Diagnosis
To plan appropriate medical or surgical therapy, patients with perianal Crohn’s disease must be classified as having simple or complex perianal disease (refer to the original guideline document for details). Diagnosis of simple fistulas or complex perianal disease by physical examination and rectosigmoid endoscopy may be sufficient for many patients when medical therapy is the initial treatment strategy. Additional diagnostic evaluation by examination under anesthesia (EUA) and either anorectal endoscopic ultrasonography (EUS) or pelvic magnetic resonance imaging (MRI) is indicated in those patients with pain, fluctuation, or stricture on digital rectal examination, in those patients in whom surgical therapy is the initial treatment strategy (because up to 10% of patients with perianal fistulas will be misclassified by EUA alone and fistulotomy of a high fistula misclassified as a low fistula may lead to incontinence and/or poor wound-healing and in some instances subsequent proctectomy), and in those failing medical or surgical therapy. It is recognized that this recommendation represents a change in practice, even for gastroenterologists and colorectal surgeons with great expertise in the management of perianal Crohn’s disease, but acknowledges that EUA is not 100% accurate and that inaccurate diagnosis before surgical intervention may lead to irreversible functional consequences.
General Treatment of Crohn’s Disease
In addition to the specific medical and surgical treatments outlined as follows, any active proximal luminal disease should also be treated as appropriate with budesonide, conventional corticosteroids, azathioprine, 6-mercaptopurine, methotrexate, infliximab, and surgical resection.
Postoperative bile salt diarrhea or steatorrhea should be treated as indicated with loperamide, diphenoxylate and atropine, codeine, cholestyramine, and low-fat diet. These measures are all aimed at reducing stool liquidity, with the goal of decreasing the quantity of fistula drainage.
Treatment of Simple Perianal Fistulas
Potential treatments for simple fistulas include antibiotics, fistulotomy, and possibly azathioprine or 6-mercaptopurine and infliximab. Antibiotics are widely used to treat simple fistulas and are recommended in practice guidelines and previous treatment algorithms but have not been evaluated in placebo-controlled trials. Fistulotomy is widely used by surgeons to treat simple fistulas, resulting in a high rate of healing that is often sustained. The prevailing view among surgeons is that those patients with a simple fistula who do not respond to a short course of antibiotics are best treated with fistulotomy. However, reported surgical series have been small, there are no controlled trials comparing fistulotomy with sham operation or medical therapy, and some patients fail to heal and may require proctectomy. The immunosuppressive medications azathioprine and 6-mercaptopurine can be used to treat simple fistulas and are recommended in practice guidelines but have not been evaluated in placebo-controlled trials in which fistula reduction or closure was the primary end point. These agents are slow acting and thus may be of more utility for maintaining fistula closure than for the initial induction of fistula closure. Infliximab has been proven effective in placebo-controlled trials for the indications of both reduction in the number of draining fistulas and maintenance of that reduction, and a 3-dose induction regimen and a maintenance regimen every 8 weeks are approved by the U.S. Food and Drug Administration (FDA) for treatment of fistulas; however, infliximab is expensive, concomitant immunosuppressive therapy is probably required to counteract the formation of human antichimeric antibodies that may lead to infusion reactions and loss of efficacy, and rarely serious infections may occur. There are insufficient high-quality data (level 1 evidence [population-based natural history studies and randomized, double-blind, placebo-controlled trials of diagnostic modalities and therapeutic interventions]) to make a clear recommendation as to whether antibiotics, fistulotomy, azathioprine or 6-mercaptopurine, or infliximab is the preferred strategy for simple fistulas. Tacrolimus and cyclosporine are not appropriate treatment for simple fistulas because of toxicity.
Treatment of Complex Perianal Fistulas
Potential treatments for complex fistulas include antibiotics, azathioprine and 6-mercaptopurine, infliximab, tacrolimus and cyclosporine, and surgery (dilation of anal strictures, placement of noncutting setons, endorectal advancement flap, repair of rectovaginal fistulas, fecal diversion, and proctectomy). Antibiotics are widely used to treat complex fistulas and are recommended in practice guidelines and treatment algorithms but have not been evaluated in placebo-controlled trials. Relapse rates are high after antibiotic therapy for complex fistulas is discontinued, and their use should probably be adjunctive in combination with other medical agents or surgery in this setting. Similarly, the immunosuppressive medications azathioprine and 6-mercaptopurine are used to treat complex fistulas and are recommended in practice guidelines but have not been evaluated in placebo-controlled trials in which fistula reduction or closure was the primary end point. Furthermore, these agents are slow acting and thus are of more utility for maintaining fistula closure than for the initial reduction in the number of draining fistulas.
In contrast to antibiotics and immunosuppressive medications, infliximab has been proven to be effective in placebo-controlled trials for reduction in the number of draining fistulas and maintenance of that reduction and treatment of fistulas with a 3-dose induction regimen and a maintenance regimen every 8 weeks is approved by the U.S. Food and Drug Administration (FDA). Finally, tacrolimus or cyclosporine can rarely be considered in selected patients who fail multimodality treatment with other medical and surgical therapies, including infliximab. This practice is based on uncontrolled case series with cyclosporine and a single short-term placebo-controlled trial with tacrolimus that showed a reduction in the number of draining fistulas; however, nephrotoxicity and other side effects occur frequently and these agents should be used with caution. The trials examining tacrolimus and cyclosporine have been of short duration, without determining whether maintenance therapy after initial fistula closure is safe and effective.
Surgical therapy for complex perianal disease is largely palliative. Perianal abscesses should be drained and anal strictures dilated. Noncutting setons can be placed in fistula tracts in patients with macroscopic rectal inflammation, and endorectal advancement flap procedures for high perianal fistulas and rectovaginal fistulas can be performed in patients without rectal inflammation. The recurrence rates following removal of noncutting setons and following endorectal advancement flap procedures are both relatively high. Setons can be left in place indefinitely; however, given the alternative of suppressive medical therapy, patients may not prefer this option. Because infliximab therapy can completely close all fistula tracks in many patients with complex fistulas, most gastroenterologists now believe that infliximab is the initial treatment of choice in this setting (it is debated by surgeons whether infliximab or noncutting setons is the initial treatment of choice for the subgroup of patients with complex perianal fistulas who do not have active rectal disease, because there are no data on patient acceptance of long-term noncutting setons versus treatment with infliximab). Azathioprine, 6-mercaptopurine, or methotrexate should be coadministered routinely both to counteract an immunogenic reaction to infliximab and as maintenance of remission therapy. Some patients will require combination maintenance therapy with azathioprine, 6-mercaptopurine, or methotrexate and infliximab. Temporary adjunctive therapy with antibiotics may be considered. Routine EUA and seton placement before initiating infliximab therapy is not mandatory.
Patients with complex fistulas who initially fail treatment with infliximab should undergo anorectal endoscopic ultrasonography or pelvic MRI as well as EUA with placement of setons as indicated while continuing treatment with infliximab, azathioprine or 6-mercaptopurine, and antibiotics. Tacrolimus or cyclosporine can be considered in patients who fail this multimodality approach. As a last resort, fecal diversion or proctectomy may be undertaken.
Specific Treatment of Rectovaginal Fistulas
Potential treatments for rectovaginal fistulas include both medical therapy and surgery. 6-Mercaptopurine, infliximab, cyclosporine, and tacrolimus have all been used to treat rectovaginal fistulas in uncontrolled series. A controlled trial of maintenance infliximab infusions in patients with fistulas who responded to infliximab included a subgroup of patients with rectovaginal fistulas. Surgical treatment of rectovaginal fistulas can only be performed when there is endoscopic healing of the rectosigmoid mucosa. Standard medical therapy with conventional corticosteroids, azathioprine, 6-mercaptopurine, methotrexate, or infliximab should be administered as indicated to control active luminal inflammatory disease in the rectosigmoid colon. If the rectovaginal fistula persists after the patient has received medical therapy to treat both the fistula itself and the rectosigmoid mucosa, and there is no evidence of an anorectal stricture or active rectal disease, then surgical repair with transanal or transvaginal advancement flaps, or laparotomy with primary closure or sleeve advancement flap can be performed. Advancement flap surgery should be reserved for patients with disabling symptoms because of the risk of worsening symptoms in those patients in whom the operation fails. As a last resort, fecal diversion or proctectomy may be undertaken. Some women may choose to accept residual fistula drainage over proctectomy with an ostomy to optimize their overall quality of life.
