Management of anal fistulas in Crohn's disease after failure of Infliximab.

INTRODUCTION: Treatment of complex perianal fistulas in Crohn's disease remains a challenge especially after the failure of Infliximab. AIM: Update on the different therapeutic alternatives for anal fistula in Crohn's disease after failure of Infliximab. METHODS: A research in the medical literature on PubMed and Google Scholar was carried out. We included cohort studies, reviews and randomized double-blinded therapeutic trials. Case reports and fundamental research studies have been excluded. RESULTS: Anti-TNF therapy, notably Infliximab remain the therapeutic option of choice. Since Infliximab efficacy has been estimated at 60%, with a significant loss-of response rate, new therapeutic strategies have been evaluated and may offer new opportunities for the management of anal fistulas: for example, Ustekinumab could be effective after failure of anti-TNF therapy, although further studies are required. Recent guidelines suggest that injection of mesenchymal stem cells is an effective and safe treatment for complex fistulas. Other surgical options have been proposed, such as endorectal advancement flap, fibrin glue injection, anal fistula plug and ligation of the intersphincteric fistula tract, but all with limited and debatable efficacy. Given the failure rate of all these options, new strategies are currently being evaluated. CONCLUSION: Anal fistulas in Crohn's disease are a real therapeutic challenge. New medical and surgical therapies are currently being evaluated, with promising results.

Clinical Study on the Treatment of Complex Anal Fistula by Phased Chinese Herbal Sitz Bath Based on "Fuzheng Quxie" Theory.

Objective: To evaluate the clinical efficacy of a phased Chinese herbal sitz bath for the treatment of complex anal fistula based on the traditional Chinese medicine theory of "Fuzheng Quxie." Methods: We enrolled 200 patients with complex anal fistula who were hospitalized and treated surgically in the Department of Anorectal Medicine of Suining Central Hospital from June 2021 to December 2022. The patients were randomly divided into 2 groups of 100 patients each: sitz bath group 1 (postoperation, the patients used a sitz bath with a self-formulated decoction of "Qingre Zaoshi Zhitong" formula, once in the morning and once in the evening) and sitz bath group 2 (postoperation, the patients used the same decoction as the sitz bath group 1, and when the incision began to heal, the patients then used a sitz bath with a self-formulated decoction of "Yiqi Fuzheng" formula, once in the morning and once in the evening). Both groups were treated for 6 weeks. The assessments included wound symptom score, incision healing time, clinical efficacy after treatment, and serum-related growth factor concentrations and anorectal dynamics indicators before and after treatment. Results: After treatment, sitz bath group 2 had less wound pain, edema, exudate, and granulation growth scores than sitz bath group 1 (P < .05). Postoperative incision healing time was faster in sitz bath group 2 22.96 (1.96) d than in sitz bath group 1 26.19 (2.62) d (t = 9.872, P < .001). The total effective rate after treatment was higher in sitz bath group 2 96% (96/100) than in sitz bath group 1 88% (88/100) (χ2 = 4.4, P = .04). Serum transforming growth factor ß, epidermal growth factor, and basic fibroblast growth factor concentrations were higher in both groups after treatment than before treatment, and the concentrations of the growth factors after treatment were higher for sitz bath group 2 than for sitz bath group 1 (P < .001). Anal rest pressure and anal maximum contraction pressure were higher in both groups after treatment than before treatment, and the pressures after treatment were higher for sitz bath group 2 than for sitz bath group 1 (P < .05). Conclusion: Based on the theory of Fuzheng Quxie, the effectiveness and superiority of a phased Chinese herbal sitz bath for the treatment of complex anal fistula were remarkable, which could promote the improvement of wound symptoms and anal function. This may be related to increases in growth factor concentrations and anorectal dynamics indicators.

Development of an MRI-Based Prediction Model for Anti-TNF Treatment Failure in Perianal Crohn's Disease: A Multicenter Study.

BACKGROUND & AIMS: Clinical and radiologic variables associated with perianal fistula (PAF) outcomes are poorly understood. We developed prediction models for anti-tumor necrosis factor (TNF) treatment failure in patients with Crohn's disease-related PAF. METHODS: In a multicenter retrospective study between 2005 and 2022 we included biologic-naive adults (>17 years) who initiated their first anti-TNF therapy for PAF after pelvic magnetic resonance imaging (MRI). Pretreatment MRI studies were prospectively reread centrally by blinded radiologists. We developed and internally validated a prediction model based on clinical and radiologic parameters to predict the likelihood of anti-TNF treatment failure, clinically, at 6 months. We compared our model and a simplified version of MRI parameters alone with existing imaging-based PAF activity indices (MAGNIFI-CD and modified Van Assche MRI scores) by De Long statistical test. RESULTS: We included 221 patients: 32 ± 14 years, 60% males, 76% complex fistulas; 68% treated with infliximab and 32% treated with adalimumab. Treatment failure occurred in 102 (46%) patients. Our prediction model included age at PAF diagnosis, time to initiate anti-TNF treatment, and smoking and 8 MRI characteristics (supra/extrasphincteric anatomy, fistula length >4.3 cm, primary tracts >1, secondary tracts >1, external openings >1, tract hyperintensity on T1-weighted imaging, horseshoe anatomy, and collections >1.3 cm). Our full and simplified MRI models had fair discriminatory capacity for anti-TNF treatment failure (concordance statistic, 0.67 and 0.65, respectively) and outperformed MAGNIFI-CD (P = .002 and < .0005) and modified Van Assche MRI scores (P < .0001 and < .0001), respectively. CONCLUSIONS: Our risk prediction models consisting of clinical and/or radiologic variables accurately predict treatment failure in patients with PAF.

Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up.

BACKGROUND: Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life. METHODS: A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks. FINDINGS: Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders. INTERPRETATION: Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing. FUNDING: This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.

[Analysis on the efficacy of dual vein induction therapy of Ustekinumab in complex perianal fistulizing Crohn's disease].

Objectives: To analyze the efficacy of dual vein induction therapy of Ustekinumab (UST) in complex perianal fistulizing Crohn's disease (PFCD). Methods: Clinical data of patients diagnosed with complex PFCD in the Second Affiliated Hospital of Wenzhou Medical University from January 2022 to March 2023 were retrospectively analyzed. After sufficient single intravenous infusion of UST (6 mg/kg) at week 0 and 8, every patient received single subcutaneous injection of UST 90 mg every 8 weeks for maintenance treatment. At week 8, 16, and 22-26, clinical outcomes of anal fistula were evaluated using perianal disease activity index (PDAI), and overall activity of the patients was evaluated using Harvey Bradshaw index (HBI). At week 22-26, Van Assche Index (VAI) was used to evaluate imaging outcome of anal fistula, and simplified endoscopic score of Crohn's disease (SES-CD) was employed to assess intestinal outcome events. The above indexes were compared in the patients before and after UST treatment. PFCD patients were divided into first-line UST treatment group and non first-line UST treatment group according to whether first-line UST treatment was used, the differences in anal fistula response rate and remission rate, intestinal response rate and remission rate as well as overall activity response rate and remission rate were compared between the two groups. Results: A total of 60 PFCD patients were included, including 46 males and 14 females, aged [M (Q1, Q3)] 25.0 (20.8, 30.0) years old. The clinical response rates of anal fistula [41.7% (25/60), 55.0% (33/60) and 63.3% (38/60), respectively, P=0.056] and the clinical remission rates of anal fistula [21.7% (13/60), 31.7% (19/60) and 43.3% (26/60), respectively, P=0.002] gradually increased at week 8, 16, 22-26. The overall activity response rates [53.3% (32/60), 70.0% (42/60), 83.3% (50/60), respectively, P=0.040] and the overall activity response rates [41.7% (25/60), 61.7% (37/60), 75.0% (45/60), respectively, P=0.001] also gradually increased at week 8, 16, 22-26. At week 22-26, the partial response rate and fistula healing rate of anal fistula imaging were 45.0% (27/60) and 38.3% (23/60), respectively. The endoscopic response rate and endoscopic response rate were 73.7% (44/60) and 45.0% (27/60), respectively. The endoscopic response rate of patients receiving first-line UST treatment [23 males and 8 females, aged 22.0 (21.0, 39.0) years] was higher than that of patients receiving non first-line UST treatment[23 males and 6 females, aged 26.5 (20.0, 30.0) years,87.1% vs 58.6%, P=0.013]. Conclusion: The dual vein induction therapy of UST could effectively improve the clinical efficacy in patients with complex PFCD.

Clinical research progress in Traditional Chinese Medicine in treating wound healing after anal fistula surgery.

In the study of the mechanism of wound healing after anal fistula surgery, how to scientifically and efficiently promote wound healing is of great significance. At present, modern medical treatment of wounds after anal fistula surgery mostly focuses on physical therapy intervention, new wound dressing and packing, and external application of growth factors. However, these therapies have many problems, and there is still no consensus on their clinical use. Traditional Chinese Medicine (TCM) has several methods to promote wound healing, such as oral administration, rubbing, and fumigation, which have a long history and obvious efficacy, but research in this area is relatively scattered and lacks classification and summarizing. Therefore, this paper analyzes and summarizes the existing research on TCM for promotion of wound healing after anal fistula surgery, carries out targeted analyses according to different clinical syndromes and treatment methods, and analyzes the defects in current research and anticipates future research trends in order to provide theoretical support for the advantages of TCM in promoting wound healing after anal fistula surgery.

Superior Efficacy of Infliximab Versus Adalimumab for First-Line Treatment of Crohn's Perianal Fistulae.

BACKGROUND: Crohn's disease perianal fistulae (CD-PAF) occur in 25% of patients and are notoriously challenging to manage. Tumor necrosis factor inhibitors are first line agents. AIMS: The aim of this study was to compare infliximab (IFX) versus adalimumab (ADA) efficacy in CD-PAF healing over time. METHODS: A retrospective study at two large-tertiary medical centers was performed. Inclusion criteria were actively draining CD-PAF and initial treatment with IFX or ADA following CD-PAF diagnosis. The primary endpoints were perianal fistula response and remission at 6 and 12 months. Secondary endpoints included biologic persistence over time and dose escalation at 6 and 12 months. RESULTS: Among 151 patients included in the study, 92 received IFX and 59 received ADA as first line agents after CD-PAF diagnosis. At 6 months, the 64.9% of the IFX group and 34.8% of the ADA group demonstrated CD-PAF clinical improvement (p < 0.01). Univariate and multivariate analyses demonstrated significant differences among the IFX and ADA groups for clinical response at 6-months and 12-months (p = 0.002 and p = 0.042, respectively). There were no factors that predicted response, with the exception of concomitant immunomodulator affecting the 6-month clinical response (p = 0.021). Biologic persistence, characterized by Kaplan Meier methods, was significantly longer in the IFX group compared to the ADA group (Log-rank p = 0.01). CONCLUSION: IFX induction and maintenance is associated with higher rates of response and remission in CD-PAF healing as well as higher treatment persistence compared to ADA. Additionally, our study supports the use of concomitant immunomodulator therapy for CD-PAF healing and remission.

A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease. METHODS: This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points. RESULTS: Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months. CONCLUSIONS: Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease.

Pathogenesis of Perianal Fistulising Crohn's Disease: Current Knowledge, Gaps in Understanding, and Future Research Directions.

Fistulising perianal involvement is a common presentation of Crohn's disease. Perianal Crohn's disease dramatically impairs patients' social and sexual life and its management remains a critical challenge in field of inflammatory bowel disease. No medical therapy is specifically designed for the treatment of perianal Crohn's disease, largely due to the poorly understood pathophysiology. Limited evidence from preclinical and clinical studies suggests that the initiation, progression, and maintenance of Crohn's disease-associated perianal fistulas involves complex interactions between host, microbial, and environmental factors. This review intends to discuss the possible roles of genetic predisposition, mucosal immunity, and gut microbiome in perianal Crohn's disease, and considers how epithelial-to-mesenchymal transition may contribute to the pathogenesis. It also summarises recent advances on the development of animal models and new therapies for perianal Crohn's disease. At the end, we discussed future directions in basic, translational, and clinical research that may dramatically improve our understanding of perianal Crohn's disease and open avenues for novel therapeutic strategies with a multidisciplinary approach. Overall, this review aims to identify current gaps in understanding of perianal fistulising Crohn's disease and to explore future research priorities for this debilitating condition.

Autologous fat graft injections for the treatment of perianal fistulas in Crohn's disease: a systematic review and single-arm meta-analysis.

BACKGROUND: Crohn's perianal fistulas are often refractory to standard management. Fat graft injections are hypothesised to improve fistula healing rates. We evaluated the treatment efficacy of fat graft injections for Crohn's perianal fistulas in a systematic review (PRISMA). METHODS: We completed database searches of MEDLINE (Ovid), Embase, and PubMed. All studies published in English in full text or abstract, from January 2001 to August 2021, evaluating fat graft injections for Crohn's perianal fistulas were selected. Included randomized controlled trials, single-arm intervention trials, cohort studies, and case series; excluded single case reports. Primary outcome was pooled clinical healing, defined as non-draining treated fistulas, or closure, defined as closure of treated fistulas. Secondary outcomes were clinical healing, clinical closure, radiologic response, and adverse events. RESULTS: Of 1258 publications identified, 891 articles were assessed for eligibility, and 107 relevant for manuscript review. Forty-nine patients received fat graft injections for Crohn's perianal fistulas across four single-arm intervention trials. Clinical healing or closure was achieved in 74% in a pooled single-arm meta-analysis (95% confidence interval: 57%, 85%), with moderate heterogeneity between studies. Clinical healing was achieved in 20% and 60% at 3 and 12 months, respectively. Clinical closure was achieved in 83% at 6 months. Variable parameters were used to define radiologic response, with success rates from 20% to 67%. Minimal adverse events were reported. CONCLUSION: Fat graft injections show promise as a novel treatment for Crohn's perianal fistulas in this systematic review and meta-analysis. Assessment in controlled matched studies is warranted.

Examination Under Anesthesia May Not Be Universally Required Prior to Anti-TNF Therapy in Perianal Crohn's Disease: A Comparative Cohort Study.

BACKGROUND: Multidisciplinary care involving exam under anesthesia (EUA) and tumor necrosis factor (TNF) inhibitors is recommended for perianal Crohn's disease. However, the impact of this combined approach is not well established. METHODS: We performed a comparative cohort study between 2009 and 2019. Patients with perianal Crohn's disease treated with EUA before anti-TNF therapy (combined modality therapy) were compared with anti-TNF alone. The primary outcome was fistula closure assessed clinically. Secondary outcomes included subsequent local surgery and fecal diversion. Multivariable analysis adjusted for abscesses, concomitant immunomodulators, and time to anti-TNF initiation was performed. RESULTS: Anti-TNF treatment was initiated 188 times in 155 distinct patients: 66 (35%) after EUA. Abscesses (50% vs 15%; P < .001) and concomitant immunomodulators (64% vs 50%; P = .07) were more common in the combined modality group, while age, smoking status, disease duration, and intestinal disease location were not significantly different. Combined modality therapy was not associated with higher rates of fistula closure at 3 (adjusted odds ratio [aOR], 0.7; 95% confidence interval [CI], 0.3-1.8), 6 (aOR, 0.8; 95% CI, 0.4-2.0) and 12 (aOR, 1.0; 95% CI, 0.4-2.2) months. After a median follow-up of 4.6 (interquartile range, 5.95; 2.23-8.18) years, combined therapy was associated with subsequent local surgical intervention (adjusted hazard ratio, 2.2; 95% CI, 1.3-3.6) but not with fecal diversion (adjusted hazard ratio, 1.3; 95% CI, 0.45-3.9). Results remained consistent when excluding patients with abscesses and prior biologic failure. CONCLUSIONS: EUA before anti-TNF therapy was not associated with improved clinical outcomes compared with anti-TNF therapy alone, suggesting that EUA may not be universally required. Future prospective studies controlling for fistula severity are warranted.

This comparative cohort study found that an exam under anesthesia before initiation of anti-tumor necrosis factor therapy in perianal Crohn's disease was not associated with higher rates of fistula closure, suggesting that an exam under anesthesia may not be universally required in patients with perianal Crohn's disease.

Rates and Predictors of Long-term Clinical Outcomes in Patients With Perianal Crohn's Disease on Biologic Therapy.

BACKGROUND AND GOALS: Perianal Crohn's disease (pCD) represents an aggressive phenotype with limited studies on long-term outcomes. We evaluated 5-year outcomes of these patients on biologic therapies. METHODS: We performed a retrospective analysis of patients with pCD at a tertiary medical center. We used Kaplan-Meier curves to estimate rates and multivariate logistic regression to identify predictors of long-term outcomes. RESULTS: We included 311 patients with pCD of which 168 patients were started on biologics [138 anti-tumor necrosis factor (TNF) α, 14 vedolizumab, 16 ustekinumab] at the time of diagnosis. Anti-TNF use at the time of diagnosis was associated with decreased rates of perianal abscess recurrence [hazard ratio (HR)=0.48, 95% confidence interval (CI): 0.32-0.74], whereas ustekinumab use was associated with increased rates of perianal fistula closure (HR=3.58, 95% CI: 1.04-12.35) and decreased rates of perianal abscess recurrence (HR=0.20, 95% CI: 0.07-0.56) at follow-up. Among patients who failed their first anti-TNF, switching to another anti-TNF was associated with decreased rates of colectomy (HR=0.20, 95% CI: 0.04-0.90) and permanent diversion (HR=0.16, 95% CI: 0.03-0.94) compared with ustekinumab, whereas vedolizumab use was associated with decreased perianal fistula closure (HR=0.22, 95% CI: 0.05-0.96) compared with ustekinumab. Predictors of colectomy included colonic disease (odds ratio=2.71, 95% CI: 1.36-5.38) and anal stenosis (odds ratio=4.44, 95% CI: 1.59-12.43). CONCLUSION: Type of biologic use at the time of pCD diagnosis or after first anti-TNF failure may be associated with long-term outcomes in patients with pCD.

Characteristics of Patients with Crohn's Disease With or Without Perianal Fistulae in the CorEvitas Inflammatory Bowel Disease Registry.

BACKGROUND: There are limited real-world data characterizing perianal fistulae in patients with Crohn's disease (CD). AIM: To describe characteristics of patients with CD with and without perianal fistulae. METHODS: In this cross-sectional study, characteristics, treatment history, and health outcomes of patients with CD enrolled in the CorEvitas IBD Registry were described according to perianal fistula status (current/previous or none). RESULTS: Eight hundred and seventy-eight patients were included. Compared with patients with no perianal fistulae (n = 723), patients with current/previous perianal fistulae (n = 155) had longer disease duration since CD diagnosis (mean 16.5 vs 12.3 years; difference 4.3 years; 95% CI, 2.0, 6.6) and fewer had Harvey-Bradshaw Index scores indicative of remission (0-4, 56.8% vs 69.6%; difference - 12.9%; 95% CI, - 21.6, - 4.2). More patients with current/previous fistulae reported a history of IBD-related emergency room visits (67.7% vs 56.1%; difference 11.6%; 95% CI, 3.4, 19.8), hospitalizations (76.1% vs 58.4%; difference 17.7%; 95% CI, 10.1, 25.4), and surgeries (59.4% vs 27.7%; difference 31.7%; 95% CI, 23.3, 40.1), and a history of treatment with tumor necrosis factor inhibitors (81.3% vs 60.7%; difference 20.6%; 95% CI, 13.5, 27.7), immunosuppressants (51.6% vs 31.2%; difference 20.4%; 95% CI, 11.9, 29.0), and antibiotics (50.3% vs 23.7%; difference 26.6%; 95% CI, 18.2, 35.1) than patients without perianal fistulae. CONCLUSIONS: Patients with CD with current/previous perianal fistulae have more symptomatic experiences of disease, higher medication use, hospitalization rates, and emergency room visits than patients without perianal fistulae. Interventions to prevent/reduce risk of developing fistulae may help improve outcomes in CD.

Approaches in the treatment of perianal fistula in Crohn disease

Perianal fistula is a common complication of Crohn disease, and it is a great burden on the life and psychology of patients, but its treatment is still a difficult problem to face. In recent years, progress in the treatment of Crohn disease has progressed rapidly due to the advent of biological agents, but there has been a lack of research on perianal fistula in Crohn disease, and the direction of research has been scattered; therefore, the author reviews the traditional treatment of perianal fistula in Crohn disease in the context of the available literature and discusses emerging and potential therapeutic approaches. (AU)

Autologous Bioactive Compound Concentrated Growth Factor Ameliorates Fistula Healing of Anal Fistula in a Pig Model and Promotes Proliferation and Migration of Human Skin Fibroblasts via Regulating the MEK/ERK Pathway.

Recent evidence suggested that autologous concentrated growth factor (CGF), a new bioactive compound from autologous blood is used widely as an ingenious biomaterial in tissue regeneration with anti-inflammatory properties. This study investigated whether CGF could be involved in the treatment of fistula healing in the anal fistula. For this purpose, the porcine anal fistula model was conducted using the rubber band ligation method and collected pig autogenic CGF to treat the fistulas. CGF treatment promoted fistula healing, which was reflected in the downregulation of inflammatory factors, upregulation of growth factors, and promoted epithelial-mesenchymal transition with increased collagen synthesis. Besides, 16S rRNA gene sequencing analysis of fistula tissues between the control and CGF groups showed that the microbial populations exhibiting significant differences were VadinCA02, Blastomonas, Deinococcus, Devosia, Sphingomonas, Rubrobacteria, and GW_34. CGF of volunteers were collected to process small interfering RNA- (siRNA-) ERK or siRNA-negative control transfected human skin fibroblasts (HSF). The results showed that CGF also promoted the proliferation and extracellular matrix-related functions in HSF, as well as activated the MEK/ERK pathway in vitro and in vivo. Finally, knockdown ERK reversed the effects of CGF in promoting wound healing in HSF. Collectively, our results suggest that the CGF as the bioactive compound from autologous blood exhibited great potential for repairing fistulas as well as promoting the proliferation and migration of human skin fibroblasts by triggering MEK/ERK signaling. These findings provided a fresh perspective for understanding the role of CGF in the management of fistulas.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn's disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn's disease.