Introduction

Perianal fistulizing Crohn’s disease (CD) is frequent (in up to one quarter of patients within two decades of the diagnosis) (1) and represents a chronic, highly debilitating and difficult-to-treat condition. Whereas the efficacy and safety of darvastrocel (a suspension of expanded human allogeneic, adipose-derived mesenchymal stem cells) have been demonstrated in a phase 3 randomized double-blind placebo-controlled multicenter trial (ADMIRE-CD 1), a second randomized trial (ADMIRE CD 2) was recently reported negative. Real life data about the long-term efficacy of darvadstrocel for treating perianal fistulas in Crohn’s disease (CD) remain scarce.

Aims & Methods

Aim: to report the effectiveness and safety of darvadstrocel therapy to close perianal fistula in a real-life cohort of CD patients.
Methods: We retrospectively collected data from all CD patients with draining perianal fistulas treated with a single local injection of darvadstrocel. All patients with nonactive or mildly active luminal CD with complex anoperineal fistula who were treated with darvadstrocel were enrolled. Darvadstrocel was locally injected following the standardized procedure of ADMIRE trial. All patients underwent removal of seton, fistula curettage, transanal closure of internal opening(s) by suture followed by local injection of 120 million of mesenchymal stem cells in outpatient surgery.
The primary endpoint was clinical remission (closure of all external openings with no discharge at pressure) at week 24. Combined remission (defined as clinically plus MRI-assessed fistula closure) were also assessed at week 24 and 52.Incidence and time to fistula relapse assessed by Kaplan Meier estimates or new fistula occurrence as well as need for anal surgery were recorded. Short and long-term adverse events were also collected.

Results

A total of 36 refractory CD patients (19 Male, mean age 38.5 years) from 2 referral French IBD centers were included with a median follow up of 16 months. Patients had CD for a mean (±SD) of 10.5 ± 8.5 years and all had received previous immunosuppressants in the past 6 months and were also receiving concomitant immunosuppressive medications. One quarter of them had a history of diverting stomas. The vast majority of patients had a transphincteric fistula tract (83 %) and only one internal opening (80 %). Clinical remission was achieved in 17 out of 36 patients (47.2 %) and combined remission in 15 out of 36 patients (41.6 %) at week 24. At week 52, clinical and combined remission was achieved in 17 out of 36 patients (47.2 %) and in 15 out of 33 evaluable patients (45.4 %), respectively. The probabilities of relapse-free survival was 87.1 %, 74.2 % and 55.6 % at week 24, 40 and 60, In responders at week 12, fistula relapse occurred in 50 % of patients with a median time of 34 weeks (10-71) and no new fistula was clinically and radiologically evidenced. We failed to detect any predictors of response. No new safety issues, including changes in anal continence, tumorigenity or ectopic tissue formation were recorded throughout the study period.

Conclusion

This real-life based study shares additional experience on the effectiveness and safety of a single local injection of darvadstrocel for treating complex perianal fistula in a particularly severe and refractory cohort of patients with CD. Clinical remission was achieved in 47.2 % of patients at week 24 and combined remission in one more than 4 out of 10 patients at 52 weeks. Long-term larger studies are needed to better identify predictors of sustained fistula healing using darvadstrocel in perianal fistulizing CD.

Introduction

Approximately 10-15% of patients with Crohn's Disease (CD) experience penetrating complications during disease course, which significantly burdens patients' lives and impacts the healthcare system. Efficacy and safety of adipose-derived mesenchymal stem cell (MSC) transplantation (darvastrocel) in treating CD complicated by complex perianal fistulas are contradicting and real-world data are lacking.

Aims & Methods

Our study aimed to assess the effectiveness and safety of MSC therapy in managing perianal Crohn’s disease. This was a retrospective, multicenter cohort study enrolling CD patients with perianal fistulas. Baseline is defined as the day of MSC treatment while the follow-up is set at 6 to 12 months. Primary outcome was perianal clinical remission at w26 (defined by closure of all external openings), while secondary outcomes were clinical response rate, perianal clinical activity (defined by Perianal Disease Activity Index [PDAI]), and adverse events. Demographic, clinical, and surgical data were recorded at baseline, w12, w26, and at w52. Predictors of treatment failure were analyzed by logistic regression models.

Results

Overall, data of 69 patients (male/female ratio was 0.52 and median age was 36 [IQR 31-44]) were analyzed with a median follow-up duration of 52 [IQR 48-53] weeks. Perianal clinical remission was achieved in 49.3% until w26 and 44.9% (intention-to-treat) and 53.44% (per protocol) until w52, while baseline PDAI (OR 0.77, p = 0.043) score was associated with treatment failure. Characteristics of perianal fistulas were not linked to primary outcome. Clinical response rates were 69.6% at w26 and 78.3% (intention-to-treat) and 74.1% (per protocol) at w52. PDAI scores were decreased to w52 (5.2 [±3.1] to 3.2 [±2.8], p < 0.001). Worsening of perianal symptoms were not recorded, while improvement was reported in 78.8%, 81.1%, and 85.7% of cases at w12, w26, and w52. Total adverse events occurred in 8.7%, which were needed surgical reintervention. Furthermore, emerging stenosis, anal incontinence and severe infection were not registered.

Table 1. Baseline demographic and clinical characteristics of enrolled patients

Conclusion

Efficacy data are consisted with the registration ADMIRE study, more than 80% of patients benefit from the treatment, however the appearance of spontaneous closure is high in the literature. The safety profile is reassuring, and patients’ satisfaction is high.

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

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 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.