Transcending conventional therapies: the role of biologic and other novel therapies

Biologic and other novel therapies targeted to specific pathogenic processes offer the potential for improved treatment outcomes in patients with Crohn's disease and alteration of the course of the disease. Therapies targeted to tumor necrosis factor alpha (TNF-alpha) include anti-TNF-alpha monoclonal antibodies (infliximab and CDP-571), TNF-binding neutralizing fusion proteins (etanercept), and TNF-alpha production inhibitors (thalidomide). In placebo-controlled trials, infliximab has rapidly induced clinical response and remission in patients with moderately to severely active Crohn's disease refractory to conventional therapy and patients with fistulizing Crohn's disease, with minimal toxicity; retreatment with infliximab in patients who experienced an initial response maintained their clinical improvement. Clinical experience suggests that infliximab may also be effective when administered as corticosteroid-sparing therapy. Infliximab is the only anti-TNF-alpha therapy currently available in clinical practice for the treatment of active Crohn's disease. Controlled trials of the investigational anti-TNF-alpha agent CDP-571 show benefit for induction of clinical improvement and steroid-sparing, but further investigation is needed. A pilot study of etanercept suggested a beneficial effect, but its efficacy was not confirmed in a controlled trial. In open-label trials, thalidomide has demonstrated efficacy in patients with refractory Crohn's disease; however, the therapeutic potential of thalidomide may be severely limited by the high incidence of drug-induced side effects. Other novel agents, including anti-alpha4 integrin antibodies, interleukin (IL)-10 and IL-11, and the immunomodulators tacrolimus and mycophenolate mofetil have been evaluated as treatment in patients with severely active or fistulizing Crohn's disease in open-label and controlled trials, with varied results reported to date. The development of these new therapies is an exciting advance that promises to improve the management of Crohn's disease and expand current knowledge of underlying pathophysiologic mechanisms.     

Treatment of Crohn's disease with anti-TNF alpha antibodies (infliximab): results of a multicentric and retrospective study

OBJECTIVE: To evaluate the results of infliximab therapy, an anti-TNF-alpha antibody, in patients with severe and refractory Crohn's disease or with fistulas, treated outside the setting of a therapeutic trial. METHODS: All Crohn's disease patients treated at the Departments of Gastroenterology of the University Hospitals of Bordeaux, Nantes, Poitiers, Rennes and Tours were retrospectively analyzed. RESULTS: Sixty-nine patients were treated with a total of 170 infusions of infliximab, 32 patients being treated for refractory Crohn's disease and 37 for fistulas. The median follow-up was 8 months (extremes 1-20). An objective response was observed in 79% of refractory Crohn's disease patients and 78% of fistulazing patients. A remission was observed in 72% and 70% of the patients respectively. Forty-five percent of patients had relapsed within 4 months (extremes 2-7). Immunosuppressive therapy was associated with a lower relapse rate (18% with versus 56% without, P=0.004). Infliximab resulted in a steroid-sparing effect in 73% of patients. Forty adverse events, none of severe grade, were observed in 22% of the patients, without any influence of steroids or immunosuppressive therapy. CONCLUSION: This study confirms that infliximab is very effective in steroid-dependent and fistulazing Crohn's disease. Infliximab has a steroid-sparing effect and immunosuppressive therapy is associated with a reduced relapse rate. Although the tolerance is good in the short term, long term safety remains to be established by further studies.     

Combining infliximab with 6-mercaptopurine/azathioprine for fistula therapy in Crohn's disease

OBJECTIVES: Fistulas occur in about one third of patients with Crohn's disease and rarely heal spontaneously. Conventional medical and surgical therapy often fails. The anti-TNF-alpha antibody infliximab offers a novel therapeutic option. By this approach, closure of fistulas was reported in 45% of cases. However, after discontinuation of therapy, most fistulas recurred. Azathioprine and 6-mercaptopurine (6-MP) are effective drugs in Crohn's disease and lead to closure of fistulas in 30-40% of cases. Thus, the aim of this study was to evaluate the combination of infliximab with 6-mercaptopurine/azathioprine as therapy for fistulas in patients with Crohn's disease. METHODS: A total of 16 patients (mean age 37 yr) with Crohn's fistulas resistant to conventional measures were treated with a combination of three or four infusions of infliximab and long term 6-MP/azathioprine. In all, 13 patients had perianal fistulas, two had abdominal fistulas, and one patient had both perianal and recto-vaginal fistulas. Therapy success was defined as complete closure of fistulas for a minimum observation period of 6 months after fistula closure. RESULTS: In 12 (75%) of the 16 patients, we observed complete closure of the fistulas that persisted for >6 months (median follow-up 10 months, range 6-11 months). The median time to complete closure of fistulas was 14 days (range 2-36 days). In four patients, therapy success was not achieved. CONCLUSION: Our pilot study reveals that concomitant and long term 6-MP/azathioprine therapy could prolong the effect of an initial infliximab therapy on fistula closure in patients with Crohn's disease. These data prompt larger controlled trials.     

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.     

Infliximab therapy improves the bone metabolism in fistulizing Crohn's disease

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the pathogenesis of inflammatory bowel diseases and bone resorption as well. Limited data exist about the effect of anti-TNF-alpha infliximab on bone metabolism in inflammatory-type Crohn's disease (CD). AIM: Our aim was to evaluate the effect of infliximab treatment on rapid changes of bone metabolism in fistulizing CD patients. METHODS: 27 patients with fistulizing CD were treated with three series of infliximab. Serum osteocalcin (OC) and beta-CrossLaps (bCL) were measured before administration of each infliximab infusion. 54 patients with inactive CD were controls. RESULTS: In treated patients, there were significant differences in bCL concentrations on days 0 and 14 (p < 0.01) and days 0 and 42 (p < 0.05). OC levels increased significantly between day 0 and 42 (p < 0.05). The values of bCL and OC of control groups differed from serum levels in active patients before the treatment, but not on day 42. Bone markers improved significantly in responder patients, but not in non-responders. CONCLUSION: The beneficial effect of infliximab to the bone metabolism is more expressive in patients whose fistulizing disease improves with this therapy. Our results suggest that TNF-alpha has an important role in the alteration of bone metabolism in fistulizing CD patients.     

Infliximab: lack of efficacy on perforating complications in Crohn's disease

BACKGROUND: Infliximab (Remicade), a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF-alpha), has emerged as promising therapeutic option in perianal fistulizing Crohn's disease (CD). However, little knowledge exists about its use for the treatment of internal fistulas in CD. We present our experience with infliximab in this situation. METHODS: Four patients with CD who had internal fistulas (Case 1: entero-enteral and entero-abdominal; Case 2: entero-enteral; Case 3: entero-enteral and parastomal; Case 4: entero-vesical) were treated with 3 infusions of infliximab (5 mg/kg body weight) with intervals of 2 and 4 weeks. In addition, 3 patients had strictures and 2 patients had perianal fistulas. RESULTS: After the three infusions of infliximab (5 mg/kg body weight), internal fistulas remained unchanged in all patients. The perianal fistulas present in 2 cases were healed. Administration of infliximab was safe and well tolerated in all cases. CONCLUSION: Treatment with 3 infusions of infliximab (5 mg/kg body weight) led to healing of only the perianal fistulas, whereas the internal fistulas were not influenced. We conclude that in these 4 cases, infliximab was well tolerated but not effective for the management of internal fistulas and was no alternative for surgery.     

Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease

BACKGROUND & AIMS: Infliximab is effective in closing fistulas in patients with Crohn's disease. We examined the effect of infliximab maintenance treatment on hospitalizations, surgeries, and procedures in patients with fistulizing Crohn's disease enrolled in the ACCENT II study. METHODS: After 5 mg/kg infliximab at weeks 0, 2, and 6, a total of 282 patients were separately randomized at week 14 as responders (at least a 50% reduction from baseline in the number of draining fistulas at both weeks 10 and 14) or nonresponders to receive placebo or 5 mg/kg infliximab maintenance every 8 weeks. At week 22 and later, patients who lost response could be treated with a maintenance dose 5 mg/kg higher. Data on Crohn's disease-related hospitalizations, surgeries, and procedures were compared between the treatment groups for responders and all randomized patients. RESULTS: A total of 282 patients were randomized at week 14, of whom 195 were randomized as responders. Among patients randomized as responders, those who received infliximab maintenance had significantly fewer mean hospitalization days (0.5 vs. 2.5 days; P < .05), mean numbers (per 100 patients) of hospitalizations (11 vs. 31; P < .05), all surgeries and procedures (65 vs. 126; P < .05), inpatient surgeries and procedures (7 vs. 41; P < .01), and major surgeries (2 vs. 11; P < .05), compared with those who received placebo maintenance. CONCLUSIONS: In patients with fistulizing Crohn's disease, infliximab 5 mg/kg every 8 weeks significantly reduced hospitalizations, surgeries, and procedures compared with placebo.     

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.     

Tumour necrosis factor-alpha (TNF-alpha) levels and influence of -308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis

OBJECTIVE: To investigate the influence of -308 tumour necrosis factor-alpha (TNF-alpha) promoter polymorphism and circulating TNF-alpha levels in the clinical response to the infliximab treatment in patients with rheumatoid arthritis (RA). METHODS: One hundred and thirty-two RA patients were genotyped for TNF-alpha promoter by polymerase-chain reaction restriction fragment-length polymorphism (PCR-RFLP) analysis. Ten patients with the -308 TNF-alpha gene promoter genotype G/A, and 10 with the G/G genotype were selected and received 3 mg/kg of infliximab at Weeks 0, 2, 6, and 14. RESULTS: Both groups showed a significant improvement with treatment in all variables studied. Total mean TNF-alpha levels increased significantly with respect to basal levels in most of patients after treatment [probability (p)=0.04]. Only patients from G/A showed a statistically significant correlation between ACR 50 and the increase of TNF-alpha levels (p<0.03). CONCLUSION: A relationship was detected between ACR criteria of improvement and increased circulating TNF-alpha levels in RA patients subjected to anti-TNF-alpha therapy.     

Thalidomide reduces tumour necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn's disease.

BACKGROUND: Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor alpha (TNF-alpha) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated. AIM: The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD). METHODS: Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-alpha, interleukin (IL)-1 beta, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide. RESULTS: Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-alpha and IL-12 decreased during treatment with thalidomide: LPMC (TNF-alpha: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-alpha: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1 beta and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-alpha and IL-12 production. CONCLUSION: The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-alpha and IL-12.     

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.     

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.     

Treatment of rheumatoid arthritis patients with anti-TNF-alpha monoclonal antibody is accompanied by down-regulation of the activating Fcgamma receptor I on monocytes

OBJECTIVES: To study the effect of anti-TNF-alpha therapy on activating IgG Fc receptor (FcgammaR) expression on monocytes of RA patients in relation to changes in disease activity. METHODS: RA patients were treated with anti-TNF-alpha mAb (infliximab). At baseline, 2 and 14 weeks after the start of anti-TNF-alpha treatment, FcgammaR expression levels on circulating monocytes were evaluated. Changes in expression were correlated to changes in disease parameters. To study the direct effects of TNF-alpha blockade on monocytic FcgammaR expression levels, monocytes were isolated and cultured with anti-TNF-alpha mAb. The effects were compared with those induced by TNF-alpha. RESULTS: Two weeks after the start of anti-TNF-alpha mAb therapy, monocytic FcgammaRI expression levels were decreased, whereas FcgammaRIIa and IIIa expression levels were unchanged. At 14 weeks, 8 weeks after the last gift of anti-TNF-alpha mAb, FcgammaRI expression levels returned to baseline levels. FcgammaRIIa and IIIa expression levels remained unchanged. The change in FcgammaRI correlated with changes in CRP and ESR levels. In vitro, anti-TNF-alpha mAb treatment did not alter expression of FcgammaRI on monocytes, but increased FcgammaRIIa and IIIa. TNF-alpha down-regulated all activating FcgammaRs, mainly FcgammaRIIa and IIIa, but also the inhibitory FcgammaRIIb. CONCLUSION: Anti-TNF-alpha mAb treatment of RA patients is accompanied by down-regulation of FcgammaRI expression levels on monocytes. This is likely an indirect effect of TNF-alpha blockade on disease activity, since in vitro anti-TNF-alpha mAb does not directly change FcgammaRI expression on monocytes. In contrast, TNF-alpha down-regulated all activating FcgammaRs. Thus, blocking TNF-alpha may relieve the negative feedback mechanism of TNF-alpha as down-regulator of FcgammaRs. Strategies to reduce activating FcgammaRs may have additional value in the treatment of RA patients with TNF-alpha blockade by diminishing immune complex-mediated activation of monocytes/macrophages.     

Anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis: correlation of TNF-alpha serum level with clinical response and benefit from changing dose or frequency of infliximab infusions

OBJECTIVE: To determine the relationship between serum TNF-alpha level and clinical response in rheumatoid arthritis patients treated by infliximab. This could be of value to predict clinical response to infliximab and to determine the optimal dose and interval between dosing of infliximab. RA patients who did not respond adequately to conventional doses (3 mg/kg) of infliximab were studied to see if increasing the dose or frequency of infliximab infusions would be more effective. METHODS: Fifty-five RA patients who fulfilled the American College of Rheumatology criteria and were receiving treatment by anti-TNF-alpha (infliximab 3 mg/kg body weight every 8 weeks) were evaluated by: clinical disease activity using the Richie score index before receiving their scheduled infliximab infusion. Serum level of TNF-alpha, as measured by competitive ELISA assay, was determined immediately before and 9-11 days after receiving infliximab. RA patients who did not respond adequately to treatment with infliximab were given either a larger dose of infliximab or given the infusion at six-week intervals. Their clinical response was then evaluated sixteen months later. RESULTS Patients were divided into 2 groups according to Richie score, active group with score > 10 (score 20.3 +/- 7.7 mean +/- standard deviation, n = 25) and inactive group with scores < or = 10 (score 4.1 +/- 3.2, n = 30). TNF-alpha serum levels pre-infliximab infusion were significantly higher in the active group 76.1 pg/ml than the inactive group 38.0 pg/ml (P < 0.02). Whereas TNF serum level significantly dropped post infliximab in the inactive group (P < 0.05), it did not drop in the active group. The mean level of the post-infusion TNF-alpha serum level was higher (76.6 +/- 93.4 ng/ml) in the-active than the mean level of the post-infusion serum TNF-alpha levels in the inactive group (26.4 ng/ml +/- 7.9) P < 0.01 using the t-test. Increasing the frequency was superior in RA patients' clinical outcome than increasing the dose of infliximab infusions. CONCLUSION: RA patients who responded well to infliximab and had inactive disease at the time of the study have lower levels of serum TNF-alpha which could be further suppressed by the recommended doses of infliximab. RA patients with active disease have higher serum levels of TNF-alpha which could not be suppressed after the recommended doses of infliximab infusion. Changing the frequency of infliximab infusions in the active group was more effective than increasing the dose of infliximab in inducing improved clinical outcome. We suggest that the lack of suppression of TNF-alpha in the active group could be due to inadequate dosing of infliximab or to the presence of a neutralizing antibody directed against infliximab. It remains to be seen if serum TNF-alpha levels could be used as a guide in determining the dose and intervals between dosing of anti-TNF therapy in RA in order to achieve the desired clinical response.     

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.     

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.     

Increased production of tumour necrosis factor-alpha interleukin-1 beta, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease.

BACKGROUND: Increasing evidence points to a important role for inflammatory cytokines for the pathogenesis of Crohn's disease. AIM: To compare the secretion rate of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) by morphologically normal and inflamed intestinal mucosa from patients with Crohn's disease. RESULTS: Organ cultures of intestinal biopsy specimens taken from areas of affected mucosa from patients with Crohn's disease spontaneously produced increased amounts of TNF-alpha, IL-1 beta, and IL-6 compared with controls but also biopsy specimens taken in macroscopically and microscopically unaffected areas in the same patients. Concentrations of IL-1 beta and IL-6 measured in the supernatant fluid of biopsy cultures were positively correlated with the degree of tissue involvement measured by both endoscopic and histological grading. By contrast, TNF-alpha concentrations were not correlated to endoscopic and histological grading. CONCLUSIONS: These consistently raised TNF-alpha, IL-1 beta and IL-6 secretions by normal appearing mucosa from patients with Crohn's disease provide evidence for a sustained immune stimulation in Crohn's disease even in the absence of patent inflammation. The results shed a new light on the role of inflammatory cytokines in the onset of intestinal tissue damage in Crohn's disease and suggest that the range of intestinal lesions in Crohn's disease may be wider than suspected on the basis of regular endoscopic and histological examinations.     

Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series

OBJECTIVE: Although tumor necrosis factor-alpha (TNF-alpha) antagonists are effective in the treatment of refractory psoriasis, some cases have suggested that psoriasis might be induced as a result of treatment prescribed mainly for rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. To investigate anti-TNF-alpha induced psoriasis, we conducted a systematic analysis of the 6 cases we observed among our inflammatory patient cohort treated with anti-TNF-alpha (infliximab or etanercept). METHODS: We report 6 cases of psoriasis with onset during TNF-alpha antagonist therapy (infliximab and etanercept); characteristics and skin lesions are described. RESULTS: No patient had a personal or family history of psoriasis. The development of psoriasis was seen in all the types of inflammatory diseases we treated with TNF-alpha antagonists. There was great variation in the age of affected patients and in the onset of psoriasis after initiation of TNF-alpha antagonists. Both TNF-alpha antagonists studied were associated with development of psoriasis. In 2 cases psoriasis was associated with 2 different TNF-alpha antagonists in the same patient. In half our patients, skin lesions started in the inguinal and pubic regions, but palmoplantar pustulosis was also common. In half the cases, skin lesions responded favorably with topical agents despite continuation of TNF-alpha antagonist therapy. CONCLUSION: In light of previously published cases describing psoriasis or psoriasiform lesions after TNF-alpha antagonist therapy, our series strongly confirms that TNF-alpha antagonists may induce psoriasis in some patients. Further studies are needed to identify risk factors for TNF-alpha antagonist induced psoriasis.     

Combining infliximab with methotrexate for the induction and maintenance of remission in refractory Crohn's disease: a controlled pilot study

OBJECTIVES: Immunosuppression of chronic active Crohn's disease resistant or intolerant to purine antimetabolites still remains a clinical challenge. To obtain long-lasting effects with the anti-TNF-alpha antibody infliximab repeated infusions are often required. Methotrexate has been shown to be a moderately effective drug in maintaining remission in Crohn's disease. The aim of the present pilot study was to evaluate the combination of infliximab and methotrexate as therapy for refractory Crohn's disease. METHODS: Nineteen patients with chronic active Crohn's disease resistant or intolerant to azathioprine were enrolled. Patients received either two infusions of infliximab (5 mg/kg) alone (n=8) or in combination with long-term methotrexate at a dosage of 20 mg/week (n=11) over 48 weeks. RESULTS: Two out of eight patients receiving infliximab monotherapy and four out of 11 patients treated with infliximab and concomitant methotrexate had discontinued study treatment by week 48, solely because of lack of efficacy. Clinical remission at week 48 was observed in five out of seven patients treated with infliximab and methotrexate, but only in two out of six patients receiving infliximab monotherapy. In addition, patients treated with concomitant methotrexate achieved remission earlier (median time 2 versus 18 weeks) and needed fewer steroids (median prednisolone dose 0 versus 11.8 mg). Despite an increased mean number of adverse events per patient in the methotrexate group, the proportions of patients experiencing any adverse events and serious adverse events were similar across treatment groups. CONCLUSIONS: The combination of infliximab with long-term methotrexate may be a promising concept in refractory Crohn's disease. Our data prompt larger trials.     

Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy

OBJECTIVE: With rising numbers of anti-tumour necrosis factor alpha (TNF-alpha) treatments for rheumatoid arthritis (RA), Crohn's disease and other conditions, physicians unaware of potential pitfalls are increasingly likely to encounter associated severe infections. Our purpose was to assess the incidence and nature of severe infections in our RA patients under anti-TNF-alpha therapy. METHODS: We reviewed patient charts and records of the Infectious Disease Unit for serious infections in patients with RA in the 2 yr preceding anti-TNF-alpha therapy and during therapy. RESULTS: Serious infections affected 18.3% of patients treated with infliximab or etanercept. The incidence was 0.181 per anti-TNF-alpha treatment year vs 0.008 in the 2 yr preceding anti-TNF-alpha therapy. In several cases, only a few signs or symptoms indicated the severity of developing infections, including sepsis. CONCLUSIONS: A high level of suspicion of infection is necessary in patients under anti-TNF-alpha therapy. We suggest additional strategies for the prevention, rapid identification and pre-emptive therapy of such infections.