Lack of anti-TNF drugs levels in fistula tissue - a reason for nonresponse in Crohn's perianal fistulating disease?

INTRODUCTION: Anti-TNF therapy is recommended as treatment for patients with Crohn´s perianal fistulas. However, a significant proportion of patients have a sub-optimal response to anti-TNF therapy. Higher serum levels of anti-TNF agents have been associated with improved outcomes in perianal Crohn's disease. Currently, it is unknown whether anti-TNF agent levels can be detected in tissue from fistula tracts themselves and whether this is associated with response. AIMS AND METHODS: We undertook a pilot study to measure fistula tissue levels of anti-TNF medication (infliximab and adalimumab). We used a previously validated targeted proteomic technique, employing ultraperformance liquid chromatography-mass spectrometry, to detect/quantify anti-TNF drugs. Biopsies were obtained from fistula tracts of patients with Crohn's disease on maintenance treatment; with idiopathic (cryptoglandular) fistula tissues used as negative controls as well as positive controls (by spiking the latter tissues with anti-TNF drugs). RESULTS: Tissue was sampled from the fistula tracts of seven patients with Crohn's perianal disease (five patients were on adalimumab and two patients were on infliximab). The anti-TNF drugs, infliximab and adalimumab, were not detected in fistula samples from any of the Crohn's patients despite detection in 'spiked' positive control samples. CONCLUSION: Absence of detection of the anti-TNF drugs in fistula tissue raises the question on the role of tissue penetrance of anti-TNF drugs in response to therapy. Further work is required in a larger number of patients to validate the findings observed and investigate if any correlation exists between tissue and serum levels of anti-TNF and clinical outcome. SUMMARY: Predicting response in Crohn's fistula patients on biologic therapy is difficult with no reliable biomarkers. This pilot study uses targeted proteomics to investigate the potential role of tissue drug levels in acting as a biomarker of treatment response.

Emerging Data on Fistula Laser Closure (FiLaC) for the Treatment of Perianal Fistulas; Patient Selection and Outcomes.

Fistula laser closure (FiLaC) is a relatively new sphincter-sparing technique in fistula surgery that was initially reported in 2011. It involves the radial dissipation of laser energy in the fistula tract and, through a combination of coagulation and shrinkage of the tract, is proposed to result in progressive sealing of fistulas. Early studies have suggested minimal impact on continence and touted the advantage of minimal morbidity with potential of repeat procedures if the technique fails initially. Despite early promising results, ten years on, questions remain on the technique, patient selection and long-term outcomes. This narrative review assesses the evidence reported to-date of radially emitting laser fistula surgery in the treatment of perianal fistulas.

Current review of the management of fistulising perianal Crohn's disease.

Perianal manifestations of Crohn's disease constitute a distinct disease phenotype commonly affecting patients and conferring an increased risk of disability and disease burden. Much research has gone into management of fistulising manifestations, with biological therapy changing the landscape of treatment. In this article, we discuss the up-to-date surgical and medical management of perianal fistulas, highlighting current consensus management guidelines and the evidence behind them, as well as future directions in management.

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.

Differences in amino acid and lipid metabolism distinguish Crohn's from idiopathic/cryptoglandular perianal fistulas by tissue metabonomic profiling and may offer clues to underlying pathogenesis.

INTRODUCTION: Few studies have investigated perianal fistula etiopathogenesis, and although the cryptoglandular theory is widely accepted in idiopathic cases, in Crohn's disease, it is thought to involve the interplay between microbiological, immunological and genetic factors. A pilot study was conducted to assess for metabolic variations in Crohn's perianal fistula tissue that might differ from that of idiopathic (cryptoglandular) perianal fistula tissue as a comparator. The goal was to identify any potential biomarkers of disease, which may improve the understanding of pathogenesis. AIMS AND METHODS: Fistula tract biopsies were obtained from 30 patients with idiopathic perianal fistula and 20 patients with Crohn's anal fistula. Two different assays were used in an ultra-high-performance liquid chromatography system coupled with a mass spectrometric detector to achieve broad metabolome coverage. Univariate and multivariate statistical data analyses were used to identify differentiating metabolic features corresponding to the perianal fistula phenotype (i.e. Crohn's disease vs. idiopathic). RESULTS: Significant orthogonal partial least squares discriminant analysis predictive models (validated with cross-validated-analysis of variance P value <0.05) differentiated metabolites from tissue samples from Crohn's vs. idiopathic anal fistula patients using both metabolic profiling platforms. A total of 41 metabolites were identified, suggesting alterations in pathways, including amino acid, carnitine and lipid metabolism. CONCLUSION: Metabonomics may reveal biomarkers of Crohn's perianal fistula. Further work in larger numbers is required to validate the findings of these studies as well as cross-correlation with microbiome work to better understand the impact of host-gut/environment interactions in the pathophysiology of Crohn's and idiopathic perianal fistulas and identify novel therapeutic targets.

Development and initial psychometric validation of a patient-reported outcome measure for Crohn's perianal fistula: the Crohn's Anal Fistula Quality of Life (CAF-QoL) scale.

INTRODUCTION: Crohn's perianal fistulas are challenging for patients and clinicians. Many do not respond to available treatments and despite recommendations by a global consensus, there are currently no specific patient-derived quality of life tools to measure response to treatment. We present a new validated patient-reported outcome measure (PROM) for this complicated disease phenotype. METHODS: A draft questionnaire was generated using unstructured qualitative patient interviews on the experience of living with Crohn's perianal fistula, a nationwide multidisciplinary consensus exercise, a systematic review of outcomes assessing medical/surgical/combined treatment and a patient and public involvement day. Psychometric properties were assessed including construct validity (by comparison with the Hospital Anxiety and Depression Scale (HADS) and the UK Inflammatory Bowel Disease Questionnaire (UK-IBDQ)), and reliability and responsiveness was assessed by test-retest analysis. RESULTS: Data from 211 patients contributed to development of a final 28-item questionnaire. The Crohn's Anal Fistula Quality of Life (CAF-QoL) demonstrated good internal consistency (Cronbach's alpha 0.88), excellent stability (intraclass correlation 0.98) and good responsiveness and construct validity, with positive correlation with the UK-IBDQ and HADS. CONCLUSION: The CAF-QoL scale is ready for use as a PROM in research and clinical practice. It complements objective clinical evaluation of fistula by capturing impact on the patient.

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.

Medical-surgical Combined Approach in Perianal Fistulizing Crohn's Disease (CD): Doing it Together.

Fistulising perianal Crohn's disease (pCD) is an aggressive phenotype, and patients not only suffer from perianal manifestations but also a worsening course for their luminal disease. This article describes the 6 key steps clinicians need to consider when managing patients with pCD which include; (i) ensuring a prompt diagnosis, (ii) multi-disciplinary management, (iii) psychological support, (iv) using multimodal medical and surgical treatment strategies, (v) continually monitoring and optimising therapy and (vi) ensuring that patients have a way of accessing care if required. Patients with fistulising pCD often have an unpredictable disease course and complete remission can be elusive. As such, a considered and nuanced approach is essential keeping the wider multi-disciplinary team and the patient involved in all decision making.

Developing a core outcome set for fistulising perianal Crohn's disease.

OBJECTIVE: Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn's disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. DESIGN: Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback from their panel (in the second round) and all participants (in the third round) to allow refinement of their scores. RESULTS: A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study. The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). CONCLUSION: A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care.

Persistent Fistula After Anorectal Abscess Drainage: Local Experience of 11 Years.

BACKGROUND: The characteristics of patients who develop a fistula-in-ano after an anorectal abscess are unclear. OBJECTIVE: Our study explored this relationship and patient factors associated with fistula development. DESIGN: International Classification of Diseases, 10 Revision, and Classification of Interventions and Procedures, version 4, codes were used to identify all of the patients with a primary anorectal abscess. Multivariable analysis was used to identify factors predictive of fistula formation. SETTINGS: The study was conducted in a district general hospital. PATIENTS: Patients with anorectal abscess who were admitted to our institution (2004-2015) were included. MAIN OUTCOMES MEASURES: The rate of subsequent fistula formation was measured. RESULTS: A total of 1970 abscess patients were identified; 70.0% (n = 1379) were men, and 7.3% (n = 144) had Crohn's disease. Fistulas occurred in 16.2% (n = 319) at a median of 7 months (interquartile range, 3-7 mo). Patients with Crohn's disease were more than twice as likely to develop a fistula than patients without Crohn's disease (32.6% vs 14.9%; OR = 2.5 (95% CI, 1.7-3.7); p < 0.001). Patients with Crohn's disease with a fistula were more likely to be women (55.3% vs 34.6%; p = 0.007) and aged <30 years (51.1% vs 24.3%; p< 0.001) versus patients without Crohn's disease with a fistula. At multivariable analysis of the entire cohort, male sex (OR = 0.7 (95% CI, 0.5-0.9); p = 0.005) and diabetes mellitus (OR = 0.5 (95% CI, 0.3-0.9); p = 0.027) were associated with a reduced likelihood of developing a fistula after abscess formation. LIMITATIONS: The study was limited by its single-center scope, retrospective analysis, and lack of a standardized definition for Crohn's disease. CONCLUSIONS: Abscesses are more common in men, but progression to fistula is more likely in women. The rate of fistula progression in Crohn's disease is twice that in patients without Crohn's disease. Identification of patients at risk may help delineate those who will benefit from a more conservative surgical approach, enhanced follow-up, or investigation after abscess drainage. See Video Abstract at http://links.lww.com/DCR/A798.

Anti-TNF Therapy in Crohn's Disease.

Crohn's disease (CD) accounts for a variety of clinical manifestations or phenotypes that stem from chronic inflammation in the gastrointestinal tract. Its worldwide incidence is increasing including younger or childhood-onset of disease. The natural history of Crohn's disease is characterized by a remitting and relapsing course that progresses to complications and surgery in most patients. The goals of treatment are to achieve clinical and endoscopic remission, to avoid disease progression and minimise surgical resections. Medical treatment usually features antibiotics, corticosteroids, immunomodulators (thiopurines, methotrexate). Anti-TNF (tumour necrosis factor) therapy was approved for use in Crohn's disease in 1998, and has changed the paradigm of treatment, leading to improved rates of response and remission in patients. There are significant considerations that need to be borne in mind, when treating patients including immunogenicity, safety profile and duration of treatment.

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.

Medical and surgical management of perianal Crohn's disease.

Crohn's disease is increasingly thought to encompass multiple possible phenotypes. Perianal manifestations account for one such phenotype and represent an independent disease modifier. In its more severe form, perianal Crohn's disease confers a higher risk of a severe and disabling disease course, relapses, hospital admissions and operations. This, in turn, imposes a considerable burden and disability on patients. Identification of the precise manifestation is important, as management is nuanced, with both medical and surgical components, and is best undertaken in a multidisciplinary setting for both diagnosis and ongoing treatment. The introduction of biologic medication has heralded a significant addition to the management of fistulizing perianal Crohn's disease in particular, albeit with modest results. It remains a very challenging condition to treat and further work is required to optimize management in this group of patients.

Volume assessment magnetic resonance imaging technique for monitoring perianal Crohn's fistulas.

BACKGROUND: Perianal Crohn's fistula and their response to anti-tumour necrosis factor (TNF) therapies are best assessed with magnetic resonance imaging (MRI), but radiologist reporting is subjective and variable. This study investigates whether segmentation software could provide precise and reproducible objective measurements of fistula volume. METHODS: Retrospective analysis of patients with perianal Crohn's fistula at our institution between 2007 and 2013. Pre- and post-biologic MRI scans were used with varying time intervals. A total of two radiologists recorded fistula volumes, mean signal intensity and time taken to measure fistula volumes using validated Open Source segmentation software. A total of three radiologists assessed fistula response to treatment (improved, worse or unchanged) by comparing MRI scans. RESULTS: A total of 18 cases were reviewed for this pilot study. Inter-observer variability was very good for volume and mean signal intensity; intra-class correlation (ICC) 0.95 [95% confidence interval (CI) 0.91-0.98] and 0.95 (95% CI 0.90-0.97) respectively. Intra-observer variability was very good for volume and mean signal intensity; ICC 0.99 (95% CI 0.97-0.99) and 0.98 (95% CI 0.95-0.99) respectively. Average time taken to measure fistula volume was 202 s and 250 s for readers 1 and 2. Agreement between three specialist radiologists was good [kappa 0.69 (95% CI 0.49-0.90)] for the subjective assessment of fistula response. Significant association was found between objective percentage volume change and subjective consensus agreement of response (p = 0.001). Median volume change for improved, stable or worsening fistula response was -67% [interquartile range (IQR): -78, -47], 0% (IQR: -16, +17), and +487% (IQR: +217, +559) respectively. CONCLUSION: Quantification of fistula volumes and signal intensities is feasible and reliable, providing an objective measure of perianal Crohn's fistula and response to treatment.

A Systematic Review: The Management and Outcomes of Ileal Pouch Strictures.

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis removes the diseased tissue in ulcerative colitis but also allows gastrointestinal continuity and stoma-free living. Pouch strictures are a complication with a reported incidence of 5-38%. The three areas where pouch strictures occur are in the pouch inlet, mid-pouch and pouch-anal anastomosis. AIM: To undertake a systematic review of the literature and to identify management strategies available for pouch-anal, mid-pouch and pre-pouch ileal strictures and their outcomes. METHODS: A computer-assisted search of the online bibliographic databases MEDLINE and EMBASE limited to 1966 to February 2016 was performed. Randomized controlled trials, cohort studies, observational studies and case reports were considered. Those where data could not be extracted were excluded. RESULTS: Twenty-two articles were considered eligible. Pouch-anal strictures have been initially managed using predominately dilators which include bougie and Hegar dilators with various surgical procedures advocated when initial dilatation fails. Mid-pouch strictures are relatively unstudied with both medical, endoscopic and surgical management reported as successful. Pouch inlet strictures can be safely managed using a combined medical and endoscopic approach. CONCLUSION: The limited evidence available suggests that pouch-anal strictures are best treated in a stepwise fashion with initial treatment to include digital or instrumental dilatation followed by surgical revision or resection. Management of mid-pouch strictures requires a combination of medical, endoscopic and surgical management. Pouch inlet strictures are best managed using a combined medical and endoscopic approach. Future studies should compare different treatment modalities on separate stricture locations to enable an evidenced-based treatment algorithm.

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.