Ulcerative colitis (UC) is a chronic inflammatory disease characterized by recurrent bleeding, diarrhea, and abdominal pain [1], with a disease course ranging from mild symptoms to severe, potentially life-threatening conditions such as acute severe UC [2]. Given this wide spectrum of disease severity, timely selection of an appropriate and effective therapy is crucial, particularly for patients with moderate-to-severe UC.
The growing number of approved advanced therapies for UC has provided clinicians with more treatment options than ever, but has also made therapeutic decision-making increasingly complex. Beyond balancing efficacy, safety, and patient preference, a critical question is whether the initial therapeutic choice influences the success of subsequent treatments. The APPETISER study by M’Baye et al. [3] provides important insights into this issue.
In this real-world study, the authors compared effectiveness-based sequencing (EBS; infliximab or vedolizumab) with acceptability-based sequencing (ABS; adalimumab or golimumab) as first-line biologic therapy. Patients receiving EBS spent significantly more time in corticosteroid-free remission based on the 2-item patient-reported outcome over 24 months than those receiving ABS (74.2% vs. 46.6%), and this advantage persisted despite subsequent treatment adjustments in both groups.
Most importantly, subsequent treatment did not fully compensate for a less effective initial strategy. Although most patients in the ABS group subsequently received infliximab or vedolizumab as second-line therapy, the difference in disease control persisted, suggesting that delayed use of an effective therapy may not be equivalent to its early use.
The SLIT-UC study by Galts et al. [4] similarly demonstrated a lower clinical response at 1 year when infliximab was used as second-line or later therapy than when it was used as first-line therapy. However, this effect may not be universal across therapeutic sequences, as data from the UK IBD BioResource showed preserved effectiveness of anti-tumor necrosis factor therapy after vedolizumab failure [5]. Together, these findings suggest that the impact of therapeutic sequencing may depend on the individual agent and preceding treatment rather than simply the number of prior therapies.
With the recent expansion of therapeutic options for UC, advanced therapies now extend well beyond the biologics evaluated in the APPETISER study to include small molecules and newer biologic agents. Recent network meta-analyses suggest that upadacitinib ranks among the most effective therapies, while newer interleukin-23 inhibitors, including risankizumab and guselkumab, also demonstrate high efficacy [6]. The emergence of highly effective oral agents such as upadacitinib may blur the traditional distinction between effectiveness- and acceptability-based strategies.
Consequently, the key question may no longer be whether efficacy or acceptability should be prioritized, but rather whether highly effective therapies should be positioned earlier in the treatment sequence to maximize cumulative disease control.
Nevertheless, selecting the optimal therapy for an individual patient remains challenging and requires careful consideration of efficacy, safety, comorbidities, treatment burden, patient preference, and cost. The APPETISER study highlights the potential importance of early therapeutic choices; however, further prospective studies comparing different treatment sequences are needed to determine how best to integrate these factors and guide individualized treatment strategies that maximize long-term disease control.