http://informahealthcare.com/pgm ISSN: 0032-5481 (print), 1941-9260 (electronic) Postgrad Med, 2015; 127(3): 266–272 DOI: 10.1080/00325481.2015.1023160
CLINICAL FOCUS: GASTROENTEROLOGY, HEPATOLOGY & NEPHROLOGY REVIEW
Perianal Crohn’s disease: A review Anna C. Juncadella1, Amer M. Alame2, Laurence R. Sands3 and Amar R. Deshpande4
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1
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA, 2Department of Surgery, Division of Colon and Rectal Surgery, St. John Hospital and Medical Center, Grosse Pointe Woods, MI, USA, 3Department of Surgery, Division of Colon and Rectal Surgery, University of Miami Miller School of Medicine, Miami, FL, USA, and 4Department of Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL, USA Abstract
Keywords
Perianal involvement in Crohn’s disease (CD), which encompasses fistulas, ulcers, abscesses, strictures and cancer, can lead to significant impairment in quality of life. The objective of this article is to review the major perianal complications of CD and the current medical and surgical modalities used to treat them. Antibiotics are commonly used despite a lack of controlled trials to validate their use and should be used as a bridge to maintenance therapy. The anti-metabolites azathioprine and 6-MP have shown a positive response in terms of fistula closure, although these data are mostly from trials looking at this as a secondary endpoint. Infliximab is an effective agent for induction and maintenance of treatment of fistulizing CD. Further studies to evaluate the use of subcutaneous anti-tumor necrosis factors are needed to convincingly prove their efficacy for perianal fistulizing disease. In CD, clinicians should avoid surgery as a first-line approach for skin tags, hemorrhoids or fissures in the setting of proctitis. Surgery, particularly lateral internal sphincterotomy, in combination with medical therapy is associated with higher fissure healing rates in the absence of proctitis. Fistulotomy is curative for most simple low perianal fistulae, but complex fistulas often require sphincter-sparing surgical procedures. Less invasive approaches such as a chemical sphincterotomy should be used first, with therapy escalated only if this fails.
Perianal, Crohn’s disease, medical, surgical, management, fistula
Introduction Perianal involvement is a common, often debilitating manifestation of Crohn’s disease (CD) that is frequently an indication of more severe disease [1]. Major perianal complications include fistulas (low, high and rectovaginal), ulcers, abscesses, strictures and cancer [2]. Evidence suggests that the etiology of perianal CD involves a combination of genetic, microbiologic and immunologic factors [3]. In this article, we will review the major perianal complications of CD and the current medical and surgical treatment modalities.
History Received 25 September 2014 Accepted 23 February 2015 Published online 7 March 2015
Perianal fistulas have been found to occur in 21%–23% of CD patients and seem to be more closely linked with upper GI tract and large bowel disease than with small bowellimited disease. Perianal fistulas were reported in 12% of those with small intestinal CD, 15% with combined ileocolonic CD, 41% with colonic CD without rectal involvement and 92% of those with colonic CD with rectal involvement [6-9]. As many as 5% of patients present with isolated perianal fistulas [10,11]. The cumulative probability for any perianal lesion other than fistulas in those with perianal fistulizing CD was 21.3% at 5 years and 29.2% at 10 years [12].
Epidemiology The frequency of anal complications in CD has varied in the literature, with reports ranging from 43.7% to 93% in large bowel disease. The inconsistent inclusion of hypertrophied skin tags and hemorrhoids as perianal manifestations of CD may explain the discrepancy in the literature. Nevertheless, there is an obvious trend towards higher rates of perianal disease in patients with colorectal involvement (52% vs 14%), even nearing 100% in the setting of more distal disease [4-6]. There is an association of inflammatory bowel disease-5 risk haplotype H2 with CD, most prominent in patients with perianal CD [7].
Classification systems Although the American Gastroenterological Association referred to the Parks classification of fistulas (superficial, intersphincteric, transsphincteric, suprasphincteric and extrasphincteric) as more anatomically precise, it has proposed a classification of fistulas as simple versus complex for the sake of practicality in the clinical setting. A simple fistula is superficial, has one opening, is not connected to adjacent structures and is not associated with an abscess. In contrast, a
Correspondence: Anna C. Juncadella, MD, Department of Medicine, Massachusetts General Hospital, 1 Emerson Place, Apt 11-E, Boston, MA 02114, USA. Tel: +1 617 889 8580. Fax: +1 617 889 8579. E-mail: [email protected] 2015 Informa UK Ltd.
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DOI: 10.1080/00325481.2015.1023160
complex fistula involves more of the anal sphincters, has more than one opening, crosses the midline and is associated with an abscess or connects to adjacent structures [2,13]. Classification schema such as the CD Activity Index fails to satisfactorily measure perianal disease independently of luminal disease; the Perianal Disease Activity Index (PDAI) is a reliable 5-item assessment of perianal disease activity [14]. The Fistula Drainage Assessment Measure (FDAM) classifies fistulas as being either open and actively draining or closed. FDAM was used as the primary end point in the trial of Infliximab for the treatment of fistulas in CD [15].
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Diagnosis Careful evaluation should include a comprehensive history, inquiring about anorectal pain, purulent discharge or persistent drainage from the anoperineal region, rectal bleeding, recurrent urinary tract infections and/or fecal incontinence. It is important to evaluate for abscesses, perianal and rectovaginal fistulas, and anorectal strictures, which may be difficult to distinguish from skin tags and hemorrhoids [16]. Endoscopy should be performed in search of macroscopic evidence of disease [10]. Other modalities used in the diagnosis and classification of perianal CD include examination under anesthesia (EUA), anorectal endoscopic ultrasound (EUS) and pelvic magnetic resonance imaging (MRI), all of which are helpful tests. A prospective triple-blinded study of 34 patients to assess the accuracy of rectal EUS, pelvic MRI and surgical EUA in the evaluation of perianal fistulas reported that rectal EUS correctly classified 91% of patients, pelvic MRI 87% and EUA 91%; the difference between tests was not significant, most likely due to sample size. The combination of any two of these modalities is ideal, reaching ~ 100% accuracy in classification with each of the three combinations [7,17]. Considering cost, the combination of EUA with either MRI or EUS is preferable to avoid incurring the cost of a third test if intervention is required, and the expertise of the local institution should dictate the decision to use MRI versus EUS [17]. Fistulography and computed tomography have low diagnostic accuracy and are no longer recommended [18-20].
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a monoclonal antibody against IL-6 [21]. IL-1b, IL-6 and TNF-a most likely play an important role in perianal CD and mucosal levels of IL-6 and IL-12 have prognostic value for recurrence and need for surgery [22].
Medical treatment Antibiotics The use of metronidazole has been based solely on case series and uncontrolled trials. A retrospective study of the effect of metronidazole on 21 patients with chronic unremitting perineal CD showed improvement in all patients, complete healing in 10/18 patients, and at least significant healing in another five patients who were treated for at least 2 months. A follow-up study showed that decreasing the dosage was associated with exacerbation of disease, healing quickly when the full dose was restarted. The efficacy of ciprofloxacin alone and in combination with metronidazole for the treatment of perianal CD is also only supported by uncontrolled trials and case series. A randomized controlled study of ciprofloxacin or metronidazole for the treatment of perianal fistulas in 25 CD patients showed more frequent remission and response in patients treated with ciprofloxacin; nevertheless, these differences did not achieve statistical significance. Although initial response rates to antimicrobial therapy are high in perianal CD, dose-related paresthesias, other potential long-term side effects and the inevitable emergence of drug resistance will likely continue to limit their chronic use [23-29]. Limited response as maintenance suggests that antibiotic therapy may only be effective as a bridge to maintenance therapy with other agents, including azathioprine [30]. Combination therapy with ciprofloxacin and infliximab was found to offer a clinical advantage (defined as ‡ 50% reduction in draining fistulas) over infliximab alone, but the difference was not statistically significant [31]. A study by West et al. suggests that perianal fistulas are mainly colonized by gram-positive organisms and that bacterial flora did not change after treatment with ciprofloxacin, suggesting a possible alternative mechanism to the efficacy of ciprofloxacin, such as an immunosuppressive property [32]. Future studies should evaluate the role of antimicrobials with greater gram-positive coverage.
Cytokines Cytokines have been described as messengers of inflammatory cells and play a key role in CD inflammation. Anti-tumor necrosis factor (TNF) agents are imperfect in the treatment of perianal CD, suggesting that other cytokines likely play a role in the inflammatory aspect of this disease. In a study analyzing the cytokine network in order to identify possible targets for neutralizing antibody therapy (as has been done with anti-TNF therapy), TNF levels correlated with PDAI and presence of anal fistulas, interleukin-12 (IL-12) levels were significantly higher in the presence of anal strictures, and IL-6 significantly correlated with the presence of active fistulas and inversely correlated with presence of anal strictures. This study sheds doubt on the efficacy of anti-IL12 therapy in the setting of chronic perianal CD or indeterminate colitis without anal strictures but suggests a possible role for
Immune modulator therapies Azathioprine and 6-mercaptopurine are anti-metabolite agents with immunosuppressive properties. Although shown to be effective in the setting of luminal CD, fistula response to azathioprine or 6-MP has only been addressed as a secondary end point in a meta-analysis [33]. The combined results of five placebo-controlled trials, in which 66% of the pooled patients came from a single study by Present et al., showed fistula response in 54% of patients treated with an antimetabolite versus 21% receiving placebo [34]. An odds ratio of 4.44 (CI 1.50–13.20) favoring healing or decreased discharge with anti-metabolites was reported [33]. Common side effects seen with the use of azathioprine and 6-MP include leukopenia, allergic reactions, infection, pancreatitis and drug-induced hepatitis [11].
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Calcineurin inhibitors Cyclosporine acts as a potent inhibitor of cell-mediated immunity by hindering the production of IL-2 by T-helper cells [35]. A Cochrane meta-analysis of 4 controlled trials studying cyclosporine ultimately determined that it is not effective for the treatment of active CD and there are no controlled trials supporting its use for fistulizing or perianal CD [36]. Although several uncontrolled studies have suggested benefit of cyclosporine in the setting of treatment-refractory fistulizing CD, a majority of these patients tend to relapse when therapy is discontinued, most likely due to inadequate duration of overlap with more slowly acting anti-metabolites [35,37]. Uncontrolled trials have demonstrated efficacy of tacrolimus, also a calcineurin inhibitor, in the treatment of fistulizing CD [38-40]. A randomized controlled trial to determine the efficacy of tacrolimus for the treatment of fistulizing CD showed that it is effective for fistula improvement but not induction of remission in perianal CD [41]. The secondary end point of remission could possibly have been limited by small sample size. Adverse events associated with tacrolimus include nephrotoxicity, headache, insomnia, paresthesias and tremor; these can usually be managed with dose reduction. Other immunosuppressants A retrospective review of the use of methotrexate for inflammatory bowel disease and particularly fistulizing CD showed that a mean dose of 18.2 mg/week achieved fistula improvement in 44.4% of CD patients who completed 6 months of treatment; however, this study did not specifically address perianal fistulas. The combination of azathioprine and methotrexate does not appear to confer an advantage over methotrexate therapy alone [42]. Other immunosuppressive agents that could potentially be used for the treatment of perianal CD include sargramostim, mycophenolate mofetil and thalidomide, although further studies are needed to establish their efficacy [43-45]. Tumor necrosis alpha antagonists and other biologics A systematic review and meta-analysis performed by Ford et al. clearly showed the benefit of biologics for the treatment of fistulas in CD [46]. The most proven of these biologics in induction and maintenance therapy of fistulizing CD is infliximab, a murine-human chimeric monoclonal antibody to TNF-a. TNF-a is a pro-inflammatory cytokine involved in the pathogenesis of inflammatory bowel disease. In a randomized, multicenter, double-blind, placebocontrolled trial of infliximab for the treatment of fistulas in patients with CD, 68% of the patients who received 5 mg/kg of infliximab achieved the primary end point of reduction of 50% or more from baseline in the number of draining fistulas compared to 56% and 26% in the 10 mg/kg infliximab and placebo arms, respectively (p = 0.002 and p = 0.02). Fifty-five percent of the patients who received 5 mg/kg of infliximab achieved the secondary end point of closure of all fistulas compared to 38% and 13% in the 10 mg/kg of
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infliximab and placebo arms, respectively (p = 0.001 and p = 0.04). The effects of this therapy were noted within approximately 2 weeks and lasted for an average of 3 months. Given the lack of superiority of 10 mg/kg over 5 mg/kg, the study supported the use of a 5 mg/kg dose of infliximab at 0, 2 and 6 weeks. Maintenance infliximab therapy has been shown to significantly reduce hospitalizations, surgeries and procedures compared with placebo. An ACCENT II trial post hoc analysis established the effectiveness of infliximab for short-term and maintenance of rectovaginal fistula closure in particular. Adverse effects associated with infliximab and all anti-TNF agents include infectious complications like reactivation of hepatitis B and tuberculosis, hematologic malignancies and autoimmune phenomena like demyelination and psoriasis [15,47-50]. In two randomized controlled trials, the CLASSIC I trial and the GAIN study, adalimumab, a subcutaneously administered human monoclonal antibody targeting TNF, failed to show superiority over placebo for the treatment of fistulas [51,52]. In contrast, in the CHARM study, adalimumab was associated with improved fistula closure compared to placebo [53]. Closure of all draining fistulas was achieved in 30% and 13% of patients receiving adalimumab and placebo, respectively, at week 26 (p = .043) and 33% and 13% at week 56 (p = .016). An open-label extension of this trial was conducted, and all groups were given adalimumab 40 mg every other week for up to 2 years. At the end of the 2 years, clinical remission rates were 37.6%, 41.9% and 49.8% in those originally randomized to placebo, adalimumab every other week, and adalimumab weekly, respectively [54]. In the CHOICE trial, patients with moderate-to-severe CD who had failed infliximab therapy received open-label adalimumab for induction and maintenance following an 8-week washout period. Complete fistula healing was achieved in 39% of patients with baseline fistulas. Results were sustained over a 2-year period, even in those that were primary nonresponders to infliximab [55]. Certolizumab is another subcutaneously administered antiTNF agent that differs from the other two anti-TNF agents in that it is pegylated. The PRECISE I and II studies did not convincingly show the efficacy of subcutaneous anti-TNFs in perianal fistulizing disease [56,57]. An assessment of maintenance of fistula closure was assessed after continuation of Certolizumab therapy for 26 weeks. At the 26-week evaluation, 36% of patients in the Certolizumab group had maintained fistula closure versus 17% of patients in the placebo group. This difference was not statistically significant [58]. Further studies to assess their use in this context are warranted. A recent study showed improved outcomes in regards to treatment of fistulizing disease with the use of infliximab and thiopurine combination therapy [59]. Two monoclonal antibodies against alpha 4 integrin, natalizumab and vedolizumab, are alternatives to anti-TNF therapy, the latter lacking the risk of PML secondary to reactivation of JC Virus [60]. Vedolizumab gained FDA approval in May 2014 for use in moderate-to-severe CD. There is no primary data yet on the efficacy of these drugs for perianal CD in particular.
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Further studies are also needed to establish the efficacy of ustekinumab, an IgG monoclonal antibody against IL-12 and IL-23, as well as tofacitinib and other JAK inhibitors [61,62]. Interestingly, a recent meta-analysis looking at the rate of response to placebo in RCTs of pharmacologic agents for fistulizing CD, found that fistulas closed in 1/6 of these patients [63].
Surgical treatment
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Skin tags Left untreated, 68% of skin tags in patients with CD will persist at 10 years [64]. However, due to the benign nature of skin tags, surgical excision is not warranted unless they restrict the patient from maintaining hygiene or are persistently symptomatic [65]. Surgery for skin tags in a patient with CD carries with it a higher chance of poor wound healing, infection and fistula formation [66]. Abscesses and fistulae In CD patients, infections in closed spaces have to be drained and fistulas are initially managed with a non-cutting seton to promote drainage. Sixty-seven per cent of peri-rectal abscesses will completely heal after drainage and 33% will develop into a fistula [67]. After control of local sepsis, optimizing medical therapy prior to definitive surgical treatment provides the best outcome [68-70]. EUA remains important to evaluate the extent of proctitis and prevent post-operative non-healing wounds. EUA also provides a chance to evaluate and classify the perianal fistulas to plan future surgical treatment. Almost all simple low perianal fistulae can be managed with fistulotomy as cure [71]. Complex fistulas or those that involve more than 30% of the external sphincter are best managed by sphincter-sparing surgical approaches to avoid iatrogenic injury to the sphincter and an unacceptable higher risk of incontinence [72]. It is the authors’ practice to treat complex fistulas in CD initially with a fistula infill material such as a fistula plug [73]. A lower success rate should be accepted given the minimally invasive surgical approach infill materials offer [74,75]. In the background of persistent inflammation and failure of closure using minimally invasive techniques, maintenance of the fistula tract with the use of draining setons is acceptable until the CD patient is medically optimized [76]. Left in place, as the inflammatory process progresses, draining setons form a mature fibrous fistulous tract. At the time of seton removal, definitive management of the fibrous fistulous tract can be undertaken. Fistula plugs offer a first-line minimally invasive surgical therapy with an acceptable closure rate albeit lower in patients with inflammatory bowel disease [77]. If a collagen plug fails, therapy can be escalated and the option of a trans-anal mucosal advancement flap. Mucosal advancement flaps with or without the addition of fibrin glue has been shown to result in healing rate as high as 62% of complex fistulas [78]. A similar healing rate is obtained in rectovaginal fistulas [79].
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Fissures Medical management with nitroglycerin paste, calcium channel blockers or botulinum toxin injections constitutes firstline therapy for a patient presenting with anal fissures [80]. Optimizing medical treatment of proctitis in CD patients with anal fissures is central to the success of non-operative management. In patients without proctitis, surgical therapy, particularly lateral internal sphincterotomy, is associated with a higher fissure healing rate (88%) as compared to medical treatment alone (26%) [81,82]. Lateral internal sphincterotomy is the mainstay of surgical treatment for anal fissures in the setting of CD. Hemorrhoids Chronic diarrhea exacerbates symptoms of hemorrhoids in patients with CD. Surgical intervention is usually avoided due to the increased risks of poor wound healing, infection and stenosis [83]. Surgery in the setting of acute exacerbation of hemorrhoidal disease and aggressive approaches to remove all hemorrhoids puts the patient at a higher risk of developing anal canal stenosis and should be avoided [84]. However, in patients whose anorectal disease is well controlled, hemorrhoidectomy for symptomatic relief carries acceptable risks. In that selective subgroup of patients, excisional hemorrhoidectomy or banding of symptomatic internal hemorrhoids offers a success rate that approaches 90% [85-87]. Monitoring of fistula healing EUS and MRI can be useful in monitoring fistula healing after combined medical and surgical treatment. Considering that fistulas can still be active even after they stop draining, these imaging modalities can be helpful to guide therapeutic strategies such as medication adjustments and seton removal [88-90].
Conclusion Perianal involvement is a common manifestation of CD, particularly in large bowel disease. This frequently presents a significant impact on patients’ quality of life, and for this reason, many medical and surgical modalities have been studied. Diagnostic approach should include a careful history, physical and endoscopic/anoscopic evaluation. These, together with a combination of EUA plus either MRI or EUS depending on institutional expertise, provide a cost-effective diagnostic strategy with close to 100% accuracy, allowing for an appropriate therapeutic approach. Use of antibiotic treatment, although widespread, is supported solely based on uncontrolled studies and case series. The limitations imposed by the failure of a majority of patients to maintain response upon discontinuation of therapy, the potential long-term side effects, and the emergence drug resistance all support the use of antibiotics as a bridge to maintenance therapy. The use of anti-metabolites such as azathioprine and 6-MP for fistulizing CD was addressed as a secondary end point in a meta-analysis of five
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placebo-controlled trials and showed a positive clinical response. A controlled trial supporting the use of cyclosporine for fistulizing or perianal CD has yet to be reported and the systemic toxicities likely do not justify its use. Improvement of fistulas with tacrolimus was shown in a controlled trial, although these results did not translate into significant improvements in remission rates. Infliximab has clearly been shown to be effective as an induction and maintenance agent for perianal and rectovaginal fistulizing CD. Further studies evaluating the use of subcutaneous anti-TNFs and other biologics are needed since existing studies have failed to convincingly show their efficacy in the setting of fistulizing CD. In the case of skin tags, surgical intervention is preferably avoided unless they are persistently symptomatic. Similarly, aggressive surgical approaches to hemorrhoids can cause more harm than benefit. Perianal infections in the acute setting are best managed with incision and drainage with the evaluation in the operative setting of the presence of an Anal Fistula. Should a fistula be found, draining setons are indicated to promote drainage and prevent a relapsing course of infections. Fistulotomy is curative in the majority of simple low perianal fistulae. Complex fistulas or those that involve more than 30% of the external sphincter should be approached with the aim of sparing the sphincter of iatrogenic injury, using less invasive approaches such as infill materials initially and escalating therapy if needed. Non-operative management is preferred for anal fissures in the setting of proctitis. In the absence of proctitis, surgical therapy, with lateral internal sphincterotomy being the mainstay, in addition to medical management is associated with higher healing rates.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
References [1] Tarrant KM, Barclay ML, Frampton CMA, Gearry RB. Perianal disease predicts changes in Crohn’s disease phenotype- results of a population –based study of Inflammatory bowel disease phenotype. Am J Gastroenterol 2008;103:3082–93. [2] American Gastroenterological Association Clinical Practice Committee. American Gastroenterological Association Medical Position Statement: Perianal Crohn’s Disease. Gastroenterology 2003;125:1503–7. [3] Tozer PJ, Whelan K, Phillips RKS, Hart A. Etiology of perianal Crohn’s disease: role of genetic, microbiological, and immunological factors. Inflamm Bowel Dis 2009;15:1591–8. [4] Williams JA. The place of surgery in Crohn’s disease. Gut 1971;12:739–49. [5] Williams DR, Coller JA, Corman ML, Nugent FW, Veidenheimer MC. Anal Complications in Crohn’s disease. Dis Colon Rectum 1981;24:22–4.
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[6] Hellers G, Bergstrand O, Ewerth S, Holmstrom B. Occurrence and outcome after primary treatment of anal fistulae in Crohn’s disease. Gut 1980;21:525–7. [7] Wiese DM, Schwartz DA. Managing Perianal Crohn’s disease. Curr Gastroenterol Rep 2012;14:153–61. [8] Schwartz DA, Loftus EV, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology 2002;122:875–80. [9] Tang LY, Rawsthorne P, Bernstein CN. Are perineal and luminal fistulas associated in Crohn’s disease? a population-based study. Clin Gastroenterol Hepatol 2006;4:1130–4. [10] Ruffolo C, Citton M, Scarpa M, Angriman I, Massani M, Caratozzolo E, Bassi N. Perianal Crohn’s disease: is there something new? World J Gastroenterol 2011;17:1939–46. [11] Schwartz DA, Pemberton JH, Sandborn WJ. Diagnosis and Treatment of Perianal Fistulas in Crohn Disease. Ann Intern Med 2001;135:906–18. [12] Peyrin-Biroulet L, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Perianal Crohn’s disease findings other than fistulas in a population-based cohort. Inflamm Bowel Dis 2012;18(1):43–8. [13] Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-in-ano. Br J Surg 1976;63:1–12. [14] Irvine EJ. Usual therapy improves perianal Crohn’s disease as measured by a new disease activity index. J Clin Gastroenterol 1995;20:27–32. [15] Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–405. [16] Steele SR. Operative management of Crohn’s disease of the colon including anorectal disease. Surg Clin North Am 2007;87:611–31. [17] Schwartz DA, Wiersema MJ, Dudiak KM, Fletcher JG, Clain JE, Tremaine WJ, et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology 2001;121:1064–72. [18] Schratter-Sehn AJ, Lochs H, Vogelsang H, Schurawitzki H, Herold C, Schratter M. Endoscopic ultrasonography versus computed tomography in the differential diagnosis of perianorectal complications in Crohn’s disease. Endoscopy 1993;25:582–6. [19] Berliner L, Redmond P, Purow E, Megna D, Sottile V. Computed tomography in Crohn’s disease. Am J Gastroenterol 1982;77:548– 53. [20] Ardizzone S, Maconi G, Cassinotti A, Massari A, Bianchi Porro G. Imaging of perianal Crohn’s disease. Dig Liver Dis 2007;39:970–8. [21] Ruffolo C, Scarpa M, Faggian D, Romanato G, De Pellegrin A, Filosa T, et al. Cytokine network in chronic perianal CD and indeterminate colitis after colectomy. J Gastrointest Surg 2007;11:16– 21. [22] Ruffolo C, Scarpa M, Faggian D, Pozza A, Navaglia F, D’Incà R, et al. Cytokine network in rectal mucosa in perianal Crohn’s disease: relations with inflammatory parameters and need for surgery. Inflamm Bowel Dis 2008;14:1406–12. [23] Ursing B, Kamme C. Metronidazole for Crohn’s disease. Lancet 1975;1:775–7. [24] Bernstein LH, Frank MS, Brandt LJ, Boley SJ. Healing of perineal Crohn’s disease with metronidazole. Gastroenterology 1980;79:357–65. [25] Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn’s disease: a follow-up study. Gastroenterology 1982;83:383–7. [26] Jakobovits J, Schuster M. Metronidazole therapy for Crohn’s disease and associated fistulae. Am J Gastroenterol 1984;79:533–40. [27] Turunen U, Farkkila M, Seppala K. Long-term treatment of perianal or fistulous Crohn’s disease with ciprofloxacin. Scand J Gastroenterol Suppl 1989;24:144. [28] Korelitz BI, Present DH. Combination ciprofloxacin and metronidazole in severe perineal Crohn’s disease. Can J Gastroenterol 1993;7:571–3. [29] Thia KT, Mahadevan U, Feagan BG, Wong C, Cockeram A, Bitton A, et al. Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis 2009;15:17–24.
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DOI: 10.1080/00325481.2015.1023160
[30] Dejaco C, Harrer M, Waldhoer T, Miehsler W, Vogelsang H, Reinisch W. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn’s disease. Aliment Pharmacol Ther 2003;18:1113–20. [31] West RL, Van der Woude CJ, Hansen BE, Felt-Bersma RJ, van Tilburg AJ, Drapers JA, Kuipers EJ. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn’s disease with infliximab: a double-blind placebocontrolled study. Aliment Pharmacol Ther 2004;20:1329–36. [32] West RL, Van der Woude CJ, Endtz H, Hansen BE, Ouwedijk M, Boelens HA, et al. Perianal fistulas in Crohn’s disease are predominately colonized by skin flora: implications for antibiotic treatment? Dig Dis Sci 2005;50:1260–3. [33] Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-Mercaptopurine in Crohn disease: a meta-analysis. Ann Intern Med 1995;122:132–42. [34] Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302:981–7. [35] Sandborn WJ. A critical review of cyclosporine therapy in inflammatory bowel disease. Inflamm Bowel Dis 1995;1:48–63. [36] McDonald JW, Feagan BG, Jewell D, Brynskov J, Stange EF, Macdonald JK. Cyclosporine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2005;2:CD000297. [37] Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing CD with intravenous cyclosporine. Am J Gastroenterol 1998;93:442–8. [38] Lowry PW, Weaver AL, Tremaine WJ, Sandborn WJ. Combination therapy with oral tacrolimus (FK 506) and azathioprine or 6mercaptopurine for treatment refractory Crohn’s disease perianal fistulae. Inflamm Bowel Dis 1999;5:239–45. [39] Ierardi E, Principi M, Rendina M, Francavilla R, Ingrosso M, Pisani A, et al. Oral tacrolimus (FK 506) in Crohn’s disease complicated by fistulae of the perineum. J Clin Gastroenterol 2000;30:200–2. [40] Fellermann K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid unresponsive acute attacks of inflammatory bowel disease: immunomodulation by Tacrolimus. Am J Gastroenterol 1998;93:1860–6. [41] Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology 2003;125:380–8. [42] Yang Soon S, Ansari A, Yaneza M, Raoof S, Hirst J, Sanderson JD. Experience with the use of low-dose methotrexate for inflammatory bowel disease. Euro J Gastroenterol Hepatol 2004;16:921–6. [43] Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ; Sargramostim in Crohn’s Disease Study Group. Sargramostim for active Crohn’s Disease. N Engl J Med 2005;352:2193–201. [44] Wenzl HH, Hinterleitner TA, Aichbichler BW, Fickert P, Petritsch W. Mycophenolate mofetil for Crohn’s Disease: shortterm efficacy and long-term outcome. Aliment Pharmacol Ther 2004;19:427–34. [45] Plamondon S, Ng SC, Kamm MA. Thalidomide in luminal and fistulizing Crohn’s disease resistant to standard therapies. Aliment Pharmacol Ther 2007;25:557–67. [46] Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systemic review and meta-analysis. Am J Gastroenterol 2011;106:644–59. [47] Knight DM, Trinh H, Le J. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30:1443–53. [48] Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876–85. [49] Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing crohn’s disease. Gastroenterology 2005;128:862–9.
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[50] Sands BE, Blank MA, Patel K, Van Deventer SJ. Long-term treatment of rectovaginal fistulas in CD: response to infliximab in the ACCENT II Study. Clin Gastroenterol Hepatol 2004;2:912–20. [51] Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in CD: the CLASSIC-I trial. Gastroenterology 2006;130:323–33. [52] Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829–38. [53] Colombel JF, Schwartz DA, Sandborn WJ, Kamm MA, D’Haens G, Rutgeerts P, et al. Adalimumab for the treatments of fistulas in patients with Crohn’s disease. Gut 2009;58:940–8. [54] Panaccione R, Colombel JF, Sandborn WJ, Rutgeerts P, D’Haens GR, Robinson AM, et al. Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn’s disease. Aliment Pharmacol Ther 2010;31:1296–309. [55] Lichtiger S, Binion DG, Wolf DC, Present DH, Bensimon AG, Wu E, et al. The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn’s disease who failed prior infliximab therapy. Aliment Pharmacol Ther 2010;32:1228–39. [56] Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn’s Disease. N Engl J Med 2007;357:228–38. [57] Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OØ, Hanauer SB, Bloomfield R, et al. Maintenance therapy with certolizumab pegol for CD. N Engl J Med 2007;357:239–50. [58] Schreiber S, Lawrence IC, Thomsen OO, Hanauer SB, Bloomfield R, Sandborn WJ. Randomised clinical trial: certolizumab pegol for fistulas in Crohn’s disease- subgroup results from a placebo-controlled study. Aliment Pharmacol Ther 2011;33:185–93. [59] Bouquen G, Siproudhis L, Gizard E, Wallenhorst T, Billioud V, Bretagne JF, et al. Long-term outcome of perianal fistulizing Crohn’s disease treated with infliximab. Clin Gastroenterol Hepatol 2013;8:975–81. [60] Sandborn WJ, Feagan BG, Rutgeerts PR, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711–21. [61] Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012;367:1519–28. [62] Boland BS, Sandborn WJ, Chang JT. Update on janus kinase antagonists in inflammatory bowel disease. Gastronenterol Clin North Am 2014;43:603–17. [63] Ford AC, Luthra P, Hanauer SB, Travis SP, Harris MS, Reinisch W. Placebo response rate in clinical trials of fistulizing Crohn’s disease: systemic revew and meta-analysis. Clin Gastroenterol Hepatol 2014;12:1981–90. [64] Buchmann P, Keighley MR, Allan RN, Thompson H, Alexander-Williams J. Natural history of perianal CD. Ten year follow-up: a plea for conservatism. Am J Surg 1980;140:642–4. [65] Singh B, McC Mortensen NJ, Jewell DP, George B. Perianal CD. Br J Surg 2004;91:801–14. [66] Keighley MR, Allan RN. Current status and influence of operation on perianal Crohn’s disease. Int J Colorectal Dis 1986;1:104–7. [67] Michelassi F, Melis M, Rubin M, Hurst RD. Surgical treatment of anorectal complications in Crohn’s disease. Surgery 2000;128:597– 603. [68] Regueiro M, Mardini H. Treatment of perianal fistulizing Crohn’s disease with infliximab alone or as an adjunct to exam under anesthesia with seton placement. Inflamm Bowel Dis 2003;9:98–103. [69] Topstad DR, Panaccione R, Heine JA, Johnson DR, MacLean AR, Buie WD. Combined seton placement, infliximab infusion and maintenance immunosuppressive improve healing rate in fistulizing anorectal Crohn’s disease: a single center experience. Dis Colon Rectum 2003;46:577–83. [70] Schwartz DA, White CM, Wise PE, Herline AJ. Use of endoscopic ultrasound to guide combined medical and surgical therapy for patients with Crohn’s perianal fistulas. Inflamm Bowel Dis 2005;11:727–32.
Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/26/15 For personal use only.
272
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[71] Wolkomir AF, Luchtefeld MA. Surgery for symptomatic hemorrhoids and anal fissures in CD. Dis Colon Rectum 1993;36:545–7. [72] Alexander-Williams J, Steinberg DM, Fielding JS, Thompson H, Cooke WT. Proceedings: perianal Crohn’s disease. Gut 1974;15:822–3. [73] Swinscoe MT, Ventakasubramaniam AK, Jayne DG. Fibrin glue for fistula-in-ano: the evidence reviewed. Tech Coloproctol 2005;9:89–94. [74] Vitton V, Gasmi M, Barthet M, Desjeux A, Orsoni P, Grimaud JC. Long-term healing of Crohn’s anal fistulas with fibrin glue injection. Aliment Pharmacol Ther 2005;21:1453–7. [75] Cestaro G, De Rosa M, Gentile M. Treatment of fistula in ano with fibrin glue: preliminary results from a prospective study. Minerva Chir 2014;69:225–8. [76] Atienza P, Ksiaa M. Particular aspects of proctology for anoperineal lesions in Crohn’s disease. J Visc Surg 2015. [Epub ahead of print]. [77] Cintron JR, Abcarian H, Chaudry V, Singer M, Hunt S, Birnbaum E, et al. Treatment of fistula-in-ano using a porcine small intestinal submucosa anal fistula plug. Tech Coloproctol 2013;17:187–91. [78] Marchesa P, Hull TL, Fazio VW. Advancement sleeve flaps for treatment of severe perianal Crohn’s disease. Br J Surg 1998;85:1695–8. [79] Hull TL, Fazio VW. Surgical approaches to low anovaginal fistula in Crohn’s disease. Am J Surg 1997;173:95–8. [80] Madoff RD, Fleshman JW. AGA technical review on the diagnosis and care of patients with anal fissure. Gastroenterology 2003;124:235–45.
Postgrad Med, 2015; 127(3):266–272
[81] Fleshner PR, Schoetz DJ Jr, Roberts PL, Murray JJ, Coller JA, Veidenheimer MC. Anal fissure in Crohn’s disease: a plea for aggressive management. Dis Colon Rectum 1995;38:1137–43. [82] Jonas M, Scholefield JH. Anal fissure. Gastroenterol Clin North Am 2001;30:167–81. [83] Jeffery PJ, Parks AG, Ritchie JK. Treatment of Haemorrhoids in patients with inflammatory bowel disease. Lancet 1977;1:1084–5. [84] Mukta V, Rocco R. Anal stenosis. Surg Clin North Am 2010;90:137–45. [85] Wolkomir AF, Luchtefeld MA. Surgery for symptomatic hemorrhoids and anal fissures in Crohn’s disease. Dis Colon Rectum 1993;36:545–7. [86] Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB; American Gastroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn’s Disease. Gastroenterology 2003;125:1508–30. [87] Steele SR. Operative management of Crohn’s Disease of the colon including anorectal disease. Surg Clin North Am 2007;87:611–31. [88] Schwartz DA. What is the optimal maintenance treatment for perianal Crohn’s disease? Inflamm Bowel Dis 2008;14:S269–70. [89] Van Assche G, Vanbeckevoort D, Bielen D, Coremans G, Aerden I, Noman M, et al. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease. Am J Gastroenterol 2003;98:332–9. [90] Guidi L, Ratto C, Semeraro Roberto I, De Vitis I, Papa A, et al. Combined therapy with infliximab and seton drainage for perianal fistulizing Crohn’s disease with anal endosonographic monitoring: a single-centre experience. Tech Coloproctol 2008;12:111–17.
CLINICAL FOCUS: GASTROENTEROLOGY, HEPATOLOGY & NEPHROLOGY REVIEW
Perianal Crohn’s disease: A review Anna C. Juncadella1, Amer M. Alame2, Laurence R. Sands3 and Amar R. Deshpande4
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1
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA, 2Department of Surgery, Division of Colon and Rectal Surgery, St. John Hospital and Medical Center, Grosse Pointe Woods, MI, USA, 3Department of Surgery, Division of Colon and Rectal Surgery, University of Miami Miller School of Medicine, Miami, FL, USA, and 4Department of Medicine, Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL, USA Abstract
Keywords
Perianal involvement in Crohn’s disease (CD), which encompasses fistulas, ulcers, abscesses, strictures and cancer, can lead to significant impairment in quality of life. The objective of this article is to review the major perianal complications of CD and the current medical and surgical modalities used to treat them. Antibiotics are commonly used despite a lack of controlled trials to validate their use and should be used as a bridge to maintenance therapy. The anti-metabolites azathioprine and 6-MP have shown a positive response in terms of fistula closure, although these data are mostly from trials looking at this as a secondary endpoint. Infliximab is an effective agent for induction and maintenance of treatment of fistulizing CD. Further studies to evaluate the use of subcutaneous anti-tumor necrosis factors are needed to convincingly prove their efficacy for perianal fistulizing disease. In CD, clinicians should avoid surgery as a first-line approach for skin tags, hemorrhoids or fissures in the setting of proctitis. Surgery, particularly lateral internal sphincterotomy, in combination with medical therapy is associated with higher fissure healing rates in the absence of proctitis. Fistulotomy is curative for most simple low perianal fistulae, but complex fistulas often require sphincter-sparing surgical procedures. Less invasive approaches such as a chemical sphincterotomy should be used first, with therapy escalated only if this fails.
Perianal, Crohn’s disease, medical, surgical, management, fistula
Introduction Perianal involvement is a common, often debilitating manifestation of Crohn’s disease (CD) that is frequently an indication of more severe disease [1]. Major perianal complications include fistulas (low, high and rectovaginal), ulcers, abscesses, strictures and cancer [2]. Evidence suggests that the etiology of perianal CD involves a combination of genetic, microbiologic and immunologic factors [3]. In this article, we will review the major perianal complications of CD and the current medical and surgical treatment modalities.
History Received 25 September 2014 Accepted 23 February 2015 Published online 7 March 2015
Perianal fistulas have been found to occur in 21%–23% of CD patients and seem to be more closely linked with upper GI tract and large bowel disease than with small bowellimited disease. Perianal fistulas were reported in 12% of those with small intestinal CD, 15% with combined ileocolonic CD, 41% with colonic CD without rectal involvement and 92% of those with colonic CD with rectal involvement [6-9]. As many as 5% of patients present with isolated perianal fistulas [10,11]. The cumulative probability for any perianal lesion other than fistulas in those with perianal fistulizing CD was 21.3% at 5 years and 29.2% at 10 years [12].
Epidemiology The frequency of anal complications in CD has varied in the literature, with reports ranging from 43.7% to 93% in large bowel disease. The inconsistent inclusion of hypertrophied skin tags and hemorrhoids as perianal manifestations of CD may explain the discrepancy in the literature. Nevertheless, there is an obvious trend towards higher rates of perianal disease in patients with colorectal involvement (52% vs 14%), even nearing 100% in the setting of more distal disease [4-6]. There is an association of inflammatory bowel disease-5 risk haplotype H2 with CD, most prominent in patients with perianal CD [7].
Classification systems Although the American Gastroenterological Association referred to the Parks classification of fistulas (superficial, intersphincteric, transsphincteric, suprasphincteric and extrasphincteric) as more anatomically precise, it has proposed a classification of fistulas as simple versus complex for the sake of practicality in the clinical setting. A simple fistula is superficial, has one opening, is not connected to adjacent structures and is not associated with an abscess. In contrast, a
Correspondence: Anna C. Juncadella, MD, Department of Medicine, Massachusetts General Hospital, 1 Emerson Place, Apt 11-E, Boston, MA 02114, USA. Tel: +1 617 889 8580. Fax: +1 617 889 8579. E-mail: [email protected] 2015 Informa UK Ltd.
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DOI: 10.1080/00325481.2015.1023160
complex fistula involves more of the anal sphincters, has more than one opening, crosses the midline and is associated with an abscess or connects to adjacent structures [2,13]. Classification schema such as the CD Activity Index fails to satisfactorily measure perianal disease independently of luminal disease; the Perianal Disease Activity Index (PDAI) is a reliable 5-item assessment of perianal disease activity [14]. The Fistula Drainage Assessment Measure (FDAM) classifies fistulas as being either open and actively draining or closed. FDAM was used as the primary end point in the trial of Infliximab for the treatment of fistulas in CD [15].
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Diagnosis Careful evaluation should include a comprehensive history, inquiring about anorectal pain, purulent discharge or persistent drainage from the anoperineal region, rectal bleeding, recurrent urinary tract infections and/or fecal incontinence. It is important to evaluate for abscesses, perianal and rectovaginal fistulas, and anorectal strictures, which may be difficult to distinguish from skin tags and hemorrhoids [16]. Endoscopy should be performed in search of macroscopic evidence of disease [10]. Other modalities used in the diagnosis and classification of perianal CD include examination under anesthesia (EUA), anorectal endoscopic ultrasound (EUS) and pelvic magnetic resonance imaging (MRI), all of which are helpful tests. A prospective triple-blinded study of 34 patients to assess the accuracy of rectal EUS, pelvic MRI and surgical EUA in the evaluation of perianal fistulas reported that rectal EUS correctly classified 91% of patients, pelvic MRI 87% and EUA 91%; the difference between tests was not significant, most likely due to sample size. The combination of any two of these modalities is ideal, reaching ~ 100% accuracy in classification with each of the three combinations [7,17]. Considering cost, the combination of EUA with either MRI or EUS is preferable to avoid incurring the cost of a third test if intervention is required, and the expertise of the local institution should dictate the decision to use MRI versus EUS [17]. Fistulography and computed tomography have low diagnostic accuracy and are no longer recommended [18-20].
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a monoclonal antibody against IL-6 [21]. IL-1b, IL-6 and TNF-a most likely play an important role in perianal CD and mucosal levels of IL-6 and IL-12 have prognostic value for recurrence and need for surgery [22].
Medical treatment Antibiotics The use of metronidazole has been based solely on case series and uncontrolled trials. A retrospective study of the effect of metronidazole on 21 patients with chronic unremitting perineal CD showed improvement in all patients, complete healing in 10/18 patients, and at least significant healing in another five patients who were treated for at least 2 months. A follow-up study showed that decreasing the dosage was associated with exacerbation of disease, healing quickly when the full dose was restarted. The efficacy of ciprofloxacin alone and in combination with metronidazole for the treatment of perianal CD is also only supported by uncontrolled trials and case series. A randomized controlled study of ciprofloxacin or metronidazole for the treatment of perianal fistulas in 25 CD patients showed more frequent remission and response in patients treated with ciprofloxacin; nevertheless, these differences did not achieve statistical significance. Although initial response rates to antimicrobial therapy are high in perianal CD, dose-related paresthesias, other potential long-term side effects and the inevitable emergence of drug resistance will likely continue to limit their chronic use [23-29]. Limited response as maintenance suggests that antibiotic therapy may only be effective as a bridge to maintenance therapy with other agents, including azathioprine [30]. Combination therapy with ciprofloxacin and infliximab was found to offer a clinical advantage (defined as ‡ 50% reduction in draining fistulas) over infliximab alone, but the difference was not statistically significant [31]. A study by West et al. suggests that perianal fistulas are mainly colonized by gram-positive organisms and that bacterial flora did not change after treatment with ciprofloxacin, suggesting a possible alternative mechanism to the efficacy of ciprofloxacin, such as an immunosuppressive property [32]. Future studies should evaluate the role of antimicrobials with greater gram-positive coverage.
Cytokines Cytokines have been described as messengers of inflammatory cells and play a key role in CD inflammation. Anti-tumor necrosis factor (TNF) agents are imperfect in the treatment of perianal CD, suggesting that other cytokines likely play a role in the inflammatory aspect of this disease. In a study analyzing the cytokine network in order to identify possible targets for neutralizing antibody therapy (as has been done with anti-TNF therapy), TNF levels correlated with PDAI and presence of anal fistulas, interleukin-12 (IL-12) levels were significantly higher in the presence of anal strictures, and IL-6 significantly correlated with the presence of active fistulas and inversely correlated with presence of anal strictures. This study sheds doubt on the efficacy of anti-IL12 therapy in the setting of chronic perianal CD or indeterminate colitis without anal strictures but suggests a possible role for
Immune modulator therapies Azathioprine and 6-mercaptopurine are anti-metabolite agents with immunosuppressive properties. Although shown to be effective in the setting of luminal CD, fistula response to azathioprine or 6-MP has only been addressed as a secondary end point in a meta-analysis [33]. The combined results of five placebo-controlled trials, in which 66% of the pooled patients came from a single study by Present et al., showed fistula response in 54% of patients treated with an antimetabolite versus 21% receiving placebo [34]. An odds ratio of 4.44 (CI 1.50–13.20) favoring healing or decreased discharge with anti-metabolites was reported [33]. Common side effects seen with the use of azathioprine and 6-MP include leukopenia, allergic reactions, infection, pancreatitis and drug-induced hepatitis [11].
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Calcineurin inhibitors Cyclosporine acts as a potent inhibitor of cell-mediated immunity by hindering the production of IL-2 by T-helper cells [35]. A Cochrane meta-analysis of 4 controlled trials studying cyclosporine ultimately determined that it is not effective for the treatment of active CD and there are no controlled trials supporting its use for fistulizing or perianal CD [36]. Although several uncontrolled studies have suggested benefit of cyclosporine in the setting of treatment-refractory fistulizing CD, a majority of these patients tend to relapse when therapy is discontinued, most likely due to inadequate duration of overlap with more slowly acting anti-metabolites [35,37]. Uncontrolled trials have demonstrated efficacy of tacrolimus, also a calcineurin inhibitor, in the treatment of fistulizing CD [38-40]. A randomized controlled trial to determine the efficacy of tacrolimus for the treatment of fistulizing CD showed that it is effective for fistula improvement but not induction of remission in perianal CD [41]. The secondary end point of remission could possibly have been limited by small sample size. Adverse events associated with tacrolimus include nephrotoxicity, headache, insomnia, paresthesias and tremor; these can usually be managed with dose reduction. Other immunosuppressants A retrospective review of the use of methotrexate for inflammatory bowel disease and particularly fistulizing CD showed that a mean dose of 18.2 mg/week achieved fistula improvement in 44.4% of CD patients who completed 6 months of treatment; however, this study did not specifically address perianal fistulas. The combination of azathioprine and methotrexate does not appear to confer an advantage over methotrexate therapy alone [42]. Other immunosuppressive agents that could potentially be used for the treatment of perianal CD include sargramostim, mycophenolate mofetil and thalidomide, although further studies are needed to establish their efficacy [43-45]. Tumor necrosis alpha antagonists and other biologics A systematic review and meta-analysis performed by Ford et al. clearly showed the benefit of biologics for the treatment of fistulas in CD [46]. The most proven of these biologics in induction and maintenance therapy of fistulizing CD is infliximab, a murine-human chimeric monoclonal antibody to TNF-a. TNF-a is a pro-inflammatory cytokine involved in the pathogenesis of inflammatory bowel disease. In a randomized, multicenter, double-blind, placebocontrolled trial of infliximab for the treatment of fistulas in patients with CD, 68% of the patients who received 5 mg/kg of infliximab achieved the primary end point of reduction of 50% or more from baseline in the number of draining fistulas compared to 56% and 26% in the 10 mg/kg infliximab and placebo arms, respectively (p = 0.002 and p = 0.02). Fifty-five percent of the patients who received 5 mg/kg of infliximab achieved the secondary end point of closure of all fistulas compared to 38% and 13% in the 10 mg/kg of
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infliximab and placebo arms, respectively (p = 0.001 and p = 0.04). The effects of this therapy were noted within approximately 2 weeks and lasted for an average of 3 months. Given the lack of superiority of 10 mg/kg over 5 mg/kg, the study supported the use of a 5 mg/kg dose of infliximab at 0, 2 and 6 weeks. Maintenance infliximab therapy has been shown to significantly reduce hospitalizations, surgeries and procedures compared with placebo. An ACCENT II trial post hoc analysis established the effectiveness of infliximab for short-term and maintenance of rectovaginal fistula closure in particular. Adverse effects associated with infliximab and all anti-TNF agents include infectious complications like reactivation of hepatitis B and tuberculosis, hematologic malignancies and autoimmune phenomena like demyelination and psoriasis [15,47-50]. In two randomized controlled trials, the CLASSIC I trial and the GAIN study, adalimumab, a subcutaneously administered human monoclonal antibody targeting TNF, failed to show superiority over placebo for the treatment of fistulas [51,52]. In contrast, in the CHARM study, adalimumab was associated with improved fistula closure compared to placebo [53]. Closure of all draining fistulas was achieved in 30% and 13% of patients receiving adalimumab and placebo, respectively, at week 26 (p = .043) and 33% and 13% at week 56 (p = .016). An open-label extension of this trial was conducted, and all groups were given adalimumab 40 mg every other week for up to 2 years. At the end of the 2 years, clinical remission rates were 37.6%, 41.9% and 49.8% in those originally randomized to placebo, adalimumab every other week, and adalimumab weekly, respectively [54]. In the CHOICE trial, patients with moderate-to-severe CD who had failed infliximab therapy received open-label adalimumab for induction and maintenance following an 8-week washout period. Complete fistula healing was achieved in 39% of patients with baseline fistulas. Results were sustained over a 2-year period, even in those that were primary nonresponders to infliximab [55]. Certolizumab is another subcutaneously administered antiTNF agent that differs from the other two anti-TNF agents in that it is pegylated. The PRECISE I and II studies did not convincingly show the efficacy of subcutaneous anti-TNFs in perianal fistulizing disease [56,57]. An assessment of maintenance of fistula closure was assessed after continuation of Certolizumab therapy for 26 weeks. At the 26-week evaluation, 36% of patients in the Certolizumab group had maintained fistula closure versus 17% of patients in the placebo group. This difference was not statistically significant [58]. Further studies to assess their use in this context are warranted. A recent study showed improved outcomes in regards to treatment of fistulizing disease with the use of infliximab and thiopurine combination therapy [59]. Two monoclonal antibodies against alpha 4 integrin, natalizumab and vedolizumab, are alternatives to anti-TNF therapy, the latter lacking the risk of PML secondary to reactivation of JC Virus [60]. Vedolizumab gained FDA approval in May 2014 for use in moderate-to-severe CD. There is no primary data yet on the efficacy of these drugs for perianal CD in particular.
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Further studies are also needed to establish the efficacy of ustekinumab, an IgG monoclonal antibody against IL-12 and IL-23, as well as tofacitinib and other JAK inhibitors [61,62]. Interestingly, a recent meta-analysis looking at the rate of response to placebo in RCTs of pharmacologic agents for fistulizing CD, found that fistulas closed in 1/6 of these patients [63].
Surgical treatment
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Skin tags Left untreated, 68% of skin tags in patients with CD will persist at 10 years [64]. However, due to the benign nature of skin tags, surgical excision is not warranted unless they restrict the patient from maintaining hygiene or are persistently symptomatic [65]. Surgery for skin tags in a patient with CD carries with it a higher chance of poor wound healing, infection and fistula formation [66]. Abscesses and fistulae In CD patients, infections in closed spaces have to be drained and fistulas are initially managed with a non-cutting seton to promote drainage. Sixty-seven per cent of peri-rectal abscesses will completely heal after drainage and 33% will develop into a fistula [67]. After control of local sepsis, optimizing medical therapy prior to definitive surgical treatment provides the best outcome [68-70]. EUA remains important to evaluate the extent of proctitis and prevent post-operative non-healing wounds. EUA also provides a chance to evaluate and classify the perianal fistulas to plan future surgical treatment. Almost all simple low perianal fistulae can be managed with fistulotomy as cure [71]. Complex fistulas or those that involve more than 30% of the external sphincter are best managed by sphincter-sparing surgical approaches to avoid iatrogenic injury to the sphincter and an unacceptable higher risk of incontinence [72]. It is the authors’ practice to treat complex fistulas in CD initially with a fistula infill material such as a fistula plug [73]. A lower success rate should be accepted given the minimally invasive surgical approach infill materials offer [74,75]. In the background of persistent inflammation and failure of closure using minimally invasive techniques, maintenance of the fistula tract with the use of draining setons is acceptable until the CD patient is medically optimized [76]. Left in place, as the inflammatory process progresses, draining setons form a mature fibrous fistulous tract. At the time of seton removal, definitive management of the fibrous fistulous tract can be undertaken. Fistula plugs offer a first-line minimally invasive surgical therapy with an acceptable closure rate albeit lower in patients with inflammatory bowel disease [77]. If a collagen plug fails, therapy can be escalated and the option of a trans-anal mucosal advancement flap. Mucosal advancement flaps with or without the addition of fibrin glue has been shown to result in healing rate as high as 62% of complex fistulas [78]. A similar healing rate is obtained in rectovaginal fistulas [79].
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Fissures Medical management with nitroglycerin paste, calcium channel blockers or botulinum toxin injections constitutes firstline therapy for a patient presenting with anal fissures [80]. Optimizing medical treatment of proctitis in CD patients with anal fissures is central to the success of non-operative management. In patients without proctitis, surgical therapy, particularly lateral internal sphincterotomy, is associated with a higher fissure healing rate (88%) as compared to medical treatment alone (26%) [81,82]. Lateral internal sphincterotomy is the mainstay of surgical treatment for anal fissures in the setting of CD. Hemorrhoids Chronic diarrhea exacerbates symptoms of hemorrhoids in patients with CD. Surgical intervention is usually avoided due to the increased risks of poor wound healing, infection and stenosis [83]. Surgery in the setting of acute exacerbation of hemorrhoidal disease and aggressive approaches to remove all hemorrhoids puts the patient at a higher risk of developing anal canal stenosis and should be avoided [84]. However, in patients whose anorectal disease is well controlled, hemorrhoidectomy for symptomatic relief carries acceptable risks. In that selective subgroup of patients, excisional hemorrhoidectomy or banding of symptomatic internal hemorrhoids offers a success rate that approaches 90% [85-87]. Monitoring of fistula healing EUS and MRI can be useful in monitoring fistula healing after combined medical and surgical treatment. Considering that fistulas can still be active even after they stop draining, these imaging modalities can be helpful to guide therapeutic strategies such as medication adjustments and seton removal [88-90].
Conclusion Perianal involvement is a common manifestation of CD, particularly in large bowel disease. This frequently presents a significant impact on patients’ quality of life, and for this reason, many medical and surgical modalities have been studied. Diagnostic approach should include a careful history, physical and endoscopic/anoscopic evaluation. These, together with a combination of EUA plus either MRI or EUS depending on institutional expertise, provide a cost-effective diagnostic strategy with close to 100% accuracy, allowing for an appropriate therapeutic approach. Use of antibiotic treatment, although widespread, is supported solely based on uncontrolled studies and case series. The limitations imposed by the failure of a majority of patients to maintain response upon discontinuation of therapy, the potential long-term side effects, and the emergence drug resistance all support the use of antibiotics as a bridge to maintenance therapy. The use of anti-metabolites such as azathioprine and 6-MP for fistulizing CD was addressed as a secondary end point in a meta-analysis of five
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placebo-controlled trials and showed a positive clinical response. A controlled trial supporting the use of cyclosporine for fistulizing or perianal CD has yet to be reported and the systemic toxicities likely do not justify its use. Improvement of fistulas with tacrolimus was shown in a controlled trial, although these results did not translate into significant improvements in remission rates. Infliximab has clearly been shown to be effective as an induction and maintenance agent for perianal and rectovaginal fistulizing CD. Further studies evaluating the use of subcutaneous anti-TNFs and other biologics are needed since existing studies have failed to convincingly show their efficacy in the setting of fistulizing CD. In the case of skin tags, surgical intervention is preferably avoided unless they are persistently symptomatic. Similarly, aggressive surgical approaches to hemorrhoids can cause more harm than benefit. Perianal infections in the acute setting are best managed with incision and drainage with the evaluation in the operative setting of the presence of an Anal Fistula. Should a fistula be found, draining setons are indicated to promote drainage and prevent a relapsing course of infections. Fistulotomy is curative in the majority of simple low perianal fistulae. Complex fistulas or those that involve more than 30% of the external sphincter should be approached with the aim of sparing the sphincter of iatrogenic injury, using less invasive approaches such as infill materials initially and escalating therapy if needed. Non-operative management is preferred for anal fissures in the setting of proctitis. In the absence of proctitis, surgical therapy, with lateral internal sphincterotomy being the mainstay, in addition to medical management is associated with higher healing rates.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
References [1] Tarrant KM, Barclay ML, Frampton CMA, Gearry RB. Perianal disease predicts changes in Crohn’s disease phenotype- results of a population –based study of Inflammatory bowel disease phenotype. Am J Gastroenterol 2008;103:3082–93. [2] American Gastroenterological Association Clinical Practice Committee. American Gastroenterological Association Medical Position Statement: Perianal Crohn’s Disease. Gastroenterology 2003;125:1503–7. [3] Tozer PJ, Whelan K, Phillips RKS, Hart A. Etiology of perianal Crohn’s disease: role of genetic, microbiological, and immunological factors. Inflamm Bowel Dis 2009;15:1591–8. [4] Williams JA. The place of surgery in Crohn’s disease. Gut 1971;12:739–49. [5] Williams DR, Coller JA, Corman ML, Nugent FW, Veidenheimer MC. Anal Complications in Crohn’s disease. Dis Colon Rectum 1981;24:22–4.
Postgrad Med, 2015; 127(3):266–272
[6] Hellers G, Bergstrand O, Ewerth S, Holmstrom B. Occurrence and outcome after primary treatment of anal fistulae in Crohn’s disease. Gut 1980;21:525–7. [7] Wiese DM, Schwartz DA. Managing Perianal Crohn’s disease. Curr Gastroenterol Rep 2012;14:153–61. [8] Schwartz DA, Loftus EV, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology 2002;122:875–80. [9] Tang LY, Rawsthorne P, Bernstein CN. Are perineal and luminal fistulas associated in Crohn’s disease? a population-based study. Clin Gastroenterol Hepatol 2006;4:1130–4. [10] Ruffolo C, Citton M, Scarpa M, Angriman I, Massani M, Caratozzolo E, Bassi N. Perianal Crohn’s disease: is there something new? World J Gastroenterol 2011;17:1939–46. [11] Schwartz DA, Pemberton JH, Sandborn WJ. Diagnosis and Treatment of Perianal Fistulas in Crohn Disease. Ann Intern Med 2001;135:906–18. [12] Peyrin-Biroulet L, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Perianal Crohn’s disease findings other than fistulas in a population-based cohort. Inflamm Bowel Dis 2012;18(1):43–8. [13] Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-in-ano. Br J Surg 1976;63:1–12. [14] Irvine EJ. Usual therapy improves perianal Crohn’s disease as measured by a new disease activity index. J Clin Gastroenterol 1995;20:27–32. [15] Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–405. [16] Steele SR. Operative management of Crohn’s disease of the colon including anorectal disease. Surg Clin North Am 2007;87:611–31. [17] Schwartz DA, Wiersema MJ, Dudiak KM, Fletcher JG, Clain JE, Tremaine WJ, et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology 2001;121:1064–72. [18] Schratter-Sehn AJ, Lochs H, Vogelsang H, Schurawitzki H, Herold C, Schratter M. Endoscopic ultrasonography versus computed tomography in the differential diagnosis of perianorectal complications in Crohn’s disease. Endoscopy 1993;25:582–6. [19] Berliner L, Redmond P, Purow E, Megna D, Sottile V. Computed tomography in Crohn’s disease. Am J Gastroenterol 1982;77:548– 53. [20] Ardizzone S, Maconi G, Cassinotti A, Massari A, Bianchi Porro G. Imaging of perianal Crohn’s disease. Dig Liver Dis 2007;39:970–8. [21] Ruffolo C, Scarpa M, Faggian D, Romanato G, De Pellegrin A, Filosa T, et al. Cytokine network in chronic perianal CD and indeterminate colitis after colectomy. J Gastrointest Surg 2007;11:16– 21. [22] Ruffolo C, Scarpa M, Faggian D, Pozza A, Navaglia F, D’Incà R, et al. Cytokine network in rectal mucosa in perianal Crohn’s disease: relations with inflammatory parameters and need for surgery. Inflamm Bowel Dis 2008;14:1406–12. [23] Ursing B, Kamme C. Metronidazole for Crohn’s disease. Lancet 1975;1:775–7. [24] Bernstein LH, Frank MS, Brandt LJ, Boley SJ. Healing of perineal Crohn’s disease with metronidazole. Gastroenterology 1980;79:357–65. [25] Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn’s disease: a follow-up study. Gastroenterology 1982;83:383–7. [26] Jakobovits J, Schuster M. Metronidazole therapy for Crohn’s disease and associated fistulae. Am J Gastroenterol 1984;79:533–40. [27] Turunen U, Farkkila M, Seppala K. Long-term treatment of perianal or fistulous Crohn’s disease with ciprofloxacin. Scand J Gastroenterol Suppl 1989;24:144. [28] Korelitz BI, Present DH. Combination ciprofloxacin and metronidazole in severe perineal Crohn’s disease. Can J Gastroenterol 1993;7:571–3. [29] Thia KT, Mahadevan U, Feagan BG, Wong C, Cockeram A, Bitton A, et al. Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis 2009;15:17–24.
Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/26/15 For personal use only.
DOI: 10.1080/00325481.2015.1023160
[30] Dejaco C, Harrer M, Waldhoer T, Miehsler W, Vogelsang H, Reinisch W. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn’s disease. Aliment Pharmacol Ther 2003;18:1113–20. [31] West RL, Van der Woude CJ, Hansen BE, Felt-Bersma RJ, van Tilburg AJ, Drapers JA, Kuipers EJ. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn’s disease with infliximab: a double-blind placebocontrolled study. Aliment Pharmacol Ther 2004;20:1329–36. [32] West RL, Van der Woude CJ, Endtz H, Hansen BE, Ouwedijk M, Boelens HA, et al. Perianal fistulas in Crohn’s disease are predominately colonized by skin flora: implications for antibiotic treatment? Dig Dis Sci 2005;50:1260–3. [33] Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-Mercaptopurine in Crohn disease: a meta-analysis. Ann Intern Med 1995;122:132–42. [34] Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302:981–7. [35] Sandborn WJ. A critical review of cyclosporine therapy in inflammatory bowel disease. Inflamm Bowel Dis 1995;1:48–63. [36] McDonald JW, Feagan BG, Jewell D, Brynskov J, Stange EF, Macdonald JK. Cyclosporine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2005;2:CD000297. [37] Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing CD with intravenous cyclosporine. Am J Gastroenterol 1998;93:442–8. [38] Lowry PW, Weaver AL, Tremaine WJ, Sandborn WJ. Combination therapy with oral tacrolimus (FK 506) and azathioprine or 6mercaptopurine for treatment refractory Crohn’s disease perianal fistulae. Inflamm Bowel Dis 1999;5:239–45. [39] Ierardi E, Principi M, Rendina M, Francavilla R, Ingrosso M, Pisani A, et al. Oral tacrolimus (FK 506) in Crohn’s disease complicated by fistulae of the perineum. J Clin Gastroenterol 2000;30:200–2. [40] Fellermann K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid unresponsive acute attacks of inflammatory bowel disease: immunomodulation by Tacrolimus. Am J Gastroenterol 1998;93:1860–6. [41] Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology 2003;125:380–8. [42] Yang Soon S, Ansari A, Yaneza M, Raoof S, Hirst J, Sanderson JD. Experience with the use of low-dose methotrexate for inflammatory bowel disease. Euro J Gastroenterol Hepatol 2004;16:921–6. [43] Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ; Sargramostim in Crohn’s Disease Study Group. Sargramostim for active Crohn’s Disease. N Engl J Med 2005;352:2193–201. [44] Wenzl HH, Hinterleitner TA, Aichbichler BW, Fickert P, Petritsch W. Mycophenolate mofetil for Crohn’s Disease: shortterm efficacy and long-term outcome. Aliment Pharmacol Ther 2004;19:427–34. [45] Plamondon S, Ng SC, Kamm MA. Thalidomide in luminal and fistulizing Crohn’s disease resistant to standard therapies. Aliment Pharmacol Ther 2007;25:557–67. [46] Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systemic review and meta-analysis. Am J Gastroenterol 2011;106:644–59. [47] Knight DM, Trinh H, Le J. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30:1443–53. [48] Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876–85. [49] Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing crohn’s disease. Gastroenterology 2005;128:862–9.
Perianal Crohn’s disease
271
[50] Sands BE, Blank MA, Patel K, Van Deventer SJ. Long-term treatment of rectovaginal fistulas in CD: response to infliximab in the ACCENT II Study. Clin Gastroenterol Hepatol 2004;2:912–20. [51] Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in CD: the CLASSIC-I trial. Gastroenterology 2006;130:323–33. [52] Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829–38. [53] Colombel JF, Schwartz DA, Sandborn WJ, Kamm MA, D’Haens G, Rutgeerts P, et al. Adalimumab for the treatments of fistulas in patients with Crohn’s disease. Gut 2009;58:940–8. [54] Panaccione R, Colombel JF, Sandborn WJ, Rutgeerts P, D’Haens GR, Robinson AM, et al. Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn’s disease. Aliment Pharmacol Ther 2010;31:1296–309. [55] Lichtiger S, Binion DG, Wolf DC, Present DH, Bensimon AG, Wu E, et al. The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn’s disease who failed prior infliximab therapy. Aliment Pharmacol Ther 2010;32:1228–39. [56] Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn’s Disease. N Engl J Med 2007;357:228–38. [57] Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OØ, Hanauer SB, Bloomfield R, et al. Maintenance therapy with certolizumab pegol for CD. N Engl J Med 2007;357:239–50. [58] Schreiber S, Lawrence IC, Thomsen OO, Hanauer SB, Bloomfield R, Sandborn WJ. Randomised clinical trial: certolizumab pegol for fistulas in Crohn’s disease- subgroup results from a placebo-controlled study. Aliment Pharmacol Ther 2011;33:185–93. [59] Bouquen G, Siproudhis L, Gizard E, Wallenhorst T, Billioud V, Bretagne JF, et al. Long-term outcome of perianal fistulizing Crohn’s disease treated with infliximab. Clin Gastroenterol Hepatol 2013;8:975–81. [60] Sandborn WJ, Feagan BG, Rutgeerts PR, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711–21. [61] Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012;367:1519–28. [62] Boland BS, Sandborn WJ, Chang JT. Update on janus kinase antagonists in inflammatory bowel disease. Gastronenterol Clin North Am 2014;43:603–17. [63] Ford AC, Luthra P, Hanauer SB, Travis SP, Harris MS, Reinisch W. Placebo response rate in clinical trials of fistulizing Crohn’s disease: systemic revew and meta-analysis. Clin Gastroenterol Hepatol 2014;12:1981–90. [64] Buchmann P, Keighley MR, Allan RN, Thompson H, Alexander-Williams J. Natural history of perianal CD. Ten year follow-up: a plea for conservatism. Am J Surg 1980;140:642–4. [65] Singh B, McC Mortensen NJ, Jewell DP, George B. Perianal CD. Br J Surg 2004;91:801–14. [66] Keighley MR, Allan RN. Current status and influence of operation on perianal Crohn’s disease. Int J Colorectal Dis 1986;1:104–7. [67] Michelassi F, Melis M, Rubin M, Hurst RD. Surgical treatment of anorectal complications in Crohn’s disease. Surgery 2000;128:597– 603. [68] Regueiro M, Mardini H. Treatment of perianal fistulizing Crohn’s disease with infliximab alone or as an adjunct to exam under anesthesia with seton placement. Inflamm Bowel Dis 2003;9:98–103. [69] Topstad DR, Panaccione R, Heine JA, Johnson DR, MacLean AR, Buie WD. Combined seton placement, infliximab infusion and maintenance immunosuppressive improve healing rate in fistulizing anorectal Crohn’s disease: a single center experience. Dis Colon Rectum 2003;46:577–83. [70] Schwartz DA, White CM, Wise PE, Herline AJ. Use of endoscopic ultrasound to guide combined medical and surgical therapy for patients with Crohn’s perianal fistulas. Inflamm Bowel Dis 2005;11:727–32.
Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/26/15 For personal use only.
272
A. C. Juncadella et al.
[71] Wolkomir AF, Luchtefeld MA. Surgery for symptomatic hemorrhoids and anal fissures in CD. Dis Colon Rectum 1993;36:545–7. [72] Alexander-Williams J, Steinberg DM, Fielding JS, Thompson H, Cooke WT. Proceedings: perianal Crohn’s disease. Gut 1974;15:822–3. [73] Swinscoe MT, Ventakasubramaniam AK, Jayne DG. Fibrin glue for fistula-in-ano: the evidence reviewed. Tech Coloproctol 2005;9:89–94. [74] Vitton V, Gasmi M, Barthet M, Desjeux A, Orsoni P, Grimaud JC. Long-term healing of Crohn’s anal fistulas with fibrin glue injection. Aliment Pharmacol Ther 2005;21:1453–7. [75] Cestaro G, De Rosa M, Gentile M. Treatment of fistula in ano with fibrin glue: preliminary results from a prospective study. Minerva Chir 2014;69:225–8. [76] Atienza P, Ksiaa M. Particular aspects of proctology for anoperineal lesions in Crohn’s disease. J Visc Surg 2015. [Epub ahead of print]. [77] Cintron JR, Abcarian H, Chaudry V, Singer M, Hunt S, Birnbaum E, et al. Treatment of fistula-in-ano using a porcine small intestinal submucosa anal fistula plug. Tech Coloproctol 2013;17:187–91. [78] Marchesa P, Hull TL, Fazio VW. Advancement sleeve flaps for treatment of severe perianal Crohn’s disease. Br J Surg 1998;85:1695–8. [79] Hull TL, Fazio VW. Surgical approaches to low anovaginal fistula in Crohn’s disease. Am J Surg 1997;173:95–8. [80] Madoff RD, Fleshman JW. AGA technical review on the diagnosis and care of patients with anal fissure. Gastroenterology 2003;124:235–45.
Postgrad Med, 2015; 127(3):266–272
[81] Fleshner PR, Schoetz DJ Jr, Roberts PL, Murray JJ, Coller JA, Veidenheimer MC. Anal fissure in Crohn’s disease: a plea for aggressive management. Dis Colon Rectum 1995;38:1137–43. [82] Jonas M, Scholefield JH. Anal fissure. Gastroenterol Clin North Am 2001;30:167–81. [83] Jeffery PJ, Parks AG, Ritchie JK. Treatment of Haemorrhoids in patients with inflammatory bowel disease. Lancet 1977;1:1084–5. [84] Mukta V, Rocco R. Anal stenosis. Surg Clin North Am 2010;90:137–45. [85] Wolkomir AF, Luchtefeld MA. Surgery for symptomatic hemorrhoids and anal fissures in Crohn’s disease. Dis Colon Rectum 1993;36:545–7. [86] Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB; American Gastroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn’s Disease. Gastroenterology 2003;125:1508–30. [87] Steele SR. Operative management of Crohn’s Disease of the colon including anorectal disease. Surg Clin North Am 2007;87:611–31. [88] Schwartz DA. What is the optimal maintenance treatment for perianal Crohn’s disease? Inflamm Bowel Dis 2008;14:S269–70. [89] Van Assche G, Vanbeckevoort D, Bielen D, Coremans G, Aerden I, Noman M, et al. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease. Am J Gastroenterol 2003;98:332–9. [90] Guidi L, Ratto C, Semeraro Roberto I, De Vitis I, Papa A, et al. Combined therapy with infliximab and seton drainage for perianal fistulizing Crohn’s disease with anal endosonographic monitoring: a single-centre experience. Tech Coloproctol 2008;12:111–17.
