Ustekinumab in the Management of Perianal Fistulizing Crohn’s Disease: Current Evidence and Practical Strategies

Abstract

Perianal fistulizing Crohn’s disease (PFCD) is a severe and complex manifestation associated with high morbidity and limited treatment durability. Ustekinumab is a monoclonal antibody targeting the interleukin-12/23 pathway, which is involved in the pathogenesis of PFCD. Evidence from post hoc analyses and real-world studies has shown the therapeutic potential of ustekinumab in both anti-tumor necrosis factor-experienced and selected biologic-naïve patients with PFCD. Preliminary evidence has indicated that the treatment effect may be improved when used in combination with surgical interventions such as seton placement or sphincter-preserving procedures. Adjunctive antibiotics during induction and early monitoring of clinical and radiologic response may further enhance outcomes. While ustekinumab is increasingly being incorporated into multidisciplinary PFCD management, prospective fistula-specific trials are needed to clarify its optimal positioning. Future research should also focus on predictive biomarkers and treatment algorithms to support personalized and durable care.

Key Points

Ustekinumab is a monoclonal antibody targeting the interleukin-12/23 pathway, which plays an important role in the inflammation and epithelial-to-mesenchymal transition process in perianal fistulizing Crohn’s disease.

Post hoc analysis and real-world studies have demonstrated treatment effect of ustekinumab for perianal fistulizing Crohn’s disease, with a quick and sustained response.

A favorable response with ustekinumab was seen in both anti-tumor necrosis factor-experienced and biologic-naïve patients, indicating its potential to be used as either the first- or subsequent-line biologic for perianal fistulizing Crohn’s disease.

Introduction

Perianal fistulizing Crohn’s disease (PFCD) is a severe and complex phenotype of Crohn’s disease (CD) that affects approximately 17–43% of patients. Among those with rectal involvement, the risk of developing perianal fistulas exceeds 90% [1, 2]. Notably, 70–80% of PFCD cases are classified as complex fistulas, necessitating individualized and multidisciplinary treatment approaches [3, 4]. Clinically, PFCD is often characterized by chronic suppuration, pain, and impaired continence, leading to considerable psychological and physical distress.

Over time, treatment goals have shifted from symptom control only to achieving durable fistula closure and preventing recurrence [1]. Current management relies on a combination of surgical and medical interventions, emphasizing the importance of coordinated, multidisciplinary care [5]. Among biologic therapies, anti-tumor necrosis factor (anti-TNF) agents, such as infliximab and adalimumab, remain the cornerstone of treatment. However, their long-term efficacy is undermined by secondary loss of response and immunogenicity [5–8]. Infliximab remains the only biologic supported by randomized controlled trial (RCT) evidence specifically in PFCD [9], yet approximately one-third of responders experience loss of response during maintenance therapy [10].

Despite advancements in biologic therapies, a critical gap remains in understanding the efficacy and safety of newer agents in this particularly refractory phenotype. Ustekinumab, with a mechanism of action targeting pathways involved in the pathogenesis of fistulizing CD, has been investigated as a potential treatment option for PFCD. The American Gastroenterological Association (AGA) clinical practice guidelines include ustekinumab as a conditional recommendation for the medical management of adult outpatients with CD and active perianal fistula, although further evidence is warranted [7]. This narrative review examines the available evidence on ustekinumab in PFCD, exploring its immunological mechanism of action, clinical trial results, real-world data, and comparative outcomes. It also addresses practical considerations, including patient selection, combination strategies, and monitoring approaches.

Mechanistic Rationale for Ustekinumab in PFCD

The potential therapeutic effect of ustekinumab in PFCD is based on targeting the interleukin (IL)−12/23 signaling axis, a critical driver of chronic inflammation in CD [11]. Ustekinumab is a fully human monoclonal antibody that binds the shared p40 subunit of IL-12 and IL-23, blocking the activation of both Th1 and Th17 pathways (Fig. 1) [12]. This reduces downstream production of pro-inflammatory cytokines such as interferon-γ, TNF-α, IL-17, and IL-22, which are implicated in sustaining mucosal damage, impairing epithelial repair, and promoting fistula persistence.

Fig. 1.

Ustekinumab mechanism of action. Ustekinumab targets the shared p40 subunit of IL-12 and IL-23, blocking their binding to IL-12Rβ1 receptors. This inhibits downstream signaling, cell activation, and inflammatory cytokine release in various cells, including NK cells. IL interleukin, IL-12Rβ1 interleukin-12 receptor beta 1, NK natural killer

In PFCD specifically, IL-23 plays a key role in perpetuating local inflammation and has been shown to induce epithelial-to-mesenchymal transition, a process thought to underlie fistula tract formation [13]. Ustekinumab’s ability to suppress IL-23 signaling may therefore disrupt epithelial-to-mesenchymal-associated remodeling in fistulizing disease. In addition, by downregulating matrix metalloproteinases and cytokine-driven neutrophilic infiltration, ustekinumab may further limit tissue destruction in PFCD [13].

While anti-TNF therapies target a single inflammatory cytokine, ustekinumab acts upstream of multiple inflammatory pathways, offering a broader and more durable control, particularly in patients who have failed or are intolerant to anti-TNF agents. While the mechanistic rationale for ustekinumab in PFCD appears sound, direct clinical trial evidence demonstrating this benefit remains limited.

Clinical Evidence for Ustekinumab in PFCD

To comprehensively assess the current evidence of ustekinumab in patients with PFCD, a search was conducted using PubMed, Chinese Scientific Journal Database, Wanfang Data MED Online, and China National Knowledge Infrastructure. The search terms used in English were “(Ustekinumab) AND (Perianal Fistulizing Crohn’s Disease OR Perianal Crohn’s Disease),” while the Chinese search term was “Ustekinumab.” The search included studies published up to January 2026. A total of 18 studies, including both subgroup analyses from larger trials and retrospective observational studies involving patients with PFCD who were treated with ustekinumab, were identified. The efficacy outcomes are summarized in Table 1. The results summarized below are presented by post hoc analyses of RCTs and real-world studies in Sects. 3.1 and 3.2.

Table 1.

Efficacy outcomes of ustekinumab in patients with PFCD

Author year, (data collection period)	Country, city, study design	Patient characteristics	Treatment	Efficacy endpoints
RCTs
Wils 2026 [14]	France, prospective	N = 32	UST (6 mg/kg IV at baseline followed by 90 mg SC at week 8, then every 8 weeks) or placebo	Week 12: Combined clinical remission: 62% Clinical remission: 69% Radiologic remission: 87.5% Week 48: Combined clinical remission: 31%
Post hoc analysis of RCTs
Sands 2017 (NA) [16]	Multinational (pooled subgroup data from UNITI-1, UNITI-2, CERTIFI, IM-UNITI trials), prospective	N = 161 (pooled)	Pooled data from treatment groups: UST 1 mg/kg group, 3 mg/kg group, 6 mg/kg group, and 130 mg group	Week 8 (UNITI-1, UNITI-2, CERTIFI): Fistula response: 26.0% Fistula resolution: 24.7% Week 22 (CERTIFI): Fistula response: 47.4% Week 24 (IM-UNITI): Fistula response: 80.0%
Peyrin-Biroulet 2022 [17]	Multinational (subgroup data from SEAVUE and STARDUST trials), prospective	SEAVUE N = 13 STARDUST N = 19	SEAVUE Induction (IV infusion): UST 6 mg/kg body weight at baseline Maintenance (SC injection): UST 90 mg every 8 weeks STARDUST Induction (IV infusion): UST 6 mg/kg body weight at baseline 90 mg at week 8 Maintenance (SC injection): at week 16, standard of care (90 mg SC every 12 or 8 weeks) or treat-to-target (90 mg SC every 12 or 8 weeks)	Week 48 (STARDUST): Fistula resolution: 47.4% Week 52 (SEAVUE): Fistula resolution: 53.8%
Prospective observational study
Biemans 2020 (December 2016–January 2019) [19]	The Netherlands (multicenter), prospective	N = 28	Induction (IV infusion): UST at baseline was weight-based following label (260 mg < 55 kg, 390 mg between 55 and 85 kg, 520 mg > 85 kg). The first SC induction dose was 90 mg at week 8. Maintenance (SC injection): UST 90 mg every 8 or 12 weeks	Week 24: Fistula clinical response: 14.3% Fistula clinical remission: 35.7%
Retrospective real-world studies
Kopylov, 2014 (March 2011–November 2013) [23]	Canada, Montreal, retrospective	N = 13 Prior biologics: 100.0%	Induction: UST 45 mg at weeks 0 and 4, or 90 mg at weeks 0, 1, and 2 or weeks 0 and 4 Maintenance: UST 45 mg every 12 weeks or 90 mg every 4, 8, or 12 weeks	Week 12: Clinical response: 69.2% Week 52: Clinical response: 23.1%
Khorrami 2016 (Mar 2010–Dec 2014) [31]	Spain, multicenter, retrospective	N = 58 Prior biologics: 100.0%	Induction: the most frequent regimen was 90 mg of UST at weeks 0, 1, 2, and 3 (47%) Maintenance: the most frequent regimen was 90 mg every 8 weeks (75%)	Week 52: Clinical response: 61%
Wils 2016 (March 2011–December 2014) [43]	France and Switzerland, multicenter, retrospective	N = 12 Prior biologics: 100.0%	Induction: the most frequent regimen was 90 mg of UST at weeks 0 and 4 (47%)	Week 12: Clinical benefit: 66.6%
Ma 2017 (January 2011–July 2016) [22]	Canada, Calgary and Edmonton, retrospective	N = 45/167 Prior biologics: 95.2%	Induction (SC injection): the most common regimens were 90 mg at weeks 0 and 4 (35.1%), 90 mg at weeks 0, 1, and 2 (35.8%), and 270 mg at week 0 + 180 mg at weeks 1 and 2 (7.4%) Maintenance: the most frequent regimen was 90 mg every 8 weeks (82.6%) and every 12 weeks (15.6%)	Week 52: Fistula response: 48.9% Clinical remission: 26.7% Radiological fistula healing: 31.1%
Tsistrakis and Oikonomou 2017 (September 2016–June 2017) [44]	USA, New York, retrospective	N = 9 Female: 55.6% Prior biologics: 100%	IV infusion followed by SC injection	Week 12: Clinical response: 67% Fistula response: 44% Fistula healing: 11%
Chapuis-Biron 2022 (October 2017–June 2018) [24]	France (multicenter), retrospective	N = 148 Female: 64.9% Mean age: 38.4 years Mean disease duration: 14.3 years Prior biologics: 98.6%	Induction followed by SC injection of UST 90 mg every 4 or 6 weeks. Among patients with active perianal lesions at initiation, ustekinumab dose was optimized every 4 or 6 weeks	Week 12: Clinical efficacy: 61.5% Week 26: Clinical efficacy: 48.6% Clinical success: 38.5% Week 52: Clinical efficacy: 36.5% MRI efficacy: 50%
Attauabi 2020 (January 2015–January 2020) [27]	Denmark, retrospective	N = 18 Male: 61.1% Median age: 34 years Median disease duration: 17.3 years Prior biologics: 100% Complex fistula: 55.6%	Induction (IV infusion): UST 6 mg/kg body weight at baseline Maintenance (SC injection): UST 90 mg every 8 weeks	Week 8: Fistula response: 16.7% Week 16: Fistula response: 53.8% Week 52: Fistula response: 63.6%
Brewer 2021 [20]	USA, retrospective	N = 31 Male: 32.3% Median age at UST initiation: 36 years Disease duration at time of induction: 12.5 years	UST 260, 390, or 520 mg: 30 patients UST 270 mg: 1 patient	6 months: Perianal fistula response: 48.1% (13/27) Perianal fistula remission: none
Plevris 2020 [45]	Scotland, multicenter, retrospective	N = 216 Median age: 39.0 years Male: 42.1% Perianal disease: 17.1%	UST: week 0 IV loading plus week 8, 90 mg of SC dose	Week 26 Fistula response: 12.5% Week 52: Fistula response: 53.1%
Li 2023 (January 2020–March 2022) [21]	Nanjing, China, retrospective	N = 64	UST combined with sphincter-preserving surgery	Week 8: Clinical remission: 46.9% Clinical response: 68.8% Fistula response: 23.4% Week 16: Clinical remission: 59.4% Clinical response: 79.7% Fistula response: 40.6% Follow-up endpoint: Fistula remission: 21.9% Fistula response: 51.6% MRI fistula remission: 9.3%
Yao 2023 (March 2020–October 2022) [30]	Guangzhou, China, retrospective	N = 108 Male: 74.1% Mean age: 29.2 years Disease duration: 4.3 years Complex fistulas: 43.5%	Perianal surgeries: Performed before the initiation of UST if needed. UST treatment: Induction (IV infusion): UST 260 mg for BW < 55 kg, 390 mg for BW between 55 and 85 kg, and 520 mg for BW > 85 kg Maintenance (SC injection): UST 90 mg every 8 or 12 weeks	Weeks 16/20: Intestinal clinical remission: 65.7% Intestinal clinical response: 71.3% Endoscopic remission: 31.5% Endoscopic response: 45.4% Fistula clinical remission: 40.7% Fistula clinical response: 63.0% MRI fistula healing: 44.8% MRI partial response: 31.4%
Chen 2023 (October 2020–March 2023) [29]	Suzhou, China, retrospective	N = 44 Prior biologics: 0.0%	Traditional therapy: Had received 1–2 weeks and had not received biologics before UST UST treatment: Induction (IV infusion): UST 260 mg for BW < 55 kg, 390 mg for BW between 55–85 kg, and 520 mg for BW > 85 kg Maintenance (SC injection): UST 90 mg every 8 or 12 weeks	Week 24: Closure rate of anal lesions: 87.2% Week 48: Closure rate of anal lesions: 100.0%
Zhang 2023 (January 2022–March 2023) [25]	Wenzhou, China, retrospective	N = 60 Male: 76.7% Mean age: 25.0 years Complex fistulas: 100%	UST treatment: Induction (IV infusion): UST 6 mg/kg body weight at weeks 0 and 8 Maintenance (SC injection): UST 90 mg every 8 weeks	Week 8: Clinical response: 41.7% Intestinal clinical response: 53.3% Clinical remission of anal fistula: 21.7% Fistula clinical response: 41.7% Week 16: Intestinal clinical remission: 61.7% Intestinal clinical response: 70.0% Clinical remission of anal fistula: 31.7% Fistula clinical response: 55.0% Weeks 22–26: Intestinal clinical remission: 75.0% Intestinal clinical response: 83.3% Clinical remission of anal fistula: 43.3% Fistula clinical response: 63.3% MRI fistula healing: 38.3% MRI partial response: 45.0%
Chen 2024 (NR) [26]	Nanjing, China, retrospective	N = 131 Prior biologics: 69.5% Mean follow-up: 70.4 weeks	Had at least 1 year of follow-up after initiation of UST and began UST between November 2020 and September 2022	Last follow-up: Intestinal clinical remission: 84.7% Intestinal clinical response: 90.8% Fistula clinical remission: 62.6% Fistula clinical response: 90.8%
Chen 2025 (November 2020–March 2023) [32]	China, retrospective	N = 143 Prior biologics: 65.7 % Mean follow-up: 136.4 weeks	UST treatment: Induction (IV infusion): UST 260 mg for BW < 55 kg, 390 mg for BW between 55–85 kg, and 520 mg for BW > 85 kg Maintenance (SC injection): UST 90 mg every 8 or 12 weeks	Last follow-up: Clinical remission: 73.9 % Maintained remission: 69.7 % Deep remission: 40%

BW body weight, IV intravenous, MRI magnetic resonance imaging, NA not available, NR not reported, PFCD perianal fistulizing Crohn’s disease, RCT randomized controlled trial, SC subcutaneous, UST ustekinumab

RCTs and Post Hoc Analyses of RCTs

In the recent randomized controlled USTAP trial, 32 adult patients with active draining PFCD were randomized to either ustekinumab or placebo after seton placement [14]. At week 12, clinical remission was 69% with ustekinumab versus 31% with placebo; while radiologic remission was 87.5% versus 75%. Post hoc analyses of large trials in moderate-to-severe CD have also provide valuable insights into the efficacy of ustekinumab in terms of fistula healing (Table 1). In the UNITI-1 and UNITI-2 phase III induction studies that targeted patients with prior failure to anti-TNF treatment or conventional therapy, ustekinumab demonstrated numerically higher fistula response rates than placebo. A pooled analysis of data from UNITI-1, UNITI-2, and the CERTIFI phase IIb study found that, at week 8, 26.0% of ustekinumab-treated patients with active fistulas at baseline achieved a fistula response (≥ 50% reduction in draining fistulas) versus 16.9% of patients in the placebo group [15]. Complete fistula resolution (100% reduction) was observed in 24.7% of ustekinumab-treated patients compared with 14.1% of placebo-treated patients [16]. These differences did not reach statistical significance, likely owing to limited sample sizes, and the trials were not designed with perianal fistula as the primary endpoint.

Post hoc analyses of clinical trials have provided preliminary evidence on the sustained efficacy of ustekinumab in fistula healing. In the maintenance study phase, fistula response rates were consistently higher with ustekinumab versus placebo: 47% versus 30% at week 22 (CERTIFI) and 80% versus 45.5% at week 44 (IM-UNITI) [16]. The phase IIIb STARDUST and SEAVUE trials demonstrated complete fistula closure in 47.4% (week 48) and 53.8% (week 52) of ustekinumab-treated patients, respectively [17]. However, these findings should be interpreted with caution owing to their retrospective nature, small subgroup sizes, and lack of statistical power for perianal endpoints. While they suggest ustekinumab’s therapeutic effects may deepen over time, prospective trials with dedicated fistula endpoints are needed for confirmation, particularly given the high placebo response rates observed in recent PFCD RCTs [18]. Efficient trial design that minimizes placebo rates could mitigate this issue and enhance detection of the true treatment difference between ustekinumab and placebo.

The efficacy of ustekinumab in PFCD across 8–52 weeks is illustrated in Fig. 2.

Fig. 2.

Efficacy of ustekinumab in patients with PFCD across different durations of treatment. PFCD perianal fistulizing Crohn’s disease

Real-World Studies

Real-world data offer additional insights into the use of ustekinumab in PFCD (Table 1). Multiple retrospective cohort studies have demonstrated fistula response rates of 35.7–48.9% and clinical remission rates of 26.7–59.4% over follow-up periods ranging from 16 to 52 weeks [19–22]. Kopylov et al. observed early response in 69.2% of TNF-refractory patients at week 12, with sustained response in 23.1% at week 52 [23]. A large French multicenter study by Chapuis-Biron et al. showed 38.5% treatment success at 6 months in patients with heterogeneous PFCD presentations (primary lesions, secondary lesions, and long-term inflammatory complications), with sustained response rates of 61.5% at week 12 and 36.5% at week 52. Magnetic resonance imaging (MRI) improvement occurred in 50% of patients who underwent imaging, and among those with inactive PFCD history, recurrence-free survival was 75.1% at week 52 [24].

Evidence for ustekinumab in complex PFCD, which is known to be more treatment-resistant, shows encouraging outcomes. Zhang et al. demonstrated increasing clinical response (from 41.7% at week 8 to 63.3% at weeks 22–26) and remission (21.7–43.3%) over time, with notable radiological (73.7%) and endoscopic (45.0%) improvements [25]. A large retrospective study by Chen et al. followed 131 patients with PFCD for over 1 year, reporting week 52 remission rates of 77.1% (intestinal) and 55.0% (fistula), which rose to 84.7% and 62.6%, respectively, at the last follow-up [26].

A meta-analysis by Attauabi et al. synthesized findings from observational studies and estimated pooled fistula response and remission rates of 41.0% and 17.1% at week 8, maintained at 55.9% and 16.7% by week 52, respectively [27]. Inter-study heterogeneity was high, and the observational nature of these studies limits definitive conclusions. Overall, these results suggest that ustekinumab may have a role in managing PFCD, though the magnitude of benefit and optimal patient selection remain to be fully defined. On the basis of the collective evidence shown above, ustekinumab has shown activity for PFCD as early as week 8, with responses maintained in some patients up to week 52.

Comparative Efficacy: Ustekinumab versus Anti-TNF Agents as First-Line Therapy

Although anti-TNF agents have historically served as the first-line biologic therapy for PFCD, emerging data suggest that ustekinumab may offer comparable efficacy in biologic-naïve patients (Fig. 3). In addition, a meta-analysis reported that approximately half of the patients with PFCD who discontinued anti-TNF therapy experienced a relapse within 2 years [28]. Given its distinct mechanism of action targeting the IL-12/23 pathway, together with a favorable safety and immunogenicity profile, and high relapse rates associated with discontinuing anti-TNF therapy, ustekinumab could be considered a viable first-line option for PFCD management in selected patients.

Fig. 3.

Efficacy of ustekinumab in biologic-naïve and biologic-experienced patients with PFCD. PFCD perianal fistulizing Crohn’s disease

In the only available head-to-head comparison, a subgroup analysis of the SEAVUE trial in biologic-naïve patients demonstrated a numerically greater rate of complete fistula resolution with ustekinumab than adalimumab at week 52 (53.8% versus 37.5%, respectively) [17]. However, this analysis was not statistically powered for PFCD-specific outcomes, and the difference did not reach statistical significance. These findings provided preliminary evidence that ustekinumab performs at least as well as a standard anti-TNF agent in this population.

In addition, real-world evidence has provided exploratory data on ustekinumab as a first-line agent. In a retrospective cohort of 44 biologic-naïve patients with PFCD, Chen et al. reported perianal lesion closure in 84.1% of patients at week 24 and 100% at week 48 following ustekinumab induction [29]. Similarly, Zhang et al. observed that biologic-naïve patients treated with ustekinumab achieved significantly higher rates of fistula clinical remission (54.8% versus 31.0%), MRI-based healing (48.4% versus 27.6%), and endoscopic remission (54.8% versus 34.5%) compared with patients previously exposed to biologics [25]. Yao et al. further reported better intestinal and perianal outcomes with ustekinumab in TNF-naïve patients than TNF-treated patients, including a significantly higher intestinal clinical remission rate (78.9% versus 58.6%, P = 0.033), fistula clinical remission (52.6% versus 34.3%), endoscopic remission (40.0% versus 26.6%), and radiological remission (56.0% versus 38.1%) [30]. Although available evidence is limited, it suggests a possible favorable response in patients with PFCD who receive ustekinumab as the first biologic treatment.

These findings collectively support the consideration of ustekinumab as a reasonable option not only in the second-line setting for PFCD after anti-TNF failure but also as a first-line biologic in patients with high-risk features, intolerance to TNF inhibitors, or early in the disease course. Well powered, prospective trials specifically designed to compare ustekinumab with anti-TNF agents in biologic-naïve patients with PFCD are warranted to guide treatment algorithms more definitively.

Practical Management Strategies

Anti-TNF Failure

Appropriate patient selection is critical to optimizing ustekinumab therapy in PFCD. Ustekinumab has traditionally been employed as a second-line biologic in patients who experienced inadequate response, secondary loss of response, or intolerance to anti-TNF agents. In this context, ustekinumab provides a mechanistically distinct option by targeting the IL-12/23 pathway, and its low immunogenicity may reduce the risk of anti-drug antibody formation, which is an important consideration in patients with prior biologic exposure.

Real-world data suggest activity of ustekinumab in this treatment-refractory population. Clinical response and remission rates following transition from anti-TNF therapy range from 48.1 to 60.3% at 6 months, and up to 63.6% at 12 months [19, 20, 22, 23, 27, 31]. These findings are particularly notable in patients with secondary loss of response, who may retain a pro-inflammatory cytokine profile responsive to IL-12/23 inhibition. In a more recent study in Chinese patients, the majority of whom received prior biologic therapy and had active perianal fistulas, 73.9% achieved clinical remission with ustekinumab initiation, while deep remission was achieved in 40% of evaluable patients [32]. Longer treatment duration is required to achieve deep remission, and as such in this retrospective study, patients continued to receive treatment for a median of 32.1 weeks after clinical remission. This was still shorter than with anti-TNF therapy [33, 34]. Notably, 83 patients (69.7%) maintained sustained remission throughout the entire follow-up period without relapse after initial fistula healing [32]. Only seven patients (6.3%) experienced relapse, with a 2-year relapse-free survival rate of 93.4%, indicating a low relapse rate.

Maintenance Therapy

The optimal duration of maintenance therapy after achieving clinical remission in perianal CD remains controversial. However, current available evidence supports continuing ustekinumab treatment for at least 6 months after achieving clinical remission to reduce the risk of adverse outcomes, particularly relapse [17, 32]. Even when perianal lesions achieve clinical remission, continued maintenance therapy is recommended, which is consistent with the approach for intestinal disease management.

Ustekinumab as a First-Line Biologic

Simultaneously, emerging but limited evidence suggests the potential benefit of ustekinumab as a first-line biologic in carefully selected patients with PFCD. In biologic-naïve cohorts, ustekinumab has demonstrated encouraging rates of perianal lesion closure, fistula clinical remission, and radiologic improvement [25, 29, 30]. In one study, the authors found that previous biologic exposure (hazard ratio [HR] 0.38) and ileocolonic disease location (HR 0.47) were significantly negatively associated with achieving deep remission [32]. This suggests a potential role for ustekinumab as an initial treatment, especially in patients who are unsuitable for anti-TNF therapy owing to comorbidities such as serious infections, demyelinating disorders, or elevated malignancy risk. The position of ustekinumab in the treatment algorithm for PFCD warrants a revisit, and ustekinumab may be considered as an initial pharmacological treatment for patients with CD and active perianal fistula, which is a conditional recommendation in the AGA clinical practice guidelines [7].

Combination Therapy

Given the multifactorial and treatment-resistant nature of PFCD, ustekinumab as a standalone therapy could be ineffective. Instead, it may achieve better results when incorporated into a comprehensive, multidisciplinary management plan that includes surgical and, when appropriate, antibiotic interventions.

Surgical optimization is particularly important. Procedures such as seton placement or sphincter-preserving surgery play a critical role in managing sepsis, maintaining tract drainage, and establishing conditions conducive for patients to receive biologic treatment. The use of seton to control sepsis initially, followed by gradual removal after achieving response with a biologic agent to achieve closure with medication only, is an established practice [35, 36]. Chapuis-Biron et al. found that 32.9% of patients starting ustekinumab therapy with setons in place were able to achieve successful seton removal during follow-up [24]. Furthermore, in a real-world study by Li et al., patients with PFCD treated with ustekinumab in conjunction with sphincter-preserving surgery achieved a clinical remission rate of 46.9% and a fistula response rate of 23.4% by week 8 [21], suggesting a potential synergy between surgical and biologic co-management. On the basis of the available evidence and experience with other biologics, using seton drainage prior to ustekinumab may improve fistula healing, and combining ustekinumab with surgical fistula closure in amenable patients may lead to better outcomes, although evidence from clinical trials is required.

Adjunctive antibiotic therapy, such as ciprofloxacin or metronidazole, may provide short-term benefit during the induction phase, particularly in patients with persistent drainage or local signs of infection. While direct evidence for antibiotic use alongside ustekinumab is limited [37, 38], extrapolation from anti-TNF literature supports this approach [39, 40]. Early use of antibiotics may reduce bacterial burden and inflammation, enhancing early symptom control and biologic efficacy.

Additional Interventions

Additional perianal disease management may be required to optimize ustekinumab outcomes. In Chen et al., 90 of the 119 patients (75.6%) with active PFCD required additional intervention while on ustekinumab. This included dose intensification or interval shortening, intravenous reinduction therapy, and surgery [32]. Management of PFCD is dynamic as it is based on the disease activity in both intestinal and perianal sites; therefore, treatment switching or optimization should be guided by intestinal disease control. Perianal lesions often benefit from aggressive surgical intervention to improve healing rates. While perianal disease alone should not drive biologic switching decisions, it could be considered if the intestinal disease is well controlled, but the perianal lesions remain poorly controlled despite adequate surgical drainage.

Predictors of Treatment Response

Identifying predictors of clinical and deep remission can optimize treatment. Absence of involvement, male sex, and younger age at disease onset are associated with deep remission or better clinical response with anti-TNF therapy [41]. For ustekinumab, prior biologic exposure was significantly associated with both clinical remission and deep remission with ustekinumab use [24, 30, 32]; ileocolonic lesions are an independent predictor of deep remission, and the presence of complex fistulas is associated with deep remission [32, 34], while extraphincteric fistulas are independent predictors of clinical remission [32]. On the contrary, supra-sphincteric fistulas are associated with poor fistula outcomes [32, 42].

Monitoring Treatment Response

Monitoring treatment response is essential to guiding ongoing ustekinumab therapy. Clinical improvement, defined by reductions in drainage, pain, and perianal induration, should be evaluated within 8–12 weeks of the initiation of treatment. In cases where deep tract activity or healing status is uncertain, pelvic MRI can aid in assessing radiologic response and determining whether surgical or medical adjustments are needed. Treatment decisions should be dynamic and informed by symptom trajectory, structural healing, and overall disease control.

The complexity of fistula anatomy should also inform treatment decisions. While ustekinumab has shown benefit in complex perianal fistulas, outcomes are typically improved when preceded by appropriate surgical intervention, particularly in the presence of active abscesses or undrained sepsis. As with all biologic agents, infectious control and tract stabilization should be confirmed prior to initiating therapy. This approach aligns with current guidelines and expert recommendations [35, 36].

In summary, ustekinumab may perform better within a staged, integrated multimodal treatment approach that combines tailored biologic therapy with surgical drainage, tract management, and targeted symptom monitoring. Future studies should aim to refine standardized treatment pathways that reflect this multimodal paradigm, especially for complex or refractory PFCD.

Future Directions

Despite growing evidence supporting the use of ustekinumab in PFCD, several important gaps remain and warrant further investigation. Most current data are derived from post hoc analyses or real-world cohorts, with limited RCTs specifically designed to evaluate perianal outcomes. There is a pressing need for prospective, PFCD-focused RCTs with standardized definitions of response, remission, and imaging endpoints to validate the role of ustekinumab more definitively.

Another critical area for advancement is the integration of objective monitoring tools, such as MRI-based response indices and biomarkers (e.g. fecal calprotectin, C-reactive protein), into routine clinical practice. Establishing validated composite endpoints that combine clinical, radiological, and patient-reported outcomes could greatly enhance disease assessment and treatment personalization.

Furthermore, the optimal sequencing and positioning of ustekinumab relative to other advanced therapies, such as vedolizumab, risankizumab, and Janus kinase inhibitors, remains unclear. Head-to-head trials and comparative effectiveness studies, particularly in biologic-naïve populations, are needed to inform treatment algorithms. The potential role of combination biologic therapy or sequential induction strategies also deserves exploration, especially in highly refractory or structurally complex cases.

Finally, there is increasing interest in precision medicine approaches that integrate fistula phenotype, immunologic profiling, microbiome signatures, and host genetics to guide therapy selection. Future research should aim to identify predictive biomarkers of response to ustekinumab, which could enable earlier, more effective treatment for high-risk patients.

Conclusions

Ustekinumab represents a potential therapeutic option for the management of PFCD, particularly in patients who are refractory to, or intolerant of, anti-TNF agents. By targeting the IL-12/23 axis, ustekinumab demonstrates sustained efficacy in achieving fistula response, with real-world evidence supporting response rates of 35.7–48.9% and clinical remission in 26.7–59.4% of patients over 16–52 weeks. While commonly used in the second-line setting, following anti-TNF progression, emerging data suggest its potential as a first-line treatment in selected biologic-naïve patients, particularly those contraindicated for anti-TNF therapy. Optimizing clinical response and remission rates of ustekinumab in PFCD requires a combination of interventions such as surgical drainage and adjunctive interventions. Prospective, adequately powered clinical trials with perianal-specific endpoints are needed to refine its use, define its place in treatment algorithms, and optimize long-term outcomes for this challenging and burdensome phenotype.

Author Contributions

Bolin Yang conceptualized the study design, performed the literature search, analyzed the data, performed data interpretation, and wrote and approved the final version.

Funding

This study was sponsored by Johnson & Johnson Innovative Medicine.

Data Availability

Not applicable.

Code Availability

Not applicable.

Declarations

Conflicts of Interest

Bolin Yang has no conflicts to disclose.

Ethics Approval

Not applicable.

Consent to Participate

Note applicable.

Consent for Publication

Not applicable.