Combined therapy with early initiation of infliximab following drainage of perianal fistulising Crohn’s disease: a retrospective cohort study

Background Recent studies have confirmed that combined surgery and anti-TNF therapy could improve outcomes in patients with perianal fistulising Crohn’s disease (PFCD). However, the optimal timing for infliximab infusion after surgical intervention is uncertain. We aimed to determine the long-term efficacy of early initiation of infliximab following surgery among PFCD patients. Methods We performed a retrospective cohort study of PFCD patients who received combined infliximab and surgical treatment between 2010 and 2018 at a tertiary referral hospital. Patients were grouped according to the time interval between surgery and infliximab infusion, with < 6 weeks into early infliximab induction group and > 6 weeks into delayed infliximab induction group. The primary outcome was to compare surgical re-intervention between early and delayed infliximab induction groups. The secondary outcomes were fistula healing and predictors associated with these outcomes of early infliximab induction approach. Results One hundred and seventeen patients were included (73 in early infliximab induction, 44 in delayed infliximab induction). The median interval between surgery and infliximab initiation was 9.0 (IQR 5.5–17.0) days in early infliximab induction group and 188.0 (IQR 102.25–455.75) days in delayed infliximab induction group. After followed-up for a median of 36 months, 61.6% of patients in early infliximab induction group and 65.9% in delayed infliximab induction group attained fistula healing (p = 0.643). The cumulative re-intervention rate was 23%, 32%, 34% in early infliximab induction group and 16%, 25%, 25% in delayed infliximab induction group, at 1, 2, and 3 years respectively (p = 0.235). Presence of abscess at baseline (HR = 5.283; 95% CI, 1.61–17.335; p = 0.006) and infliximab maintenance therapy > 3 infusions (HR = 3.691; 95% CI, 1.233–11.051; p = 0.02) were associated with re-intervention in early infliximab induction group. Presence of abscess at baseline also negatively influenced fistula healing (HR = 3.429, 95% CI, 1.216–9.668; p = 0.02). Conclusion Although no clear benefit was shown compared with delayed infliximab induction group, early initiation of infliximab after surgery could achieve promising results for PFCD patients. Before infliximab infusion, durable drainage is required for patients with concomitant abscess or prolonged infliximab maintenance therapy.

Molecular differences of adipose-derived mesenchymal stem cells between non-responders and responders in treatment of transphincteric perianal fistulas

Background Injection of autologous adipose tissue (AT) has recently been demonstrated to be an effective and safe treatment for anal fistulas. AT mesenchymal stem cells (AT-MSCs) mediate the healing process, but the relationship between molecular characteristics of AT-MSCs of the injected AT and fistula healing has not been adequately studied. Thus we aimed to characterize the molecular and functional properties of AT-MSCs isolated from autologous AT injected as a treatment of cryptogenic high transsphincteric perianal fistulas and correlate these findings to the healing process. Methods 27 patients (age 45 ± 2 years) diagnosed with perianal fistula were enrolled in the study and treated with autologous AT injected around the anal fistula tract. AT-MSCs were isolated for cellular and molecular analyses. The fistula healing was evaluated by MRI scanning after 6 months of treatment. AT-MSC phenotype was compared between responders and non-responders with respect to fistula healing. Results 52% of all patients exhibited clinical healing of the fistulas as evaluated 6 months after last injection. Cultured AT-MSCs in the responder group had a lower short-term proliferation rate and higher osteoblast differentiation potential compared to non-responder AT-MSCs. On the other hand, adipocyte differentiation potential of AT-MSCs was higher in non-responder group. Interestingly, AT-MSCs of responders exhibited lower expression of inflammatory and senescence associated genes such as IL1B, NFKB, CDKN2A, TPB3,TGFB1. Conclusion Our data suggest that cellular quality of the injected AT-MSCs including cell proliferation, differentiation capacity and secretion of proinflammatory molecules may provide a possible mechanism underlying fistula healing. Furthermore, these biomarkers may be useful to predict a positive fistula healing outcome. Trial registration: NTC04834609, Registered 6 April 2021. https://clinicaltrials.gov/ct2/show/NCT04834609

Treatment of Fistulizing Perianal Crohn’s Disease by Autologous Microfat Enriched With Adipose-Derived Regenerative Cells

In this pilot study, short-term efficacy and safety of fat graft enriched with Adipose-Derived Regenerative Cells (ADRC) in the treatment of Crohn’s high anal fistula was evaluated. Clinical fistula healing was achievable in 75% of cases, by a single treatment.

Efficacy and safety of autologous adipose-derived stromal vascular fraction enriched with platelet-rich plasma in flap repair of transsphincteric cryptoglandular fistulas

Background Transanal advancement flap repair of transsphincteric fistulas is a sphincter-preserving procedure, which frequently fails, probably due to ongoing inflammation in the remaining fistula tract. Adipose-derived stromal vascular fraction (SVF) has immunomodulatory properties promoting wound healing and suppressing inflammation. Platelet-rich plasma (PRP) reinforces this biological effect. The aim of this study was to evaluate the efficacy and safety of autologous adipose-derived SVF enriched with PRP in flap repair of transsphincteric cryptoglandular fistulas. Methods A prospective cohort study was conducted including consecutive patients with transsphincteric cryptoglandular fistula in a tertiary referral center. During flap repair, SVF was obtained by lipoharvesting and mechanical fractionation of adipose tissue and combined with PRP was injected around the internal opening and into the fistulous wall. Endpoints were fistula healing at clinical examination and fistula closure on postoperative magnetic resonance imaging (MRI). Adverse events were documented. Results Forty-five patients with transsphincteric cryptoglandular fistula were included (29 males, median age 44 years [range 36–53 years]). In the total study population, primary fistula healing was observed in 38 patients (84%). Among the 42 patients with intestinal continuity at time of surgery, primary fistula healing was observed in 35 patients (84%). In one patient, the fistula recurred, resulting in a long-term healing rate of 82%. MRI, performed in 37 patients, revealed complete closure of the fistula tract in 33 (89.2%). In the other patients, the tract was almost completely obliterated by scar tissue. During follow-up, none of these patients showed clinical signs of recurrence. The postoperative course was uneventful, except for three cases; venous thromboembolism in one patient and bleeding under the flap, necessitating intervention in two patients. Conclusions Addition of autologous SVF enriched with PRP during flap repair is feasible, safe and might improve outcomes in patients with a transsphincteric cryptoglandular fistula. Trial registration Dutch Trial Register, Trial Number: NL8416, https://www.trialregister.nl/

Prospective randomised controlled trial of adults with perianal fistulising Crohn’s disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol

IntroductionPerianal fistulising Crohn’s disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates; however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy.Methods and analysisPatients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18–80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with diverting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate.Ethics and disseminationResults will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12621000023853); Pre-results.

Healing of rectal advancement flaps for anal fistulas in patients with and without Crohn’s disease: a retrospective cohort analysis

Background Surgical closure of anal fistulas with rectal advancement flaps is an established standard method, but it has a high degree of healing failure in some cases. The aim of this study was to identify risk factors for anal fistula healing failure after advancement flap placement between patients with cryptoglandular fistulas and patients with Crohn’s disease (CD). Methods From January 2010 to October 2020, 155 rectal advancement flaps (CD patients = 55, non-CD patients = 100) were performed. Patients were entered into a prospective database, and healing rates were retrospectively analysed. Results The median follow-up period was 189 days (95% CI: 109–269). The overall complication rate was 5.8%. The total healing rate for all rectal advancement flaps was 56%. CD patients were younger (33 vs. 43 years, p < 0.001), more often female (76% vs. 30%, p < 0.001), were administered more immunosuppressant medication (65% vs. 5%, p < 0.001), and had more rectovaginal fistulas (29% vs. 8%, p = 0.001) and more protective stomas (49% vs. 2%, p < 0.001) than patients without CD. However, no difference in healing rate was noted between patients with or without CD (47% vs. 60%, p = 0.088). Conclusions Patients with anal fistulas with and without Crohn’s disease exhibit the same healing rate. Although patients with CD display different patient-specific characteristics, no independent factors for the occurrence of anal fistula healing failure could be determined. Trial registration Not applicable due to the retrospective study design.

Fecal Diversion for Perianal Crohn Disease in the Era of Biologic Therapies: A Multicenter Study

Background The natural history of perianal Crohn disease (PCD) after fecal diversion in the era of biologics is poorly understood. We assessed clinical and surgical outcomes after fecal diversion for medically refractory PCD and determined the impact of biologics. Methods We performed a retrospective, multicenter study from 1999 to 2020. Patients who underwent fecal diversion for refractory PCD were stratified by diversion type (ostomy with or without proctectomy). Times to clinical and surgical outcomes were estimated using Kaplan-Meier methods, and the association with biologics was assessed using multivariable Cox proportional hazards models. Results Eighty-two patients, from 3 academic institutions, underwent a total of 97 fecal diversions: 68 diversions without proctectomy and 29 diversions with proctectomy. Perianal healing occurred more commonly after diversion with proctectomy than after diversion without proctectomy (83% vs 53%; P = 0.021). Among the patients who had 68 diversions without proctectomy, with a median follow-up of 4.9 years post-diversion (interquartile range, 1.66-10.19), 37% had sustained healing, 31% underwent surgery to restore bowel continuity, and 22% underwent proctectomy. Ostomy-free survival occurred in 21% of patients. Biologics were independently associated with avoidance of proctectomy (hazard ratio, 0.32; 95% confidence interval, 0.11-0.98) and surgery to restore bowel continuity (hazard ratio, 3.10; 95% confidence interval, 1.02-9.37), but not fistula healing. Conclusions In this multicenter study, biologics were associated with bowel restoration and avoidance of proctectomy after fecal diversion without proctectomy for PCD; however, a minority of patients achieved sustained fistula healing after initial fecal diversion or after bowel restoration. These results highlight the refractory nature of PCD.

Healing of rectal advancement flap for anal fistula in patients with and without Crohn’s disease: a retrospective cohort analysis

Background Surgical closure of anal fistulas with rectal advancement flap is an established standard method, but in some cases, it has a high degree of healing failure. There are few studies in literature with a small number of cases examining differences between patients with and without Crohn's disease (CD). The aim of this study was to identify risk factors for anal fistula healing failure after advancement flap between patients with cryptoglandular fistulas and patients with CD. Methods From January 2010 to October 2020, 155 rectal advancement flaps (CD patients = 55, non-CD patients = 100) were performed. Patients were entered into a prospective database and retrospectively analyzed for healing rates. Results Median follow up was 189 days (95 % CI: 109–269). Overall complication rate was 5.8 %. Total healing rate for all rectal advanced flaps was 56 %. CD patients were younger (33 vs. 43 years, p < 0.001), more often female (76 vs. 30 %, p < 0.001), had more immunosuppressant medication (65 vs. 5 %, p < 0.001), more vaginal fistulas (29 vs. 8 %, p = 0.001) and more protective stomas (49 vs. 2 %, p < 0.001) than patients without CD. However, there was no difference in the healing rate of patients with or without CD (47 % vs. 60 %, p = 0.088). Conclusions Patients with anal fistulas without and with Crohn’s disease have the same healing rate. Although patients with CD differ in their patient-specific characteristics, no independent factors for the occurrence of anal fistula healing failure could be determined. Trial registration: Not applicable due to the retrospective study design.

Insertion of Transnasal Abscess Drainage Tube, Decompression Tube, and Jejunal Nutrition Tube Under Fluoroscopy to Treat Esophagojejunal Anastomotic Fistula After Gastrectomy for Gastric Cancer

Background Esophagojejunal anastomotic leakage is a serious complication after total gastrectomy. This study evaluated the safety and efficacy of transnasal placement of drainage tube, jejunal decompression tube, and jejunal nutrition tube under fluoroscopy for treatment of esophagojejunal anastomotic fistula after gastrectomy in gastric cancer patients. Methods Retrospective review of patients with esophagojejunal anastomotic fistula treated with transnasal placement of abscess drainage tube, decompression tube, and jejunal nutrition tube under fluoroscopy. Fistula healing time, patient survival, and Eastern Cooperative Oncology Group (ECOG) performance status before and after treatment were evaluated. Results Thirty-eight patients were included in the study. Insertion of the transnasal abscess drainage tube, jejunal decompression tube, and nutrition tube was successful on the first attempt in all patients. Simple transnasal drainage was used in 27 patients (one drainage tube placed plus one drainage tube replacement in 15 patients, and one drainage tube placed in 12 patients), and transnasal drainage plus percutaneous abscess drainage in 11 patients. After placement of the tube, the mean volume of drainage was 120 ml (10–850 mL); the amount steadily decreased from then on. The fistula healed in 33 patients. Median time to fistula healing was 78 days (6-248 days). Two patients suffered gastrointestinal bleeding after the procedure but one patient died. Conclusions Transnasal insertion of transnasal abscess drainage tube, jejunal decompression tube, and jejunal nutrition tube under fluoroscopy appears to be a simple, minimally invasive, effective, and safe method for treating esophagojejunal anastomotic fistula after gastrectomy for gastric cancer.