Prognostic factors associated with unhealed perineal wounds post-proctectomy for perianal Crohn's disease: a two-centre study.

AIM: The aim of this work was to determine the factors associated with poor wound healing in patients with perianal Crohn's disease (pCD) who had undergone proctectomy in the era of biologic therapies. METHOD: Case record review was performed on 103 patients with pCD who underwent proctectomy at St Mark's Hospital, Harrow and the Western General Hospital, Edinburgh between 2005 and 2017. Healing rates at 6 and 12 months post-proctectomy were considered; univariate analysis was performed. RESULTS: Sixty out of 103 patients (58.3%) had failure of wound healing at 6 months and 41/103 (39.8%) at 12 months. In total, 63.1% (65/103) patients received biologic therapies prior to proctectomy; however, exposure to biologics was not a significant factor in predicting failure of wound healing at 12 months (infliximab p = 0.255; adalimumab p = 0.889; vedolizumab p = 0.153). Male gender was the only variable associated with poor wound healing at 12 months on univariate analysis (p = 0.017). A lower pre-operative C-reactive protein was associated with early wound healing at 6 months compared with at 12 months (p = 0.041) on univariate analysis. Other parameters not associated with rates of wound healing included smoking status, corticosteroid exposure, thiopurine exposure, number of previous biologics, perianal sepsis on MRI within the last 12 months, duration of CD prior to proctectomy and pre-operative albumin. CONCLUSION: More than a third of patients had unhealed wounds 12 months after proctectomy. We report that unhealed wounds are more common in male patients. Importantly, our results also suggest that exposure to biologics does not affect rates of wound healing.

Burden of disease and adaptation to life in patients with Crohn's perianal fistula: a qualitative exploration.

BACKGROUND: Perianal fistulas are a challenging manifestation of Crohn's disease. Best medical and surgical therapy results in only about a third of patients remaining in remission at one year on maintenance treatment and sustained healing is often elusive. There is little published data on patient perspective of living with the condition or coping strategies in the face of non-curative/non-definitive treatment. We aimed to understand the experience of living with perianal fistula(s) and their impact on quality of life and routine functioning. METHODS: This exploratory qualitative study used purposive sampling to recruit participants with current / previous diagnosis of Crohn's anal fistulas, from national IBD / bowel disease charities. The "standards for reporting qualitative research" (SRQR) recommendations were followed. Unstructured individual face-to-face interviews were audio recorded, transcribed and analysed thematically. Early themes were reviewed by the study team including patient advocates, clinicians and qualitative researchers. RESULTS: Twelve interviews were conducted, achieving apparent data saturation. Three broad themes were uncovered: Burden of symptoms; Burden of treatment; and Impact on emotional, physical and social well-being. Each included several sub-themes, with considerable interplay between these. The impact of perianal fistula(s) on patients with CD is intense and wide reaching, negatively affecting intimate, close and social relationships. Fistulas cause losses in life and work-related opportunities, and treatments can be difficult to tolerate. CONCLUSION: Crohn's perianal fistulas exert a heavy negative physical and emotional impact on patients. These findings will inform development of a patient reported outcome measure to assess treatment effectiveness and quality of life for patients living with this challenging condition.

Innovation in the imaging perianal fistula: a step towards personalised medicine.

BACKGROUND: Perianal fistula is a topic both hard to understand and to teach. The key to understanding the treatment options and the likely success is deciphering the exact morphology of the tract(s) and the amount of sphincter involved. Our aim was to explore alternative platforms better to understand complex perianal fistulas through three-dimensional (3D) imaging and reconstruction. METHODS: Digital imaging and communications in medicine images of spectral attenuated inversion recovery magnetic resonance imaging (MRI) sequences were imported onto validated open-source segmentation software. A specialist consultant gastrointestinal radiologist performed segmentation of the fistula, internal and external sphincter. Segmented files were exported as stereolithography files. Cura (Ultimaker Cura 3.0.4) was used to prepare the files for printing on an Ultimaker 3 Extended 3D printer. Animations were created in collaboration with Touch Surgery™. RESULTS: Three examples of 3D printed models demonstrating complex perianal fistula were created. The anatomical components are displayed in different colours: red: fistula tract; green: external anal sphincter and levator plate; blue: internal anal sphincter and rectum. One of the models was created to be split in half, to display the internal opening and allow complexity in the intersphincteric space to better evaluated. An animation of MRI fistulography of a trans-sphincteric fistula tract with a cephalad extension in the intersphincteric space was also created. CONCLUSION: MRI is the reference standard for assessment of perianal fistula, defining anatomy and guiding surgery. However, communication of findings between radiologist and surgeon remains challenging. Feasibility of 3D reconstructions of complex perianal fistula is realized, with the potential to improve surgical planning, communication with patients, and augment training.

Symptom Amelioration in Crohn's Perianal Fistulas Using Video-Assisted Anal Fistula Treatment (VAAFT).

BACKGROUND AND AIMS: A third of patients with Crohn's disease develop perianal fistulas. These are associated with a significant burden of symptoms and negative impact on quality of life. This study reports the use of video-assisted anal fistula treatment [VAAFT] as a means of symptom improvement; this is a minimally invasive technique to access fistula track, and diagnose/facilitate drainage of deep/complex secondary extensions with cauterization of excess inflammatory tissue. METHODS: Consecutive patients with complex Crohn's fistula undergoing VAAFT for symptomatic Crohn's anal fistula were included. They were identified from a prospectively maintained database, which was interrogated from June 2015 to November 2017. Patients underwent diagnostic fistuloscopy and fulguration of tracts/secondary extensions. Setons were sited/replaced after the procedure to maintain postoperative drainage. The primary endpoint was completion of the 'Measure your medical outcome profile' [MYMOP2] quality of life [QoL] questionnaire at 6 weeks postoperatively. Secondary outcome measures were a decisional regret scale [DRS], postoperative complications and the 30-day re-operation rate. RESULTS: Twenty-five patients underwent the procedure during the study period. In total, 21/25 patients [84%] provided MYMOP2 QoL data demonstrating a statistically significant improvement in both pain and discharge scores. Eighty-one per cent of patients who completed the questionnaire agreed/strongly agreed that the procedure was the right decision and no patient regretted undergoing the procedure. There was one re-operation but otherwise no complications. CONCLUSIONS: This study demonstrates the feasibility, safety and importantly an improvement in patient-reported outcomes in a series of patients undergoing VAAFT for complex Crohn's anal fistula. VAAFT reduces the main symptoms [pain and discharge] in patients with complex refractory anal fistulas.

Review of local injection of anti-TNF for perianal fistulising Crohn's disease.

BACKGROUND: Perianal fistulising Crohn's disease (PFCD) affects a third of Crohn's disease patients and represents a disabling phenotype with poor outcome. The anti-tumour necrosis factor alpha (TNF) therapies have been shown to maintain clinical remission in a third of patients after 1 year of treatment. Maintenance therapy with systematic administration schedules confers greatest benefit, but exposes patients to risks/side effects of continued systemic use and led to consideration of local drug delivery (first described in 2000). In this review, we analyse all published articles on local anti-TNF therapy in the treatment of PFCD. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to systematically search Medline and Embase using the medical subject headings 'fistula', 'anus', 'Crohn disease', 'infliximab' and 'adalimumab'. This was combined with free text searches, e.g. 'local injection' and 'Crohn's perianal disease'. Studies/abstracts describing local injection treatment with anti-TNF were included in this review. RESULTS: Six pilot studies including a total of 92 patients were included in this review. Outcomes reported were mostly clinical and included 'complete/partial response' to therapy and short-term results varied between 40 and 100%. There were no significant adverse events and the local injections were well tolerated. CONCLUSIONS: There is paucity of data assessing this treatment modality. Local anti-TNF therapy appears safe, but outcome reporting is heterogeneous, subjective and long-term data are unavailable. Our review suggests a potential role may be in those in whom systemic treatment is contraindicated and calls for standardised reporting of outcomes in this field to enable better data interpretation.

Pathogenesis and persistence of cryptoglandular anal fistula: a systematic review.

Anal fistulas continue to be a problem for patients and surgeons alike despite scientific advances. While patient and anatomical characteristics are important to surgeons who are evaluating patients with anal fistulas, their development and persistence likely involves a multifaceted interaction of histological, microbiological, and molecular factors. Histological studies have shown that anal fistulas are variably epithelialized and are surrounded by dense collagen tissue with pockets of inflammatory cells. Yet, it remains unknown if or how histological differences impact fistula healing. The presence of a perianal abscess that contains gut flora commonly leads to the development of anal fistula. This implies a microbiological component, but bacteria are infrequently found in chronic fistulas. Recent work has shown an increased expression of proinflammatory cytokines and epithelial to mesenchymal cell transition in both cryptoglandular and Crohn's perianal fistulas. This suggests that molecular mechanisms may also play a role in both fistula development and persistence. The aim of this study was to examine the histological, microbiological, molecular, and host factors that contribute to the development and persistence of anal fistulas.

Pilot study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a cytokine elevated in inflammatory bowel disease enterocutaneous fistula (IBD ECF). Dendritic cells are antigen presenting cells that orchestrate the immune responses and regulate the production of cytokines by immune cells including T cells. No study to date has assessed the level of TNF-α or the presence of dendritic cells in non-IBD ECF. The aim of this study was to assess the inflammatory activity, with a particular emphasis on TNF-α in non-IBD ECF when compared with control small bowel tissue. METHODS: Tissue biopsies were obtained from ECF at operation from non-IBD patients and from terminal ileum in normal colonoscopy control patients. After overnight culture, accumulation of intracellular TNF-α was measured by flow cytometry in cells treated with monensin to assess the on-going cytokine production. Data were acquired using FACS Canto II. Unpaired Student's t-test was used to compare variables between groups and p < 0.05 was regarded as significant. RESULTS: The on-going production of TNF-α from dendritic cells (p = 0.0007), putative monocyte and B cell populations (p = 0.04) and CD3+ T cells (p = 0.04) was significantly higher in non-IBD ECF tissue than that from control tissue. CONCLUSIONS: This study reveals results which provide evidence for the potential use of anti-TNF-α agents in the treatment of non-IBD ECF. A pilot study to evaluate this treatment as an alternative option in an already surgically challenging group of patients is planned. Positive findings would be a major medical advance with a new use for anti-TNF-α agents.

Etiology of perianal Crohn's disease: role of genetic, microbiological, and immunological factors.

Perianal fistulation is a common complication of Crohn's disease (CD). Fistulating perianal CD appears to represent a distinct phenotype of CD, separate from luminal fistulating disease, with differing disease behavior and which often requires different therapeutic strategies. The etiology of Crohn's perianal fistulae appears to have genetic, microbiological, and immunological components. Relationships with IBD5, which codes for the organic/cation transporter and IRGM, important in the autophagy pathway, have been identified but further genetic associations remain elusive. The partially efficacious use of antibiotics and fecal diversion imply a microbiological component and, similarly, the partial efficacy of immunosuppressants and anti-tumor necrosis factor alpha (TNFalpha) treatments suggest not only that an immunological process is taking place, but also that microbiota alone cannot account for the pathogenesis. Recent work implicates failures in the tissue injury/repair process with myofibroblasts, matrix metalloproteinases, and an epithelial-to-mesenchymal transition being possible culprits. We examine these areas in a review of the current understanding of the etiology of Crohn's perianal fistulae.