Addition of Platelet-Rich Plasma to Endorectal Advancement Flap Repair Does Not Enhance the Healing of Cryptoglandular Transsphincteric Fistulas.

BACKGROUND: Endorectal advancement flap repair is often performed for the treatment of cryptoglandular transsphincteric fistulas. However, this procedure fails in approximately 1 of 4 patients. Based on its supposed healing properties, platelet-rich plasma might enhance the outcome of this procedure. OBJECTIVE: To evaluate and compare the short-term and long-term outcomes after endorectal advancement flap repair with and without platelet-rich plasma injection in patients with a cryptoglandular transsphincteric fistula. DESIGN: Retrospective cohort study. SETTING: Tertiary referral hospital for proctology in the Netherlands. PATIENTS: Consecutive patients with a cryptoglandular transsphincteric fistula. Inverse propensity score-weighted comparison was used to adjust for confounding and selection bias. INTERVENTIONS: Endorectal advancement flap repair with and without platelet-rich plasma injection. MAIN OUTCOME MEASURES: Clinical fistula closure within 1 year without need for a reintervention (primary healing), clinical fistula closure within 1 year corrected for reinterventions (secondary healing), overall fistula healing within 1 year, and long-term outcomes assessed by a questionnaire. RESULTS: In total, 219 patients underwent an endorectal advancement flap repair. In 88 patients (40.2%), platelet-rich plasma was injected. No significant difference was observed in primary healing (67.0% vs 69.5%, p = 0.71), secondary healing (37.5% vs 43.5%, p = 0.60), or overall healing (73.9% vs 77.1%, p = 0.58) between patients treated with and without platelet-rich plasma injection. Long-term follow-up was available in 67.1% of the patients with a mean follow-up of 6.8 years (SD: 3.7 years). Among all patients who reached fistula healing, whether primary or secondary, within 1 year and had available long-term follow-up data, recurrence rates were also not significantly different (6.3% vs 2.9%, p = 0.37). Propensity score-weighted analysis showed that patients treated with a platelet-rich plasma injection were not more likely to achieve primary healing (OR 1.0; 95% CI, 0.5-1.9), secondary healing (OR 1.1; 95% CI, 0.2-3.2), overall healing (OR 0.9; 95% CI, 0.5-1.7), or recurrence at long-term follow-up (OR 1.1; 95% CI, 0.4-18.8) compared with patients without platelet-rich plasma injection. LIMITATIONS: Retrospective design, lack of postoperative imaging, and assessment of long-term follow-up using a questionnaire. CONCLUSION: Addition of platelet-rich plasma injection does not improve the short-term and long-term outcomes of endorectal advancement flap repair in patients with a cryptoglandular transsphincteric fistula treated in a tertiary referral center. See Video Abstract . ADICIN DE PLASMA RICO EN PLAQUETAS A LA REPARACIN DEL COLGAJO DE AVANCE ENDORRECTAL NO MEJORA LA CURACIN DE LAS FSTULAS TRANSESFINTERIANAS CRIPTOGLANDULARES: ANTECEDENTES:La reparación con colgajo de avance endorrectal a menudo se realiza para el tratamiento de fístulas transesfinterianas criptoglandulares. Sin embargo, este procedimiento falla en aproximadamente uno de cada cuatro pacientes. Basándose en sus supuestas propiedades curativas, el plasma rico en plaquetas (PRP) podría mejorar el resultado de este procedimiento.OBJETIVO:Evaluar y comparar los resultados a corto y largo plazo después de la reparación con colgajo de avance endorrectal con y sin inyección de PRP en pacientes con una fístula transesfintérica criptoglandular.DISEÑO:Estudio de cohorte retrospectivo.ÁMBITO:Hospital terciario de referencia para proctología en los Países Bajos.PACIENTES:Pacientes consecutivos con fístula transesfintérica criptoglandular. Se utilizó una comparación ponderada por puntuación de propensión inversa para ajustar los factores de confusión y el sesgo de selección.INTERVENCIONES:Reparación del colgajo de avance endorrectal con y sin inyección de PRP.PRINCIPALES MEDIDAS DE VALORACIÓN:Cierre clínico de la fístula dentro de un año sin necesidad de reintervención (cicatrización primaria), cierre clínico de la fístula dentro de un año corregido por reintervenciones (cicatrización secundaria), curación general de la fístula dentro de un año y resultados a largo plazo evaluados mediante un cuestionario.RESULTADOS:En total, 219 pacientes se sometieron a una reparación con colgajo de avance endorrectal. En 88 pacientes (40,2%) se inyectó PRP. No se observaron diferencias significativas en la curación primaria (67,0% frente a 69,5%, p = 0,71), curación secundaria (37,5% frente a 43,5%, p = 0,60) y curación general (73,9% frente a 77,1%, p = 0,58).) entre pacientes con y sin inyección de PRP, respectivamente. El seguimiento a largo plazo estuvo disponible en el 67,1% de los pacientes con un seguimiento medio de 6,8 años (desviación estándar: 3,7 años). Dentro de todos los pacientes que alcanzaron la curación de la fístula, tanto primaria como secundaria, dentro de un año y tenían datos de seguimiento a largo plazo disponibles, las tasas de recurrencia tampoco fueron significativamente diferentes (6,3% vs. 2,9%, p = 0,37). El análisis ponderado por puntuación de propensión mostró que los pacientes tratados con una inyección de PRP no tenían más probabilidades de lograr la curación primaria (odds ratio [OR] 1,0; intervalo de confianza [IC] del 95 %: 0,5 - 1,9), curación secundaria (OR 1,1; IC del 95 % 0,2 - 3,2), curación general (OR 0,9; IC 95 % 0,5 - 1,7) o recurrencia en el seguimiento a largo plazo (OR 1,1; IC 95 % 0,4 - 18,8) en comparación con pacientes sin inyección de PRP.LIMITACIONES:Diseño retrospectivo, falta de imágenes postoperatorias y evaluación del seguimiento a largo plazo mediante un cuestionario.CONCLUSIÓN:La adición de la inyección de PRP no mejora el resultado a corto y largo plazo de la reparación con colgajo de avance endorrectal en pacientes con una fístula transesfintérica criptoglandular tratados en un centro de referencia terciario. (Traducción- Dr. Ingrid Melo ).

Short-term anti-TNF therapy with surgical closure versus anti-TNF therapy alone for Crohn's perianal fistulas (PISA-II): long-term outcomes of an international, multicentre patient preference, randomised controlled trial.

Background: The PISA-II trial showed that short-term anti-tumour necrosis factor (anti-TNF) therapy followed by surgical closure induces radiological healing of perianal fistulas in patients with Crohn's disease more frequently than anti-TNF therapy alone after 18 months. This study aimed to compare long-term outcomes of both treatment arms. Methods: Follow-up data were collected from patients who participated in the PISA-II trial, an international patient preference randomised controlled trial. This multicentre trial was performed in nine hospitals in the Netherlands and one hospital in Italy. Patients with Crohn's disease above the age of 18 years with an active high perianal fistula and a single internal opening were asked to participate. Patients were allocated to anti-TNF therapy (intravenous infliximab, or subcutaneous adalimumab, at the discretion of the gastroenterologist) for one year, or surgical closure combined with 4-months anti-TNF therapy. Patients without a treatment preference were randomised (1:1) using random block randomisation (block sizes of six without stratification), and patients with a treatment preference were treated according to their preferred treatment arm. For the current follow-up study, data were collected until May 2022. Primary outcome was radiological healing on magnetic resonance imaging (MRI), including all participants with a MRI made less than 6 months ago at the time of data collection. Analysis was based on observed data. Findings: Between September 14, 2013, and December 7, 2019, 94 patients were enrolled in the trial. Long-term follow-up data were available in 91 patients (36/38 (95%) anti-TNF + surgical closure, 55/56 (98%) anti-TNF). A total of 14/36 (39%) patients in the surgical closure arm were randomly assigned, which was not significantly different in the anti-TNF treatment arm (16/55 (29%) randomly assigned). Median follow-up was 5.7 years (interquartile range (IQR) 5-7). Radiological healing occurred significantly more often after anti-TNF + surgical closure (15/36 = 42% versus 10/55 = 18%; P = 0.014). Clinical closure was comparable (26/36 = 72% versus 34/55 = 62%; P = 0.18) in both groups. However, clinical closure in the surgical group was achieved with less re-interventions 4/26 (= 15%) versus 18/34 (= 53%), including (redo-)surgical closure procedures. Recurrences occurred in 0/25 (0%) patients with radiological healing versus 27/76 (36%) patients with clinical closure, sometime during follow-up. Anti-TNF trough levels were higher in patients with long-term clinical closure in both groups (P = 0.031 and P = 0.014). In 6/11 (55%) patients in the anti-TNF group with available trough levels, recurrences were diagnosed within three months of a drop under 3.5ug/ml. 36 patients stopped anti-TNF, after which 0/14 (0%) patients with radiological healing developed a recurrence and 9/22 (41%) with clinical closure. Self-rated (in)continence was comparable between groups, and 79% (60/76) of patients indicated comparable/improved continence after treatment. Decision-regret analysis showed that all (30/30) anti-TNF + surgical closure patients agreed or strongly agreed that surgery was the right decision versus 78% (36/46) in the anti-TNF arm. All surgical closure patients would go for the same treatment again, whereas this was 89% (41/46) in the anti-TNF arm. Interpretation: This study confirmed that surgical closure should be considered in amenable patients with perianal fistulas and Crohn's disease as long-term outcomes were favourable, and that radiological healing should be the aim of treatment as recurrences only occurred in patients without radiological healing. In patients with complete MRI closure, anti-TNF could be safely stopped. Funding: None.

A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn's Disease.

BACKGROUND: Myeloid cells are critical determinants of the sustained inflammation in Crohn's Disease (CD). Targeting such cells may be an effective therapeutic approach for refractory CD patients. Bromodomain and extra-terminal domain protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also possess wide-ranging toxicities. In the current study, we make use of a BET inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid cells. METHODS: We profiled CES1 protein expression in the intestinal biopsies, peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were evaluated in healthy donor CD14+ monocytes and fCD cells, using cytometric beads assay or RNA-sequencing. RESULTS: CES1 was specifically expressed in monocyte, macrophage, and dendritic cell populations in the intestinal tissue, peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1ß, IL6, and TNFα secretion from healthy donor CD14+ monocytes and fCD immune cells, with 10- to 26-fold more potency over iBET in isolated CD14+ monocytes. Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior potency over iBET. CONCLUSIONS: We demonstrate specific CES1 expression in mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells and exerts robust anti-inflammatory effects, which could be beneficial in refractory CD patients.

Role of the Mesentery in Crohn's Terminal Ileitis.

Despite the longstanding awareness of the presence of mesenteric alterations in Crohn's disease, the functional and clinical consequences of these alterations remain a topic of debate. Guidelines advise a limited resection without resection of the adjacent mesentery to prevent short bowel syndrome and postoperative complications. However, recently mesenteric resection has been proposed as an alternative to reduce recurrence rates in Crohn's disease patients. Here, we evaluate the data available on this topic in terminal ileitis, both from a fundamental research point of view and clinical perspective.

Anatomical Variation in Mesenteric Macrophage Phenotypes in Crohn's Disease.

INTRODUCTION: Clinical trials are currently investigating whether an extended mesenteric resection for ileocecal resections could reduce postoperative recurrence in Crohn's disease. Resection of the mesorectum, which contains proinflammatory macrophages, during proct(ocol)ectomy, is associated with reduced recurrent inflammation and improved wound healing. We aimed to characterize the macrophages in the ileocecal mesentery, which were compared with those in the mesorectum, to provide a biological rationale for the ongoing trials. METHODS: In 13 patients with Crohn's disease and 4 control patients undergoing a proctectomy, tissue specimens were sampled at 3 locations from the mesorectum: distal (rectum), middle, and proximal (sigmoid). In 38 patients with Crohn's disease and 7 control patients undergoing ileocecal resections, tissue specimens also obtained from 3 locations: adjacent to the inflamed terminal ileum, adjacent to the noninflamed ileal resection margin, and centrally along the ileocolic artery. Immune cells from these tissue specimens were analyzed by flow cytometry for expression of CD206 to determine their inflammatory status. RESULTS: In the mesorectum, a gradient from proinflammatory to regulatory macrophages from distal to proximal was observed, corresponding to the adjacent inflammation of the intestine. By contrast, the ileocecal mesentery did not contain high amounts of proinflammatory macrophages adjacent to the inflamed tissue, and a gradient toward a more proinflammatory phenotype was seen in the central mesenteric area. DISCUSSION: Although the mesentery is a continuous structure, the mesorectum and the ileocecal mesentery show different immunological characteristics. Therefore, currently, there is no basis to perform an extended ileocecal resection in patients with Crohn's disease.