Progression of Disease When Mesalamine Fails

Dr Maia Kayal, from the Icahn School of Medicine at Mount Sinai, reviewed the progressive nature of ulcerative colitis (UC) and treatment options for patients who experience disease progression on mesalamine therapy.¹

UC as Progressive Disease

The mainstay of therapy for patients with mild or moderate UC consists of 5-ASA, which have been established as superior to placebo as maintenance therapy. For patients with proctitis, 5-ASA are generally administered as rectal-based therapy (eg, enemas or suppositories), whereas patients with left-sided colitis or extensive pancolitis are typically treated with a combination of oral and rectal 5-ASA formulations. The majority (88%-97%) of patients with mild or moderate UC receive 5-ASA within 1 year of diagnosis.² However, there are limitations to this treatment, as approximately 37% of these patients will experience disease relapse within 6 to 12 months.³

It is important to promptly identify patients with UC who experience a disease flare on 5-ASA therapy, as UC progression is associated with significant risks, including proximal disease extension, neoplasia, bowel damage, and reduced rectal compliance.⁴ Specifically, disease extension is a significant risk factor for colectomy.⁵ Up to 50% of patients with UC will have proximal disease extension, with this risk increasing over time.⁶ Several risk factors for proximal disease extension have been identified, including a younger age at diagnosis (HR, 0.979; 95% CI, 0.959-0.999) and presence of sclerosing cholangitis (HR, 12.83; 95% CI, 1.36-121.10). Recognizing when patients relapse, particularly in the context of proximal disease extension, is imperative because of associated adverse outcomes such as hospitalization and colectomy.⁷

Thus, the goal should be not only to recognize patients with moderate-to-severe UC requiring treatment beyond 5-ASA, but also to understand that patients with mild or moderate UC also meet the same criteria after they have relapsed on 5-ASA and should be treated as such.

Nonbiologic Therapy Options Post–5-ASA

A multitude of therapies are now available to treat patients who experience relapse of their UC while receiving 5-ASA therapy. Newer therapies have been investigated as an option for patients who are flaring on 5-ASA but are hesitant to progress to a biologic or small molecule agent.

The nutraceutical CurQD, a combination of curcumin and QingDai, was found to have greater efficacy than placebo for inducing response and remission among a small cohort of patients with active UC.⁸ CurQD also appears to reduce bowel urgency in patients, an important outcome for those experiencing disease flare.⁹

The sphingosine-1 phosphate (S1P) receptor modulator etrasimod was found to be effective as induction and maintenance therapy in patients with moderately to severely active UC in the ELEVATE UC 52 and ELEVATE UC 12 phase 3 trials.¹⁰ A post hoc analysis of week 12 and 52 data from these trials, with a focus on patients previously exposed to or receiving 5-ASA prior to enrollment, demonstrated that etrasimod was significantly beneficial in this group.¹¹ Patients treated with etrasimod vs placebo were significantly more likely to achieve clinical remission at week 12 (34.8% vs 6.5%; P<.001) and week 52 (42.0% vs 2.6%; P<.001), and also significantly more likely to experience endoscopic improvement at week 12 (45.2% vs 12.9%; P<.001) and week 52 (49.4% vs 10.5%; P<.001). In a separate post hoc analysis of a subset of patients with isolated proctitis, etrasimod showed significant increases compared with placebo in rates of clinical remission (week 12: 42.9% vs 13.6%, P<.001; week 52: 44.4% vs 11.1%, P<.001) and endoscopic improvement (week 12: 52.4% vs 22.7%, P=.001; week 52: 51.9% vs 33.3%, P=.125). This is a particularly important consideration, as these patients tend to be undertreated and therefore at risk for proximal disease extension.^12,13

The novel S1P receptor antagonist amiselimod was compared with placebo in a randomized, double-blind, phase 2 trial for the induction of remission in patients with mild-to-moderate active UC.¹⁴ The primary endpoint, which was change from baseline to week 12 in modified Mayo score (the sum of endoscopy subscore, rectal bleeding subscore, and stool frequency sub-score), was significantly improved with both doses of amiselimod (decrease of 2.3 points for both the 0.2 mg/day and 0.4 mg/day groups) vs placebo (decrease of 1.6 points; P<.01 for both comparisons). The week 12 secondary endpoint of clinical remission was significantly improved with amiselimod (33.6% and 31.1% for the 0.2 mg/day and 0.4 mg/day groups, respectively, vs 17.8% for the placebo group; P=.01 and P=.03, respectively). Similarly, significant improvements in endoscopic remission were also observed (42.1% and 43.4% for the 0.2 mg/day and 0.4 mg/day amiselimod groups, respectively, vs 23.4% for the placebo group; P<.01 for both comparisons).

Biologic and Small Molecule Therapy Options Post–5-ASA

The VARSITY study was a clinical practice–changing head-to-head phase 3b trial of vedolizumab (n=383) vs adalimumab (n=386) in patients with moderate-to-severe UC.¹⁵ At week 52, significantly greater rates of clinical remission were observed in the vedolizumab group compared with the adalimumab group (31.3% vs 22.5%; 8.8% difference; 95% CI, 2.5-15.0; P=.006). Vedolizumab was also superior to adalimumab for achieving endoscopic improvement (39.7% vs 27.7%; 11.9% difference; 95% CI, 5.3-18.5; P<.001). The rates of corticosteroid-free clinical remission were 12.6% in the vedolizumab group and 21.8% in the adalimumab group (-9.3% difference; 95% CI, -18.9 to 0.4). This landmark study established vedolizumab as a first-line treatment for patients who have moderate-to-severe UC.

When mesalamine fails for the treatment of UC, there are now multiple drug classes that are effective for first-line advanced therapy. Taking disease severity, treatment efficacy, risk of adverse events, and patient preference into account, we should tailor our treatment decisions, as our best shot for controlling UC is the next drug we select after mesalamine.

— Corey A. Siegel, MD, MS

The retrospective, real-world EVOLVE study compared the efficacy of an anti-TNFT agent when given either prior to (first line) or after (second line) vedolizumab therapy in biologic-naive patients with UC (n=604) or CD (n=491).¹⁶ Two important conclusions arose from these data. First, vedolizumab and anti-TNF agents were found to be equally effective as first-line therapies for controlling disease symptoms in biologic-naive patients with UC; vedolizumab was shown to have a more favorable safety profile. Second, there was no decrease in efficacy noted with the use of an anti-TNF agent in the second line, providing a robust second-line option for patients.

A recent network meta-analysis of 36 studies compared the relative efficacy of a subset of biologics and small molecules in 14,270 patients with moderate-to-severe UC.¹⁷ This analysis found that upadacitinib appeared slightly superior to other therapies in achieving clinical remission, endoscopic improvement and remission, and histologic remission. However, novel biologics such as risankizumab and guselkumab also ranked high in achieving these outcomes.

It is well established that patients with active moderate-to-severe UC have their highest rates of response and remission with their first-line therapy, and show progressively lower rates after failure of 1 or more other advanced therapies.¹⁸ Thus, there is an increasing understanding that therapeutic decisions should position agents in order to give these patients the best possible chance to achieve clinical and endoscopic remission. To this end, the American Gastroenterological Association (AGA) recently published a living clinical practice guideline to provide clinicians with recommendations for the pharmacologic management of moderate-to-severe UC (Figure 3).¹⁹ In these guidelines, the AGA suggests using a higher- or intermediate-efficacy medication, as opposed to a lower-efficacy medication, for the first-line treatment of advanced therapy–naive patients. In these guidelines, higher-efficacy medications include infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab. Intermediate-efficacy medications include golimumab, ustekinumab, tofacitinib, filgotinib (not available in the United States), and mirikizumab, whereas lower-efficacy medications include adalimumab. When discussing these options with patients, the conversation should balance disease-related complications with the risk of treatment-related complications.

Figure 3.

Considerations for choosing the first therapy. ^aThe US Food and Drug Administration label recommends the use of Janus kinase inhibitors only in patients with prior failure or intolerance to tumor necrosis factor antagonists. Filgotinib is not available for use in the United States. Adapted from Kayal M. Progression of disease when mesalamine fails. Presented at: 2024 Advances in Inflammatory Bowel Disease Conference; December 9-11, 2024; Orlando, Florida.¹