Portal de Periódicos da CAPES

Perianal Fistulizing Crohn’s Disease: A Call to Action

2007; Elsevier BV; Volume: 6; Issue: 1 Linguagem: Inglês

10.1016/j.cgh.2007.10.010

1542-7714

Michael A. Kamm, Siew C. Ng,

Autoimmune and Inflammatory Disorders

The advent of biological therapies has focused attention on the importance of healing luminal Crohn’s disease, thereby modifying the disease course. Perianal fistulas are common in Crohn’s disease and often have a poor prognosis, with permanent sphincter and perineal tissue destruction. The importance of healing these fistulas has been less well appreciated. Management still often is left in surgical hands alone, rather than the optimal combination of surgery, infection control, and immunosuppression. Drug therapy often is haphazard, and the means of assessing healing over a long time period has been characterized poorly. Recent studies have suggested that many of these patients can achieve fistula healing, at least in the medium term. We therefore call for more active intervention, with the goal of healing, in these sick patients. Perianal fistulas lead to substantial physical and emotional distress because of pain, discharge, incontinence, perineal and genital disfigurement, and slow resolution even with treatment. The advent of accurate anal imaging, improved knowledge of surgical outcomes, and potent biological therapies make it timely to reflect on current best-management strategies. The advent of biological therapies has focused attention on the importance of healing luminal Crohn’s disease, thereby modifying the disease course. Perianal fistulas are common in Crohn’s disease and often have a poor prognosis, with permanent sphincter and perineal tissue destruction. The importance of healing these fistulas has been less well appreciated. Management still often is left in surgical hands alone, rather than the optimal combination of surgery, infection control, and immunosuppression. Drug therapy often is haphazard, and the means of assessing healing over a long time period has been characterized poorly. Recent studies have suggested that many of these patients can achieve fistula healing, at least in the medium term. We therefore call for more active intervention, with the goal of healing, in these sick patients. Perianal fistulas lead to substantial physical and emotional distress because of pain, discharge, incontinence, perineal and genital disfigurement, and slow resolution even with treatment. The advent of accurate anal imaging, improved knowledge of surgical outcomes, and potent biological therapies make it timely to reflect on current best-management strategies. Perianal fistulas occur in a quarter to a half of all patients with Crohn’s disease. A community-based study showed a cumulative risk of developing a fistula of 50%, including a perianal fistula in 26%, at 20 years.1Schwartz D.A. Loftus Jr, E.V. Tremaine W.J. et al.The natural history of fistulising Crohn’s disease in Olmsted County, Minnesota.Gastroenterology. 2002; 122: 875-880Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar Eighty-three percent of patients with fistulas required surgery. Crohn’s fistulas are thought to derive either from the anal glands at the dentate line in the anal canal or from ulceration in the anal canal or rectum. Infection leads to abscess formation and subsequent tracking away from the anal canal. The direction of the track, and its complexity, influence the type of therapeutic approach required.2Bell S.J. Williams A.B. Wiesel P. et al.Clinical course of fistulating Crohn’s disease.Aliment Pharmacol Ther. 2003; 17: 1145-1151Crossref PubMed Scopus (178) Google Scholar Superficial fistulas that do not traverse the sphincter complex are easier to treat and have a less complicated course than complex fistulas. An association of perianal Crohn’s disease with a susceptibility locus on chromosome 5 recently was described.3Armuzzi A. Ahmad T. Ling K.L. et al.Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31.Gut. 2003; 52: 1133-1139Crossref PubMed Scopus (153) Google Scholar The Montreal Classification divides Crohn’s disease into 3 categories: age of diagnosis, disease location, and disease behavior (B1, nonstricturing, nonpenetrating; B2, stricturing; B3, penetrating; and p, perianal disease modifier). Perianal Crohn’s disease has been given a separate subclassification because there is substantial evidence that perianal fistulizing Crohn’s disease often is not associated with internal fistulizing disease.4Satsangi J. Silverberg M.S. Vermeire S. et al.The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications.Gut. 2006; 55: 749-753Crossref PubMed Scopus (2262) Google Scholar The clinical course of Crohn’s anal fistula now is appreciated better. In one series of 87 patients, before the advent of biological drugs, one third had a single fistula and two thirds had 2 or more fistulas.2Bell S.J. Williams A.B. Wiesel P. et al.Clinical course of fistulating Crohn’s disease.Aliment Pharmacol Ther. 2003; 17: 1145-1151Crossref PubMed Scopus (178) Google Scholar On long-term follow-up evaluation 68% had healed, 7% had a seton in situ with no sepsis, and 25% had persistent fistulas without sepsis. It took a median of 2.6 years, and 3 surgical treatments, to heal anorectal fistulas. Of those with a complex fistula (transsphincteric, translevator, supralevator, or extrasphincteric), 38% required abdominal surgery, including stoma formation, resection, or proctectomy. Half of those with a proctectomy healed their fistulas and perineum, but when healing did occur it took a median of 32 weeks. This series highlights that multiple procedures and a long time course often are required to achieve healing. Fistula complexity predicts the likelihood of healing and the likely surgical course. Assessment should include the following: (1) endoscopy to assess proximal disease and specifically assess for the presence and extent of rectal disease; (2) pelvic floor imaging with magnetic resonance imaging (MRI) or anal endosonography to delineate fistula anatomy, extent, and relationship of the tracks to the sphincter muscles; and (3) examination under anesthetic to include surgical drainage and/or seton placement if necessary. MRI and anal endosonography both can provide anatomic delineation of fistula tracks, and identify complicating factors such as an abscess. MRI provides the most accurate means of identifying the full extent of fistula tracks. However, it is so sensitive when detecting the fluid associated with inflammation that it sometimes can overreport the presence of a collection. Such possible collections should be confirmed at examination under anesthetic. Anal endosonography is accurate at identifying tracks close to the anal canal, but loses resolution of more extensive tracks at a distance from the anal canal. In a prospective blinded study that compared the accuracy of MRI, anal endosonography, and examination under anesthetic in 34 patients with suspected Crohn’s perianal fistulas, there was good agreement between all 3 methods (anal endosonography, 91%; MRI, 87%; examination under anesthetic, 91%). The combination of any 2 investigations yielded an accuracy of 100%.5Schwartz D.A. Wiersema M.J. Dudiak K.M. et al.A comparison of endoscopic ultrasound, magnetic resonance imaging, and examination under anesthesia for evaluation of Crohn’s perianal fistulas.Gastroenterology. 2001; 121: 1064-1072Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar Treatment is most effective when antibacterial, immune suppression, and physical factors such as drainage are addressed. The traditional mainstay of treatment has been largely surgical, including drainage and use of a nondissolving thread (seton) inserted loosely through the fistula track to maintain patency. The seton can be removed when the track is healing, or left in situ long term if healing is not occurring. This surgical approach prevents sphincter damage by preventing recurrent abscess formation. The presence of active proctitis reduces the chance of fistula healing. Proctitis needs to be treated aggressively if fistula healing is to be achieved. The presence of rectal inflammation also influences surgical treatment. If Crohn’s rectal inflammation is quiescent then superficial fistulas can be laid open. Deeper fistula tracks can be cored out and the ends closed. Secondary branches must be identified and dealt with. Invasive surgical treatment, that is, extensive dissection, can threaten continence if much of the sphincter complex is divided. Division of the internal sphincter muscle is particularly liable to lead to incontinence.6Lunniss P.J. Kamm M.A. Phillips R.K. Factors affecting continence after surgery for anal fistula.Br J Surg. 1994; 81: 1382-1385Crossref PubMed Scopus (168) Google Scholar In an intractable situation in which there is extensive perianal disease and seton drainage proves inadequate, the creation of a stoma, to divert the fecal stream away from the anal canal, sometimes is considered. In one series this led to early remission of anal disease in 81% of patients, but three quarters of these patients relapsed at a median of 2 years after stoma formation.7Yamamoto T. Allan R.N. Keighley M.R. Effect of fecal diversion alone on perianal Crohn’s disease.World J Surg. 2000; 24: 1258-1262Crossref PubMed Scopus (132) Google Scholar Most patients with a stoma ultimately required a proctectomy. Intestinal continuity was restored in only 10% of patients. Nonetheless, in the rare situation when gross sepsis and tissue destruction is present, the creation of a stoma may be the only practical means of controlling infection and achieving healing. When resection is being considered for unresponsive colonic and anorectal disease, proctocolectomy is favored over preservation of the rectum because of a high incidence of persistent disease if the rectum is left in situ.8Guillem J.G. Roberts P.L. Murray J.J. et al.Factors predictive of persistent or recurrent Crohn’s disease in excluded rectal segments.Dis Colon Rectum. 1992; 35: 768-772Crossref PubMed Scopus (51) Google Scholar Although drugs play an important role in managing this condition, there are few controlled studies. Antibiotics are useful in the short term. Infliximab or adalimumab, with or without concomitant immunosuppressive agents, now are first-line drug therapies. Other potential alternatives include azathioprine or 6-mercaptopurine, thalidomide, prolonged treatment with tacrolimus, or local injection of infliximab in those with limited anal disease. Repeat imaging may be helpful in assessing for deeper healing and in guiding the duration of treatment. Metronidazole was shown to heal fistulas in 83% of 21 patients in an open series.9Bernstein L.H. Frank M.S. Brandt L.J. et al.Healing of perineal Crohn’s disease with metronidazole.Gastroenterology. 1980; 79: 599Abstract Full Text PDF PubMed Scopus (106) Google Scholar Subsequent open studies have produced healing in a third to a half of patients, with improvement over a period of 6 to 8 weeks. Although useful short term or intermittently, there are problems associated with long-term use of antibiotics. These include nausea and peripheral neuropathy with metronidazole. Ciprofloxacin often is used as an alternative, but data supporting this use are scarce. There are no long-term healing data supporting the use of antibiotics. Although they may be useful for associated rectal inflammation, corticosteroids and mesalamine are not effective in the treatment of perianal fistulizing Crohn’s disease.10Lichtenstein G.R. Treatment of fistulising Crohn’s disease.Gastroenterology. 2000; 119: 1132-1147Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Immunosuppression with azathioprine or 6-mercaptopurine produces fistula closure in only a minority of patients, but inflammation, discharge, and discomfort often are reduced markedly. Relapse occurs on drug cessation. A meta-analysis of the controlled trials in Crohn’s disease that included patients with fistulas has shown a response rate to these drugs of 54% compared with 21% for placebo.11Pearson D.C. May G.R. Fick G.H. et al.Azathioprine and 6-mercaptopurine in Crohn disease A meta-analysis.Ann Intern Med. 1995; 123: 132-142Crossref PubMed Scopus (947) Google Scholar Intravenous cyclosporin12Hanauer S.B. Smith M.B. Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporine.Am J Gastroenterol. 1993; 88: 646-649PubMed Google Scholar and oral tacrolimus13Sandborn W.J. Present D.H. Isaacs K.L. et al.Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial.Gastroenterology. 2003; 125: 380-388Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 14Ng S.C. Arebi N. Kamm M.A. Medium term results of oral tacrolimus for treatment of refractory inflammatory bowel disease.Inflamm Bowel Dis. 2007; 13: 129-134Crossref PubMed Scopus (65) Google Scholar, 15Gonzalez-Lama Y. Abreu L. Vera M.I. et al.Long term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn’s disease.Inflamm Bowel Dis. 2005; 11: 8-15Crossref PubMed Scopus (70) Google Scholar both improve or heal a substantial proportion of patients short term, but they often relapse on stopping the drug. The only controlled trial of oral tacrolimus showed a significantly positive effect on improvement compared with placebo, but did not show fistula healing when patients were treated for 10 weeks.13Sandborn W.J. Present D.H. Isaacs K.L. et al.Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial.Gastroenterology. 2003; 125: 380-388Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar A more recent open study by Gonzalez-Lama et al15Gonzalez-Lama Y. Abreu L. Vera M.I. et al.Long term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn’s disease.Inflamm Bowel Dis. 2005; 11: 8-15Crossref PubMed Scopus (70) Google Scholar of 10 patients showed substantial healing with 40% achieving a complete clinical response and 50% achieving a partial response, but patients were treated for 6 to 24 months. Longer-term therapy therefore may be required to achieve healing using this medication. Preliminary data from a randomized controlled trial also showed that topical tacrolimus is effective in the treatment of perianal or anal ulcerating Crohn’s disease, but not fistulizing perianal disease.16Hart A.L. Plamondon S. Kamm M.A. Topical tacrolimus in the treatment of perianal Crohn’s disease: exploratory randomized controlled trial.Inflamm Bowel Dis. 2007; 13: 245-253Crossref PubMed Scopus (90) Google Scholar Fibrin glue does not have an established place in treating Crohn’s fistulas.17Loungnarath R. Dietz D.W. Mutch M.G. et al.Fibrin glue treatment of complex anal fistulas has low success rate.Dis Colon Rectum. 2004; 47: 432-436Crossref PubMed Scopus (236) Google Scholar, 18Vitton V. Gasmi M. Baqrthet M. et al.Long-term healing of Crohn’s anal fistulas with fibrin glue injection.Aliment Pharmacol Ther. 2005; 21: 1453-1457Crossref PubMed Scopus (68) Google Scholar Great interest has surrounded the use of infliximab for this condition. In the trial by Present et al,19Present D.H. Rutgeerts P. Targan S. et al.Infliximab for the treatment of fistulas in patients with Crohn’s disease.N Engl J Med. 1999; 340: 1398-1405Crossref PubMed Scopus (2512) Google Scholar 94 patients received 3 infusions. Most patients had perianal fistulas. Sixty-eight percent of patients had a clinical response, with 55% closing all fistulas. Most impressive was the median time to achieve a response of 2 weeks. The A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen 2 (ACCENT 2) trial has extended these findings.20Sands B.E. Anderson F.H. Bernstein C.N. et al.Randomised controlled trial of infliximab maintenance therapy for fistulizing Crohn’s disease (Accent II).N Engl J Med. 2004; 350: 876-885Crossref PubMed Scopus (1931) Google Scholar Of 306 actively treated patients, 64% of patients had an initial response with 50% or more of fistulas closing. Of these initial responders treated with infliximab, 36% were healed at 1 year after regular infliximab treatment, compared with 19% treated with placebo after the initial response. In the ACCENT 2 study the hospitalization episodes, days in hospital, and surgical episodes (65 vs 126; P < .05) all were reduced significantly in patients treated with maintenance infliximab compared with placebo.21Lichtenstein G.R. Yan S. Bala M. et al.Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulising Crohn’s disease.Gastroenterology. 2005; 128: 862-869Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar Patients generally start infliximab therapy after sepsis has been drained, and often have a seton in situ. Removal of the seton within a few weeks of starting infliximab therapy is necessary to facilitate track healing, although in some patients with extensive complex fistulas this may be delayed until there is some evidence of healing. An important issue with infliximab treatment is whether deep or permanent healing is achieved, and whether, or when, treatment can be stopped. Healing of external fistula openings can occur without deep healing, leading to abscess formation. Recent imaging studies with ultrasound, or the more sensitive MRI, of patients treated with infliximab reveal that many patients have a track that remains unhealed despite cutaneous healing.22Bell S.J. Halligan S. Windsor A.C.J. et al.Response of fistulating Crohn’s disease to infliximab treatment assessed by magnetic resonance imaging.Aliment Pharmacol Ther. 2003; 17: 387-393Crossref PubMed Scopus (142) Google Scholar, 23Van Assche G. Vanbeckevoort D. Bielen D. et al.Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease.Am J Gastroenterol. 2003; 98: 332-339Crossref PubMed Scopus (355) Google Scholar Unsuspected collections may be detected before treatment and may predict later abscess formation. MRI scanning to assess deep healing also may be helpful in determining the required duration of treatment, although this remains to be proven prospectively. There are very few long-term data on the response of fistulas to drug therapy. In one retrospective study 36 patients with perineal fistulas received 10 to 37 infusions over 5 years. Approximately half required an increase in dose greater than 5 mg/kg each 8 weeks during the course of therapy. Approximately one third healed their fistulas and a further third had some response.24Shih C.E. Bayless T.M. Harris M.C. Maintenance of long term response to infliximab over 1 to 5 years in Crohn’s disease including shortening dosing intervals or increasing dosage.Gastroenterology. 2004; 126: W1414Google Scholar Not all patients are suitable candidates for infliximab therapy, including those with severe stricturing luminal disease. Others either respond incompletely or lose clinical response. Loss of response often relates to the development of antibodies directed against the biological drug, or to the loss of biological effectiveness. In one study 73% of patients either required surgery or still had open fistulas despite infliximab therapy.25Poritz L.S. Rowe W.A. Koltun W.A. Remicade® does not abolish the need for surgery in fistulizing Crohn’s disease.Dis Colon Rectum. 2002; 45: 771-775Crossref PubMed Scopus (123) Google Scholar Most patients with fistulizing perianal disease also have active luminal disease. However, for those with limited anal disease, or a contraindication to systemic therapy such as proximal luminal stenosis, an alternative approach to therapy involves the application of local infliximab directly into fistula tracts. Two recent open-label studies have shown potential benefit. The first study showed healing of perianal fistulas in 10 of 15 patients after 3 to 12 infusions of 15 to 21 mg of infliximab into the fistula tracts under general anesthesia.26Poggioli G. Laureti S. Pierangeli F. et al.Local injection of infliximab for the treatment of perianal Crohn’s disease.Dis Colon Rectum. 2005; 48: 768-774Crossref PubMed Scopus (89) Google Scholar In the second study, 6 of 11 patients were in clinical response and 4 of 11 patients maintained fistula healing at a mean of 10.5 months of follow-up evaluation.27Asteria C.R. Fiacari F. Bagnoli S. et al.Treatment of perianal fistulas in Crohn’s disease by local injection of antibody to TNF-α accounts for a favourable clinical response in selected cases: a pilot study.Scand J Gastroenterol. 2006; 41: 1064-1072Crossref PubMed Scopus (72) Google Scholar Side effects were minimal. This approach remains to be evaluated in larger controlled studies. Thalidomide, an immunomodulatory and anti-inflammatory agent, has re-emerged as an effective therapy for both luminal and fistulizing Crohn’s disease. An open series conducted in 12 male patients with active, steroid-dependent Crohn’s disease showed a 58% response rate and a 17% remission rate at 4 weeks. Six patients in this study had fistulas, of whom 5 improved significantly.28Vasiliauskas E.A. Kam L.Y. Abreu-Martin M.T. et al.An open-label pilot study of low-dose thalidomide in chronically active, steroid dependent Crohn’s disease.Gastroenterology. 1999; 117: 1278-1287Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar A further open-label study included 13 patients with fistulizing disease using higher doses of thalidomide of up to 300 mg/day; clinical remission of fistulas was observed in 6 patients at 12 weeks.29Ehrenpreis E.D. Kane S.V. Cohen L.B. et al.Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial.Gastroenterology. 1999; 117: 1271-1277Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar In a recent series, 9 of 11 patients with active fistulizing Crohn’s disease resistant to other therapies, including infliximab, responded to thalidomide. Three of these 9 patients achieved complete fistula healing.30Plamondon S. Ng S.C. Kamm M.A. Thalidomide in luminal and fistulising Crohn’s disease resistant to standard therapy.Aliment Pharmacol Ther. 2007; 25: 557-567Crossref PubMed Scopus (68) Google Scholar Teratogenicity remains a key safety issue, sedation is common, and the frequent development of peripheral neuropathy limits its long-term use. Infliximab is the only biological drug that has been evaluated in a controlled trial devoted to fistula patients. However, the next generation of anti–tumor necrosis factor-α antibodies offer further opportunities for the treatment of fistulizing disease. In an open-label study of adalimumab in 24 patients with active Crohn’s disease who had lost response or became intolerant of infliximab, 9 patients had fistulas. Three patients had fistula closure and a further 5 experienced a decrease of at least 50% in the number of open draining fistulas at 12 weeks.31Sandborn W.J. Hanauer S. Loftus Jr, E.V. et al.An open-label study of human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease.Am J Gastroenterol. 2004; 99: 1984-1989Crossref PubMed Scopus (279) Google Scholar In the recent large placebo-controlled Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance trial, designed to assess the efficacy of adalimumab in treating luminal disease, 113 patients also had perianal fistulas. Two thirds of patients had 1 fistula whereas one third of patients had more than 1 fistula. Patients received adalimumab 80 mg initially, then 40 mg 2 weeks later, followed by 40 mg every 2 weeks, 40 mg weekly, or placebo. Patients with draining fistulas were evaluated for healing at weeks 26 and 56. Thirty percent (21 of 70) of all randomized patients on active adalimumab maintenance treatment had complete healing at both time points, compared with 13% (6 of 47) on placebo maintenance.32Colombel J.F. Sandborn W.J. Rutgeerts P. et al.Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM Trial.Gastroenterology. 2007; 132: 52-65Abstract Full Text Full Text PDF PubMed Scopus (1904) Google Scholar, 33Kamm M.A. Colombel J.F. Sandborn W.J. et al.Adalimumab maintains clinical remission and response, induces and maintains healing of draining fistulas in patients with active Crohn’s disease (abstr).Gut. 2007; 56: A21Google Scholar Complicated anorectal disease, including fistulas and extensive ulceration, may be associated with an increased malignant risk. In a study of 2500 consecutive Crohn’s disease patients, recorded in a prospective database between 1940 and 1992, there were 15 lower-gastrointestinal cancers.34Connell W.R. Sheffield J.P. Kamm M.A. et al.Lower gastrointestinal malignancy in Crohn’s disease.Gut. 1994; 35: 347-352Crossref PubMed Scopus (156) Google Scholar Of these, 12 occurred in the lower rectum and anus, usually in patients with strictures and fistulas. This provides an added impetus to try and achieve healing, and a reminder to check for malignancy by examination under anesthetic if there are any atypical features. In summary, when treating Crohn’s disease anal fistulas, accurate imaging and conservative therapy to achieve drainage and minimize sphincter damage remain central to effective treatment. Although azathioprine or 6-mercaptopurine still often are regarded as first-line drug therapies, biological agents often are needed. Both infliximab and adalimumab undoubtedly are effective in a relatively short period of time. Patients can cross to the other anti–tumor necrosis factor antibody if response is lost. Thalidomide, local injection of infliximab, and prolonged treatment with tacrolimus are potential alternatives that require further evaluation. MRI is likely to play an important role in influencing the duration of treatment. Anorectal Crohn’s disease often is undertreated. Its treatment is an area par excellence in which cooperation between a conservative surgeon, proactive gastroenterologist, and expert radiologist is likely to lead to the greatest therapeutic success.