-free (recurrence defined as 4 or more bowel movements/day, greater than normal frequency, associated with urgency, abdominal pain, and/or rectal bleeding).

In another study, multimatrix mesalamine 2.4 g once daily demonstrated non-inferiority compared with delayed-release mesalamine 1.6 g (daily total dose) twice daily in a percentage of patients who maintained endoscopic remission at month 6 (83.7% versus 81.5%, per protocol population; 95% confidence interval [CI] for difference: -3.9%, 8.1%).13 AEs were experienced by 37.1% and 36.0% of the multimatrix and delayed-release mesalamine groups, respectively, and the most common AEs (UC and headache) were similar for both groups.13

A once-daily oral formulation of extended-release mesalamine granules has also shown efficacy in maintaining UC remission.14,15 In one study, 78.9% of UC patients who took mesalamine granules 1.5 g once daily remained relapse-free versus 58.3% on placebo (P < 0.001).14 Relapse was defined as scores of 1 or higher (at least streaks of blood) on rectal bleeding and 2 or more (at least moderate friability) on mucosal appearance subscales of the modified UCDAI.

In another study,15 significantly more patients who switched to mesalamine granules 1.5 g once daily from another 5-ASA remained relapse-free (78.3%) compared to patients who switched to placebo (58.8%; P < 0.001). To date, no published data directly compare the efficacy of different 5-ASA formulations.

Oral 5-ASA formulations have a favorable safety profile. A systematic review of 5-ASA formulations for maintenance of UC remission, including olsalazine, controlled-release mesalamine and delayed-release mesalamine, showed no significant differences among these formulations and placebo in the proportions of patients who experienced AEs or discontinued due to AEs.16 multimatrix mesalamine and extended-release mesalamine have demonstrated acceptable tolerability in maintenance studies of UC patients, with the majority of reported AEs being of mild or moderate severity.11-15

For patients unresponsive to or intolerant of oral 5-ASAs, other maintenance therapy options may be considered (see table). Topical 5-ASAs (enemas, foam, suppositories) may be used as adjunctive therapy or monotherapy. The combination oral and topical 5-ASA therapies can induce remission faster than oral agents alone.2 Some UC patients may find weekly enemas or suppositories necessary to maintain remission and avoid flares.2

Another option, adjunctive corticosteroids, is effective in inducing remission but has not shown efficacy in maintenance and is not recommended for long-term therapy due to the frequency and severity of associated AEs (e.g., glaucoma, cataracts, infections, cushingoid features and emotional and psychiatric disturbances).2

Thiopurine treatment is widely used as adjunctive and steroid-sparing therapy for patients who cannot tolerate or whose disease is refractory to 5-ASAs and those who need multiple courses of steroids.2 AEs associated with thiopurines include bone marrow suppression and increased risk of opportunistic infections. Concurrent thiopurine and 5-ASA use may increase leukopenia risk.2

Infliximab, an intravenous monoclonal antibody treatment targeting tumor necrosis factor-α, is indicated for patients with moderate to severe active UC and an insufficient response to conventional therapies. In the Active Ulcerative Colitis Trials 1 and 2 (ACT1 and ACT2),17 significantly more moderate to severe UC patients who received infliximab versus placebo were in clinical remission (defined as Mayo total score 2 or less, with individual subscores 1 or less) at 30 weeks (ACT1, 34% to 37% infliximab versus 16% placebo; P £ 0.001; ACT2, 26% to 36% infliximab versus 11% placebo; P < 0.01). Common AEs associated with infliximab include infection, infusion reactions, headache and abdominal pain. Infliximab has also been associated with increased risk of lymphoma and serious infections, particularly tuberculosis.2

 

Importance of Treatment Adherence

Although oral 5-ASAs have proven effective in preventing relapse, 40% to 60% of UC patients do not adhere to maintenance therapy.4 Lack of adherence is associated with increased risk of recurrence or flares.4 One study18 reported a fivefold greater risk of recurrence in nonadherent versus adherent patients (hazard ratio, 5.47; 95% CI, 2.26 to 13.22; P < 0.001) and another study12 demonstrated that adherence (80% or higher) resulted in lower recurrence rates at 12 months (31.2% for adherent versus 52.5% for nonadherent patients; P = 0.01).

Nonadherence has also been associated with increased medical costs.4,19 In a retrospective analysis of a medical claims database,19 adherence to 5-ASA treatment was associated with a 49.8% decrease in total health care costs (P < 0.001); adherent patients incurred 12.5% lower medical costs versus nonadherent patients (P = 0.03).

Factors associated with nonadherence include single status, full-time employment, dosing of three times daily, and disease duration.4, 5 UC patients have also cited forgetfulness (50%), the high number of tablets (30%) and uncertainty about the need for the prescribed amount of medication (20%) as reasons for nonadherence.18 Therapies that only require once-daily administration may therefore help optimize adherence. An analysis of a pharmacy database showed that more patients taking multimatrix mesalamine (20%) persisted with treatment than patients on formulations with divided dosing (e.g., olsalazine, 10%; controlled-release mesalamine, 10%; and delayed-release mesalamine, 9%; P < 0.001).20

 

The Role of NPs in UC Management

Improved communication between providers and patients may promote treatment adherence and lead to reductions in relapses or flare-ups. UC patients have reported feeling inadequately informed about their disease, and nonadherence has been associated with insufficient understanding of medication regimen instructions and uncertainty about the importance of treatment adherence.4

Nurse practitioners can promote successful self-management of UC through patient education.5 Among the NP core competencies defined by the National Organization of Nurse Practitioner Faculties is providing patient-centered care, recognizing the patient as a full partner in healthcare decisions.21 In one study, improved provider-patient communication in the form of telephone counseling of UC patients by nurses resulted in significantly higher mesalamine adherence rates at 6 months than expected rates based on retrospective claims database analyses (P < 0.001).22

NPs can also address the psychosocial burdens of UC, the condition's effects on quality of life, patient attitudes toward treatment, and patient goal setting.4,5 In one survey,23 62% of UC patients reported that their disease made leading a normal life difficult, and only 42% believed that remission meant living without symptoms. Thus, healthcare providers need to reset expectations and educate patients about the natural history of the disease, how to recognize disease progression, and the side effects of medical therapies for UC. Patients who receive formalized training about UC report higher satisfaction than those who receive ad hoc training,24 emphasizing patients' desire for more information and the role that NPs can play in providing hands-on training.5

 

Adherence Is the Answer

Current maintenance therapy options for UC are effective in preventing disease recurrence. However, treatment adherence is a critical factor in reducing the risk of recurrence, and more convenient dosing regimens may improve patient adherence to long-term therapy. Nurse practitioners can contribute significantly to treatment adherence, patient satisfaction and improved disease management in UC patients.

 

References

1. Irvine EJ. Quality of life of patients with ulcerative colitis: past, present, and future. Inflamm Bowel Dis. 2008;14(4):554-565.

2. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523.

3. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365(18):1713-1725.

4. Kane SV. Systematic review: adherence issues in the treatment of ulcerative colitis. Aliment Pharmacol Ther. 2006;23(5):577-585.

5. Dudley-Brown S. Optimizing Outcomes in Ulcerative Colitis Requires Open Communication: A Nurse Practitioner's Perspective. http://www.medscape.org/viewarticle/748394

6. Robinson A. Review article: improving adherence to medication in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2008;27(Suppl 1):9-14.

7. Dissanayake AS, Truelove SC. A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphazalazine (Salazopyrin). Gut. 1973;14(12):923-926.

8. Wright JP, et al. Olsalazine in maintenance of clinical remission in patients with ulcerative colitis. Dig Dis Sci. 1993;38(10):1837-1842.

9. Miner P, et al. Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group. Dig Dis Sci. 1995;40(2):296-304.

10. An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. A randomized, placebo-controlled trial. The Mesalamine Study Group. Ann Intern Med. 1996;124(2):204-211.

11. Kamm MA, et al. Randomised trial of once- or twice-daily multimatrix mesalazine for maintenance of remission in ulcerative colitis. Gut. 2008;57(7):893-902.

12. Kane S, et al. Strategies in maintenance for patients receiving long-term therapy (SIMPLE): a study of multimatrix mesalamine for the long-term maintenance of quiescent ulcerative colitis. Inflamm Bowel Dis. 2012;18(6):1026-1033.

13. D'Haens G, et al. Once-Daily multimatrix(R) mesalamine for endoscopic maintenance of remission of ulcerative colitis. Am J Gastroenterol. 2012;107(7):1064-1077.

14. Lichtenstein GR, et al. Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial. Aliment Pharmacol Ther. 2010;32(8):990-999.

15. Lichtenstein GR, et al. Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials. Aliment Pharmacol Ther. 2012;36(2):126-134.

16. Loftus EV Jr., et al. Systematic review: short-term adverse effects of 5-aminosalicylic acid agents in the treatment of ulcerative colitis. Aliment Pharmacol Ther. 2004;19(2):179-189.

17. Rutgeerts P, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462-2476.

18. Kane S, et al. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med. 2003;114(1):39-43.

19. Kane S, Shaya F. Medication non-adherence is associated with increased medical health care costs. Dig Dis Sci. 2008;53(4):1020-1024.

20. Kane SV, et al. Twelve-month persistency with oral 5-aminosalicylic acid therapy for ulcerative colitis: results from a large pharmacy prescriptions database. Dig Dis Sci. 2011;56(12):3463-3470.

21. Thomas AC, et al. Nurse practitioner core competencies April 2011 amended 2012. http://c.ymcdn.com/sites/www.nonpf.org/resource/resmgr/competencies/npcorecompetenciesfinal2012.pdf

22. Cook PF, et al. Telephone nurse counseling for medication adherence in ulcerative colitis: a preliminary study. Patient Educ Couns. 2010;81(2):182-186.

23. Rubin DT, et al. Impact of ulcerative colitis from patients' and physicians' perspectives: Results from the UC: NORMAL survey. Inflamm Bowel Dis. 2009;15(4):581-588.

24. Waters BM, et al. Effects of formal education for patients with inflammatory bowel disease: a randomized controlled trial. Can J Gastroenterol. 2005;19(4):235-244.

 

Susan Colar is a nurse at the Center for Digestive Health in Troy, Mich. James Colar is an acute care nurse practitioner at Beaumont Health System in Detroit. The authors have completed disclosure statements and state that Joy Loh, PhD, and Jason McDonough, PhD, of MedErgy provided writing assistance for this article. Shire Development LLC provided funding to MedErgy for support in writing and editing this article. The authors received no payments from Shire and are not paid consultants to Shire.




     

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