Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract that can lead to progressive bowel damage and disability. Due to the transmural nature of CD, fistulas, abscesses, and strictures frequently complicate the disease course. In particular, perianal fistulizing lesions in CD are strongly linked to more aggressive disease behavior and a poorer prognosis [1].
CD is considered multifactorial, with the microbiota and other environmental factors triggering inappropriate activation of the mucosal immune system in genetically susceptible hosts. A key pathogenic feature is the inflammatory infiltrate, which is characterized by the Th1/Th17 response with production of various proinflammatory cytokines (tumor necrosis factor [TNF]-α, interferon-γ, interleukin [IL]-1, IL-6, IL-12, and IL-23) along with impaired regulatory T-cell activity. Perianal fistulizing disease affects approximately 5% to 40% of patients during the course of their CD and is the initial manifestation of CD in approximately 10% of patients.
For most patients with fistulizing disease, multidisciplinary care from both gastroenterology and colorectal surgery is necessary. Anti-TNF agents are among the most effective therapies to induce and maintain remission in CD. Although three agents (infliximab [IFX], adalimumab, and certolizumab pegol) are approved, IFX is the only advanced therapy with a dedicated randomized controlled trial to show efficacy for the treatment of perianal disease [2,3].
It is recommended in the European Crohn’s and Colitis Organisation guidelines as a first-line medical therapy following adequate drainage of complex perianal fistulas [4]. Ustekinumab (UST; an anti-IL-12/23 p40 monoclonal antibody) is a therapy that targets alternative pathways to anti-TNF agents in the CD treatment. This drug appears to have fewer serious side effects and lower immunogenicity without the need for combination therapy with an immunomodulator.
Induction (UNITI-1 and UNITI-2) and maintenance trials have suggested that UST was effective for treating moderate to severe CD [5-7]. However, the role of UST in treating perianal CD remains limited. Recently, data from subgroup analyses from induction and maintenance trials suggested that UST resulted in some benefit for patients with perianal fistula [8].
Until now, there have been few studies on whether UST is useful in Asian patients with perianal CD. In this issue of Intestinal Research, Chen et al. [9] presented a study comparing UST with IFX to determine whether it is useful in patients with perianal fistulizing CD. Although this study is retrospective in nature and includes a relatively small number of patients, this study demonstrates the effectiveness of UST in treating perianal fistula of CD patients naive to biological agents in a real-world setting, particularly in Asian patients with perianal CD.
A key finding of this study is the comparison of the efficacy of UST and IFX as the first-line biologic used in the treatment of perianal fistulizing CD. Compared with IFX, UST exhibited significantly higher rates of treatment success (89.8% vs. 50.0%; P<0.001) and intestinal clinical response (85.7% vs.
68.8%; P=0.048). UST was shown to be as effective as IFX in terms of fistula remission, fistula response, fistula closure, intestinal clinical remission, endoscopic remission, and endoscopic response. The rates of disease relapse and operation in the IFX group were higher as compared to the UST group during follow-up.
Regarding safety, infection was the most common adverse event and there was no statistical difference in both groups. Therefore, in terms of safety issues, UST was found to be comparable to IFX. This finding shows that UST may serve as a promising alternative to IFX for the first-line biologic treatment of perianal fistulizing CD but there are several limitations to this study.
It was a single- center study with a relatively small sample size and retrospective design and a recent web-based survey conducted in Asia reported that Asian experts still overwhelmingly prefer anti-TNF agents as first-line treatment [10]. To overcome these limitations, larger prospective long-term comparative studies are thought to be necessary.