Friton, Jessica

AbstractIntroductionUlcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes.MethodsThis retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models.ResultsAmong 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P < 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy.DiscussionThis study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.

Abstract Background Crohn’s rectovaginal fistulizing disease remains notoriously difficult to treat. A phase I clinical trial to evaluate the safety and feasibility of a novel protocol using a mesenchymal stem cell (MSC)–coated Gore Bio-A fistula plug for the treatment of medically and surgically refractory Crohn’s rectovaginal fistulas was conducted. Methods Five patients underwent an autologous subcutaneous adipose tissue harvest via a 2-cm abdominal wall incision at time of exam under anesthesia (EUA) with seton placement. MSCs were isolated, expanded, and impregnated on the plug. After 6 weeks, patients returned to the operating room for placement of the MSC-coated plug. The primary end points were safety and feasibility; the secondary end point was clinical and radiographic healing at 6 months. Results Five female patients (median age [range], 49 [38–53] years) with a median disease duration (range) of 23 (7–34) years who were on biologic (n = 5) or combination therapy (n = 3) had successful harvest and expansion of MSCs and delivery of the Gore Bio-A plug. There were no serious adverse events or adverse events related to the MSCs or plug during the 6-month follow-up. At 6 months, 3 patients had complete cessation of drainage, and 2 had >50% reduction in drainage; all had a persistent fistula tract identified on magnetic resonance imaging and EUA at 6 months. Conclusions Surgical placement of an autologous adipose-derived MSC-coated fistula plug in diverted patients with Crohn’s rectovaginal fistulas was safe and feasible. All patients had a reduction in the size of their fistula tract, and 3 of 5 had cessation of drainage, but none achieved complete healing. This was a phase I clinical trial of autologous mesenchymal stem cells on a plug for rectovaginal Crohn’s fistulas.

BACKGROUND: Management of transsphincteric cryptoglandular fistulas remains a challenging problem and the optimal surgical approach remains elusive. Mesenchymal stem cells, increasingly being utilized for perianal Crohn’s disease, offer a novel therapy to treat cryptoglandular fistulas. OBJECTIVES: This study aimed to determine safety and feasibility of using an autologous mesenchymal stem cell-coated fistula plug in patients with transsphincteric cryptoglandular fistulas. DESIGN: This study is a phase I clinical trial. SETTING: This study was conducted at a tertiary academic medical center. PATIENTS: Adult (>18 years) male and female patients with transsphincteric cryptoglandular fistulas were selected. MAIN OUTCOMES MEASURES: The primary outcomes measured were the safety, feasibility, and efficacy of a mesenchymal stem cell-coated fistula plug in patients with transsphincteric fistulas. RESULTS: Fifteen patients (8 women, mean age 39.8 years) with a single-tract transsphincteric fistula received a mesenchymal stem cell-loaded fistula plug and were followed for 6 months. Duration of disease at the time of study enrollment was a median of 3.0 years (range, 1–13 years) with a median of 3.5 (range, 1–20) prior surgical interventions. Adverse events included 1 plug extrusion, 1 abdominal wall seroma, 3 perianal abscesses requiring drainage, and 1 patient with perianal cellulitis. There were no serious adverse events. At 6 months, 3 patients had complete clinical healing, 8 had partial healing, and 4 patients showed no clinical improvement. Radiographic improvement was seen in 11 of 15 patients. LIMITATIONS: This study was limited by the small cohort and short follow-up. CONCLUSIONS: Autologous mesenchymal stem cell-coated fistula plug treatment of transsphincteric cryptoglandular fistulas was safe and feasible and resulted in complete or partial healing in a majority of patients. See Video Abstract at http://links.lww.com/DCR/A897.

AbstractBackgroundIt is important to identify patients with inflammatory bowel disease [IBD] refractory to anti-tumour necrosis factor [TNF] therapy, to avoid potential adverse effects and to adopt different treatment strategies. We aimed to identify and validate clinical and genetic factors to predict anti-TNF response in patients with IBD.Materials and MethodsMayo Clinic and Washington University IBD genetic association study cohorts were used as discovery and replicate datasets, respectively. Clinical factors included sex, age at diagnosis, disease duration and phenotype, disease location, bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy.ResultsOf 474 patients with IBD treated with anti-TNF therapy, 41 [8.7%] were refractory to therapy and 433 [91.3%] had response. Multivariate analysis showed history of immunomodulator use (odds ratio 10.2, p = 8.73E-4) and bowel resection (odds ratio 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents. Among genetic loci, two [rs116724455 in TNFSF4/18, rs2228416 in PLIN2] were successfully replicated and another four [rs762787, rs9572250, rs144256942, rs523781] with suggestive evidence were found. An exploratory risk model predictability [area under the curve] increased from 0.72 [clinical predictors] to 0.89 after adding genetic predictors. Through identified clinical and genetic predictors, we constructed a preliminary anti-TNF refractory score to differentiate anti-TNF non-responders (mean [standard deviation] score, 5.49 [0.99]) from responders (2.65 [0.39]; p = 4.33E-23).ConclusionsNovel and validated genetic loci, including variants in TNFSF, were found associated with anti-TNF response in patients with IBD. Future validation of the exploratory risk model in a large prospective cohort is warranted.