Treatment of fistulizing Crohn's disease

GASTROENTEROLOGY2000;119:1132-1147

SPECIAL REPORTS AND REVIEWS Treatment of Fistulizing Crohn's Disease GARY R. LICHTENSTEIN Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

The appropriate treatment of patients with fistulas in the setting of Crohn's disease requires a knowledge of the specific medical and surgical literature of fistulizing Crohn's. The patient with symptomatic fistulizing Crohn's disease may respond differently to specific medical therapy than a patient with symptomatic obstructing Crohn's disease. Certain medications that are useful for the treatment of patients with obstructive Crohn's disease may not be helpful in the treatment of fistulas in patients with fistulizing Crohn's disease (e.g., corticosteroids and mesalamine); in fact, some medications are believed to be detrimental (e.g., corticosteroids). Few studies have been performed to assess the efficacy of specific medications on fistulas directly. To date, there has been only one published prospective randomized controlled trial that was designed to assess the efficacy and safety of a specific medication on fistulas in patients with Crohn's disease; it showed clinical efficacy over placebo in a statistically significant manner. The judicious use of surgery remains an integral part of the management of certain presentations of fistulizing Crohn's disease, and the appropriate integration of surgical and medical therapy is of paramount importance in the management of these patients. This review provides an overview of pertinent medical and surgical literature as it pertains to management of patients with fistulizing Crohn's disease.

lthough Hippocrates (460 BC) wrote about anal fistulas and discussed specific treatment methods, 1 the first description of a fistula in a patient who was reported to have multinucleated giant cells is credited to Gabriel in 1921. 2 The presence of fistulas in patients with Crohn's disease was noted in the initial report of Crohn et al. ~ in 1932. Six of their initial 14 patients are noted to have fistulizing disease. They noted in the article, "There is a marked tendency to the formation of internal fistulas, the sigmoid colon having been the seat of fistulous involvement 4 times and the ascending colon and cecum one each." They also noted that "Fistula formation is a constant feature of the disease process. The most common site of adherence is the sigmoid colon; next in frequency is the cecum and the ascending colon

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and, occasionally, the hepatic flexure. As the necrotizing process of the mucosa of the ileum progresses through its several coats, the serosa becomes involved. Any hollow viscus, usually the colon, now becomes adherent to the point of threatened perforation. A slowly progressive perforation is thus walled off, but results in a fistulous tract being formed between the 2 viscera." They describe different examples of fistulas they had observed: an enterovaginal fistula, an enterocutaneous fistula, and a sigmoid fistula tract of undefined origin (which is actually a sinus tract because, strictly defined, a fistula is an abnormal communication from one epithelial surface to another; when a tract extends from one surface, such as the mucosa of the bowel, to a blind end, this is referred to as a sinus). They did not observe perianal fistulous disease in their patients. In 1934, Bissell 4 drew attention to the association between anal and small bowel Crohn's disease. Subsequently, it was appreciated that the perianal lesions of Crohn's disease may even precede the intestinal manifestations by many years. 5

Introduction The transmural inflammatory process of Crohn's disease predisposes to the formation of fistulas. The presence of fistulas signifies that the transmural inflammation has penetrated into adjacent organs, tissue, or skin. The classification of fistulas is based on their location and their connection with contiguous organs. In the literature, fistulas have been described as either (1) internal fistulas if they terminate into adjacent organs (e.g., enteroenteric, enterovesical, ileocolic, gastrocolic, or rectovaginal) or into the nearby mesentery; or (2) external fistulas if they terminate on the surface of the patients body (e.g., enterocutaneous, parastomal, or perianal). Abbreviations used in this paper: AZA, azathioprine; CyA, cyclosporin

A; MTX, methotrexate; 6-MP, 6-mercaptopurine; TNF, tumor necrosis factor.

© 2000 by the American Gastroenterological Association 0016-5085/00/$10.00 doi:10.1053/gast.2000.18165

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Abscesses and fistulas in patients with Crohn's disease may coexist or may follow the other. Their pathophysiologies of these 2 disorders are not completely understood but are believed to be somewhat similar. 6 The treatment of abscesses will not be the primary focus of this review and thus will not be discussed in detail. Frequently, external fistulas (most commonly enterocutaneous or perianal) are associated with the presence of local pain, drainage, and possible abscess formation. However, internal fistulas may be asymptomatic and unrecognized. Internal fistulas can be "major" fistulas (such as a gastrocolic fistula, which has the potential to cause short gut syndrome by bypassing the majority of the luminal intestinal tract) or "minor" fistulas (such as ileocecal or ileoileal fistulas, which typically do not lead to significant symptoms and commonly are asymptomatic). The lifetime risk for the development of a fistula in patients with Crohn's disease has been reported to typically range from 20% t o 4 0 % , 7-9 although in some series their presence has varied from as low as 17 % to as high as 85%. l° The treatment for fistulas is dependent on location, severity of symptoms, number and complexity of tracts, and the presence or absence of rectal disease. The history of previous local surgical procedures and sphincter function also influence the decision regarding a conservative nonsurgical approach or a more aggressive surgical approach. On one end of the spectrum, patients may have perianal fistulas that may be painful and may be associated with abscess formation often requiring surgical drainage with or without seton placement, or in severe cases, proctectomy. On the other end of the sPectrum, patients may have internal fistulas such as ileoileal or ileocecal fistulas that are asymptomatic and require no intervention. This review focuses on many different aspects of therapy for fistulizing Crohn's disease. The treatment of patients with fistulizing Crohn's disease is complex and is dependent on several important factors such as nutritional state (in terms of timing of interventions, possible use of temporary ostomy), timing of occurrences of fistulas (e.g., postoperative fistulas), and comorbidity/fitness of the patient for surgery. When defining the healing of fistulas, various definitions have been used in the literature for following patients. There is currently no well-accepted fistula disease activity index (such as the Crohn's Disease Activity Index) for assessing the response of a patient to a specific therapy (medical or surgical). It has recently been proposed that complete healing is defined as a lack of drainage despite gentle compression on the external fis-

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tula orifice for a duration of 1 month. This is not a standardized definition in the literature and varies from study to study. Additionally, there is no standard time to onset of healing. This varies with the specific therapy being used. It is important to perform placebo-controlled trials because the 2 controlled trials in the literature assessing effect of 6-mercaptopurine (6-MP) and infliximab demonstrated a 6% and 13% complete fistula closure rate, respectively. 24,42

Medical Therapy of Fistulous Crohn's Disease Few studies have focused on the efficacy of medical therapy specifically directed at fistulous disease in patients with Crohn's disease.

Am inosalicylates Sulfasalazine and mesalamine derivatives have been shown to be effective for the induction of remission and for the maintenance of remission in patients with Crohn's disease. There is no specific mention of their effect on fistulas in Crohn's disease.

Corticosteroids Despite being extremely effective for the induction of remission in patients with active Crohn's disease, corticosteroids have not been shown to be efficacious for the treatment of fistulizing Crohn's disease. In two, large, uncontrolled trials there was a suggestion that the use of corticosteroids increased the need for surgery 11,.2 and the deaths in a controlled trial only occurred in patients who had abdominal masses, resultant from fistulas, who were taking corticosteroids. 13

Antibiotics Ciprofloxacin. To date, there have been no controlled trials that were designed with the specific endpoint of fistula healing assessing antibiotics in patients with Crohn's disease. Ciprofloxacin, a fluoroquinolone antibiotic, has a broad spectrum of coverage including gram-negative aerobic organisms. Two small, uncontrolled trials have been performed evaluating the efficacy of ciprofloxacin in severe perineal Crohn's disease. In 1989, Turunen et al. 14 reported results of use of ciprofloxacin in 8 patients who had active perineal Crohn's disease refractory to metronidazole and various surgical procedures. All treated patients received medication at doses of 1 0 0 0 - 1 5 0 0 g daily for a range of 3-12 months and showed improvement in physician and patient global assessments. In 1990, Wolff 5 reported resolution ofperianal pain in 4 of 5 patients with active perineal Crohn's

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after receiving 4 days to 5 weeks of therapy with ciprofloxacin. Ciprofloxacin and metronidazole. The use of combination therapy with ciprofloxacin and metronidazole has been advocated subsequent to the rationale that metronidazole has antimicrobial activity against anaerobic bacteria and ciprofloxacin is efficacious against gramnegative organisms. In 1993, Solomon et al. 16 reported their retrospective study on 14 patients; 9 had complex fistulas, and 1 had a rectovaginal fistula. After 12 weeks of medical therapy with 500-1500 mg metronidazole daily and 1000-1500 mg ciprofloxacin daily, improvement in 9 patients and healing in 3 patients was noted, whereas 1 patient was unchanged and another worsened, requiring proximal diversion. W i t h cessation of medication, patients became symptomatic, necessitating repeat administration in 9 of 14 patients. Metronidazole. Metronidazole alone has been studied in uncontrolled trials for fistulous perianal Crohn's disease. In an uncontrolled study evaluating 21 patients by Bernstein et al. iv in 1980, 21 patients with fistulous Crohn's disease who had symptoms present for more than 5 years were treated with 20 mg/kg metronidazole daily. A clinical response was observed in 20 of 21 patients (95%) with complete healing appreciated in 10 of 18 (56%) if the medication was maintained. Symptomatic improvement occurred in 90% within 2 weeks, and the remaining 10% noted improvement within 6 - 8 weeks. In 1982, Brandt et al. 18 reported that they observed this group of patients and 9 additional patients, and reported symptomatic recurrence in 78% of patients within 4 months of stopping metronidazole. Another small trial by Jakobovits and Schuster 19 was reported in 1984 evaluating 8 consecutive patients who had fistulous Crohn's disease; it showed that 50% of the fistulas healed entirely with treatment. A subsequent European study reported similar efficacy. Closure of active fistulas was appreciated in 40% of all treated patients with another 20% showing a decrease in fistula drainage. 2° These trials were uncontrolled; thus, the placebo effect in these patients is unknown. It is known that metronidazole must be used for maintenance to be effective because there is a high recurrence rate on discontinuation of medication. Patients who are treated with metronidazole may develop adverse effects related to medication use, including paresthesias, 21 which are almost always reversible and typically are dose- and duration-related. 22 When combining physical examination and nerve conduction studies, it has been found that 85% of individuals may have abnormal findings, often asymptomatic. 23 Other side effects observed in patients using metronidazole include dys-

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pepsia, a metallic taste, and a disulfiram-like effect (limiting patient's ability to ingest ethanol). Irnmunomodulators 6-MP and azathioprine. A s a general rule, immunomodulatory medications have excellent efficacy for the treatment of fistulizing Crohn's disease. The agents that have received the most widespread attention are 6-MP and azathioprine (AZA). These 2 medications are discussed interchangeably because there has been no controlled trial that has compared the efficacy of these 2 medications in inflammatory bowel disease (IBD), and because AZA is nonenzymatically converted to 6-MP. Thus far, only 1 controlled trial has evaluated the effect of 6-MP on fistulas in Crohn's disease. This landmark study by Present et al. 24 assessed patients' clinical response, complete fistula healing, and corticosteroid dose reduction. Medical therapy with 6-MP was efficacious in all areas evaluated. Thirty-six patients with 40 fistulas were evaluated. Complete fistula closure was achieved in 9 of 29 patients (31%) compared with 1 of 17 (6%) in the placebo arm (P = NS). A partial response was shown in 7 of 29 patients (24%) compared with a partial response in 3 of 17 patients (18%) who received placebo in this study. Thus, the overall response rate (partial and complete response) was 55% for patients who received active medication (6-MP) vs. 24% for those individuals who received placebo. Approximately 5 years later, the authors published an uncontrolled follow-up study 25 reporting a total of 34 patients who received medication (6-MP) for treatment of fistulas at a dose of 1.5 mg/kg daily. There were 34 patients with fistulas, such that 24 patients had single fistulas and 10 had multiple fistulas with the following location distribution: 18 perirectal fistulas, 8 abdominal wall fistulas, 7 enteroenteric fistulas, 6 rectovaginal fistulas, and 2 vulvar fistulas. Overall, the authors reported a 39% complete closure rate with another 26% improving with a mean time to response of 3.1 months. By the fourth month, 77% of patients responded, and 100% of patients who respond will do so by 8 months. Of the 13 patients who had complete fistula closure, 6 remained on 6-MP with continued fistula closure, whereas of the 7 who discontinued medication, 5 fistulas were reopened. Reinstitution of 6-MP closed the fistulas again. Similarly, O'Brien et al. 26 in an uncontrolled trial reviewed their experience with 78 patients who received AZA. Twenty-six patients had 35 fistulas, with complete closure of all fistulas noted in 31% of patients and 54% had partial healing of their fistulas. The use of 6-MP or AZA is not only effective for the closure of perineal fistulas, but it is also effective for the

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closure of gastrocolic and enterovesicular fistulas. In a review of the literature, Pichney et al. 27 reported in 1992 that there were a total of 27 gastrocolic fistulas reported, with 24 of these patients being treated surgically. All 3 patients treated with 6-MP or AZA responded. In a similar fashion, enterovesicular fistulas can close using 6-MP/AZA. In a recent abstract, 28 18 of 31 patients (58%) responded and 12 of 31 (39%) maintained their response. It is important to stress that the trials by Pichney and Hull are uncontrolled. There have been no published controlled trials assessing the utility of medical therapy for enterovesicular or gastrocolic fistulas to date.

Methotrexate Methotrexate (MTX) has been recently reported to be efficacious for the induction of remission in patients with Crohn's disease. In 1989, Kozarek et a129 reported that in 11 of 14 patients who received MTX, this medication was effective for induction of remission in patients with Crohn's disease when administered intramuscularly at a dose of 25 mg weekly. The response time was 4 - 8 weeks, more rapid than the typical 3 months required by use of 6-MP or AZA. This initial study lead to the randomized, placebo-controlled study by Feagan et al. 3° in which there was a 39% induction of remission rate in MTX-treated patients compared with a 19% placebo-remission rate. The dose used for M T X was 25 mg intramuscularly every week. In this controlled trial, the effect of medication on fistulas was not reported. In 2 similar controlled trials 31,32 using oral MTX, the effect of MTX on fistulas was not reported. However, recently an abstract was presented by Muhadevan et al. 33 evaluating the efficacy of MTX on 33 patients who were treated in an uncontrolled fashion with intramuscular MTX. Clinical remission was achieved in 62% of treated patients. There were 16 of 33 patients who had fistulas; with treatment 4 of 16 had closure of their fistulas and 5 of 16 patients had improvement, yielding a response rate of 56%. When medication dose was lowered or converted to oral medication, relapse was frequently observed. Another recent retrospective triaP 4 was performed for treatment of 20 patients with refractory Crohn's disease, 8 of whom were classified as having fistulizing disease. The authors relate that parenteral M T X was effective in induction of remission in 70% of patients intolerant or resistant to AZA. Unfortunately, the authors did not categorize responses based on type of disease; specifically, we are not informed of the number of patients with fistulizing disease who achieved remission.

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Cyclosporin A Cyclosporin A (CyA) has been efficacious for induction of remission in patients with Crohn's disease in 1 of 4 randomized, placebo-controlled trials that have been published to date. 35 There have been no published, randomized, placebo-controlled trials specifically designed to evaluate the efficacy of CyA on fistula closure in Crohn's disease to date. The rapidity with which clinical efficacy is observed, often within 1-2 weeks, makes CyA an attractive medication. When used at higher doses (7.6 mg/kg orally) it has been shown to be efficacious for the induction of remission in patients with active Crohn's disease, whereas when it is used at doses approximating 5 mg/kg it has been no more effective than placebo. When CyA is administered intravenously at a dose of 4 mg/kg in a continuous fashion, clinical response and efficacy in treating fistulous disease have been observed. A recent series of 16 patients treated with intravenous CyA showed that 14 of these patients (88%) responded acutely. Complete closure occurred in 7 patients (44%), with moderate improvement in the remaining 7 patients (44%). The mean time to response was 7.4 days, and it is important to highlight that 9 of 10 patients who did not respond to 6-MP/AZA responded to CyA. In 1998, a review 36 was published noting that there were a total of 39 patients treated at that time who had fistulizing Crohn's disease. O f these 39 patients 90% responded to intravenous CyA administration. These uncontrolled data suggested that intravenous CyA is efficacious for fistulizing Crohn's disease as a rapidly acting "bridge" to maintenance therapy with AZA, 6-MP, or MTX. The frequency of relapse after cessation of oral therapy (patients were administered oral therapy for a finite time after being converted from intravenous to oral therapy with CyA) was significant (82%) in this review. Thus, individuals who stopped oral CyA after a short time of using other immunosuppressants (AZA, 6-MP, or MTX) will not have adequate time for these immunosuppressants to take effect.

Tacrolimus Tacrolimus, a fungus (Streptomyces)-derived macrofide antibiotic that is similar to CyA because of its ability to inhibit the transcription of interleukin 2 in T-helper lymphocytes, has been effective for prevention of hepatic allograft rejection. As a result, case reports and an uncontrolled retrospective series 37,38 have suggested efficacy for treatment of fistulizing Crohn's disease. Another report documents healing of a rectovaginal fistula. 39 Combination therapy with oral tacrolimus and AZA or 6-MP may be effective treatment for Crohn's disease perianal

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fistulas. There is now an ongoing, controlled, clinical trial evaluating its efficacy.

Mycophenolate Mofetil Mycophenolate mofetil, another potent immunosuppressant, inhibits lymphocyte proliferation by selectively blocking the synthesis of guanosine nucleotide in T ceils. This agent has been used successfully to treat steroid-refractory Crohn's disease in a prospective, randomized, controlled trial 4° evaluating efficacy to the induction of remission in patients with active Crohn's disease. Also, there has been an uncontrolled evaluation of patients with fistulizing Crohn's disease. 41 Four patients with highly active perianal Crohn's disease and 2 patients with chronically active, steroid-dependent Crohn's disease were included and improved substantially with therapy. Future prospective trials on patients with fistulizing Crohn's disease need to be performed.

Infliximab The cytokine tumor necrosis factor (x (TNF-ix) is produced by monocytes, macrophages, and T cells. Patients with IBD have been found to have TNF-(x in the stool, serum, and intestinal tissue. The cells that express TNF-cl have been found in the mucosa and lamina propria of patients with Crohn's disease. In mucosal biopsy specimens of patients with Crohn's disease, enhanced secretion of TNF-ix and failure to release enhanced amounts of soluble TNF-ot receptors by mononuclear ceils in the lamina propria occur. Although monocytes and macrophages are considered to be the main source of TNF-ci in Crohn's disease, secretion of TNF-o~ has also been observed by intestinal lamina propria T lymphocytes. Recently, a chimeric monoclonal antibody directed against TNF-(x, infliximab, has been produced. Infliximab, formerly known as CA2 (Centocor Inc., Malvern, PA), is a chimeric monoclonal antibody to human TNF-ix, which is formed by connecting the variable regions of a mouse anti-human TNF-(x monoclonal antibody (A2) to human immuoglobulin (Ig)G1 with kappa-light chains. The IgG1 Fc fragment is important because infliximab binds to transmembrane TNF-ot in vitro, resulting in the ability to activate complement and antibody-dependent cytotoxicity in a tumor cell line, whereas an investigational IgG4 form of infliximab did not exhibit the ability to kill cells. Infliximab is administered intravenously over a 2-hour infusion. In a recent trial, the efficacy of infliximab was evaluated for the treatment of enterocutaneous fistulas in patients with Crohn's disease. This medication was shown to be remarkably efficacious.42 This trial repre-

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sents the only clinical study to date that has reported a statistically significant efficacy for the treatment of fistulous Crohn's disease in a randomized, multicenter, double-blind, placebo-controlled fashion. In this study, 94 adults with draining abdominal (10% of patients) or perianal (90% of patients) fistulas, which had been present for at least 3 months, were evaluated. Patients received 1 of 3 treatment regimens: placebo intravenously (31 patients), 5 mg/kg infliximab intravenously (31 patients), or 10 mg/kg infliximab intravenously (32 patients). All treatments were administered at weeks 0, 2, and 6. The endpoint of this study was 1 of 3 possibilities: (1) a decrease in 50% or more from baseline in the number of open draining fistulas observed over the course of at least 2 office visits (total time of 1 month), which was the primary endpoint; (2) closure of all open fistulas over the course of at least 2 office visits (total time of 1 month), which was the secondary endpoint; and (3) nonresponse, an increase in medications with failure to meet the first 2 endpoints. Sixty-eight percent of patients who received infliximab at a dose of 5 mg/kg and 56% who received infliximab at 10 mg/kg achieved the primary endpoint as compared with 26% of the patients in the placebo group (P = 0.002 and P - 0.02, respectively). Also, 55% of the patients receiving 5 mg/kg and 38% of patients receiving 10 mg/kg had closure of all fistulas as compared with 13 % of patients receiving placebo (P = 0.001 and P = 0.04, respectively). The median duration of fistula closure was approximately 3 months. Therefore, infliximab has been shown to be a very effective induction treatment for fistulas in patients with Crohn's disease. Before the widespread use of immunosuppressants and infliximab, alone or in combination, most patients ultimately came to resection of diseased bowel together with the fistulous tract with good results thereafter. It has yet to be demonstrated what role these agents will have in long-term prevention of surgery in patients with these fistulas.

CDP-571 Recently, a "humanized" chimeric monoclonal antibody to human TNF-o~ called CDP-571 (Celltech, Slough, England) was created by binding the complementary-determining regions of a mouse anti-human TNF-o~ monoclonal antibody to human IgG4 with kappa-light chains. 43 Use of this intravenously administered antibody has demonstrated efficacy in the treatment of patients with active Crohn's disease44 and also in patients with fistulizing Crohn's disease. Recently, 2 multicenter national studies were completed evaluating

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the efficacy of CDP-571 in patients with Crohn's disease. The first study was performed on 71 steroid-dependent patients who were treated for 16 weeks with an initial dose of 20 mg/kg CDP-571 and a second dose of 10 mg/kg 8 weeks later. 45 The corticosteroids were discontinued by week 10. Another study evaluated 169 patients with moderate to severe Crohn's disease including many patients who had not responded adequately to existing treatments. 46 Patients were evaluated over 24 weeks during which they were treated with either CDP571 or placebo. Two different dosages (10 and 20 mg/kg) with 2 dosing regimens were evaluated. CDP-571 treatment was assessed for its efficacy in fistula closure in patients enrolled in both studies. Overall, 50% of individuals with fistulas had -->50% closure compared with 15% in the placebo group (P = 0.074). 46

Other Anti-TNF-oLTherapies Other agents which are known to inhibit TNF-ci (e.g., pentoxifylline and Etanercept) have no published reports demonstrating efficacy or lack of efficacy in treatment of fistulizing Crohn's disease. Two recent reports have demonstrated efficacy of thalidomide in treatment of fistulizing Crohn's disease in open-label studies. 4v,48

Other Novel Therapies Other modalities and agents have been used for the treatment of fistulizing Crohn's disease including hyperbaric oxygen. Thus far, there have been case reports documenting its efficacy, and no prospective, blinded, randomized series has yet been performed. 49,5° The use of a temporary fecal diversion (such as occurs with a temporary diverting ileostomy) has also been successful. However, fistula recurrence is a commonly observed phenomenon upon takedown of the ileostomy or colostomy. 51-53 Proctectomy for individuals with severe perirectal disease has been successful in reports. 54 Preliminary data are emerging regarding the use of fibrin glue 55 and plasma factor XIII c o n c e n t r a t e 56 for perianal fistulas. Further studies need to be performed before any assessment can adequately be made.

Surgical Therapy of Fistulous Crohn's Disease In few, if any, of the above trials that have evaluated the efficacy of medical therapy for fistulous Crohn's disease has there been classification of the type ofperianal fistula that was being treated or the specific surgical therapy (if one had been performed) that had been performed. Specifically, in these studies it is difficult, if not

impossible, to determine if the fistulas are simple or complex in nature. It is important to define which specific type of fistula is present in series because of the different response rates to various interventions.

External Fistulas Spontaneous The occurrence of spontaneous external abdominal fistulas in the absence of previous surgical intervention is quite rare) v,58 In a series of 1500 patients, only 4 such fistulas were observed, with 3 being colo-umblical and 1 from the ileum to the linea alba. 59

Postoperative The majority of external fistulas that are enterocutaneous occur postoperatively and classically are ileocutaneous or colocutaneous and most commonly drain through the site of a previous scar. Enterocutaneous fistulas usually occur in the early (often within 1 week postoperatively) period because of anastomotic breakdown or at a late stage (often after 7 - 1 0 days postoperatively) subsequent to recurrent Crohn's disease (or less commonly as a result of a fistula which resulted from a contained anastomotic leak). It has been suggested that early fecal diversion with creation of an ileostomy is the procedure of choice for treatment. This may be performed in addition to resection of the fistula and anastomosis. Recently, the use of somatostatin analogue has been used in some patients for fistula closure subsequent to anastamotic breakdown postoperatively. Late fistulas, resulting from recurrent Crohn's disease, usually require operation again and/or aggressive medical therapy. Individuals who have high reoperative risks and who have low fistula outputs may be managed with appropriate medical therapy.

Peri-ileostomy Once individuals have had proctocolectomy and i l e o s t o m y , 2 different types of cutaneous fistulas may classically occur: peri-ileostomy fistulas and enteroperineal fistulas. Peri-ileostomy fistulas can occur either early or late in the postoperative period. Typically, early postoperative fistulas in this setting result from excess tension on sutures that are placed between the abdominal fascia and the bowel serosa leading to seromuscular damage or damage to the portion of the ileostomy in the abdominal wall. These fistulas can be considered as severe complications because they often present during hospitalization and require exteriorization of the ileostomy (with a second stomal maturation), which may require a laparotomy at that time. Late ileostomy fistulas usually

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occur subsequent to recurrent Crohn's disease. They may be treated with primary resection (classically the neoterminal ileum) and recreation of a neo-end ileostomy or with aggressive medical therapy. Relocation of the stoma is required if there is an abscess/infection at the previous site. Specifics of the enteroperineal fistula will be discussed in the section of enterovaginal fistulas. Perianal Fistulas Low and simple fistula in ano. Simple fistulas and fistula in ano are typically low-lying, often with only a single external opening. Other similar fistulas, which have received similar classification, include subcutaneous, low-intersphincteric, and low-transsphincteric fistulas. The common feature to all of these is that most of the anal sphincter lies above the fistula tract. (Refer to Figure 1A for normal anatomy.) Classically, these have been observed in patients without rectal involvement of their Crohn's disease. These fistulas comprise the majority of fistulas observed in patients with Crohn's disease. Despite the excellent response rate of these fistulas to fistulotomy with the low rate of associated incontinence or delayed woundhealing, gastroenterologists frequently administer repeated courses of antibiotics. Several surgical series have exhibited excellent healing rates with ranges of 7 0 % - 1 0 0 % , and rates of recurrence have been typically low ( < 2 0 % ) with minor incontinence in < 1 0 % of individuals. 6°-69 Thus, in addition to medical therapy, the use of surgical therapy is critical when dealing with perirectal disease especially. The collaboration of the gastroenterologist and the surgeon for examination under anesthesia, drainage of abscesses, is critical. Additionally, the placement of setons through fistulous tracts has been performed in select patients with the theory that this will form a reaction and create granulation tissue assisting in fistula closure over time. It is currently believed that setons prevent abscess formation by keeping a drainage tract open. Because sphincters are not divided, as with a high fistulotomy, fecal continence is preserved. It is important to stress that setons are not typically used for anovaginal or rectovaginal fistulas. The eroding effect makes the hole (fistula orifice) larger, and more symptomatic. Conservative therapy with the avoidance of musclecutting procedures and control of the infectious process is the standard approach typically followed. W h e n simple fistulas are present, surgery (without a significant risk for incontinence and without the potential risk of immunosuppressive therapy) is appropriate. Despite some investigators reporting no influence of

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the presence of rectal disease's presence on the outcome of fistulotomy, 67 some have reported better results in patients who have no rectal Crohn's involvem e n t . 66,69 Caution should be exercised in performing a fistulotomy in patients with diarrhea and in women who have an anterior fistula and short anal canal. If there is a risk for postoperative incontinence, division of the sphincter should not be performed. The performance of a partial internal sphincterotomy at the site of the internal fistula orifice has recently been performed as an alternative to the classically described fistulotomy.6v,7° The intersphincteric abscess, which is present in association with the fistula, is unroofed, but the fistulous tract is not opened. This helps to avoid the presence of perineal wounds, and removes the source of the infectious process. Complex fistulas. Despite the fact that simple fistulas can typically be treated definitively by means of surgical intervention, complex fistulas or fistulas occurring in the presence of active rectal Crohn's disease should be approached in a different fashion. (Refer to Figure 1B for prototype of complex fistula.) Complex fistulas include fistulas with many openings or those that are high, those with internal openings above the dentate line, those with horseshoe tracts, or those with high blind extensions. Additionally, fistulas that recur after fistulotomy, suprasphincteric and extrasphincteric fistulas, and fistulas that cross the sphincter at a high level are classified as complex fistulas. Typically, these cannot be healed with surgery alone without significant morbidity ensuing. Frequently, a combined medical and surgical approach with examination under anesthesia is preferred to define disease extent and to ascertain if any abscesses or infectious complications have presented. Abscesses, which were previously undetected, can be treated with drainage. Not only can fistulas that appear to be complex be treated, but on occasion, one may see fistulas that appear to be complex. However, on further evaluation they are found to be simple. This approach enables the surgeon to offer definitive therapy to the majority of those patients who actually have simple fistulas. Additionally, the surgeon is able to identify and unroof fistula tracts while curetting all infected granulation tissue. The tissue removed should be sent for pathologic analysis, because on rare occasions there have been reports of individuals who have refractory fistulas (perineal and enterocutaneous) developing a carcinoma as the etiology of refractory disease, vl-v3 These maneuvers typically permit at least partial healing of the fistula tracts with decreased drainage and less pain. Ad-

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ditionally, drains and setons can be used to facilitate drainage and prevent reaccumulation of pus. The introduction of additional medical therapy is frequently helpful in this patient population. Patients who have high fistulas in the absence or presence of rectal disease and in the presence of a complex fistula tract may have significant morbidity associated with performing a surgical fistulotomy. In these patients, the placement of a seton for a long time may be efficacious. Recently, there have been preliminary reports with few patients transposing the internal opening of the fistula tract distally to enable definitive surgical therapy to be more easily performed, r4-76

Surgical Techniques Noncutting seton. The long-term noncutting seton drainage is an excellent choice of surgical options in patients with complex fistulas, especially in patients who have local sepsis or rectal Crohn's disease. It avoids having extensive perineal wounds, prevents recurrent abscesses and associated pain while preserving sphincter function and avoiding incontinence. While the patient is under general anesthesia (having an examination under anesthesia), the fistula is identified using a metal probe and the silastic loop of material (seton) is passed through the tract and tied loosely around the sphincter after there is gentle curettage of the fistula tract. There have been significant reports demonstrating resolution of sepsis and decreased pain with use of this technique, w-v9 One of these reports showed improvement in 9098 of 10 patients with 18 fistulas. None of these patients required proctectomy or fecal diversion during their follow-up, v8 Another study reported a good effect in 23 of 27 patients, v9 There is controversy in the literature; it is uncertain how long one should leave the seton in place. Once the seton is removed there is a high recurrence rate. v4,8° Some investigators have suggested leaving the seton in place indefinitely to avoid the problem of recurrence. 81 Other literature has suggested use of the seton as the initial stage of a combined medical and surgical procedure directed at controlling the local infection and subsequently performing a more definitive procedure such as a fistulectomy82 or an endorectal advancement flap procedure. 8° Those individual patients who receive therapy with a staged fistulotomy or with a cutting seton to divide the muscle are at a higher risk for fecal incontinence. Mucosal advancement flap. The use of the mucosal advancement flap technique avoids division of the sphincter and is efficacious especially in those individuals who do not have significant proctitis, cavitary ulceration, anal stenosis, or a local abscess. Its use has been primarily

FISTULIZING CROHN'S DISEASE 1139

for patients with complicated anal disease, rectovaginal fistulas, or perineal fistulas. The technique entails (Figure 2) performing a semicircular incision at the level of the dentate line, including the internal opening in the center. Typically, a 3-4-cm flap of mucosa, submucosa, and smooth muscle is elevated. After the internal opening is excised, the tract is curetted and closed. The flap is advanced (without placing any tension on it) to the anoderm below the origin of the tract and it is sutured in place. Subsequently, the external opening is curetted and drained with a small catheter (frequently a mushroomtip catheter). Recently, several series reported significant success; in one series 75% healing in 20 patients after 2 years of follow-up, 83 in another series 7198 success in 31 patients was reported, 84 in another series 8 of 13 patients were successful with this technique. 85 In the event fistulas recur, repeat operations are possible. In a recent series, 4 of 5 patients who did not heal with the first procedure were successful after their second procedure. 84 If patients experience anal canal ulceration or stricturing, a rectal sleeve advancement with a temporary proximal diverting ileostomy should be considered in select patients. 86 This specific operation is more involved than the rectal mucosal advancement flap whereby the full thickness of the rectum is circumferentially mobilized after surgically excising the strictured or ulcerated area. Subsequently, a proctoanal anastomosis is performed in combination with a proximal diverting ileostomy. This operation is typically performed in a transanal approach but on occasion requires an abdominal approach. Other techniques. Several other techniques have also been described including flap repair using perianal skin, 8v laser ablation, and fistulectomy with sphincter r e c o n s t r u c t i o n . 75,82

Internal Fistulas Enteroenteric Fistula Ileocolic fistulas are the most common type of the enteroenteric fistulas, with the majority being ileocecal or ileosigmoid in location. Other fistulas, such as from the ileum to the transverse colon, stomach, or duodenum occur, but are not very common. Internal fistulas are usually relative indications for surgery and can be demonstrated by various techniques including enteroclysis, small-bowel radiography, barium enema, computed tomography scan, magnetic resonance image scan, or colonoscopy. Enteroenteric fistulas alone are usually associated with few symptoms unless obstructive or septic complications ensue. An example of such is the ileocecal fistula, which is usually not a problem in the absence of

1140

GARY R. LICHTENSTEIN

an intra-abdominal abscess because only a short segment of the bowel is bypassed by the fistula. Other fistulas such as ileosigmoid fistulas typically ensue from ileal disease. If this is refractory to medical therapy, then surgical intervention is frequently advocated. Some investigators advocate ileal resection with primary anastomosis and fistula repair, ss and some advocate ileal resection with primary anastomosis and sigmoid resection with primary anastomosis. 89 A classic study was performed to follow the natural course of enteroenteral fistulas. A study by Broe et al. 9° examined the natural history of 24 patients with internal fistulas and evaluated the effect of nonoperative therapy on these patients. O f these 24 patients, 10 required surgery within 1 year, and another 8 patients within a period of 9 years, mostly caused by disease intractability. The remaining 6 patients did not require surgical intervention. In those 6 patients who continued to receive nonoperative therapy, the fistulas could not be shown radiographically, and 4 of these patients remained healthy for longer than 5 years after the initial diagnosis. Thus, the presence of an enteroenteric fistula itself is not an indication for surgery. 91

Rectovaginal Fistula The discharge of fecal material or gas from the vagina signifies the presence of an abnormal internal opening between the anus or rectum and the vagina. This tract is called an anovaginal fistula or rectovaginal fistula. It was estimated in one series that these occur in 9% of women with anal Crohn's disease. 92 Most fistulas are truly anovaginal because the internal opening is located in the anal canal, whereas rectovaginal fistulas have their internal opening above the anorectal ring. Anorectal fistulas may result from deep anterior anal ulceration or less commonly from a cryptoglandular source, whereas rectovaginal fistulas are typically associated with deep rectal ulceration or proctitis. In patients who have undergone hysterectomy, ileal or sigmoid Crohn's disease can fistulize into the vagina. Symptoms may vary in individuals and be minimal in some individuals or incapacitating for others. Some women experience dyspareunia, perineal pain, passage of stool or flatus from the vagina, drainage of purulent material, yeast infections, or difficulty with hygiene. The general principles discussed in the treatment of fistula in ano also apply to the treatment of rectovaginal fistulas. Patients with minimal or no symptoms need no treatment. Individuals who have abscesses need drainage. Typically, the insertion of a seton or mushroom drain is appropriate and provides pain relief. Patients who have low anovaginal fistulas with a superficial tract can be laid

GASTROENTEROLOGY Vol. 119, No. 4

Internalsphincter

~'~" k Columnsof Morgagni ~

' ~

hemorrhoids

Superfi~ Externalhemorr~oid~ Figure 1. (A) Normal anatomy of anorectal region with relationship to pelvic musculature depicted schematically. (Reprinted with permission from Gordon PH. The anorectum: anatomic and physiologic consideration in health and disease. In: Anorectal disorders. Gastroenterol Clin North Am 1987;16:1-15.) (B) Classic location of several fistulas and their relationship to pelvic musculature depicted schematically. Anorecetal anatomy: PR, puborectalis (i.e., deep portion of external sphincter muscle [E.S.]); I.S., internal sphincter; D.L., dentate line; A.V., anal verge. (Reprinted with permission from Fazio VW. Complex anal fistulae. Gastroenterol Clin North Am 1987;16:93114.)

open. 93 In individuals who have transsphincteric and extrasphincteric rectovaginal fistulas, mucosal advancement flaps have been used successfully; however, recurrence rates tend to be higher than in patients with a n o r e c t a l fistulas. 84,92,94,95 Recent studies have reported success rates of 7 0 % - 7 5 % . 84,9e Individual patients who have the presence of significant rectal disease and cannot be treated with a mucosal flap can be treated with an anocutaneous flap; however, a 33% recurrence at 18 months has recently been reported. 96 Use of a transvaginal approach has also recently been performed with success. One report notes a 93% success rate with no recurrence in a mean follow-up of 55 months. 97 The surgical use of healthy vaginal tissue is the likely explanation for such a high success rate. All patients in this report had additional proximal diverting ileostomies. Resection of contiguous bowel should also be considered in individuals. When the fistula is the result of proximal disease that fistulizes into the vagina, it is important to ascertain the extent of disease and the site from which the fistula originates. If there is only ileal disease in the absence of colonic and rectal disease, then consideration should be given to ileal resection; if only the colon is diseased (often the sigmoid colon) with impaired sphincter muscles, a segmental resection may be considered if the rectum and remainder of the colon are unaffected by

October 2000

FISTULIZING CROHN'S DISEASE 1141

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Crohn's disease. If the remainder of the colon is involved, then consideration for a subtotal colectomy and an ileorectal anastomosis should be discussed if sphincter muscles function adequately. If the bowel anastomosis is in the region of the vaginal stump, an omental pedicle can be interposed between the anastomosis and the vagina.

When proximal diversion is performed, this should be considered as a temporary measure because recurrence is frequent on reversaP ~ (unless use of adequate medical or surgical therapy in combination with this is undertaken). If all other options fail or are inappropriate, then consideration for proctocolectomy should be discussed, and

1142

A

GARY R. LICHTENSTEIN

GASTROENTEROLOGY Vol. 119, No. 4

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B

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if perineal abscess or severe proctins is present, then a consideration for a colectomy with rectal preservation should be performed with anticipation of a completion proctectomy at a later date. A 2-stage procedure should be considered in the presence of sepsis or inflammation because it may affect perineal wound healing. 98 However, individuals who do have persistent perineal sinus tracts may be treated not only with medical therapy but also with various surgical techniques including muscle flap perineal reconstruction procedures such as gluteal muscle flaps, 99-1°1 hamstring muscle flaps-in the form of semimembranosus muscle, 1°2 or the gracilis muscle flap, 103,104 or with a rectus abdominis muscle flap. 1°~,1°6 Medical therapy has also been useful for the treatment of some patients with vaginal fistulas. Careful selection of specific agents (AZA, 6-MP, or infliximab) that might be used to treat these fistulas needs to be focused on the time to onset of action. The degree to which patients are symptomatic dictates the choice of agents. Medications that have been useful in the treatment and healing of these fistulas include infliximab, metronidazole, intravenous CyA, AZA, or 6-MP. Additionally, preliminary evidence had shown some promise for use of fibrin glue; however, results for complex fistulas in patients with

,';,

Figure 2. Depiction of rectal advancement flap procedure. This procedure requires a rhomboid-shaped incision of the mucosa of the rectum extending beyond the internal OS and dentate line. After elevation of the flap is performed, the fistula tract is excised or debrided and the internal muscular opening is sutured as illustrated. The distal portion of the flap containing the internal mucosal OS is excised; the remaining flap is drawn over the now-closed opening and secured in a tension-free manner. (Reprinted with permission from Fazio VW, Strong SA. The surgical management of Crohn's disease. In: Kirsner JB, Shorter RG, eds. Inflammatory bowel disease. 4th ed. Philadelphia: Lippincott, Williams & Wilkins, 1995:830-887.)

Crohn's disease has been disappointing and this was found to work best for long tracts (e.g., gluteal fistulas). Rectovaginal and anovaginal fistulas are very short, typically < 1 0 mm, and almost always fail. In 1985, Korelitz and Present 25 assessed the efficacy of 6-MP in the treatment of fistulizing Crohn's disease for 6 patients with rectovaginal fistulas and 2 with vulvar fistulas. In 2 of 6 patients rectovaginal fistulas closed and 1 other improved, and 1 of the patients with vulvar fistulas improved. Similarly, in a 1993 report on efficacy of intravenous CyA, Hanauer and Smith l°v reported that in 5 patients who had a total of 12 fistulas (5 enterovaginal, 3 perianal, 3 enterocutaneous, and 1 enterovesical) use of intravenous CyA resulted in decreased drainage and improvement in all fistulas. Complete resolution of drainage was observed in 10 of 12 fistulas with initial response observed after a mean of 3.6 days and complete cessation of drainage after a mean of 7.9 days. Relapse was observed in 2 perianal fistulas and in 2 enterovaginal fistulas. In 1994, Present and Lichtiger m8 reported that 16 patients (10 with perirectal fistulas and 2 with rectovaginal fistulas) were administered a 2-week course of intravenous CyA with subsequent continued oral conversion. Four patients with perirectal disease and 1 with a recto-

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FISTULIZING CROHN'S DISEASE

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vaginal fistula had fistula closure after 2 weeks of therapy. After a mean follow-up of 1 year, 7 of 10 patients with perineal disease continued their oral CyA; about half had improved and half had fistula closure. Both individuals who had rectovaginal fistulas had recurrence and 1 required surgery. To date, there has been no controlled trial performed with the endpoint of fistula closure performed assessing enterovesicular fistulas or enterovaginal fistulas.

Enterovesical Fistula It is not uncommon for the ileum to be inflamed in patients with Crohn's disease, and because of its proximity to the urinary bladder it may cause urinary frequency and urgency. When the inflammation is severe in the adjacent bowel (typically ileum or sigmoid colon) fistulas may form between the bowel and the bladder. Patients with these fistulas typically present with dysuria, pneumaturia, fecaluria, and recurrent urinary tract infections with possible urosepsis. The fistula may com-

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I Figure 3. (A) Algorithm for suggested management of patients with perianal Crohn's disease. Classification is based on patients' primary symptomatic lesion. (Adapted with permission from Steinhart AH, McLeod RS. Clinical review: medical and surgical management of perianal Crohn's disease. Inflamm Bowel Dis 1 9 9 6 ; 2 : 2 0 0 - 2 1 0 . ) (B) Algorithm for suggested medical management of patients with perianal Crohn's disease. Classification is based on patients' primary symptomatic lesion.

municate directly or indirectly with an abscess cavity, which arises from the bowel wall. Additionally, patients may pass urine through the bowel wall or have recurrent cystitis or even pyelonephritis. Classically, intravenous pyelograms and retrograde cystograms fail to reveal the fistula tract; however, a filling defect may be appreciated in the bladder. Fistula detection may be attempted by means of a barium enema, enteroclysis, computed tomography, or magnetic resonance imaging scan. In a large series of patients with IBD, enterovesical fistulas were found in 38 of 683 inpatients (5.6%) with the majority (22 fistulas) being ileovesical, 1°9 8 fistulas were colovesical, and 8 ileocolovesical, m5 The primary method of management of enterovesical fistulas parallels the management of internal fistulas. The primary goal of medical therapy is reduction of the bowel inflammation and treatment of any urinary infections. Often the management of patients with enterovesical fistulas consists of urinary antimicrobials without a significant risk for py-

1144

GARY R. LICHTENSTEIN

elonephritis 1.° along with treatment for the coexisting bowel disease. Immediate surgery is typically not required because septicemia does not commonly result from the fistula directly. If septicemia does occur, then this typically heralds the presence of an abscess that has been inadequately drained through the bladder or colon, often in the presence of severe bowel disease. When required, surgical therapy is directed at resection of diseased mucosa, which leads to the formation of the fistula, closure of the fistula, and if needed, partial bladder resection. In the presence of multiple fistulas consideration regarding proximal bowel diversion should be a temporary measure. Surgery is frequently required, although the data supporting this are based on literature that is primarily retrospective and uncontrolled. At the time of surgery the bladder is dissected away from the inflamed bowel, 111 with subsequent resection of the segment of diseased bowel (typically sigmoid or ileum) and curretting of the bladder fistula then oversewing of the defect if retroperitonealization is able to be performed in conjunction with the use of catheter drainage of the bladder for an approximate time period of 7-10 days. Recurrence of fistulas is low when treated in such a fashion, lo9,111

Fistulous Crohn's Disease: General Approach to Medical and Surgical Therapy In addition to medical therapy the use of surgical therapy is critical when dealing with perirectal disease especially. The collaboration of the gastroenterologist and the surgeon for examination under anesthesia, drainage of abscesses, and placement of setons is critical. Conservative therapy with the avoidance of muscle-cutting procedures and control of the infectious process is the standard approach typically followed. When simple fistulas are present, surgery (without a significant risk for incontinence and without the potential risk of immunosuppressive therapy) is appropriate. When complex fistulas are present, minimal surgery or avoidance of surgery may be appropriate. When internal fistulas (enteroenteric and enterovesicular fistulas) are present, it is important to ascertain the severity of the illness. In acutely ill patients in whom local abscess or toxicity is of concern, a surgical approach is often the first option, with medical maintenance therapy for Crohn's disease thereafter being important. In patients with an internal fistula who have minimal symptoms, enthusiasm about a medical approach often prevails, often with an antibiotic. If no symptoms are present it is unclear if treatment alters the natural course of disease.

GASTROENTEROLOGY Vol. 119, No. 4

The primary role of the clinician in the management of patients who have fistulas in the setting of Crohn's disease includes: (1) defining the anatomy of the fistula when indicated, (2) draining any associated sepsis, (3) attempting to eradicate the fistula tract (with a combination of medical and/or surgical therapy), (4) preventing recurrence, and (5) preserving continence and sphincter integrity. (Refer to Figure 3 for overview of medical and surgical approach to perianal Crohn's disease.) In this article, the intent was to review the current literature specifically relevant to fistulizing Crohn's disease. Not every area was able to be covered in extreme detail given the space constraints of this article. Additionally, not all investigators who have published material on fistulizing Crohn's disease have been referenced. However, there still remain many areas that are in need of further research and intense investigation. It is the hope of this review to outline areas that are well understood, as well as to emphasize those areas which are in need of further investigation.

References 1. Sainio P. Epidemiology. In: Robin KS, Lunniss PJ, eds. Anal fistula. London: Chapman & Hall, 1996:1-11. 2. Gabriel WB. Results of an experimental and histological investigation into seventy-five cases of rectal fistulae. Proc R Soc Med 1921;14:156-161. 3. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA 1932;99:1323-1329. 4. Bissell AD. Localized chronic ulcerative colitis. Ann Surg 1934; 99:957-966. 5. Gray BK, Lockhart-Mummery HE, Morson BC. Crohn's disease of the anal region. Gut 1965;6:515-524. 6. Seow-Choen F. Relation of abscess to fistula. In: Robin KS, Lunniss PJ, eds. Anal fistula. London: Chapman & Hall, 1996: 1-24. 7. Steinberg DM, Cooke WT, Alexander-Williams J. Abscess and fistulae in Crohn's disease. Gut 1 9 7 3 ; 1 4 : 8 6 5 - 8 6 9 . 8. Rankin GB, Watts HD, Melnyk CS, Kelly MI Jr. National cooperative Crohn's disease study: extraintestinal manifestations and perianal complications. Gastroenterology 1 9 7 9 ; 7 7 : 9 1 4 920. 9. Farmer RG, Hawk WA, Turnbull RB Jr. Clinical patterns in Crohn's disease: a statistical study of 615 cases. Gastroenterology 1975;68:627-635. 10. Present DH. Management of fistula disease. Inflamm Bowel Dis 1998;4:302-307. 11. Sparberg M, Kirsner JB. Long-term corticosteroid therapy for regional enteritis: an analysis of 58 courses in 54 patients. Am J Dig Dis 1 9 6 6 ; 1 1 : 8 6 5 - 8 8 0 . 12. Jones JH, Lennard-Jones JF. Corticosteroids and corticotropin in the treatment of Crohn's disease. Gut 1966;7:181-187. 13. Malchow H, Ewe EK, Brandes JW, Goebell H, Ehms H, Sommer H, Jesdinsky H. European cooperative Crohn's disease study (ECCDS): results of drug treatment. Gastroenterology 1984; 86:249-266. 14. Turunen U, Farkkila M, Seppala K. Long-term treatment of perianal or fistulous Crohn's disease with Ciprofloxacin (supp1148). Scand J Gastroenterol 1989;24:144.

October 2 0 0 0

15. Wolf J. Ciprofloxacin may be useful in Crohn's disease (abstr). Gastroenterology 1990;98:A212. 16. Solomon M, McLeod R, O'Connor B, Steinhart A, Greenberg G, Cohen Z. Combination ciprofloxacin and metronidazole in severe perianal Crohn's disease. Can J Gastroenterol 1 9 9 3 ; 7 : 5 7 1 573. 17. Bernstein LH, Frank MS, Brandt U, Riley SJ. Healing of perineal Crohn's disease with metronidazole. Gastroenterology 1980; 79:357-365. 18. Brandt L, Bernstein L, 8oley S, Frank M. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 1982;83:383-387. 19. Jakobovits J, Schuster MM. Metronidazole therapy for Crohn's disease and associated fistulae. Am J Gastroenterol 1984;79: 533-540. 20. Schneider MU, Laudage G, Guggenmoos-Holzman I, Riemann JF. Metronidazol in der behandlung des morbus Crohn. Dtsch Med Wochenschr 1 9 8 5 ; 1 1 0 : 1 7 2 4 - 1 7 3 0 . 21. Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 1982;83:383-387. 22. Stahlberg D, Barany F, Einarsson K, Ursing B, Elmqvist D, Persson A. Neurophysiologic studies of patients with Crohn's disease on long-term treatment with metronidazole. Scand J Gastroenterol 1 9 9 1 ; 2 6 : 2 1 9 - 2 2 4 . 23. Duffy LF, Daum F, Fisher SE, Selman J, Vishnubhakat SM, Aiges HW, Markowitz JF, Silverberg M. Peripheral neuropathy in Crohn's disease patients treated with metronidazole. Gastroenterology 1 9 8 5 ; 8 8 : 6 8 1 - 6 8 4 . 24. 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; 302:981-987. 25. Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of Crohn's disease. Dig Dis Sci 1 9 8 5 ; 3 0 : 5 8 - 6 4 . 26. O'Brien JJ, Bayless TM, Bayless JA. Use of azathioprine or 6-mercaptopurine in the treatment of Crohn's disease. Gastroenterology 1 9 9 1 ; 1 0 1 : 3 9 - 4 6 . 27. Pichney LS, Fantry GT, Graham SM. Gastrocolic and duodenocolic fistulas in Crohn's disease. J Clin Gaatrenterol 1992;15: 205-211. 28. Wheeler SC, Marion JF, Present DH. Medical therapy, not surgery is the appropriate first line of treatment for Crohn's enterovesical fistula. Gastroenterology 1998;114:Al113. 29. Kozaek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induced clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Int Med 1989;110:353-356. 30. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, Steinhart AH, Greenberg GR, Gillies R, Hopkins M, Hanauer SA, McDonald JWO. Methotrexate for the treatment of Crohn's disease. N Engl J Med 1995;332:292-297. 31. Oren R, Moshkowitz M, Odes S, Becker S, Keter D, Pomeranz I, Shirin C, Reisfeld I, Broide E, Lavy A, Fich A, Eliakin R, Patz J, Villa Y, Arber N, Gilat T. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. Am J Gastroenterol 1997;92:2203-2209. 32. Aurora S, Katkov W, Cooley J, Kemp JA, Johnston DE, Schapiro RH, Podolsky D. Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology 1 9 9 9 ; 4 6 : 1 7 2 4 - 1 7 2 9 . 33. Muhadevan U, Marion J, Present DH. The place of methotrexate in the treatment of refractory Crohn's disease (abstr). Gastroenterology 1997;112:A1031. 34. Vandeputte L, D'Haens G, Baert F, Rutgeerts P. Methotrexate in refractory Crohn's disease. Inflamm Bowel Dis 1 9 9 9 ; 5 : 1 1 15.

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Received January 5, 2000. Accepted July 19, 2000. Address requests for reprints to: Gary R. Lichtenstein, M.D., Gastroenterology Division, Department of Internal Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, 3400 Spruce Street, 3rd Floor, Ravdin Building, Philadelphia, Pennsylvania 19104-4283. e-mail: [email protected]; fax: (215) 349-5915. Dr. Lichtenstein is on speakers bureau, is a consultant, and has received research support from Centocor, Inc. and is a consultant and has received research support from Celltech, Inc.