Classification of ulcerative colitis

As mentioned, key factors in deciding on a treatment approach are colonic involvement and disease severity (see Table 1). The Montreal Classification classifies colonic involvement as: Proctitis (inflammation of the lining of the rectum), left-sided colitis (inflammation in the colon), or extensive colitis (affects the entire colon).²

The Truelove-Witts criteria categorise UC severity as: Mild, moderate, or severe taking into account the number of bowel movements per day, temperature, heart rate, haemoglobin level, and erythrocyte sedimentation rate.²

Left-side localisation with mild-to-moderate activity (less than six bowel movements per day, without constitutional symptoms and features of high inflammatory activity) is the most common disease presentation at diagnosis, accounting for 40% of cases.²

What are the overarching treatment goals in ulcerative colitis?

The overarching goal of UC treatment is to obtain sustained resolution of all disease symptoms (full clinical remission) along with normalisation of endoscopic findings (endoscopic remission), and ultimately to improve patients’ quality of life.³

Full clinical remission is defined as: The absence of signs and symptoms of active disease. Usually, clinical remission is considered to be up to three bowel movements per day without signs of lower gastrointestinal bleeding. Endoscopic remission is defined as: The absence of inflammatory activity in endoscopic examination.³

Achieving sustained resolution of symptoms requires treatment to induce remission, maintain improvements, and reduce the risk of relapse. Short-term goals include achieving a clinical response confirmed by objective methods (endoscopic or biochemical – mainly through the assessment of faecal calprotectin levels).³

Step-up strategy for the management of UC

According to Eder et al, pharmacological treatment of UC should follow a step-up strategy, which comprises the gradual introduction of therapeutic agents with increasing immunosuppressive potency upon failure of the previous treatment methods. It should be noted that the step-up strategy does not apply to patients with acute severe colitis.³

Pharmacological treatment should be personalised, and based on at least the following criteria:³

• Disease activity: Determined by using clinical scales (eg the Mayo Score) and endoscopic scales (the Mayo Endoscopic Sub-score). Determining disease activity is important because it can be used to guide the selection of first-choice therapy, as well as for defining the time of assessing treatment efficacy.
• Extent of inflammatory lesions: Based on endoscopic or imaging examinations. It is taken into account, for example, when selecting the route of administration of the medicine used.
• Disease history: To assess the efficacy of current treatment, the number of exacerbations, and the pharmacological therapy, which resulted in remission during previous exacerbations.

Treatment phases

The treatment of UC consists of two phases:³

• Induction treatment: Aimed at obtaining clinical remission, and preferably also endoscopic remission.
• Maintenance treatment: Aimed at sustaining remission and preventing exacerbations.

According to Eder et al, an important element in assessing treatment efficacy is evaluating mucosal lesion healing. Evidence show achieving endoscopic remission (see above for definition) is associated with a lower risk of future exacerbations.³

What pharmacotherapy do guidelines recommend?

The South African Gastroenterology Society’s (SAGES) position paper on the use of drug therapies in the management of inflammatory bowel disease, recommends oral and topical 5-ASAs as first-line therapy for the management of mild-to-moderately active UC. The choice of oral or topical therapy, or the use of both in combination, depends on the extent and activity of the disease.⁴

Furthermore, SAGES recommends 5-ASAs for the induction of remission in patients with active UC. For isolated proctitis, rectal 5-ASA therapies at a dose of 1g/day are recommended.⁴

If rectal 5-ASAs are not adequate to control active proctitis, oral 5-ASAs can be used in addition. In more extensive colitis, oral 5-ASAs (at a dose of at least 2g/day) are recommended. A meta-analysis of 11 randomised controlled trials of patients with UC treated with oral 5-ASAs demonstrated superiority of 5-ASAs in inducing remission compared with placebo.⁴

Combining oral and rectal 5-ASA therapies confers additional benefits over either alone. In left-sided UC, a meta-analysis of four randomised controlled trials using a combination of rectal 5-ASA enemas (1g/day) combined with oral 5-ASAs (at least 2 g/day) was more effective than oral 5-ASA alone for induction of remission. Patients with extensive UC also appear to benefit from combination therapy.⁴

Low-dose oral 5-ASAs (2g-2.4g/day) are preferred wherever possible over higher doses (4g-4.8g/day) in mild UC, as there is no difference in remission rates.⁴

Additional therapy is usually required to induce remission in moderate-to-severe UC. Rectal 5-ASAs at a dose of 1g/day is recommended to maintain remission. In patients with more extensive UC, oral 5-ASAs (at least 2g/day) as well as rectal 5-ASAs are recommended.⁴

Are all 5-ASAs created equal?

5-ASAs are often described as the ‘grandfather’ of UC treatment. One of the oldest 5-ASAs used in the treatment of UC is sulfasalazine, which comprises two components: sulfapyridine and 5-ASA. Sulfasalazine was originally developed for the treatment of arthritis in the 1930s and has been recommended for the treatment of UC since the 1940s due to its anti-inflammatory properties.⁵

Unfortunately, sulfasalazine is associated with a number of side effects, which limits its use in clinical practice. As a result, mesalazine was developed, which does not contain sulphur. A meta-analysis found 28% of patients treated with sulfasalazine experienced adverse events compared to 15% treated with mesalazine.⁶

Mesalazine is generally well tolerated, with similar side effect profiles between different formulations. The most common side effects include arthralgia, myalgia, flatulence, abdominal pain, nausea, diarrhoea, and headache. Rare but serious side effects include interstitial nephritis and pancreatitis.⁷

In short, the first benefit of mesalazine is an improved side effect profile. The second benefit is that mesalazine is associated with improved response and remission rates.⁷

Studies show that mesalazine is associated with response rates of between 40%-70%, and remission rates of 15%-20% in patients living with mild-to-moderate disease.⁶

The third benefit of mesalazine is improved adherence to treatment. According to the SAGES position paper, the best drug should be selected taking patient preference for formulation (for instance granules or tablets, tablet size, and number required daily) into account, in order to maximise treatment adherence. Cost is another important factor when deciding which agent to prescribe.⁴

Non-adherence is defined as taking less than 80% of prescribed medications. In patients living with UC, non-adherence rates of between 40% to 72% have been reported. Patients who are non-adherent have a five-fold greater risk of disease recurrence than those who stick to their treatment plan.⁷

Two of the main reasons for non-adherence are multi-dose regimens as well as pill burden. A meta-analysis by Claxton et al suggested that less frequent dosing is associated with higher adherence. Formulations such as multi-matrix (MMX) mesalazine require once-daily (OD) dosing, is gastro-resistant, and has a prolonged-release release system.^7,8,9,10

Lastly, mesalazine MMX has been shown to be more cost-effective compared to some other 5-ASA formulations. Prenzler et al (2009) analysed the incremental cost-effectiveness ratio of two oral formulations of 5-ASA (Mezavant^® and Asacol^®) in the treatment of patients living with mild-to-moderate UC.¹¹

The primary endpoint was cost per quality-adjusted life year (QALY). Remission rates were obtained using data from a randomised, phase III trial of Mezavant with an active Asacol reference arm and a long-term, open-label, safety, and tolerability trial of Mezavant.¹¹

Over a five-year period, healthcare costs for patients receiving Mezavant were €624 lower than for patients receiving Asacol. Additionally, patients receiving Mezavant gained 0.011 QALYs or 18 more days in remission compared with Asacol.¹¹

Furthermore, sensitivity analyses suggest a probability of 76% for cost savings and higher QALYs with Mezavant compared with Asacol. If adherence and its influence on the remission rates and the risk of developing colorectal cancer were included in the model, the results might have even been more favourable to Mezavant due to its once-daily dosing regimen.¹¹

Conclusion

Mesalazine is the cornerstone of the management of mild-to-moderate UC. Various formulations are available. Each differs in terms of enteric coating, site of drug release, and mode of drug delivery. The choice of formulation should be tailored to each individual patient, taking into consideration disease distribution, tolerability, adherence, and cost effectiveness.⁷

Table 1: Classification of severity¹²

References

1. Holvoet T, Lobaton T, Hindryckx P. Optimal Management of Acute Severe Ulcerative Colitis (ASUC): Challenges and Solutions. Clinical and Experimental Gastroenterology, 2020.
2. Solitano V, D’Amico F,Fiorino G, et al. Key Strategies to Optimize Outcomes in Mild-to-Moderate Ulcerative Colitis. J Clin Med, 2020.
3. Eder P, Łodyga M, Gawron-Kiszka M, et al. Guidelines for the management of ulcerative colitis. Recommendations of the Polish Society of Gastroenterology and the Polish National Consultant in Gastroenterology. Prz Gastroenterol,
4. Watermeyer G, Kassianides C, Deetlefs E, et al. The South African Gastroenterology Society (SAGES) position paper on the use of drug therapies in the management of inflammatory bowel disease. South African Gastroenterology Review, 2020.
5. Crohn’s and Colitis Canada. Sulfasalazine and 5-aminosalicylates (5-ASA). [Internet]. Available from: https://crohnsandcolitis.ca/About-Crohn-s-Colitis/IBD-Journey/Treatment-and-Medications/Sulfasalazine-and-5-Aminosalicylates-5-ASA#what-are-sulfasalazine-and-5-asas
6. Karagozian R, Burakoff R. The role of mesalamine in the treatment of ulcerative colitis. Ther Clin Risk Manag, 2007.
7. Ye B, van Langenberg DR. Mesalazine preparations for the treatment of ulcerative colitis: Are all created equal? World J Gastrointest Pharmacol Ther, 2015.
8. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther, 2001.
9. Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther, 2003.
10. Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology,
11. Prenzler A, Yen L, Mittendorf T, von der Schulenburg JM. Cost-effectiveness of ulcerative colitis treatment in Germany: a comparison of two oral formulations of mesalazine. BMC Health Serv Res, 2011.
12. Lichtenstein GR, Hanauer SB, Sandborn WJ. Emerging Treatment Options in Mild to Moderate Ulcerative Colitis. Gastroenterol Hepatol (NY), 2015.