Results of the Fifth Scientific Workshop of the ECCO [II]: Clinical Aspects of Perianal Fistulising Crohn s Disease the Unmet Needs

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1 Journal of Crohn's and Colitis, 2016, doi: /ecco-jcc/jjw039 Advance Access publication January 28, 2016 ECCO Scientific Workshop Paper ECCO Scientific Workshop Paper Results of the Fifth Scientific Workshop of the ECCO [II]: Clinical Aspects of Perianal Fistulising Crohn s Disease the Unmet Needs Krisztina B. Gecse, a Shaji Sebastian, b Gert de Hertogh, c Nuha A. Yassin, d Paulo G. Kotze, e Walter Reinisch, f Antonino Spinelli, g Ioannis E. Koutroubakis, h Konstantinos H. Katsanos, i Ailsa Hart, j Gijs R. van den Brink, k Gerhard Rogler, l Willem A. Bemelman m a First Department of Medicine, Semmelweis University, Budapest, Hungary b Inflammatory Bowel Disease Unit, Hull & East Yorkshire NHS Trust, Hull, UK c Department of Pathology, University of Leuven, Leuven, Belgium d Department of Colorectal Surgery, St Mark s Hospital and Academic Institute, London, UK e Colorectal Surgery Unit, Catholic University of Paraná, Curitiba, PR, Brazil f Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, ON, Canada g Colorectal Surgery Unit, Humanitas Research Hospital, Humanitas University, Milan, Italy h Department of Gastroenterology, University Hospital Heraklion, Iraklio, Greece i Division of Gastroenterology, Department of Medicine, School of Health Sciences, Ioannina, Greece j Inflammatory Bowel Disease Unit, St Mark s Hospital, London, UK k Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands l Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland m Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Corresponding author: Krisztina B. Gecse, MD, PhD, First Department of Medicine, Semmelweis University, Budapest, Hungary. krisztina.gecse@gmail.com Abstract Background and Aims: Perianal fistulas affect up to one-third of Crohn s patients during the course of their disease. Despite the considerable disease burden, current treatment options remain unsatisfactory. The Fifth Scientific Workshop [SWS5] of the European Crohn s and Colitis Organisation [ECCO] focused on the pathophysiology and clinical impact of fistulas in the disease course of patients with Crohn s disease [CD]. Methods: The ECCO SWS5 Working Group on clinical aspects of perianal fistulising Crohn s disease [pcd] consisted of 13 participants, gastroenterologists, colorectal surgeons, and a histopathologist, with expertise in the field of inflammatory bowel diseases. A systematic review of literature was performed. Results: Four main areas of interest were identified: natural history of pcd, morphological description of fistula tracts, outcome measures [including clinical and patient-reported outcome measures, as well as magnetic resonance imaging] and randomised controlled trials on pcd. Conclusions: The treatment of perianal fistulising Crohn s disease remains a multidisciplinary challenge. To optimise management, a reliable classification and proper trial endpoints are needed. This could lead to standardised diagnosis, treatment, and follow-up of Crohn s perianal fistulas and the execution of well-designed trials that provide clear answers. The prevalence and the natural history of pcd need further evaluation. Key Words: Crohn s disease; perianal fistula; treatment Copyright 2016 European Crohn s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com 758

2 Perianal Fistulising Crohn s Disease Introduction Despite the original report of Crohn s disease [CD] in 1932, it was not until 1938 that Penner and Crohn described the concomitant presence of perianal fistulas in regional ileitis. 1 According to population-based studies, every third patient with CD develops at least one fistulising episode during the course of the disease. The greatest proportion of these episodes is represented by perianal fistulas. 2 The cumulative incidence of perianal fistula increases with disease duration and the prevalence varies according to disease location, being the least common in isolated ileal disease and the most common in colonic disease involving the rectum. 3 In 10% of patients, perianal fistulisation is the initial manifestation of Crohn`s disease and this can precede the onset of luminal Crohn`s disease by several years. 2 Additionally, non-fistulising perianal manifestations, such as skin tags, fissures, ulcers, and strictures are also present in up to one-quarter of the patients. 4 Perianal disease activity frequently parallels luminal activity, although it may also be present with quiescent luminal disease in about 5% of patients. In these cases, the pressure gradient between the internal and external openings may be responsible for a persistent fistula tract. Perianal disease is associated with significant impairment in quality of life and is an independent predictor of inflammatory bowel disease [IBD]-related work disability. 5,6 The treatment of perianal fistulising CD [pcd] is complex, and optimal management requires a multidisciplinary approach. 7 However, current treatments remain unsatisfactory and, due to the complexity of the disease, inappropriate treatment is frequently applied. In an analysis of 288 patients in the Swiss IBD cohort, 22% of the patients were judged as receiving inappropriate therapy when evaluated against the European Panel on the Appropriateness of Crohn s disease Therapy. 8,9 Interestingly, appropriate therapy was more often given for complex [87%] than for simple fistulas [67%]. 8 Furthermore, in the past decade little progress was made with regard to available medical and surgical treatment options for perianal fistulas. 10 Hence, current literature has several shortcomings that limit the development of an evidence-based approach on the management of perianal fistulising CD. Randomised controlled trials [RCTs] with fistula healing as the primary endpoint are scarce, and therefore current knowledge is largely based on retrospective series, expert opinion, and subanalysis of RCTs. Perianal fistulising Crohn s disease implies significant burden on patients and requires complex clinical management. The aim of this review was to identify the major challenges of current practice and gaps in our understanding as well as areas of improvement in pcd. 2. The Natural History of Perianal Fistulising Cd Historical data showed that one-third of pcd patients had persisting perianal fistulas upon 10-year follow-up; the remainder healed either spontaneously or after surgery. 11 Additionally, clinically healed fistulas recurred in 44% of patients within 18 months. 12 In the absence of proctitis, fistulotomy is safe and offers a high healing rate in superficial and low fistulas. Fistulas are defined as low when the tract runs through the lower one-third of the external anal sphincter. 13 Conversely, in high fistulas or in the presence of proctitis fistulotomy is associated with decreased healing rate and considerable risk for postoperative incontinence. 14,15 The absence of proctitis is an independent predictor for increased healing and reduced recurrence rates. 12 Furthermore, pcd with rectal involvement is associated with a higher proctectomy rate compared with rectal sparing [ % vs %, respectively]. 16,17,18 A simple fistula is low, has a single external opening, and is not associated with abscess formation, rectovaginal fistula, or anorectal stricture, although it may be accompanied by active rectal disease. 19 A single-centre study including 232 pcd patients showed that simple fistulas were more likely to heal compared with complex fistulas [88.2% vs 64.6%; p < 0.001]. 20 Additionally, the durable remission rate for complex fistulas was only 37.0% at the end of the 10-year follow-up compared with 66.7% for simple fistulas [p < 0.001]. 20 The combination of surgical and medical therapy has additional benefits on perianal fistula healing compared with either therapy alone. Complete remission rates were 43% in the single and 52% in the combination therapy group. 21 This underlines the importance of the multidisciplinary treatment approach in perianal fistulas. Temporary faecal diversion may improve symptoms in approximately two-thirds of patients with refractory pcd. 22 However, reestablishment of intestinal continuity after faecal diversion remains low despite increasing use of biological therapies. 22,23 Colonic and rectal disease involvement and loose seton placement adversely affected successful stoma closure. 24 Interestingly, none of the medical treatments were associated with an improved outcome. 24 However, more recent data showed a decline in the proportion of patients undergoing diversion, examination under anaesthesia, or fistulotomy since 2000, suggesting better non-surgical management over time. 23 In female patients of childbearing age with established CD, the cumulative probability of developing perianal fistulas was 8%, 12%, and 21% at 1, 2, and 5 years following delivery, respectively. 25 Malignant transformation of perianal fistulas in CD rarely occurs. A systematic review in 2010 reported 61 cases and indicated significant challenges in early detection of carcinomas. 26 According to a Dutch multicentre study which included over 6000 CD patients, fistula-associated adenocarcinoma developed only in four patients. [27] The malignancies developed on average 22 years after establishment of CD and 9 years after the diagnosis of the fistula tract. 27 The unmet need in the prevalence and natural history in perianal CD is for reliable information on a population-based level with respect to the incidence of simple and complex perianal CD, its evolution over time, and complete healing and ostomy rates with or without proctectomy. 3. Morphological Description of Fistula Tracts 3.1. Milligan and Morgan Historically, the first classification dates back to 1934, before perianal fistulas were considered as manifestations of CD. Milligan and Morgan categorised perianal fistulas as those entering the anal canal below or above the anorectal ring [anatomically defined by the puborectal muscle], based on observations on postoperative incontinence Parks classification Parks classified perianal fistulas in view of possible iatrogenic injury to the external sphincter muscle, resulting in incontinence. A total of 400 consecutive patients with perianal fistulas were analysed, and the external anal sphincter served as reference as each fistula was assigned to one of four categories. 13 Fistulas were classified intersphincteric [45%] when the tract penetrated the internal sphincter and coursed through the intersphincteric space to the perianal skin. Fistulas that penetrated both the internal and the external sphincter were classified transsphincteric [30%]. Others that crossed the internal sphincter and then spread first upwards in the intersphincteric space and then downwards crossing the levator ani muscle

3 760 K. B. Gecse et al. before reaching the perianal skin, were called suprasphincteric fistulas [20%]. A fourth type of fistula was documented in a small proportion of patients [5%], where the fistula originating from the rectal wall coursed down through the levator ani muscle lateral to the external sphincter to reach the perianal skin. As these tracts do not penetrate the anal sphincter complex, they were called extrasphincteric. Vertical [intersphincteric, ischioanal, or supralevator] and horizontal [also called horsehoe ] extensions of the primary fistulas were termed secondary tracts. Later on, a fifth category was added to Parks original classification, namely superficial fistulas that course below both the internal and external sphincter, thus not involving the sphincter complex. This classification supplies an anatomically precise description of the primary and secondary fistula tracts St James University Hospital classification The St James University Hospital classification is based on magnetic resonance [MR] imaging. It consists of five grades and relates to the Parks classification. Linear superficial and intersphincteric fistulas were considered grade 1, linear superficial or intersphincteric fistulas with abscess or secondary tract were classified as grade 2, transsphincteric fistulas were graded 3, transsphincteric fistulas with abscess or secondary tract were graded 4, and supra- or trans-levator disease [ie supra- and extra-sphincteric fistulas] were considered grade 5. 13,14 It provides a detailed anatomical overview about the course of the primary and secondary tract, and additionally about associated abscesses. It has also been associated with surgical outcome, namely grades 1 and 2 needed simple surgical management, grades 3 and 4 resulted in complex surgery and possible incontinence, and grade 5 with pelvic sepsis Buchmann/Alexander-Williams classification The Buchmann/Alexander-Williams classification is detailed pathological report based on three components, namely skin lesions [maceration, erosion, ulceration, abscess, and skin tag], anal canal lesions [fissure, ulcer, stenosis], and fistulas [high, low, and rectovaginal]. 29 In contrast to previous classifications, it supplies no prognostic relevance with regard to disease outcome Cardiff classification The Cardiff classification [also mentioned as U.F.S.] is based on the presence of ulceration, fistula/abscess, and stricture where each item is scored according to clinical degree of severity [0 = not present, 1 = lesions with good prognosis, 2 = lesions associated with poor prognosis]. 30 A subsidiary classification [also mentioned as A.P.D.] was added on associated conditions, proximal and anal disease activity. This classification integrated a detailed anatomical and clinical description of perianal lesions and luminal activity. However, it supplies limited information with regard to disease prognosis, and information about the course of the fistula tracts and fistula discharge are lacking. 31, AGA technical review The AGA technical review classified perianal fistulas with an empirical approach as simple or complex. A simple fistula is low, has a single external opening, has no evidence of abscess, rectovaginal fistula, or anorectal stricture. Active rectal disease may be associated with both simple and complex disease. 19 Several more classifications were developed in an attempt to measure perianal disease severity and to determine management strategies and/or prognosis by supplying detailed anatomical description. However, early classifications did not distinguish between cryptoglandular and Crohn s fistulas. In order to appropriately determine management strategy, in addition to perianal disease activity, descriptors such as: luminal inflammation, especially with regard to proctitis and anal stricture; the number [single or multiple] and the course of the fistula tracts [high or low]; and secondary tracts and abscess formation should be noted. A combination of diagnostics comprising endoscopy, magnetic resonance imaging [MRI] and/or endoanal ultrasound [EUS], and examination under anaesthesia [EUA] provide the necessary information to classify the perianal fistulising disease. The unmet need is a comprehensive classification, which integrates all elements that are important for medical and surgical management. 4. Outcome Measures Various methods have been suggested to evaluate perianal fistula activity and disease severity at a certain time point and/or to assess response to treatment. These outcome measures are based on either clinical, radiological [mostly on MRI], or [more recently] patientreported outcome measures [PROMs] Clinical outcome measures The first attempt to measure fistula activity and response to treatment was by Present et al. in a randomised controlled trial that evaluated the efficacy of 6-mercaptopurine in the treatment of Crohn s disease. 33 In this study, five items were scored at baseline and then periodically using a 7-point scale, where a positive number indicated improvement. Although this instrument was easy to use in daily practice, it has not become widely used in subsequent clinical trials Anal disease activity index Seven symptoms related to anal disease were evaluated by using a linear analogue scale from 0 to 10 in the anal disease activity index. Three of these symptoms, namely spontaneous anal pain, pain following defaecation, and inhibition of locomotion by pain were of high discriminative value. 34 However, none of the other parameters, such as perianal itching, anal leakage, or social or sexual activity were associated with significant change after intervention. Notably, most of the therapeutic interventions were surgical [> 90%], dominated by perianal abscess drainage [> 60%], and improving pain and locomotion. Symptoms indicating fistula production were not evaluated Perianal Disease Activity Index The Perianal Disease Activity Index [PDAI] was developed to assess perianal disease severity and response to therapy. It is based on the assessment of quality of life [pain/restriction of activities, and restriction of sexual activities] and disease severity [fistula discharge, type of perianal disease, and degree of induration]. Each of the five items are rated on a 5-point Likert scale from 0 [no symptoms] to 4 [severe symptoms] and the sum of the sub-scores make up the final score. 35 The PDAI was tested for reliability and responsiveness and was validated against physicians and patients global assessments and the type of therapy prescribed for the patients. 35 Although PDAI was widely used in clinical trials, the cut-off for clinically significant response has never been determined. 36,37,38,39 The PDAI cut-off for active perianal CD was suggested as > 4, which resulted in an 87% accuracy when using clinical assessment [presence of drainage and/ or signs of local inflammation] as reference. 40 However, 10% of the

4 Perianal Fistulising Crohn s Disease 761 patients were falsely classified as having a low PDAI despite ongoing fistula drainage. Furthermore, in a prospective randomised control trial which evaluated the effect of metronidazole ointment in perianal CD, the PDAI was found insensitive to change when evaluated against Patients Global Impression of Improvement [on a 7-point Likert scale]. 41 However, evaluating a score with a therapy of previously unknown efficacy is methodologically questionable Fistula Drainage Assessment The Fistula Drainage Assessment was the index measuring response to medical therapy in the randomised controlled trial, which evaluated the efficacy of infliximab in Crohn s fistulas and led to regulatory approval. 36 A fistula was considered closed when it no longer drained despite gentle finger compression. Clinical response was defined as a reduction of 50% in the number of draining fistulas on at least two consecutive visits. Remission was defined as the absence of draining fistulas on two consecutive visits. This assessment has been used in several randomised controlled trials in the past. 42,43,44 However, evaluation on gentle finger compression remains investigator-dependent and the assessment has not been formally validated. It seems more appropriate to consider fistulas either as open, actively draining, or clinically closed. Apart from the clinical appearance, a radiological MRI-based evaluation of the presence of the fistula is of importance in clinical decision making. Several studies showed that clinical remission does not reflect deep tissue healing and radiological healing assessed by MRI is lagging behind clinical remission by a median of 12 months. 45,46,47 It seems that the site of a former fistula tract is the path of least resistance for a new fistula tract to occur. In cases when MRI indicated persisting active inflammation in the absence of clinical signs for fistula activity, relapse was observed upon discontinuation of infliximab treatment Pikarsky s Perianal Crohn s Disease Activity Index This Perianal Activity Index was developed to predict the outcome of surgical interventions. 49 The scoring system includes variables of abscess, fistula, anal ulcer or fissure, stenosis, incontinence, and concomitant luminal disease. Surgical outcome was classified as good [complete resolution], satisfactory [partial resolution], or poor [no resolution], as assessed by the treating surgeon. Importantly, information on concomitant medical therapy was not supplied, the outcomes were categorised subjectively, and the score has not been formally validated Radiological outcome measures The diagnosis of perianal fistulas in CD is based on imaging and surgical EUA. The gold-standard imaging modality for perianal CD is pelvic MRI, which has an accuracy of % to characterise fistula tracts and abscesses. 50 T2-weighted MRI sequence with fat-suppression [STIR sequences] is the optimal technique for MR fistula imaging. A gadolinium-enhanced T1-weighted sequence is useful for the differentiation between pus and granulation tissue. Additionally, its performance is not limited by anorectal strictures, and it enables visualisation of the supralevator region, clinically silent abscesses, and luminal inflammation. Transanal EUS is a useful alternative to MRI. In a pilot study, the agreement for perianal fistulas of rectal EUS and pelvic MRI was 82% and 50%, respectively, when compared with surgical findings. 51,52 Another study prospectively evaluated EUS and MRI and found that both were equally accurate in the assessment of pcd [91% vs 87%, respectively]. 51 Transcutaneous perineal ultrasound [TPUS] can also be used in selected cases; however, the accuracy can be limited by the restricted view. 53, Van Assche score An MRI-based scoring system for the evaluation of fistula was suggested to provide combined information of anatomical fistula description and features reflecting active inflammation. 46,48 Anatomical components include the number, the course [with regard to the Parks classification, without the superficial type], and the extension [with regard to the levator plane] of the fistula tracts. Active inflammation was depicted by fistula tract hyperintensity on T2-weighted images [indicating pus or fluid content], the presence of abscesses, and rectal wall involvement. Reliability was confirmed by good inter-observer concordance. 46 With regard to responsiveness, no significant difference was seen between MRI scores before and after infliximab therapy in clinical responders [defined by the Fistula Drainage Assessment], or between responders and non-responders after 6 weeks. 48 PDAI and C-reactive protein [CRP] were used as reference measures for validation. Correlation with PDAI was weak [r = 0.371, p = 0.036] and no correlation was found with CRP.[48] In contrast, 1 year of anti-tnf treatment was associated with a significant improvement of the Van Assche score, particularly with regard to T2 hyperintensity. 55 Importantly, the disappearance of contrast enhancement was the only MR feature associated with remission. Nevertheless, the score was found to be insensitive to change in a subgroup of patients with reduced fistula tract volume, upon long-term follow-up. 45 Recent data suggest that measuring fistula tract volumes by using an MRI-based 3D fistula model is feasible and may give an objective measure to monitor response to treatment with biologicals in perianal fistulas. 56 Overall, currently MRI is the gold standard to identify perianal morphology. However, there is an unmet need for a validated tool to evaluate response to treatment Patient-reported outcome measures [PROMs] The associated morbidity of pcd can have overwhelming effects on patients social life, educational activities, and professional and emotional relationships. Health-related quality of life [HRQoL] assessment tools might be able to help in quantifying the true disease impact on patients psychosocial well-being. 57 The US Food and Drug Administration has recently advised that PROMs should be the primary outcome in randomised controlled trials for CD. PROMs derived from the CDAI diary items have been suggested for use in luminal CD. 58 To date, no validated PROM exists for pcd. However the PDAI, which as a global score has been validated against patients global assessment, includes patient-reported items, such as pain or restriction of activities and restriction of sexual activities. Additionally, anti-tnf therapy improved HRQoL in patients with pcd after 12 months of treatment, as assessed by the Inflammatory Bowel Disease Questionnaire [IBDQ]. This improvement was most pronounced in patients with clinical and MRI healing. Furthermore, the IBDQ correlated significantly with the PDAI at baseline and at 12 months. 59 In order to capture all the concerns of patients living with perianal fistula, they should probably be involved in the design of an assessment tool. A new quality of life [QoL] PROM for anal fistulas has recently been designed by patients under the guidance of clinicians. To assist the development of a comprehensive anal fistula QoL assessment tool [AF-QoL], a qualitative study exploring patients experiences of perianal fistulas was conducted. This study captured

5 762 K. B. Gecse et al. the diverse experiences of patients with Crohn s anal fistulas, and used the findings to guide the design of a condition-specific assessment tool, the AF-QoL, which is currently undergoing the validation stage. 56 The most commonly used scores in clinical trials of Crohn s disease including perianal fistula patients are the Fistula Drainage Assessment, the PDAI, and the van Assche score. 35 To be able to fulfil the need for randomised controlled trials in this field, reliable endpoints for clinical trials are needed. To date, even such seemingly evident definitions as fistula healing may range anywhere between reduction of fistula drainage to absence of abnormalities visualised by MRI. In addition, there is a clear distinction between short- and long-term treatment goals in perianal fistulising disease. Short-term goals are sepsis control by abscess drainage and the reduction of symptoms. Long-term treatment goals include sustained resolution of fistula drainage and improvement of quality of life. Accordingly, to achieve these goals the treatment modalities [percutaneous/surgical drainage and antibiotics vs long-term combined immunosuppressive treatment] may significantly differ. Therefore, when evaluating outcome, these short- and long-term goals should probably be taken into consideration. Therefore, the unmet need in assessing outcome of therapy in perianal CD is for a reliable tool to assess fistula healing and improvement of symptoms from the patient perspective. Table 1. Randomised controlled trials with the primary objective of treating perianal fistulising Crohn s disease, Study Patients Intervention Comparison Duration Outcome Thia et al Ciprofloxacin Metronidazole Placebo 10w Response: 30% ciprofloxacin 0% metronidazole 12.5% placebo Placebo 4w Reduction in PDAI: ns. Maeda et al Metronidazole [ointment] West et al Ciprofloxacin + IFX IFX 18w Response: 73% ciprofloxacin + IFX 39% IFX alone, ns. Dewint et al Ciprofloxacin + ADA ADA 24w Response at w12: 71 vs 47% Response at w24: ns. Sandborn et al Tacrolimus [by mouth] Placebo 10w Response: 43% vs 8% placebo, p = Remission: ns. Placebo 12w Response: ns. Hart et al Tacrolimus [ointment] Present et al IFX Placebo 18w Response: 62% IFX vs 26% placebo Remission: 46% IFX vs 13% placebo Sands et al IFX Placebo 54w Time to loss of response: 40w IFX vs 14w placebo Response: 46% IFX vs 23% placebo Remission: 36% IFX vs 19% placebo Fukuda et al AST-120 Placebo 8w Response: 37.0% AST-120 vs 10.0% placebo, p = Remission: 29.6% AST-120 vs 6.7% placebo, p = Reinisch et al AST-120 Placebo 8w Response: 27.0 vs 34.6%, ns Grimaud et al Fibrin glue Placebo 8w Remission: 38% fibrin glue vs 16% placebo, p = 0.04 Lindsey et al Fibrin glue Conventional treatment [fistulotomy in simple and seton +/- advancement flap in complex fistulas] Senejoux et al Seton removal + Fistula plug 8w Remission: simple: 50% fistula plug vs 100% fistulotomy, p = 0.06; complex: 69% fistula plug vs 13% conventional, p = Seton removal 12w Remission: 31% fistula plug vs 23% seton removal, p = 0.19 IFX, infliximab; ADA, adalimumab; w, Week, ns, not significant; AST-120, spherical carbon adsorbent; PDAI, Perianal Disease Activity Index.

6 Perianal Fistulising Crohn s Disease Randomised Controlled Trials 5.1. Randomised clinical trials with a primary objective of treating pcd are limited A 10-week study in 25 patients only did not report difference between efficacy of ciprofloxacin, metronidazole, and placebo on fistula closure. 60 A randomised clinical trial [RCT] found that metronidazole ointment 10% was not more effective than placebo in reducing the PDAI score in pcd. 41 Two double-blind RCTs assessed the efficacy of ciprofloxacin combined with anti-tnf therapy. 38,61 The first study combined ciprofloxacin with infliximab and reported fistula response at Week 18 in 73% of patients, vs 39% with infliximab alone, however not achieving statistical significance due to the small sample size [n = 24, p = 0.12]. 38 In a recent RCT, the combination therapy of ciprofloxacin with adalimumab was found superior to adalimumab monotherapy in the short term. 61 Prospective controlled trials that assess thiopurines in the treatment of pcd are lacking [Table 1]. Prospective data are only derived from a subgroup analysis of a randomised double-blind study with 6-mercaptopurine. 33 A single, short term, placebo-controlled trial randomised 46 patients with pcd to treatment with oral tacrolimus or placebo. The primary endpoint of fistula response defined by the fistula drainage assessment was significantly higher in the tacrolimus group [p = 0.004], although the difference was not significant with regard to fistula remission as defined by the FDA. 42 Two RCTs have assessed and proven the efficacy of induction and maintenance treatment of infliximab in fistulising CD. 36,43 There are no trials with a primary endpoint on pcd for adalimumab, certolizumab, or vedolizumab. Subgroup analysis of the CHARM and PRECiSE 1 and 2 trials indicated increased clinical response rates when patients were treated with adalimumab or certolizumab, respectively, as compared with placebo. 44,62 There is a lack of RCTs for combined immunosuppressive treatment in pcd. Although 12% of patients had perianal fistulas in the SONIC trial, no separate analysis was performed for this group. The subgroup analysis of the ACCENT II trial found that concomitant immunosuppressants did not improve response rates to infliximab at 1 year. 43 Conversely, recent evidence suggests a clear association between combination therapy and fistula closure. 63 The largest [n = 249] phase III multicentre, randomised, placebo-controlled trial in pcd evaluated the efficacy of AST-120 spherical carbon adsorbent, which did not confirm the therapeutic gain previously reported from Japan. 64,65 Two RCTs compared the efficacy of fibrin glue with placebo and with conventional surgical treatment [ie fistulotomy or seton ± advancement flap]. 66,67 Clinical remission was observed in 38% of the fibrin glue-treated patients compared with 16% in the placebo group [p = 0.04]. 66 Additionally, no advantage was found for fibrin glue over fistulotomy for simple fistulas; however, it healed more complex fistulas compared with conventional treatment [p = 0.003]. 67 A recent large, phase III, randomised placebo-controlled study evaluated and proved efficacy of expanded allogenic-derived stem cells in complex perianal fistulas in inducing fistula remission in the 24-week primary analysis [p < 0.025]; the long-term follow-up is still ongoing. In a multicentre, open-label, randomised controlled trial, seton removal alone was compared with seton removal with insertion of anal fistula plug in 106 Crohn s patients. 68 Anal fistula plug was not found more effective than seton removal alone to achieve fistula closure at Week 12. There are a few ongoing RCTs. The French Society of Coloproctology is currently recruiting for a randomised, open-label study to evaluate the effect of surgery in patients treated with adalimumab after seton removal [ClinicalTrials.gov Identifier: NCT ]. A phase II trial to assess the efficacy and safety of anti-interleukin [IL]-13 monoclonal antibody in the treatment of pcd has now been completed, although no results are yet available [ClinicalTrials.gov Identifier: NCT ]. One ongoing RCT evaluates chronic seton treatment vs anti-tnf therapy vs advancement flap in the treatment of high transsphincteric fistulas. 69 There is an unmet need for well designed and powered studies with endpoints specifically aiming at perianal fistulas, evaluating medical as well as surgical and combination therapy. 6. Conclusions Although perianal fistulas are common and impose significant physical and psychological burdens on Crohn s patients, optimal treatment strategies remain challenging. Adequate classification of the fistulising disease is crucial for choosing optimal medical and/ or surgical treatment. The main factors that influence management are luminal inflammation, with special regard to proctitis and anal stricture, abscess formation, and the course and number of the fistula tracts in relation to the external sphincter and their extension. Deep tissue healing [ie deep remission of fistulising disease] can only be determined by repeated MR imaging, although a sensitive, reliable and validated scoring system is awaited. For optimising management, validated endpoints for clinical trials are needed, which could also lead to standardised diagnosis, treatment, and follow-up of Crohn s fistulas. Furthermore, reliable endpoints would further foster interest in studying treatment modalities in this major indication within CD. Funding This work was supported by ECCO within the Scientific Workshop Program [SWS5]. Conflict of Interest ECCO has diligently maintained a disclosure policy of potential conflicts of interests [CoI]. The conflict of interest declaration is based on a form used by the International Committee of Medical Journal Editors [ICMJE]. The CoI statement is not only stored at the ECCO Office and the editorial office of JCC, but is also open to public scrutiny on the ECCO website [ ecco-ibd.eu/about-ecco/ecco-disclosures.html], providing a comprehensive overview of potential conflicts of interest of authors. Author Contributions KBG, SS, and GvdH performed the systematic literature search and drafted the manuscript. NY, PK, WR, AS, IK, KK, and AH performed additional data collection and consulted the manuscript. GvdB and GR consulted on the concept. WAB supervised the concept and the manuscript preparation. All authors read and approved the final manuscript. References 1. Penner A, Crohn BB. Perianal Fistulas as a Complication of Regional Ileitis. Ann Surg 1938;108: Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. The natural history of fistulizing Crohn s disease in Olmsted County, Minnesota. Gastroenterology 2002;122:

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