Are there reliable predictive factors of nonresponse to aminosalicylates in patients with ulcerative colitis?

There is strong evidence supporting the use of aminosalicylates for induction and for maintenance of remission in patients with mild-to-moderate ulcerative colitis (UC).^1–5 Recognizing patients at risk of medical therapy failure can appropriately optimize treatment escalation based on risk stratification.⁶ Predictive factors of nonresponse to steroids–or even biologics–in the long term have been extensively studied. However, little is known about the long-term course of the disease judged by the need for treatment escalation among patients in remission with aminosalicylates.

In this context, the study by Marti-Aguado et al. evaluated predictive factors of nonresponse to aminosalicylates, defined as the need for a step-up approach over time.⁷ This was a retrospective case-control study of UC patients treated with aminosalicylates after diagnosis disease flare, from 1997 to 2017. Long-term treatment maintenance with aminosalicylates and higher therapeutic requirements were recorded, and a detailed analysis was performed to identify predictive factors of treatment with immunomodulators, biological agents or surgery.

The most relevant results of this study can be summarized as follows: A total of 457 patients were included, of whom only 28% were nonresponders to aminosalicylates, judged as the need for higher therapeutic requirements. Cumulative probability for a step-up approach within 20 years of follow-up was 35%, mainly due to steroid-dependent colitis (76%); other causes of treatment escalation included steroid-refractory colitis (13%) and extraintestinal manifestations (5%). Higher therapeutic requirements included mainly immunomodulators (97%), but also, of note, biological agents (57%) and even colectomy (13%). The cumulative probability for treatment escalation was 7%, 23%, and 30% at 1, 5, and 10 years, respectively. However, the most relevant finding of this study was the identification of clear risk factors for treatment escalation: age 27 years or younger, extensive colitis, Mayo endoscopic subscore 2 or greater, and extraintestinal manifestations.

Although undoubtedly interesting and clinically relevant, this study has several limitations that should be taken into account:

1. It was an observational and retrospective study, and thus prone to bias.

2. To be included in the study, patients had to have a minimum follow-up of one year. The exclusion of early nonresponders could affect the conclusions of the study.

3. The study cohort included patients treated with aminosalicylates after initial disease flare, but did not differentiate whether this outbreak was managed with aminosalicylates alone or combined with a first course of steroids, whereas both groups could have different evolution.

4. The initial dose of aminosalicylates, and whether and how it was optimized if necessary, was unclear. It has been reported that 2 g or more per day of oral aminosalicylates induces remission more effectively than lower doses.^4,5 Furthermore, patients with moderate disease may benefit from the higher dose of 4.8 g per day. Finally, a dose of 2 g per day or more is appropriate for maintaining remission in UC.⁸

5. The combination of oral and topical aminosalicylates is more effective than either alone. However, the role of combined treatment for the prevention of treatment escalation is unclear in the present study, even though as many as 48% of the patients were treated with this strategy.

6. It has been demonstrated that a substantial proportion of UC flares are attributable to aminosalicylates nonadherence.⁹ Unfortunately, adherence to aminosalicylates was not considered as a possible risk factor of nonresponse in the study by Marti-Aguado and colleagues.⁷

7. In addition to “treatment escalation,” no other parameters were used to assess response to aminosalicylates. Thus, no serum (C-reactive protein) or fecal (calprotectin) markers were included. Furthermore, endoscopy data confirming nonresponse to aminosalicylates were not available, although it has been recommended before treatment escalation.⁵

8. The threshold for escalating treatment in patients with mild-to-moderate UC depends on the response to aminosalicylates, but also patient preference and physician practice. For example, indefinite treatment with aminosalicylates was prescribed by only 41% of Spanish gastroenterologists in a recent survey.¹⁰ Finally, the proportion of physicians indicating thiopurines in patients with a serious flare-up of UC who have responded to treatment with corticosteroids is also highly variable.⁸ Therefore, the results of the present study may not be extrapolated to other geographical areas.

In summary, despite the aforementioned limitations, the interesting study by Marti-Aguado et al.,⁷ providing real-life information, confirmed that nonresponse to aminosalicylates–judged as the need for higher therapeutic requirements–is low and can be predicted by easily assessing factors that may affect treatment strategies: younger age, extensive colitis, endoscopic disease severity and extraintestinal manifestations. These findings may be used in our clinical practice to identify patients who will probably benefit from an early step-up approach and minimize the morbidity associated with uncontrolled UC.

Declaration of conflicting interests

Dr Gisbert has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Sandoz, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma. Dr Chaparro has served as a speaker or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, and Tillotts Pharma.