Remicade does not abolish the need for surgery in fistulizing Crohn's disease

PURPOSE: Tumor necrosis factor antagonist therapy in the form of infliximab has been shown to promote significant healing in fistulizing Crohn's disease and therefore is often considered as a possible alternative to surgery. Our aim was to evaluate the role of infliximab in supplanting surgery for fistulizing Crohn's disease. METHODS: We performed a retrospective chart review of all adult patients who received infliximab for fistulizing Crohn's disease at one institution between September 1998 and October 2000. RESULTS: Twenty-six patients (14 male; mean age, 38 years; range, 19-80 years) received a mean of three (range, one to six) doses of infliximab (5 mg/kg) with the intent to cure fistulizing Crohn's disease. Nine patients (35 percent) had perianal, 6 (23 percent) enterocutaneous, 3 (12 percent) rectovaginal, 4 (15 percent) peristomal, and 4 (15 percent) intra-abdominal fistulas. Nineteen (73 percent) of the patients had had prior surgery for Crohn' s disease. Six patients (23 percent) had a complete response to infliximab with fistula closure, 12 (46 percent) had a partial response, and 8 (31 percent) had no response to infliximab. Fourteen (54 percent) patients still required surgery for their fistulizing Crohn's disease after infliximab therapy (10 bowel resections, 4 perianal procedures), whereas half (6/12) of the patients treated with infliximab who still had open fistulas after treatment declined surgical intervention. Five of six patients with fistula closure on infliximab had perianal or rectovaginal fistulas. None of the patients with either enterocutaneous or peristomal fistulas were healed with infliximab. CONCLUSIONS: Although it was associated with a 61 percent complete or partial response rate, infliximab therapy did not supplant the need for surgical intervention in the majority of our patients with fistulizing Crohn's disease. Seventy-three percent of the patients either required surgery or still had open fistulas after infliximab therapy. Infliximab was much more effective in treating perianal disease than abdominal enterocutaneous disease.     

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.     

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.     

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.     

Effect of infliximab in the treatment of refractory inflammatory bowel disease with complication]

BACKGROUND/AIMS: Many studies on infliximab have confirmed its efficacy in the remission induction and even maintenance in refractory and fistulizing Crohn's disease. We report the treatment efficacy of infliximab in Crohn's disease and ulcerative colitis refractory to steroid treatment and the complications of infliximab treatment. METHODS: We performed infliximab administration in 5 cases (3 Crohn's disease, 2 ulcerative colitis) refractory to systemic steroid treatment and 5 cases of Crohn's disease with fistula. Patients received an intravenous infusion of infliximab at 3-5 mg/kg body weight. RESULTS: In 3 cases of refractory Crohn's patients, clinical response and remission induction were obtained in 2 (67%) and 1 cases (33%). After infusion of infliximab, the occlusion of internal fistula could be found in all 2 cases. Two out of 3 cases of anal fistula were completely healed. In two cases of refractory ulcerative colitis, one case who showed clinical manifestation of toxic megacolon had improved and avoided the colectomy, but the other case did not respond to the infusion of infliximab and underwent colon resection. CONCLUSIONS: We found that administration of infliximab is an effective alternative for refractory and fistulizing Crohn's disease but further studies are necessary for refractory ulcerative colitis.     

Infliximab in treatment of Crohn''s disease: the Milan experience

BACKGROUND: Efficacy of infliximab in treatment of patients with moderate-to-severe refractory and fistulizing Crohn's disease has been shown in controlled clinical trials. Moreover, audit data from North America and North Europe have confirmed efficacy in clinical practice comparable to that in clinical trials. AIM: To report clinical experience using infliximab in treatment of Crohn's disease in Italy, comparing efficacy and safety with those reported in clinical trials and other published series. PATIENTS AND METHODS: The study population comprised 63 patients (31 males and 32 females, median age 33 years) treated with infliximab for refractory/inflammatory (31 patients) and/or fistulizing Crohn's disease (32 patients). All patients received an infusion of infliximab at a dose of 5 mg/kg at weeks 0, 2 and 6. After the first infusion, clinical and laboratory assessments were repeated at weeks 2, 6 and 10. For refractory inflammatory Crohn's disease, clinical remission was defined as a Crohn's Disease Activity Index of < or = 150 at each scheduled visit, clinical response as a reduction in the Crohn's Disease Activity Index score of > or = 70 points in comparison to baseline. For fistulizing Crohn's disease, a complete response was defined as closure of any draining fistulae at week 10. A fistula was defined as closed when it no longer drained despite gentle finger pressure. A partial response was defined as reduction in number, size or drainage of fistulae, at the same visit. RESULTS: According to an intention-to-treat evaluation on the 31 patients with refractory/inflammatory Crohn's disease, at week 2, 42.5% (14 patients) had a clinical response and 31.3% of patients (10 patients) were in clinical remission. At week 10 (4 weeks after the end of third infusion), 80.6% (25 patients) had a clinical response and 71% (22 patients) were in clinical remission and 14/19 (74%) had discontinued steroid treatment. Of the 32 patients with fistulizing Crohn's Disease, 15 (46.9%) had a complete response, 8 (25%) a partial response, and 9 (28.1%) no response at week 10 check-up. The incidence of side-effects was low (16%) and not influenced by concurrent immunomodulatory therapy. CONCLUSION: The present experience with infliximab in clinical practice confirms its efficacy, in particular in inflammatory/refractory Crohn's disease and its safety, at least, in short-term follow-up.     

Does Infliximab Infusion Impact Results of Operative Treatment for Crohn’s Perianal Fistulas?

PURPOSE: Infliximab is an effective treatment for active intestinal Crohn's disease; however, the efficacy of infliximab in perianal Crohn's disease is controversial. This study was designed to compare patients with Crohn's disease who underwent perianal fistula surgery with or without infliximab infusion. METHODS: A retrospective chart review of 226 consecutive patients with Crohn's disease who underwent operative treatment with or without infliximab (3-6 infusions of 5 mg/kg) from March 1991 through December 2005 was completed. Patients were classified as completely healed, minimally symptomatic (seton placement with minimal drainage and/or infliximab dependence), and failure (persistent or recurrent symptomatic fistula, diverting procedure, or proctectomy). RESULTS: A total of 226 patients underwent operative treatment alone (n = 147) or in combination with infliximab infusion (n = 79). Age, gender, and preoperative history of intestinal and perianal Crohn's disease were similar between groups. Mean follow-up was 30 (range, 6-216) months. Operative treatment consisted of seton drainage (n = 112), conventional fistulotomy (n = 92), fibrin glue injection (n = 14), advancement flap (n = 5), collagen plug insertion (n = 2), and transperineal repair (n = 1). Eighty-eight patients (60 percent) healed completely with operative treatment alone, and 47 patients (59 percent) healed after operative treatment in combination with infliximab (P = not significant). CONCLUSIONS: Operative treatment of perianal fistulas in patients with Crohn's disease resulted in complete healing in approximately 60 percent of patients. Preoperative infliximab infusion did not affect overall healing rates.     

Efficacy and safety of repeated infliximab infusions for Crohn's disease: 1-year clinical experience

Data from clinical trials suggest the efficacy of the chimeric tumor necrosis factor alpha monoclonal antibody infliximab in improving clinical, endoscopic, and histologic outcomes in patients with moderately to severely active Crohn's disease (CD) and fistulizing CD. To determine whether the efficacy and safety record of infliximab reported in clinical trials would be reflected in clinical use, clinical experience with infliximab was assessed in patients with CD at the University of Chicago, Chicago, Illinois. All patients with CD at this institution receiving infliximab in the first year of its release were prospectively followed up for 1 year. Disease activity was scored at the time of the initial infusion and at 1, 3, 7, and 12 weeks after infusion. Results were analyzed separately for patients with luminal or fistulous CD. Clinical response, remission, corticosteroid tapering, and adverse event data were collected. A total of 129 patients with luminal (n = 81) or fistulous (n = 48) disease received a mean of 2.38 and 3.23 infusions of infliximab per patient, respectively. After the initial infusion course, clinical response and remission rates at 3 weeks were 65% and 31% for patients with luminal disease and 78% and 24% for patients with fistulous disease, respectively. Clinical response and remission after the first infusion occurred at a median of 8 days and 9 days, respectively. In those patients who subsequently relapsed, relapses occurred after a mean of 8.5 weeks and 12.2 weeks in patients with luminal and fistulizing disease, respectively. Corticosteroid tapering was possible in > 90% of patients (luminal disease) after the initial infusion and complete withdrawal in 54% after the second infusion, with a sustained median steroid dose of 0 mg from the 4-month time-point onward. Infusion reactions or adverse events occurred in 5-13% of patients during or immediately after the initial infusion of infliximab; most were mild and easily managed and did not increase in incidence with subsequent infusions. Clinical experience with infliximab closely mirrors the findings of controlled clinical trials. Repeated administration of infliximab was efficacious and relatively well tolerated in patients with CD and demonstrated corticosteroid-sparing benefits.     

Efficacy and safety of treatment with infliximab in Crohn's disease-the experience of single center in Korea]

BACKGROUND/AIMS: Infliximab has been shown to be effective and safe for treating refractory luminal and fistulizing Crohn's disease (CD). The aim of this study was to report the efficacy and adverse effect of infliximab therapy in patients with CD at our center. METHODS: Medical records of thirteen patients who were treated with infliximab for refractory luminal or fistulizing CD were reviewed. Clinical response was classified as complete response, partial response and nonresponse. RESULTS: Seven patients were treated for fistulizing CD, four patients for luminal CD, and two for both. The mean time of follow-up was 13.1 months (3.3-28.1 months). Clinical response was seen in 10/13 (77%); complete response 7/13 (54%), partial response 3/13 (23%), nonresponse 3/13 (23%). Mean time to response was 27.1 days (10-41 days). 4 of 10 responders (40%) maintained remission over 30 weeks. Those who started on immunosuppressive treatment more than 3 months before infliximab infusion achieved lower early recurrence rate (14%) compared with those less than 3 months (67%) (p=0.039). Steroid tapering was successful in 7/12 (58%). Five patients required surgical therapy; three nonresponders, one partial responder and one who recurred after initial complete response. Initial responders required less surgery than nonresponders (p=0.035). Acute infusion reactions were seen in 2/40 infusions (5%). One patient developed herpes zoster 20 weeks after infliximab infusion. During follow-up peried, no patient developed serious infection, tuberculosis or malignancy. CONCLUSIONS: Infliximab is effective and safe in clinical practice. Concurrent immunosuppressive use is associated with lower rate of early recurrence.     

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.     

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.     

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.     

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.     

Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn's disease

OBJECTIVE: Infliximab is an effective treatment for refractory or fistulizing Crohn's disease (CD). However, about 30% of patients do not respond to infliximab for unknown reasons. Identifying predictive factors of response is important for optimizing clinical management and for better understanding infliximab's mechanisms of action. The aim of this study was to assess whether demographic or clinical parameters influence short-term response to infliximab. METHODS: The first 240 CD patients of the Belgian Infliximab Expanded Access Program were studied for response to infliximab treatment and assessed at 4 (refractory luminal CD) or 10 wk (fistulizing CD) after the first infusion. Detailed demographic and clinical information on age, sex, type of disease (fistulizing or refractory), Crohn's Disease Activity Index score, C-reactive protein (CRP), smoking habits, disease duration, localization of disease, concomitant medication, and previous surgery were obtained from all patients. Logistic regression and decision tree analysis were performed. RESULTS: There were 73.5% responders and 26.5% nonresponders to treatment. Stepwise logistic regression identified age (OR = 0.971, 95% CI = 0.947-0.995, p = 0.018), isolated ileitis (OR = 0.359, 95% CI = 0.177-0.728, p = 0.004), and previous surgery (OR = 0.429, 95% CI = 0.233-0.787, p = 0.006) as inversely correlated with response, whereas isolated colitis (OR = 1.905, 95% CI = 1.010-3.597, p = 0.046) and concomitant immunosuppressive treatment (OR = 2.670, 95% CI = 1.430-5.016, p = 0.0022) were positively correlated with response to infliximab. Surprisingly, smoking habits were not retained as predictors for response. Decision tree analysis provided a working algorithm based on age and immunosuppressive treatment that warrants further exploration. CONCLUSIONS: In this large cohort of infliximab-treated CD patients, young age, Crohn's colitis, and concomitant immunosuppressive treatment were identified as independent variables favoring short-term response to infliximab.     

Infliximab in the treatment of Crohn''s disease: Predictors of response in an Italian multicentric open study

BACKGROUND: Almost 20% of patients with active Crohn's disease are refractory to conventional therapy. Infliximab is a treatment of proven efficacy in this group of patients and it is not clear which variables predict a good response. AIMS.: To evaluate the role of infliximab looking at the predictors of response in a large series of patients with Crohn's disease. PATIENTS AND METHODS: Five hundred and seventy-three patients with luminal refractory Crohn's disease (Crohn's Disease Activity Index (CDAI)>220-400) (312 patients) or with fistulising disease (190 patients) or both of them (71 patients) were treated with a dose of 5 mg/kg in 12 Italian referral centres. The primary endpoints of the study were clinical response and clinical remission for luminal refractory and fistulising disease. We evaluated at univariable and multivariable analysis the following variables: number of infusions, sex, age at diagnosis, smoking habit, site of disease, previous surgery, extraintestinal manifestations and concomitant therapies, and type of fistulas. RESULTS: Patients with luminal refractory disease: 322 patients (84.1%) had a clinical response and 228 (59.5%) reached clinical remission. Patients with fistulising disease: 187 patients (72%) had a reduction of 50% of the number of fistulas and in 107 (41%) a total closure of fistulas was observed. For luminal disease, single infusion (OR 0.49, 95% CI 0.28-0.86) and previous surgery (OR 0.53, 95% CI 0.30-0.93) predicted a worse response for fistulising disease. Other fistulas responded worse than perianal fistulas (OR 0.57, 95% CI 0.303-1.097). CONCLUSION: In Crohn's disease infliximab is effective in luminal refractory and in fistulising disease. A single infusion and previous surgery predicted a worse response in luminal disease whereas perianal fistulas predicted a better response than other type of fistulas.     

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.     

Type of fistula determines response to infliximab in patients with fistulous Crohn's disease

OBJECTIVES: Infliximab has been shown to be efficacious for treating perianal fistulae in patients with Crohn's disease. There is limited information regarding response to infliximab in patients with other types of fistulae. METHODS: Sixty consecutive patients with fistulous Crohn's disease and at least three months of follow-up after three infliximab infusions were evaluated. Patients with enteroenteric fistulae were excluded. Complete response was defined as complete closure of the fistulae or complete cessation of fistula drainage. RESULTS: Thirty-five patients had external fistulae, 16 had internal fistulae, and 9 had mixed (both external and internal) fistulae. Complete response rates were significantly higher in patients with external fistulae (69%) compared to those with internal fistulae (13%); p= 0.001, or those with mixed fistulae (11%); p= 0.01. In the external fistula group, patients with perianal fistulae had a higher rate of complete response (78%) compared to those with abdominal wall fistulae (38%); p= 0.04. The rate of complete response to infliximab was significantly lower among 14 patients with rectovaginal fistulae (14%) compared to those with perianal fistulae (78%); p= 0.0007. In the mixed fistula group only 11% of the patients achieved complete response. This is significantly lower than the rate observed for patients with perianal fistulae (78%); p= 0.004. The Cox proportional hazards model showed that the hazard of relapse for smokers who achieved complete response was nearly twice that of nonsmokers; however, this difference did not reach statistical significance. CONCLUSION: There is an association between type of fistulae and complete response to infliximab in patients with fistulous Crohn's disease. External fistulae in general and perianal fistulae in particular have a higher rate of closure in response to infliximab compared to other types of fistulae.     

Immunomodulators and "on demand" therapy with infliximab in Crohn's disease: clinical experience with 400 infusions

OBJECTIVES: Infliximab has been proven effective for treatment of active Crohn's and fistulizing Crohn's disease. We reviewed our experience with infliximab in patients with Crohn's disease to determine if its combination with immunomodulators leads to better response and longer periods of disease quiescence. METHODS: We performed a retrospective chart review of 122 patients with Crohn's disease who received infliximab infusions. Data were collected on patient demographics, clinical response to infliximab, fistula response, prednisone dose, infusion reactions/side effects, concomitant immunomodulator therapy, and time intervals between infliximab infusions. RESULTS: Of 122 patients receiving infliximab infusions, 117 completed more than 2 wk of follow-up (400 infusions), and five patients had no follow-up. Co-therapies included azathioprine (AZA) in 47 (40.2%) patients, 6-mercaptopurine (6-MP) in 11 (9.4%), methotrexate (MTX) in 23 (19.7%), prednisone in 64 (54.7%), mesalamine in 51 (43.6%), and antibiotics in 16 (13.7%). Mean follow-up was 52 wk (14-864 days). Overall response rate to infliximab was similar between patients receiving immunomodulators (AZA/6-MP 87.9%, MTX 82.6%) and patients receiving infliximab alone (75%), although there was a trend toward higher response with AZA/6-MP (p = 0.10). More frequent drug reactions/side effects occurred in the infliximab alone group (22.2%) compared with patients receiving MTX (13.0%) and AZA/6-MP (13.8%), but this was not statistically significant. Prednisone dosage was reduced from a mean of 19.5 mg to 7.5 mg per day overall (p < 0.05). Fistula response and dosing intervals were not affected by concomitant immunosuppression. CONCLUSIONS: Concomitant use of immunomodulators with infliximab in patients with Crohn's disease did not improve patient response to several parameters measured, including clinical response rate, dose reduction of prednisone, fistula response, and mean intervals between infliximab infusions.     

Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease

OBJECTIVES: The use of monoclonal anti-tumor necrosis factor (TNF) antibodies (infliximab, Remicade) is a new therapeutic approach for severe refractory luminal or fistulizing, Crohn's disease (CD). However, up to 30% of patients do not respond to this treatment. So far, no parameters predictive of response to anti-TNF have been identified. Our aim was to determine whether serological markers ASCA (anti-Saccharomyces cerevisiae antibodies) or pANCA (perinuclear antineutrophil cytoplasmic antibodies) could identify Crohn's patients likely to benefit from anti-TNF therapy. METHODS: Serum samples of 279 CD patients were analyzed for ASCA and pANCA before anti-TNF therapy. A blinded physician determined clinical response at week 4 (refractory luminal CD) or week 10 (fistulizing CD) after the first infusion of infliximab (5 mg/kg). RESULTS: Overall, there was no relationship between ASCA or pANCA and response to therapy. However, lower response rates were observed for patients with refractory intestinal disease carrying the pANCA+/ASCA- combination, although this lacked significance (p = 0.067). CONCLUSIONS: In this cohort of infliximab-treated patients, neither ASCA nor pANCA could predict response to treatment. However, the combination pANCA+/ASCA- might warrant further investigation for its value in predicting nonresponse in patients with refractory luminal disease.     

Inflammatory Bowel Disease A Positive Response to Infliximab in Crohn Disease: Association with a Higher Systemic Inflammation Before Treatment But Not With -308 TNF Gene Polymorphism

Background: Two-thirds to three-fourths of patients with either refractory luminal or fistulizing Crohn disease respond to infliximab treatment. The ability or inability to respond seems to persist over time. Biological characteristics and/or genetic background can influence the response to treatment. The aim was to assess the value of C-reactive protein and TNF- α serum levels before treatment as well as the TNF -308 gene polymorphism in the prediction of response to infliximab treatment in Crohn disease. Methods: Two-hundred-and-twenty-six Crohn disease patients treated in the setting of an expanded access programme to infliximab in Belgium were studied. There were 136 refractory luminal diseases and 90 refractory fistulizing diseases. Luminal diseases were treated with one single infusion; fistulizing diseases with three infusions at weeks 0, 2 and 6. A clinical response to treatment was defined as either a Crohn disease activity index <150 (complete) or a drop of 70 points (partial) at week 4, for luminal disease, and as either complete fistula healing (complete) or a decrease of at least 50% of the number of draining fistulas on two consecutive visits between weeks 0 and 18, for fistulizing disease. CRP and serum TNF- α levels were measured at week 0 before treatment and were compared between responders and non-responders. Patients were genotyped for the-308 TNF gene polymorphism, and allelic as well as genotype frequencies were compared between responders and non-responders. Results: There were 73.2% responders (46.4% complete and 26.8% partial) and 26.8% non-responders. Response rates were similar in luminal and fistulizing diseases. CRP level before treatment was significantly higher in responders than in non-responders (16.8 mg/l (5-160) versus 9.6 mg/l (5-143); P = 0.02). Furthermore, response rate was significantly higher in patients with elevated CRP (>5 mg/l) than in patients with a normal CRP value (<5 mg/l) before treatment (76% versus 46%; P = 0.004; OR: 0.26 (0.11-0.63)). Allelic and genotype frequencies for-308 TNF gene polymorphism were not significantly different between responders and non-responders - with the exception of a slightly higher TNF2 frequency in nonresponders in luminal disease (22.1% versus 11.6%; P = 0.04). However, this was not associated with a significant difference in genotype frequencies. Conclusion: A positive clinical response to infliximab was associated with a higher CRP level before treatment in our population of Crohn disease patients, but there was no relevant association with-308 TNF gene polymorphism. We therefore suggest that CRP level may help to identify better candidates for infliximab treatment.