Introduction

Perianal fistula is the most common complication of Crohn’s disease (CD), affectingapproximately 40% of patients. For patients with perianal abscesses and active draining fistula, seton or fistulotomy should be performed, followed by aggressive medical therapies, including anti-TNF agents. However, a significant proportion of patients are non-responders. There is insufficient evidence to confirm the efficacy of ustekinumab (UST), in promoting fistula closure in perianal fistulizing Crohn’s disease (CD) patients.

Aims & Methods

We aimed to evaluate the efficacy of UST in a real-world setting.
The data were retrospectively analyzed. Clinical and endoscopic changes were evaluated. Fistula radiological outcomes were determined using MRI.

Results

A total of 72 patients diagnosed with CD and receiving scheduled UST treatment were enrolled. Of these, 45 patients were excluded due to the absence of perianal fistula based on clinical symptoms and MRI scans, 5 for insufficient follow-up duration, and 5 for incomplete data. A total of 17 eligible patients were finally included, 2 patients did not have follow-up MRI, 65% (n=11) of whom were male, with a mean age of 28.2 ± 2.0 years at diagnosis and a mean disease duration of 3.4 ± 0.6 years. As for the Montreal classification, 62% of the patients were assigned to B1 (non-stricturing, non-penetrating) and 70% to L3 (ileocolonic) phenotypes. Most fistulas were inter-sphincteric (65%). After 58,66+-13,48 weeks of UST therapy, fistula closure was shown in 40% (n=6) of patients. In patients with endoscopical remission at 6 months of UST therapy, we did not detect significant difference in fistula closure (57.1% vs 42.9%, p=0.315).

Conclusion

UST is effective in promoting clinical and radiological fistula remission in patients with CD. Intestinal endoscopical remission may not be correlated with fistula outcome. Further research is needed for determining ustekinumab therapy efficacy for perianal fistula.

Introduction

Perianal Crohn’s disease (pCD) represents a challenging phenotype of Crohn's disease (CD). While risankizumab (RZB) has demonstrated efficacy in luminal CD, its role in pCD remains unknown. We aimed to evaluate the effectiveness of RZB in pCD and compare the outcomes with other biologics including anti-TNF, ustekinumab (UST), and vedolizumab (VDZ).

Aims & Methods

This retrospective multicenter study performed at nine international centers included adult patients with pCD who initiated RZB as advanced-line (second or more) therapy between 2020 and 2024. Historical controls included pairwise propensity-scored matched pCD patients treated with anti-TNF, UST, or VDZ as second- or third-line therapies. The primary outcome was clinical remission in patients with active pCD, defined as complete resolution of perianal symptoms. Secondary outcomes included clinical response (any symptomatic improvement) in active perianal disease, and relapse rates among patients with inactive pCD at baseline, defined as new or recurrent signs or symptoms of perianal disease.

Results

A total of 214 patients with active pCD were included: 59 (27.6%) received RZB, 62 (29.0%) anti-TNF, 57 (26.6%) UST, and 36 (16.8%) VDZ. Clinical remission was achieved in 58% of patients treated with RZB, compared to 32.9% of those receiving non-RZB therapies (p = 0.01), including 27% for anti-TNF, 44% for UST, and 25% for VDZ. Clinical pCD response rates were 81% for RZB, compared to 71% for anti-TNF, 88% for UST, and 44% for VDZ; p < 0.001. In propensity score–matched comparisons, remission rates with RZB were numerically higher than anti-TNF (56% vs. 31%, p = 0.056) and VDZ (58% vs. 29%, p = 0.08), and comparable to UST (53% vs. 43%, p = 0.5). The median time to clinical response with RZB was three months [IQR: 2–3.5], comparable to anti-TNF (3 [IQR: 2–4], p = 0.4), but significantly shorter than UST (5 [IQR: 4–6], p < 0.001) and VDZ (6.5 [IQR: 4–8], p < 0.001).
Among 160 patients with inactive pCD at baseline, matched analysis showed significantly lower relapse rates with RZB compared to anti-TNF (2% vs. 22%, p = 0.004) and VDZ (0% vs. 28%, p = 0.004), with no significant difference compared to UST (3% vs. 15%, p = 0.2).

Conclusion

Risankizumab demonstrates favorable clinical response, faster time to response, and higher remission rates in active pCD, along with the lowest relapse rates in inactive disease. These results support RZB as an effective therapeutic option for pCD, warranting prospective validation.

Disclosure

No conflicts of interest were declared in relation to this study.

Introduction

Local injection of darvadstrocel, a suspension of expanded adipose-derived allogenic mesenchymal stem cells with anti-inflammatory and immunomodulatory properties, represents a novel effective treatment for complex perianal fistulas in patients with Crohn's disease (CD).

Aims & Methods

The aim of this systematic review was to summarize reported evidence on the real-world outcomes of darvadstrocel for complex perianal fistulas in CD and to conduct a meta-analysis of effectiveness and safety data. A comprehensive search was led in electronic databases PubMed, Web of Science, EMBASE, Scopus and ScienceDirect until 15 April 2024 to identify observational studies evaluating darvadstrocel for complex fistulizing CD. Joanna Briggs Institute (JBI) Critical Appraisal tool was used to assess the study quality and the risk of bias. Random-effects meta-analysis model was used to calculate the pooled rates of clinical and safety outcomes. Heterogeneity across studies was assessed with the I² statistic according to Cochrane Handbook. The primary endpoint was clinical remission (closure of all treated external openings) at months 6 and 12. Adverse events (AE) were reported as incidence rates (IRs) per 100 patients-year (PY) of exposure.

Results

Of the 72 citations identified, 12 studies with 595 patients were eligible for inclusion. According to JBI criteria, 7 and 5 studies showed a low or moderate risk of bias, respectively. The pooled rate of patients achieving clinical remission was 68.1% at month 6 (95% CI 63.4-72.7) and 77.2% (95% CI 70.1-83.8) at month 12 (Table). Median time to achieve fistula closure was 6 weeks (95% CI 3.8-9.5). Combined remission defined as clinical remission and absence of collections > 2 cm confirmed by magnetic resonance imaging was reported in 60.6% and in 69.7% of patients at month 6 and month 12, respectively. Clinical response was observed in 79.9% and in 81.7% of patients at month 6 and month 12, respectively. The rate of patients with treatment failure, defined as no clinical remission, at last follow-up (mean 18.7 month; SD 9.9) was 34.5% (95% CI 25.7-43.9). Linear regression analysis indicated that failure rate was independent of follow-up time (R² = 0.001). For all effectiveness outcomes, between-study heterogeneity might not be important (Table).
Pooled IR per 100 PY of AEs and serious AEs were 19.6 and 3.2, respectively. IR per 100 PY of new perianal abscesses and reoperations were 16.9 and 7.1, respectively. For safety analyses, between-study heterogeneity ranged between moderate and substantial (Table).

Conclusion

Real-world evidence supports the efficacy and safety of darvadstrocel for complex perianal fistulas in CD. Studies reported high fistula healing rates that can be sustained long-term in most patients, with high homogeneity across studies. Darvadstrocel showed a favourable safety profile.

References

1. Panés J, García-Olmo D, Van Assche G, et al; ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388:1281-1290.
2. Panés J, García-Olmo D, Van Assche G, et al. Long-term efficacy and safety of stem cell therapy [Cx601] for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018;154:1334–42.e4.

Disclosure

CT has served as a speaker, consultant, and advisory board member for MSD, AbbVie, Pfizer, Takeda, Galapagos, Lilly, Fresenius Kabi, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, and Tillots. MAG, DO, ONL, RZ and CA have no conflicts of interest to declare.

Introduction

Perianal fistulas represent a major therapeutic challenge in Crohn’s disease, affecting up to 40% of patients and significantly impairing quality of life. Despite the advent of biologic therapies, failure rates remain high, necessitating the exploration of innovative strategies. Mesenchymal stem cells (MSCs), owing to their immunomodulatory, anti-inflammatory, and regenerative properties, have emerged as a promising therapeutic alternative.

Aims & Methods

We conducted a prospective, single-center, open-label, single-blind randomized study, enrolling 34 adult patients with Crohn’s disease complicated by complex perianal fistulas refractory to conventional therapies. All patients underwent a single local injection of autologous bone marrow-derived MSCs. Clinical, biological, and radiological assessments (pelvic MRI) were performed at 6, 12, and 24 weeks post-injection. The primary endpoints were complete clinical closure of external fistulous openings (EFOs) and radiological regression of fistulous tracts. Secondary endpoints included changes in Crohn’s Disease Activity Index (CDAI), C-reactive protein (CRP) levels, and quality of life assessed by a simplified IBDQ-9 score.

Results

• At 6 weeks: 32.3% (11/34) of patients achieved complete closure of EFOs, and 47.0% showed significant reduction in fistula drainage.
• At 12 weeks: 52.9% (18/34) achieved complete closure, and 23.5% (8/34) exhibited partial healing (>50% closure).
• At 24 weeks: 64.7% (22/34) had durable complete closure, while 20.6% (7/34) maintained partial healing.

Pelvic MRI evaluation revealed:

• A reduction in the number of active fistulous tracts in 73.5% of patients by week 12.
• Complete disappearance of fistulous tracts in 58.8% of cases by week 24.

Biological outcomes:

• CRP levels decreased from 13.8 ± 7.2 mg/L at baseline to 6.2 ± 3.4 mg/L at 6 weeks, 4.7 ± 2.5 mg/L at 12 weeks, and 3.9 ± 2.1 mg/L at 24 weeks (p < 0.001).
• CDAI scores improved from 176.2 ± 48.7 at baseline to 143.7 ± 41.2 at 6 weeks, 127.1 ± 37.5 at 12 weeks, and 122.4 ± 35.1 at 24 weeks (p < 0.001).
• Quality of life (IBDQ-9 score) improved by an average of 34% over 24 weeks (p < 0.001).

Safety:

• No serious adverse events or systemic infections were reported.

Conclusion

Our study demonstrates that autologous bone marrow-derived MSC therapy is a safe, effective, and innovative option for the management of complex perianal fistulas in Crohn’s disease. With an overall clinical response rate of 85.3% at 24 weeks, and significant improvements in inflammatory markers, fistula morphology, and quality of life, this cellular therapy emerges as a leading alternative in the therapeutic arsenal. Larger, multicenter, randomized controlled trials are warranted to validate these findings and refine optimal indications and protocols.

References

1. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in Crohn’s disease: results from the ADMIRE-CD trial extension. Lancet Gastroenterol Hepatol. 2021;6(11):889-97.
2. Lightner AL, Raffals LE, Mathis KL, Dozois EJ, Pemberton JH, Cima RR. Stem cell therapy for treatment of perianal Crohn’s disease: a systematic review and meta-analysis. Dis Colon Rectum. 2022;65(4):539-49.
3. Zhou Q, Zhou J, Qi X, Xu L, Yang H, Xie W, et al. Long-term outcomes of autologous adipose-derived stem cells in complex perianal fistulas in Crohn’s disease. Stem Cells Transl Med. 2023;12(2):210-20.

Introduction

Perianal fistulas occur in up to 30% of patients with Crohn’s disease (pfCD) and frequently require a combined medical and surgical treatment approach. Hyperbaric Oxygen Therapy (HBOT) has previously shown benefit in treatment-refractory pfCD.

Aims & Methods

In this pilot study, we aim to assess the feasibility of surgical fistula closure 4 weeks after HBOT, and efficacy of combining surgical closure and 8 weeks HBOT.
Patients with complex pfCD refractory to at least 6 months of anti-TNF therapy were included in this study. All patients received a seton prior to starting treatment with 40 sessions (8 weeks) of HBOT (each lasting 110 minutes, with 5-minute air breaks) with 100% oxygen at 2.4 atmosphere. At week 4 the seton was removed, and surgical closure of the internal fistula opening was attempted. All patients continued stable dose of medical treatment during the study. Response was assessed by the fistula drainage assessment (FDA) and the perianal disease activity index (PDAI) at week 9, 26 and 52, and by pelvic MRI at week 9 and 26. MRI response was defined as a decrease of 2 points in MAGNIFI-CD score, MRI remission as a MAGNIFI-CD ≤6. (Serious) Adverse Events (AE) were reported for 52 weeks. Univariate logistical regression was used to explore potential variates associated with PDAI response (≤4) at week 26.

Results

Ten patients completed treatment and were analyzed (Table 1). All patients completed HBOT and underwent a technically successful surgical procedure at week 4. No proctitis was encountered at week 4 during examination under anesthesia. PDAI response was achieved by 30%, 60%, 58% at week 9, 26 and 52, respectively. FDA response/remission was achieved in 50%/20%, 80%/40% and 80%/50% of patients at week 9, 26 and 52, respectively. MRI response/remission was achieved in 60%/10% and 60%/20% of patients at week 9 and 26, respectively. No significant parameters were associated with PDAI response at week 26 in univariate logistical regression. (S)AEs included one patient with a potential oxygen toxicity seizure without long term effects, and one patient reported claustrophobia, no new AEs were reported.

Table 1 Patient and fistula characteristics (n=10)

Conclusion

HBOT is feasible in combination with surgical therapy in patients with complex pfCD refractory to anti-TNF therapy. Patients had long-lasting benefit of the combined treatment approach. Further translational data are currently analyzed to clarify mechanisms of action and to explore potential biomarkers for therapy response.

Disclosure

LM, KB, JT and RvH have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this abstract. JS is President-elect of the European Society of Gastrointestinal and Abdominal Radiology. GD has served as consultant for AbbVie, Astrazeneca, Alimentiv, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson and Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus Biosciences, Tillotts and Ventyx; received speaker fees from AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly, Johnson and Johnson, Takeda, Pfizer Inc and Tillotts. CB has received grants from Boehringer Ingelheim and Roche; speakers honoraria from AbbVie, Janssen, Galapagos, Takeda, and Tillotts. KG has received grants from Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Immunic Therapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda and speaker’s honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts.