Editorial: Is Disease Clearance the Target in Ulcerative Colitis or a Stride Too Far?

Danese et al. described the association between early disease clearance and long-term outcomes in patients with ulcerative colitis (UC) treated with ustekinumab in the UNIFI study 1. In this phase 3 study, participants were randomised to intravenous ustekinumab induction (130 mg or ~6 mg/kg) or placebo, and subcutaneous ustekinumab maintenance (90 mg every 8 or 12 weeks) or placebo, with the option to enrol in the long-term extension, remaining on maintenance therapy up to 220 weeks 2. Danese et al. have described how disease clearance, defined here as combined symptomatic remission and histo-endoscopic mucosal improvement (HEMI), was associated with improved long-term clinical, endoscopic, and histologic outcomes. The term 'disease clearance' was coined in 2020 as an ambitious target in UC aimed at improving treatment outcomes, reducing complications, and potentially modifying the natural history of disease 3. Current guidelines recommend endoscopic healing, normalised quality-of-life, and absence of disability as the long-term treatment goals, with histological healing considered an aspirational target, mainly due to a dearth of interventional trials assessing this endpoint 4. Danese et al. demonstrated that disease clearance is feasible in UC as early as 8 weeks, with 15.2% and 15.1% of ustekinumab-treated patients (130 mg and 6 mg/kg, respectively) achieving this aspirational treatment target. Rates of disease clearance increased at Week 44 of maintenance treatment, with 36.6% (ustekinumab 130 mg) and 41.6% (ustekinumab 6 mg/kg) of participants achieving disease clearance. These data add to the evidence that disease clearance, beyond histological healing, is attainable in UC 5, 6. Disease clearance has been associated with significantly lower risk of UC-related hospitalisation and surgery 7. In the UNIFI study, disease clearance at Week 8 was associated with significantly higher rates of clinical remission, symptomatic remission, histological improvement, endoscopic improvement, and HEMI at Week 44 (p < 0.001 for all outcomes), when compared to those who did not achieve disease clearance. Patients who achieved disease clearance were less likely to have treatment failure than those who did not achieve either symptomatic remission or HEMI (p < 0.001), or those who achieved symptomatic remission but not HEMI (p = 0.043). While the UNIFI long-term data are encouraging for the merits of attaining disease clearance in UC, it is not presented whether disease clearance imparts prognostic benefit beyond endoscopic remission or histological improvement. Furthermore, while early disease clearance is associated with improved long-term outcomes in UC, this is vastly different to escalating therapy sequentially to achieve this target. VERDICT (NCT04259138), a randomised-controlled trial which aims to determine the optimal treatment target in moderate-to-severe UC, will shed light on whether disease clearance leads to better outcomes than corticosteroid-free histologic remission. UNIFI has established that aspirational treatment targets, including disease clearance, are achievable and associated with improved long-term outcomes in patients with UC. We await further evidence to better understand whether therapy should be escalated to achieve disease clearance, or whether this remains a stride too far. R. M. Mathias: conceptualization, writing – original draft, writing – review and editing. D. Bogatic: conceptualization, writing – original draft, writing – review and editing. R. V. Bryant: conceptualization, writing – original draft, writing – review and editing. R.M. Mathias has received honorarium travel support from Dr. Falk Pharmaceuticals. D. Bogatic has received research support from The Gutsy Group and BiomeBank. R.V. Bryant has received grant/research support/speaker honoraria/advisory board fees from AbbVie, Ferring, Janssen, Shire, Takeda, GlaxoSmithKline, Bristol Myers Squibb, and Emerge Health; and is a shareholder in BiomeBank. This article is linked to Danese et al. papers. To view this article, visit https://doi.org/10.1111/apt.70264. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.