30September2020

Y-ECCO Literature Review: Rebecca Reynolds

Rebecca Reynolds

No benefit of continuing vs stopping 5-aminosalicylates in patients with ulcerative colitis escalated to anti-metabolite therapy

Singh S, Kim J, Zhu W, Dulai P, Sandborn WJ, Jairath V

Aliment Pharmacol Ther. 2020;52:481–91.


Rebecca Reynolds
© Rebecca Reynolds 

Introduction

First introduced by Svartz in 1942, 5-aminosalicylates (5-ASAs) are a well-established and effective first-line therapy for the induction and maintenance of remission in patients with mild-to-moderate Ulcerative Colitis (UC). They remain the most frequently prescribed medication for UC and are known to be effective and well tolerated [1]. Between 87% and 98% of UC patients receive 5-ASA treatment within the first year of diagnosis and 60%–87% continue on this treatment at ten years [2, 3].

Escalation to anti-metabolites (thiopurines or methotrexate) and/or biologic or small molecule therapy is often required for UC patients with a more aggressive disease course. Whilst it is now accepted that discontinuing 5-ASA therapy when escalating to a biologic is not associated with adverse outcomes, less is known about the therapeutic benefit of continuation of 5-ASAs with an antimetabolite [2, 4].

Singh et al conducted a retrospective cohort study to evaluate the pattern of 5-ASA use in patients with UC following escalation to an antimetabolite. The study evaluated patients escalated to antimetabolite therapy (stopping 5-ASA vs short-term 5-ASA use for <6 months vs persistent 5-ASA use for >6 months) and compared the risk of clinically important complications based on the pattern of 5-ASA use in these patients. They hypothesised that continuing 5-ASA therapy would not be more beneficial than stopping it.

Methods

Data were collected from 4096 patients from a large de-identified claims database from across the United States using ICD diagnosis and procedure codes from inpatient and outpatient visits. Primary outcomes were UC-related hospital admissions, UC-related surgery, new corticosteroid prescriptions and treatment escalation.  Of the included patients, 14% stopped 5-ASA therapy, 19% continued short term and 67% had persistent use. Median follow-up in the study was 2.4 years. Results were analysed using survival analysis with Kaplan-Meier curves and Cox proportional hazard analysis, adjusting for age, sex, race, comorbidity burden and hospitalisations or ED visits, abdominal surgery and corticosteroid use in the previous 12 months. Results were taken at 12 months after the initiation of antimetabolite therapy (index date). Sensitivity analysis was also performed on the 5-ASA exposure groups [5].

Key findings

Primary analysis at 12 months after initiation of antimetabolite therapy showed that 70% of patients with persistent 5-ASA use had received corticosteroids, compared to 66% of patients with short-term use and 64% of patients who stopped 5-ASA treatment.

Approximately 32%–39% of patients were hospitalised for UC. Interestingly, however, 95% of these patients did not require escalation of therapy following hospitalisation. In the follow-up period beyond 12 months, no significant time difference was observed between the groups related to time to hospital admission (p=0.08), surgery (p=0.08) or treatment escalation (p=0.07). Patients with persistent 5-ASA use had a significantly shorter time to initiating corticosteroids than patients who stopped 5-ASA (p≤ 0.001).

On Cox proportional hazard analysis, patients with persistent 5-ASA use had a higher risk for UC-related hospitalisation (HR 1.40; 95% CI 1.07–1.80) and corticosteroid use (HR 1.48; 95% CI 1.28–1.70), without an increased risk for UC-related surgery (HR 1.32; 95% CI 0.86–2.00) or need for escalation of therapy (HR 0.80; 95% CI 0.53–1.20). No difference was observed between those who stopped 5-ASA therapy and those who continued it short term.

Sensitivity analysis using a 3-month window after initiation of anti‐metabolites showed similar results.

Discussion

The analyses performed in Singh et al’s study did not demonstrate superior clinical outcomes in patients who stopped 5-ASA therapy compared to patients who continued 5-ASA therapy when escalating to an antimetabolite. It was interesting that the study observed that persistent 5-ASA use was associated with a higher risk of UC-related hospitalisations and corticosteroid use; however, as discussed in Singh et al’s paper, this is likely to reflect confounding variables such as disease extent and severity, rather than an adverse effect of 5-ASAs.

A large proportion of the patients included in the study (two-thirds) continued on 5-ASAs for extended periods, suggesting perceived benefit of concomitant therapy by clinicians. Whilst there is limited evidence to support this practice, it may in part reflect clinical decision making in individual cases with regard to disease severity and extent. Although previous studies have alluded to a synergistic relationship between 5-ASA and thiopurines, through the influence of thiopurine methyltransferase activity and possible increase in 6-thioguanine levels, none have unequivocally demonstrated an increase in clinical effectiveness [6–8].

Another perceived benefit to concomitant therapy may be the possible protective role of 5-ASAs against colorectal cancer. Whilst chronic active inflammation has long been known to be a modifiable risk factor in the development of colorectal cancer, it is likely that the perceived chemotherapeutic effect of 5-ASAs in this area is related to maintenance of mucosal healing and, following this logic, similar benefit would be derived from antimetabolites.

In an era of ever-expanding healthcare costs and pressure to reduce expenditure, it is also important to consider the cost effectiveness of continuing low-value medications. 5-ASAs currently account for around 25% of the total healthcare costs in UC and cost £740/EUR 850 per patient per year [2].

Adherence to medication is also an important aspect of chronic disease management. Studies have repeatedly demonstrated that adherence to long-term medications, particularly in the context of asymptomatic disease, are highly variable. Higher pill burdens are further associated with reduced compliance [9–12].

In conclusion, Singh et al’s study supports existing evidence that combined therapy with 5-ASAs and antimetabolites is not superior to monotherapy with antimetabolites alone. Whilst 5-ASAs are considered a relatively safe class of drug, there are infrequent but serious side effects to consider when choosing to continue a medication that has essentially been ineffective as a first-line treatment. Further evidence of a beneficial synergistic effect between 5-ASAs and thiopurines or a role of 5-ASAs in preventing the development of colonic polyps or dysplasia would provide a rationale to continue combination therapy; however, more studies would be required in this area.

References

  1. McLean LP, Cross RK. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment. Expert Rev Gastroenterol Hepatol. 2014;8:223–40.
  2. Chapman TP, Gomes CF, Louis E, Colombel JF, Satsangi J.  Review article: withdrawal of 5‐aminosalicylates in inflammatory bowel disease. Aliment Pharmacol Ther 2020;52:73–84.
  3. Singh S, Feuerstein JD, Binion DG, Tremained WJ. AGA technical review on the management of mild-moderate ulcerative colitis. Gastroenterology. 2019;156:769–08.e29.
  4. Limketkai B, Ungaro R, Jess T, et al. Discontinuation of 5-aminosalicylates after starting biologic therapy with ulcerative colitis is not associated with adverse outcomes. J Crohns Colitis 2018;12 Supplement 1:S287–8.
  5. Singh S, Kim J, Zhu W, Dulai P, Sandborn W, Jairath V. No benefit of continuing vs stopping 5-aminosalicylates in patients with ulcerative colitis escalated to anti-metabolite therapy. Aliment Pharmacol Ther. 2020;52:481–91.
  6. Berjamo F, Gisbert J. Usefulness of salicylate and thiopurine coprescription in steroid-dependent ulcerative colitis and withdrawal strategies. Ther Adv Chronic Dis. 2010;1:107–14.
  7. Konidari A, El Matery W. Use of thiopurines in inflammatory bowel disease: safety issues. World J Gastrointest Pharmacol Ther. 2014;5:63–76.
  8. Gilissen LPL, Bierau J, Derijks JJ, et al. The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients. Aliment Pharmacol Ther 2005;22:605–11.
  9. Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol. 2001;96:2929–33.
  10. Dignass A, Veerman H. Once versus twice-daily mesalazine (Pentasa) granules for the maintenance of remission in ulcerative colitis: results from a multinational randomised controlled trial. Gut. 2008;57(Suppl 1):A1
  11. Niewiadomski O, Studd C, Hair C et al. Healthcare cost analysis in a population based inception cohort of inflammatory bowel disease patients in the first year of diagnosis. J Crohns Colitis. 2015;9:988–96.
  12. Ghosh N, Premchand PA. UK cost of care model for inflammatory bowel disease. Frontline Gastroenterol. 2015;6:169–74.

 

Rebecca Reynolds – Short biography

Rebecca Reynolds is a Clinical Research Fellow in IBD at Guy’s and St Thomas’ NHS Foundation Trust, London.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 3, Y-ECCO

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