Long-term treatment of rectovaginal fistulas in Crohn's disease: response to infliximab in the ACCENT II Study.

BACKGROUND & AIMS: The ACCENT II study (A Crohn's Disease Clinical Trial Evaluating Infiximab in a New Long-term Treatment Regimen in Patients With Fistulizing Crohn's Disease) evaluated the efficacy and safety of infliximab maintenance treatment in patients with fistulizing Crohn's disease. This post hoc analysis was conducted to determine the efficacy and safety of infliximab therapy in women with rectovaginal fistulas. METHODS: All patients received 5 mg/kg infliximab intravenously at weeks 0, 2, and 6. Patients who achieved response at weeks 10 and 14 then were randomized as responders if they had at least 50% of baseline fistulas closed, or as nonresponders, to receive placebo or infliximab 5 mg/kg every 8 weeks through week 54. RESULTS: Of 282 patients in the ACCENT II study, 25 of 138 (18.1%) women had a total of 27 draining rectovaginal fistulas at baseline. After infusions of infliximab at weeks 0, 2, and 6, 60.7% (17 of 28) and 44.8% (13 of 29) of rectovaginal fistulas were closed at weeks 10 and 14, respectively. Among responders, 72.2% (13 of 18) of rectovaginal fistulas were no longer draining at week 14. The duration of rectovaginal fistula closure was longer in the infliximab 5-mg/kg maintenance group (median, 46 wk) than in the placebo group (33 wk). CONCLUSIONS: Infliximab is effective in short-term closure of rectovaginal fistulas and maintenance treatment was more effective than placebo in prolonging rectovaginal fistula closure.     

Combined seton placement,infliximab infusion,and maintenance immunosuppressives improve healing rate in fistulizing anorectal Crohn's disease: a single center experience

PURPOSE: Infliximab (anti-TNF ) has been used for the treatment of fistulizing Crohns disease with variable efficacy. The aim of this study was to evaluate the efficacy of infliximab combined with selective seton drainage in the healing of fistulizing anorectal Crohns disease. METHODS: This was a retrospective chart review of all patients with fistulizing Crohns disease treated with infliximab between March 2000 and February 2002. RESULTS: Twenty-nine patients (12 male; mean age, 31 years) received a mean of 3 (range, 1–5) doses of infliximab 5 mg/kg. Twenty-one patients had perianal fistulas; eight had rectovaginal fistulas, four with combined rectovaginal/perianal fistula. Fourteen of 21 patients (67 percent) with perianal fistula had a complete response (mean follow-up, 9 months), 4 of the 14 relapsed (mean, 6 months), but all had a complete response to retreatment (mean, 9 months). A partial response occurred in four patients (19 percent), defined by decreased drainage (2 patients) or infliximab dependence (2 patients) requiring repeated dosing every six to eight weeks. Three patients (14 percent) had no response. Seton drainage was used before infusion in 13 perianal patients for perianal infection and 17 were treated with maintenance azathioprine or methotrexate. Of eight patients with rectovaginal fistula, complete response occurred in one, partial response in five, and no response in two. Two partial responders became infliximab dependent. A complete response was observed in one patient with isolated rectovaginal fistula, a partial response in five. No patient with a combined rectovaginal/perianal fistula had a complete response. Five rectovaginal fistula patients were taking maintenance immunosuppressive agents and two had seton drainage before infusion. CONCLUSIONS: Selective seton placement combined with infliximab infusion and maintenance immunosuppressives resulted in complete healing in 67 percent of Crohns patients with perianal fistula and partial healing in 19 percent. Relapse was successfully treated with repeat infusion. Concomitant rectovaginal fistula was a poor prognostic indicator for successful infliximab therapy.     

Treatment of perianal fistulizing Crohn's disease with infliximab alone or as an adjunct to exam under anesthesia with seton placement

Perianal fistulas occur in approximately 30% of patients with Crohn's disease (CD). Infliximab, a chimeric monoclonal antibody targeting human tumor necrosis factor alpha (TNF), is approved for the treatment of fistulizing CD. Although the initial response to infliximab is dramatic, the median duration of fistula closure is approximately 3 months, and repeated infusions are often required. An exam under anesthesia (EUA) by a surgeon allows for complete inspection of the fistula as well as incision and drainage of an abscess and placement of a seton. Our aim was to compare the rate of perianal fistula healing, relapse rate, and time to relapse in patients with fistulizing CD treated with infliximab alone or as an adjunct to surgical EUA with seton placement. Thirty-two consecutive patients with perianal fistulizing CD who completed at least 3 infusions with infliximab (5 mg/kg at 0, 2, 6 weeks) between October 1999 and October 2001 were analyzed. All patients had at least 3 months of follow-up after the third dose of infliximab. Response was defined as complete closure and cessation of drainage from the fistula. Patients with CD and perianal fistulas who had an EUA prior to infliximab infusions had a better initial response (100% vs. 82.6%, p = 0.014), lower recurrence rate (44% vs. 79%, p = 0.001), and longer time to recurrence (13.5 months vs. 3.6 months, p = 0.0001) compared with patients receiving infliximab alone. In conclusion, patients with fistulizing CD treated with infliximab are more likely to maintain fistula closure if treatment is preceded by EUA and seton placement.     

Clinical and radiological responses after infliximab treatment for perianal fistulizing Crohn's disease

OBJECTIVES: Infliximab is an effective therapy for fistulizing Crohn's disease of the perineum. We sought to determine whether the clinical improvement after infliximab is associated with radiological closure of fistula tracts. METHODS: Clinical responses and radiological imaging studies by transperineal ultrasound were evaluated in 35 patients with Crohn's disease perianal fistulas after treatment with infliximab 5 mg/kg up to 48 wk. Paired comparison of baseline and follow-up imaging studies at 8 wk and at 56 wk or discontinuation were assessed by an imaging score of perianal fistula severity, based on the Parks criteria. Complete clinical fistula closure and radiological healing were primary outcome measures. RESULTS: At 8 wk, after two infusions of infliximab at 0 and 2 wk, clinical fistula closure occurred in 49% of patients. The radiological score at 8 wk was higher for patients with clinical fistula closure than for patients with no clinical improvement (p= 0.023) and two patients showed complete radiological healing. At 56 wk, clinical fistula closure occurred in 46% patients. Clinical fistula scores correlated with radiological scores (R2= 0.52; p < 0.001) but were not associated with fistula complexity, number of fistulas, or number of collections at baseline imaging. The proportion of patients with marked radiological improvement increased from 14% at 8 wk to 43% at 56 wks (p= 0.015) and complete radiological healing occurred in 4 (11%) patients. CONCLUSIONS: For perianal fistulizing Crohn's disease, repeat dose infliximab improves clinical and radiological outcomes, although complete radiological healing occurs in a minority of patients.     

Predictors of response to infliximab in patients with fistulizing Crohn's disease.

OBJECTIVE: To evaluate the efficacy and toxicity of infliximab for the treatment of fistulizing Crohn's disease. METHODS: Consecutive patients with fistulizing Crohn's disease receiving infliximab were prospectively enrolled. Partial response was defined as a reduction of 50% or more from base-line in the number of draining fistulae. Complete response was defined as the closure of all fistulae. The influence of different variables on the efficacy of infliximab was evaluated. RESULTS: 108 patients were included. The disease was inflammatory plus fistulizing in 18% and only fistulizing in 82%. After the third infusion of infliximab the response was partial in 26% and complete in 57%. Response (%) rates (partial/complete) depending on fistula location were: enterocutaneous (25/68%), perianal (35/60%), rectovaginal (36/64%), and enterovesical (20/40%). None of the studied variables (including concomitant immunosuppressive therapy) correlated with efficacy of infliximab in the multivariate analysis. Incidence of adverse effects (21%) depending on the dose of infliximab was: first dose (5.6%), second (7.4%), and third (11.1%). CONCLUSIONS: Infliximab is an efficacious treatment for fistulizing Crohn's disease. Partial response was achieved in approximately one third of the patients, and complete response in more than half. No studied variable was predictive of response. Adverse effects were relatively infrequent and mild.     

Long-term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn's disease: a pilot study

AIMS: To evaluate efficacy and safety of oral tacrolimus in cases of fistulizing Crohn's disease (FCD), which is refractory to conventional therapy including infliximab. METHODS: Patients with fistulas, previously and unsuccessfully treated with all conventional therapy (i.e., antibiotics, azathioprine, or 6-mercaptopurine and infliximab), were enrolled in a prospective, uncontrolled, open-label study of long-term treatment with oral tacrolimus (0.05 mg/kg every 12 h). The evaluation of the clinical response was complemented by use of the perianal Crohn's disease activity index (PCDAI) and magnetic resonance imaging-based score (MRS) with determined periodicity. RESULTS: Ten patients were included in the study (enterocutaneous fistula, 3 patients; perianal fistula, 4 patients; rectovaginal fistula, 3 patients) with 6 to 24 months of follow-up. Five patients were steroid-dependent, and 4 patients needed maintenance treatment with immunosuppressant agents. Four patients (40%) achieved complete clinical responses, which were verified by PCDAI and MRS. Five patients (50%) achieved partial responses (i.e., important decreases in fistula drainage, size, discomfort, and PCDAI/MRS values). Decreases in both the PCDAI and MRS were statistically significant (P < 0.05). All steroid-dependent patients stopped therapy with prednisone, and concomitant immunosuppressive therapy was tapered. The response was maintained, and no new flare-up of the disease was observed. Only mild adverse events were detected (1 patient withdrew from treatment due to headache), and no case of nephrotoxicity or diabetes was detected. One patient had received no benefit from therapy after 6 months. CONCLUSIONS: Oral tacrolimus could be an effective and safe treatment for patients with FCD, even if there has been no response to infliximab treatment. Randomized studies are needed to compare oral tacrolimus with infliximab in terms of efficacy, safety, and costs.     

Infliximab in the treatment of Crohn's disease: a user's guide for clinicians

Induction therapy with infliximab is indicated for treatment of signs and symptoms, and induction and maintenance of remission in patients with moderate to severely active inflammatory Crohn's disease with an inadequate response to conventional therapy, and for reduction in the number of draining fistulas in patients with fistulizing Crohn's disease. Emerging indications for infliximab therapy in patients with Crohn's disease include maintenance of fistula improvement (reduction in the number of draining perianal or enterocutaneous fistulas) and complete fistula response (no draining fistulas) in patients with fistulizing Crohn's disease, steroid sparing in steroid-treated patients, early use in hospitalized patients who have not failed conventional medical therapy where there is either a severe clinical presentation or a rapid onset of action is desired, and in a variety of unusual and extra-intestinal manifestations of Crohn's disease. An infliximab dose of 5 mg/kg is recommended initally, but some patients who require maintenance dosing may benefit from increasing the infliximab dose over a range of 5-10 mg/kg. An induction regimen of 3 doses at 0, 2, and 6 weeks is the preferred dosing strategy for inducing remission. The optimal dosing interval for patients who require retreatment appears to be every 8 weeks for most patients. Concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate may result in improved outcomes due to a reduction in the frequency of human anti-chimeric antibody formation, acute infusion reactions, and a reduced risk of delayed hypersensitivity-like reactions and formation of antinuclear antibodies. Pretreatment with diphenhydramine (and in selected cases of acetaminophen and, rarely, corticosteroids) is recommended in patients with a history of infusion reactions and patients at risk for delayed hypersensitivity-like reactions. Patients with evidence of active infection should not receive infliximab until the infection is adequately treated, and all patients should be screened for tuberculosis prior to initiating infliximab therapy.     

Infliximab treatment and prognostic factors for response in patients with Crohn's disease.

OBJECTIVE: The aim of this study is to report our experience with infliximab and analyse prognostic factors for response in Crohn's disease (CD). MATERIAL AND METHODS: Consecutive patients were prospectively enrolled in the study when referred for infliximab infusion. Data collected included indication for infusion, patient epidemiological characteristics, Vienna classification, previous surgery, previous medications and extra-intestinal manifestations. Adverse events and clinical response were tabulated separately for patients with luminal or fistulous Crohn's disease. RESULTS: 28 patients were treated (7 with inflammatory and 21 with fistulizing disease). Patients received a total of 116 infusions of infliximab: 57.1% (4 of 7) of patients with luminal disease had complete response within a median of 17.5 days (range 15-28 days), and 62% (13 of 21) of patients with fistulizing disease had complete response within a median of 9 days (range 6-51 days). All patients (5) without relapse received concomitant treatment with immune modifiers. The group of patients with previous resection or perianal fistula repair had complete response more frequently p = 0.03 (OR = 30; IC 95% = 1.47-119.8). CONCLUSIONS: Infliximab is safe and beneficial in clinical practice for Crohn's disease. The re-treatment regimen of infliximab is effective in maintaining clinical response. Immunosuppressant therapy may have a role in the duration of maintained clinical remission in patients with fistulizing disease. In patients with perianal fistulizing disease infliximab treatment is more effective when previous resection or fistula repair is present.     

Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized,placebo-controlled trial

BACKGROUND & AIMS: This study determined the effectiveness of tacrolimus for the treatment of Crohn's disease fistulas. METHODS: The study was a randomized, double-blind, placebo-controlled, multicenter clinical trial. Forty-eight patients with Crohn's disease and draining perianal or enterocutaneous fistulas were randomized to treatment with oral tacrolimus 0.2 mg. kg(-1). day(-1) or placebo for 10 weeks. The primary outcome measure was fistula improvement as defined by closure of >/=50% of particular fistulas that were draining at baseline and maintenance of that closure for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks. RESULTS: Forty-three percent of tacrolimus-treated patients had fistula improvement compared with 8% of placebo-treated patients (P = 0.004). Ten percent of tacrolimus-treated patients had fistula remission compared with 8% of placebo-treated patients (P = 0.86). Adverse events significantly associated with tacrolimus, including headache, increased serum creatinine level, insomnia, leg cramps, paresthesias, and tremor, were managed with dose reduction. CONCLUSIONS: Oral tacrolimus 0.2 mg. kg(-1). day(-1) is effective for fistula improvement, but not fistula remission, in patients with perianal Crohn's disease. Adverse events associated with tacrolimus can be managed by dose reduction. Lower doses of tacrolimus should be evaluated.     

Use of endoscopic ultrasound to guide combination medical and surgical therapy for patients with Crohn's perianal fistulas

BACKGROUND: This study was performed to assess if using endoscopic ultrasound (EUS) to assess and guide combination medical and surgical therapy during fistula healing will lead to a high rate of durable fistula closure and a low or absent incidence of perianal abscess formation in patients with Crohn's perianal fistulas. METHODS: This is a retrospective analysis of 21 patients who presented with a symptomatic Crohn's perianal fistula. Patients were enrolled in a clinical practice protocol of serial EUS exams. All patients underwent a baseline rectal EUS and were placed on maximal medical treatment with 6-mercaptopurine (6-MP) or azathioprine, Cipro, and infliximab (5 mg/kg at 0, 2, and 6 wk and then every 8 wk). Patients were also assessed at baseline by a colorectal surgeon who was aware of the EUS findings. Seton placement and incision and drainage were performed when appropriate. Serial EUS examinations were performed, and the findings were used to guide therapy (i.e., the presence of fistula healing on EUS was used to guide seton removal, discontinuation of infliximab, and Cipro). RESULTS: In the 21 patients enrolled, the median duration of active perianal symptoms was 9 wks (1-36). 10 patients (48%) had previous perianal surgery and 5 (24%) had received infliximab previously. The fistulas treated included 8 trans-sphincteric, 2 superficial, 3 recto-vaginal, and 7 with multiple and horseshoe fistulas. 13 patients (62%) had associated abscesses at presentation. Eighteen of 21 patients (86%) had complete cessation of drainage initially. Median time to cessation of drainage was 10.6 weeks (range, 4-32 wk). Sixteen of 21 patients (76%) maintained long-term cessation of drainage. The median length of follow-up was 68 weeks (range, 35-101 wk). No abscess developed during treatment in any patient. EUS evidence of persistent fistula activity was seen in 10 patients (48%). Of the 11 patients (52%) in whom EUS showed no persistent fistula activity, 7 (64%) have maintained fistula closure off of infliximab and Cipro. Median duration from last infliximab infusion was 47 weeks (range, 20-80 wk). The remaining 4 patients continued infliximab to maintain remission of their luminal disease. Only 1 patient with a horseshoe fistula showed complete healing on EUS. CONCLUSION: In conclusion, using EUS to guide therapy for Crohn's perianal fistulas with infliximab, an immunosuppressive, and an antibiotic is associated with a high short and long-term fistula response rate. EUS may identify a subset of patients who can discontinue infliximab without recurrence of fistula drainage.     

Topical tacrolimus in the treatment of perianal Crohn's disease: exploratory randomized controlled trial

BACKGROUND: The aim of this study is to evaluate the efficacy of topical tacrolimus in treating perianal Crohn's disease. METHODS: Nineteen patients, stratified into 7 with ulcerating, and 12 with fistulizing, perianal Crohn's disease were randomized to topical tacrolimus 1 mg/g (1 g ointment twice a day [bid]) or placebo for 12 weeks. Sixteen patients had been on, or were currently taking, azathioprine/6-MP, and 6 had received infliximab. The primary outcome in ulcerating disease was global improvement in perianal/anal lesions, as assessed by the attending physician; for fistulas, it was reduction of > or =50% of actively draining fistulas on 2 consecutive visits. Blood tacrolimus levels and adverse events were assessed. RESULTS: Three of 4 patients treated with topical tacrolimus for ulcerating disease improved compared with none of 3 in the placebo group. Complete healing was not achieved. In fistulizing disease, topical tacrolimus was not beneficial. Two tacrolimus-treated patients developed perianal abscesses, 1 after improvement in fistula drainage. Adverse events were otherwise infrequent and mild. Whole blood tacrolimus levels were detectable in only 2 patients and were low. CONCLUSIONS: These preliminary data suggest that topical tacrolimus is effective and safe in the treatment of perianal or anal ulcerating Crohn's disease. This therapy is unlikely to be beneficial in fistulizing perianal Crohn's disease, although a larger study is required to confirm this.     

Fistula treatment: The unresolved challenge

In population-based studies, up to 50% of patients with Crohn's disease suffer from fistulas. Fistulas pose a considerable morbidity including permanent sphincter and perineal tissue destruction as well as professional and personal disabilities. Treatment options have progressed in recent years and fistula closure and fibrosis of the fistula track is achieved in some patients. Depending on severity of symptoms and fistula location, different medical and surgical therapies can be chosen. Internal fistulas such as ileoileal or ileocecal fistulas are either asymptomatic and do not require intervention or they are symptomatic and need surgery alone. They always carry a risk of abscess formation. Symptomatic perianal fistulizing disease can be treated with antibiotics (i.e. metronidazole and ciprofloxacin) for three months and/or immunosuppressant therapy (6-mercaptopurine or azathioprine). More complex cases require therapy with anti-TNF agents. Only few and preliminary data exist on cyclosporine A, tacrolimus or methotrexate in fistulizing Crohn's disease. Therefore, these therapies should mainly be used as second-line therapies. Surgery is reserved for the treatment of perianal sepsis in the presence of abscesses and refractory disease or complications of fistulas, or used in combination with pharmacological approaches. The surgical interventions in perianal disease consist of surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy. The classification of fistulas in patients with Crohn's disease remains poorly defined and largely investigator dependent. The unresolved challenges in fistula treatment warrant randomized controlled trials for existing and future treatment strategies as well as a better classification system to compare available studies.     

Combined therapy with infliximab and seton drainage for perianal fistulizing Crohn’s disease with anal endosonographic monitoring: a single-centre experience

During infliximab treatment of perianal Crohn's disease (CD), the healing of the skin opening precedes fistula tract healing and this contributes to abscess formation and fistula recurrence. The aims of this study were to evaluate the efficacy of combined treatment with infliximab and setons for complex perianal fistulas in CD and to define the optimal time for seton removal by anal endosonography (AE). Nine consecutive patients with CD were studied. Perianal sepsis was eradicated when necessary and setons were placed before infliximab therapy. Setons were removed after AE evidence of fistulous tracts healing. Patients received a mean of 10+/-2.3 infliximab infusions. At week 6 all patients showed a reduction in mean CD activity index (p<0.005) and perianal disease activity index (p<0.0001). Complete fistula response was achieved in eight of nine patients. In six patients after a mean of 9.2 infusions, infliximab treatment was discontinued. Clinical and AE response persisted at 19.4+/-8.8 months (range 3-28 months) in five of these patients. One patient had fistula recurrence 20 weeks after infliximab discontinuation and responded rapidly to retreatment. At the time of this report, two patients were still on infliximab and in remission after a mean follow-up of 25+/-5 months. Combined therapy with infliximab and setons with AE monitoring of the response showed high efficacy in the management of patients with CD with complex perianal fistulas.     

Successful management of Crohn's disease of the ileoanal pouch with infliximab.

This study reports the clinical benefit and safety of the murine chimeric anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, infliximab, in the treatment of patients who developed findings compatible with Crohn's disease after undergoing colectomy with ileal-pouch anal anastomosis (IPAA) for an original diagnosis of ulcerative colitis. Medical records of 7 patients with Crohn's disease and an IPAA treated with infliximab were reviewed. Clinical response was classified as complete response, partial response, and no response. Concurrent treatment with immune modifier agents and/or antibiotics was recorded. Seven patients with active inflammatory or fistulizing Crohn's disease and an IPAA performed for diagnosis of ulcerative colitis were treated with infliximab after they had no response to conventional therapies. Patients received 1-4 infliximab infusions at a dose of 5 mg/kg. All patients improved clinically. Six patients had a complete response, and 1 had a partial response. Four of the 5 patients with complex perianal and fistulizing disease had closure of all fistula tracts, and 1 patient improved temporarily. Six of the 7 patients underwent concurrent treatment with immune modifier drugs. One patient had myalgias and malaise after the first infliximab infusion and flu-like symptoms after the second one. No other adverse effects were observed. This case series demonstrates that the murine chimeric anti-TNF-alpha monoclonal antibody, infliximab, can be used successfully to treat patients with Crohn's disease involving an IPAA who are refractory to conventional therapies.     

Treatment of perianal fistulas in Crohn's disease by local injection of antibody to TNF-alpha accounts for a favourable clinical response in selected cases: a pilot study

OBJECTIVE: Intravenously administered infliximab, a monoclonal antibody directed against tumor necrosis factor-alpha, has been proven to be efficacious in the treatment of fistulas in patients with Crohn's disease. It has recently been suggested that local injections of infliximab might be beneficial as well. The aim of this study was to assess whether infliximab could play an effective role in the local treatment of perianal fistulas in Crohn's disease. MATERIAL AND METHODS: Local infliximab injections were administered to 11 patients suffering from Crohn's disease complicated by perianal disease. Eligible subjects included Crohn's disease patients with single or multiple draining fistulas, regardless of status of luminal disease at baseline. Patients, however, were excluded from the study if they had perianal or rectal complications, such as abscesses or proctitis or if they had previously been treated with infliximab. Twenty-milligram doses of infliximab were injected along the fistula tract and around both orifices at baseline and then every 4 weeks for up to 16 weeks or until complete cessation of drainage. No further doses were administered to patients who did not respond after three injections. Efficacy was measured in terms of response (a reduction in fistula drainage of 50% or more) and remission (complete cessation of fistula drainage for at least 4 weeks). Time to loss of response and health-related quality of life were also evaluated. RESULTS: Overall, 8/11 patients (72.7%) responded to the therapy and 4/11 (36.4%) reached remission, whereas 3/11 patients (27.2%) showed no response. Response or remission was very much dependent on the location of the fistulas, and time to loss of response was generally longer for patients who reached remission compared to patients in response. Changes in health-related quality of life, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), also reflected response or remission, with more marked improvements associated with remission. After a mean 10.5 months' follow-up (range 7-18 months), 6/11 patients (54.5%) are in response and 4/11 patients (36.4%) are in remission. No adverse events have been observed in this cohort of patients. CONCLUSIONS: Local injections of infliximab along the fistula tract seem to be an effective and safe treatment of perianal fistulas in Crohn's disease. However, further controlled clinical investigations are warranted.     

Infliximab improves quality of life in the short-term in patients with fistulizing Crohn's disease in clinical practice.

OBJECTIVES: To assess the effect of infliximab on quality of life in a series of patients with fistulizing Crohn's disease. PATIENTS AND METHODS: A prospective observational study was made. A total of 25 patients with single or multiple draining abdominal or perianal fistulas were selected for the study. All received an intravenous infusion of infliximab at a dose of 5 mg per kilogram of body weight in weeks 0, 2, and 6. The clinical activity was calculated every two weeks over a 10-week follow-up. HRQOL (SF-36 and IBDQ scores) were compared at baseline and at weeks 4 and 10. RESULTS: Sixty-four percent of patients had a clinical response to treatment with infliximab, with complete closure of fistulas. The mean values of CDAI decreased during follow-up, with a significant difference between weeks 0 and 10 (p < 0.01). Health-related quality of life (HRQOL), as measured by means of SF-36, showed an overall improvement in the physical domain (PCS) after 4 and 10 weeks (p < 0.05). An increase was also observed in IBDQ overall score on comparing the results obtained at week 0 and week 4 (p < 0.01). The social functioning domain of IBDQ was not significantly changed with treatment. CONCLUSIONS: Treatment with infliximab in active fistulizing Crohn's disease results in a significant increase in the quality of life of patients at short-term.     

Efficacy of cyclosporine in treatment of fistula of crohn's disease

Sixteen Crohn's disease patients with active fistula who had failed standard medical therapy were treated with intravenous cyclosporine. Ten patients had perirectal disease, four had enterocutaneous fistula, and two had rectovaginal fistula. Patients were initially treated with intravenous cyclosporine, 4 mg/kg/day, and then switched to oral cyclosporine, 6–8 mg/kg/day. Improvement was graded using the Present-Korelitz criteria, and success was defined as moderate to total closure of the fistula. Fourteen of 16 patients (88%) responded in the acute phase to parenteral cyclosporine. Closure of fistula occurred in seven (44%) with moderate improvement in the remaining seven (44%). Subsequently, five patients (36%) relapsed to some degree on oral cyclosporine (three severe and two mild relapses). Nine (64%) patients maintained their improvement in the chronic phase. Chronic steroids could be discontinued in 6/8 (75%) of patients. Mild side effects were common [paresthesias (75%) and hirsuitism (19%)]. A single patient had severe paresthesias requiring discontinuation of therapy. Mild hypertension was noted in four (25%) and one patient (6%) had to be withdrawn because of nephrotoxicity, which reversed after stopping cyclosporine. We conclude that intravenous cyclosporine is effective therapy for perianal, rectovaginal, and enterocutaneous fistula in Crohn's disease. Its future role awaits controlled trials as well as determination of the risk-benefit ratio.     

Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn's disease

OBJECTIVES: Although the clinical efficacy of infliximab as measured by closure of fistulas in Crohn's disease has been demonstrated, its influence on the inflammatory changes in the fistula tracks is less clear. The aim of the present study was to assess the behavior of perianal fistulas before and after infliximab treatment. METHODS: Magnetic resonance imaging (MRI) and clinical evaluation were performed in a total of 18 patients before and after treatment with infliximab. An MRI-based score of perianal Crohn's disease severity was developed using both criteria of local extension of fistulas (complexity, supralavetoric extension, relation to the sphincters and of active inflammation (T2 hyperintensity, presence of cavities/abscesses, and rectal wall involvement). RESULTS: The MRI score was reliable in assessing the fistula tracks, with a good interobserver concordance (p < 0.001). Fistula tracks with signs of active inflammation were found in all 18 patients at baseline and collections in seven. After short-term infliximab treatment, active tracks persisted in eight of 11 patients who had clinically responded to infliximab. After long-term (46 wk) infliximab therapy, MRI signs of active track inflammation had resolved in three of six patients. CONCLUSIONS: We have developed an MRI-based score of perianal Crohn's disease severity to assess the anatomical evolution of Crohn's fistulas. Our study demonstrates that despite closure of draining external orifices after infliximab therapy, fistula tracks persist with varying degrees of residual inflammation, which may cause recurrent fistulas and pelvic abscesses. Whether complete fistula fibrosis occurs over time with repeated infliximab infusions needs further study.     

Infliximab for Crohn's disease in clinical practice at the Mayo Clinic: the first 100 patients

OBJECTIVE: The aim of this study was to report the clinical outcome and adverse events in the first 100 patients with refractory inflammatory and/or fistulizing Crohn's disease treated with infliximab at the Mayo Clinic. METHODS: Patient data was abstracted from medical records. Clinical response was classified as complete response, partial response, and nonresponse. RESULTS: Indications for infliximab therapy were: inflammatory disease (61 patients), fistulizing disease (26 patients), or both (13 patients). Patients received one to seven infusions of infliximab (5 mg/kg) for a total of 242 infusions. In all, 50 patients had complete response, 22 had partial response, and 28 had nonresponse. Median time to response was 7 days (range 1-21 days). Median duration of response was 10.3 weeks (range 3-25 wk). A total of 95 patients received concomitant treatment with immune modifiers. Steroid withdrawal was possible in 29/40 patients (73%). Median time of follow-up was 34 wk (range 14-48 wk). Clinically significant adverse events after infliximab included: abscess formation in two patients (perianal, peristomal), pneumonia in two patients, varicella zoster in three patients, candida esophagitis in one patient, and infusion-related reactions in 19 patients. A total of 23 patients were continued on infliximab as maintenance treatment. CONCLUSIONS: This study provides additional evidence that infliximab is safe and beneficial in clinical practice for refractory Crohn's disease.     

Endosonographic evidence of persistence of Crohn's disease-associated fistulas after infliximab treatment, irrespective of clinical response.

PURPOSE: Infliximab has been reported to improve fistulizing Crohn's disease. Moreover, prompt healing of mucosal ulcers has been described. Whether fistulas disappear or remainders of fistulas persist is unknown. This study documents fistulous tracts before and after infliximab therapy by means of hydrogen peroxide-enhanced endosonography METHODS: Eight patients with perianal, vaginal, or perineal fistulas were treated with a triplet of infliximab 5 mg/kg infusions. At baseline, and at Week 4 after the last infusion, fistulas were documented by local inspection, digital examination, and hydrogen peroxide-enhanced anal or vaginal endosonography. RESULTS: Patients with vaginal or perineal fistulas did not respond clinically to therapy, whereas patients with perianal fistulas improved considerably. However, in all patents remainders of fistulous tracts were demonstrated by endosonographic techniques. CONCLUSIONS: Short-term treatment of Crohn's disease-associated fistulas with infliximab does not induce disappearance of fistulous tracts, irrespective of therapeutic response.