The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy.

BACKGROUND: Adalimumab induces and maintains remission in adults with Crohn's disease. AIM: To evaluate safety, fistula healing, quality of life and work productivity in adalimumab-treated patients who failed infliximab, including primary nonresponders. METHODS: After a ≥8-week infliximab washout, patients with moderate-to-severe Crohn's disease received open-label adalimumab as induction (160/80 mg at weeks 0/2) and maintenance (40 mg every other week) therapies. At/after 8 weeks, patients with flare/nonresponse could receive weekly therapy. Minimum study duration was 8 weeks, continuing until the commercial availability of adalimumab for Crohn's disease. RESULTS: Of 673 patients enrolled, 17% were infliximab primary nonresponders and 83% were initial responders. Three percent of patients had serious infections (mainly abscesses). Complete fistula healing was achieved by 34/88 (39%) patients with baseline fistulas. Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients, as well as the subgroup of primary nonresponders. CONCLUSIONS: Blinded clinical trials have shown adalimumab to be both an effective first-line therapy for anti-TNF-naïve patients and an important treatment option for infliximab-refractory or -intolerant patients. This trial presents open-label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy, including primary nonresponders (NCT00338650).

Withdrawal of corticosteroids in inflammatory bowel disease patients after dependency periods ranging from 2 to 45 years: a proposed method.

BACKGROUND: Even in the biologic era, corticosteroid dependency in IBD patients is common and causes a lot of morbidity, but methods of withdrawal are not well described. AIM: To assess the effectiveness of a corticosteroid withdrawal method. METHODS: Twelve patients (10 men, 2 women; 6 ulcerative colitis, 6 Crohn's disease), median age 53.5 years (range 29-75) were included. IBD patients with quiescent disease refractory to conventional weaning were transitioned to oral dexamethasone, educated about symptoms of the corticosteroid withdrawal syndrome (CWS) and weaned under the supervision of an endocrinologist. When patients failed to wean despite a slow weaning pace and their IBD remaining quiescent, low dose synthetic ACTH stimulation testing was performed to assess for adrenal insufficiency. Multivariate analysis was performed to assess predictors of a slow wean. RESULTS: Median durations for disease and corticosteroid dependency were 21 (range 3-45) and 14 (range 2-45) years respectively. Ten patients (83%) were successfully weaned after a median follow-up from final wean of 38 months (range 5-73). Disease flares occurred in two patients, CWS in five and ACTH testing was performed in 10. Multivariate analysis showed that longer duration of corticosteroid use appeared to be associated with a slower wean (P = 0.056). CONCLUSIONS: Corticosteroid withdrawal using this protocol had a high success rate and durable effect and was effective in patients with long-standing (up to 45 years) dependency. As symptoms of CWS mimic symptoms of IBD disease flares, gastroenterologists may have difficulty distinguishing them, which may be a contributory factor to the frequency of corticosteroid dependency in IBD patients.

Inflammatory bowel disease related osteonecrosis: report of a large series with a review of the literature.

BACKGROUND: Osteonecrosis is a major complication of inflammatory bowel disease usually associated with steroid use. There are few large series available detailing the specifics of affected patients. AIM: To identify any specific characteristics of osteonecrosis in this cohort. A major focus was placed on steroid dose, the average time between diagnosis of IBD and appearance of osteonecrosis and the frequency of multiple joint involvement. METHODS: Our study identified 23 patients in the practices of five gastroenterologists at the Mount Sinai Medical Center. We retrospectively reviewed their clinical history, as well as imaging studies. We classified osteonecrosis according to the Association Research Circulation Osseous (ARCO) staging system. RESULTS: Although our prednisone dosing data could not be used as an accurate predictor of onset or joint distribution, there was a tendency for correlation between the average daily dosing and the ARCO score. The ARCO scoring system was consistent for patients with bilateral hip involvement. The distribution of affected joints in IBD is similar to other conditions associated with osteonecrosis, with hips being the most frequently involved joints. Data showed bilateral involvement in most hips, but usually unilateral disease in the shoulders and knees. Treatment options include core decompression for early stages, whereas joint replacement surgery is required for stages 3 and 4. CONCLUSION: IBD predisposes patients to corticosteroid induced osteonecrosis. An exact threshold dose has not been determined. The data suggests that either long term therapy or short term high dose treatment increases the risk of osteonecrosis. Even if symptoms are limited to one joint, multiple joints are often involved and comprehensive testing with MRI is indicated in all cases.

Fistula response to methotrexate in Crohn's disease: a case series.

BACKGROUND: Controlled trials have demonstrated the efficacy of methotrexate in the induction and maintenance of remission in luminal Crohn's disease; however, its effect on fistulizing disease is unknown. AIM: To describe the response to methotrexate therapy in a series of patients with fistulizing Crohn's disease. METHODS: A retrospective chart review was conducted of all patients with Crohn's disease receiving methotrexate in one practice. The response of patients with fistulizing and luminal disease was assessed using clinical and laboratory criteria. Fistula response was categorized as either complete or partial closure. RESULTS: Thirty-seven courses of methotrexate therapy were given to 33 patients with luminal and/or fistulizing Crohn's disease. In 16 patients with fistulas, four (25%) had complete closure, five (31%) had partial closure and all had failed or were intolerant to 6-mercaptopurine therapy. Overall, response to methotrexate was seen in 23 of 37 (62%) treatment courses in patients with luminal and/or fistulizing Crohn's disease. Two of the 33 patients (6%) had a significant adverse event. CONCLUSIONS: In this case series, 56% of patients with Crohn's fistulas on methotrexate showed a complete or partial response to therapy. Further studies are needed to confirm the role of methotrexate alone, and in combination with other therapies, for the treatment of fistulizing Crohn's disease.

Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.

Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesalamine.

An 18-year-old woman with ulcerative colitis (UC) developed diffuse pulmonary infiltrates and hypoxemia three months after reinstitution of oral mesalamine. Lung biopsy revealed bronchiolitis obliterans with interstitial pneumonitis. Clinical and radiographic abnormalities improved upon discontinuation of mesalamine and treatment with corticosteroids. This patient presented the problem of differential diagnosis of pulmonary disease associated with inflammatory bowel disease (IBD), including lesions believed to result from lung involvement secondary to IBD, as well as adverse reactions to medications. We present and analyze evidence associating mesalamine with pulmonary toxicity in this patient, but emphasize that the distinction between adverse drug reaction and extraintestinal manifestations of IBD is difficult.

Neutropenia is not required for clinical remission during azathioprine therapy in inflammatory bowel disease.

Inflammatory bowel disease is an idiopathic chronic inflammatory process of the gastrointestinal tract. The aetiology remains unknown but probably involves a combination of genetic susceptibility, environmental triggers and abnormal immune regulation. Immunomodulators are effective in treating inflammatory bowel disease. Azathioprine and 6-mercaptopurine (6MP) are the most frequently used immunomodulator agents. These agents are probably underused by many clinicians because of concerns about myelosuppression, pancreatitis, allergic reactions and hepatotoxicity, which can occur in a fraction of patients taking these drugs. Therefore, clinicians have sought ways to optimize therapeutic response and limit toxic side effects. Neutropenia, although uncommon, can occur in patients taking azathioprine or 6MP. The question of neutropenia effecting clinical response has been raised as a possible indicator of therapeutic response. In the study from Campbell and Ghosh [7] in this issue of the European Journal of Gastroenterology and Hepatology, no difference in relapse rates was noted between neutropenic and non-neutropenic patients. In fact, severe life-threatening neutropenia was seen in four patients.

The IBD1 locus for susceptibility to Crohn's disease has a greater impact in Ashkenazi Jews with early onset disease.

OBJECTIVE: Recent studies have suggested that a susceptibility gene located on chromosome 16 and designated IBD1 may contribute to the development of Crohn's disease (CD). However, these findings were observed in predominantly non-Jewish populations; in the three studies where Ashkenazi Jews were included for analysis, the results have been widely divergent. Because Ashkenazi Jews are known to have a higher incidence of the disease than non-Jews, we sought to determine whether this previously reported linkage could be extended to the Ashkenazi population. In addition, we examined whether Ashkenazi Jewish patients with an early age of onset (< or = 21 yr) showed greater evidence of linkage to this locus. METHODS: Linkage analysis for the IBD1 region was performed on 123 Ashkenazi Jewish CD patients distributed among 53 families. Only patients with four Jewish grandparents were considered to be Jewish. Of the 123 Ashkenazi Jewish patients, 75 (61%) had an age of onset < or = 21 yr. RESULTS: Ashkenazi Jews showed only modest evidence of linkage (nonparametric linkage 1.63, p = 0.05) to the IBD1 locus. However, when the Ashkenazi population was subdivided on the basis of age of onset, there was a striking increase in linkage in families where affected individuals had an age of onset < or = 21 yr (nonparametric linkage 3.02, p = 0.002). In contrast, there was no evidence of linkage in the Jewish families where all affected individuals had an age of onset > 21 yr. CONCLUSIONS: The IBD1 gene plays a greater role in conferring susceptibility to CD in Jews with early onset disease than in Jews with late onset disease.

An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial.

BACKGROUND & AIMS: We evaluated CDP571, a humanized antibody to tumor necrosis factor, for the treatment of active Crohn's disease. METHODS: One hundred sixty-nine patients with moderate-to-severe Crohn's disease were enrolled in a 24-week placebo-controlled trial. Patients were initially randomized to a single dose of 10 or 20 mg/kg CDP571 or placebo to assess dose response. Patients were then retreated with 10 mg/kg CDP571 or placebo every 8 or 12 weeks to assess subsequent dosing intervals. The primary endpoint was clinical response at week 2, defined as a decrease in the Crohn's Disease Activity Index score > or = 70 points. RESULTS: At week 2, clinical response occurred in 45% of CDP571-treated patients compared with 27% of patients in the placebo group (P = 0.023). Patients appeared to benefit from retreatment with CDP571 over 24 weeks, but not all of the results for secondary endpoints were statistically significant. The frequency of severe or serious adverse events was similar among all groups. CONCLUSIONS: CDP571 at an initial dose of 10 or 20 mg/kg is safe and effective for treatment of patients with moderate-to-severe Crohn's disease. Preliminary evidence suggests that retreatment with 10 mg/kg CDP571 at dose intervals of 8 or 12 weeks may also be beneficial, but additional studies are needed.

Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum complicates inflammatory bowel disease in 2-3% of patients and often fails to respond to antibiotics, steroids, surgical debridement or even colectomy. METHODS: We performed a retrospective chart analysis of 11 consecutive steroid-refractory pyoderma patients (5 ulcerative colitis, 6 Crohn's disease) referred to our practice and then treated with intravenous cyclosporine. Pyoderma gangrenosum was present on the extremities in 10 patients, the face in 2, and stomas in 21. At initiation of intravenous cyclosporine, bowel activity was moderate in 3 patients, mild in 4, and inactive in 4. All patients received intravenous cyclosporine at a dose of 4 mg/kg/d for 7-22 days. They were discharged on oral cyclosporine at a dose of 4-7 mg/kg/d. RESULTS: All 11 patients had closure of their pyoderma with a mean time to response of 4.5 days and a mean time to closure of 1.4 months. All seven patients with bowel activity went into remission. Nine patients were able to discontinue steroids, and nine were maintained on 6-mercaptopurine or azathioprine. One patient who could not tolerate 6-mercaptopurine had a recurrence of pyoderma. No patient experienced significant toxicity. CONCLUSION: Intravenous cyclosporine is the treatment of choice for pyoderma gangrenosum refractory to steroids and 6-mercaptopurine should be used as maintenance therapy.

Screening and surveillance colonoscopy in chronic Crohn's colitis.

BACKGROUND & AIMS: Unlike ulcerative colitis, there are few reports on the efficacy of surveillance colonoscopy in patients with chronic Crohn's colitis and therefore little agreement as to whether routine surveillance is indicated. We report on 259 patients with chronic Crohn's colitis who underwent screening and subsequent surveillance colonoscopy and biopsy since 1980. METHODS: Biopsies were performed at 10-cm intervals and from strictures and polypoid masses. Pathology was classified as normal, dysplasia (indefinite, low-grade, high-grade), or carcinoma. RESULTS: A total of 663 examinations were performed on 259 patients. The median interval between examinations was 24 months; examinations were performed more frequently (1-6 months) in patients with dysplasia on biopsy. A thinner-caliber colonoscope was required to complete 12% of screening examinations and 23% of surveillance examinations. The pediatric colonoscope helped increase our yield of neoplasia by 19%. The screening and surveillance program detected dysplasia or cancer in 16% (10 indefinite, 23 low-grade, and 4 high-grade dysplasias and 5 cancers). A finding of definite dysplasia or cancer was associated with age >45 years and increased symptoms. By life table analysis, the probability of detecting dysplasia or cancer after a negative screening colonoscopy was 22% by the fourth surveillance examination. CONCLUSIONS: Colonoscopic surveillance should be strongly considered in chronic extensive Crohn's colitis.

How to do without steroids in inflammatory bowel disease.

This review covers the use of steroids in the treatment of both ulcerative colitis and Crohn's disease. It looks at controlled trials and uncontrolled trials as to the benefits of this agent in both inducing and maintaining remission. The review also stresses the high incidence of toxicity with prolonged use of steroids and the fact that controlled trials have clearly shown that steroids do not maintain remission in either disorder. Alternatives to initiating steroids in mild to moderately active ulcerative colitis and Crohn's disease are presented. The use of steroids in fistulizing versus nonfistulizing Crohn's is also covered. Finally, there is a review of data and discussion of the role of antibiotics, immunosuppressives, and combination therapy for both ulcerative colitis and Crohn's disease. The expectation is that the reader will consider alternatives to initiating and maintaining steroids for prolonged periods of time in the treatment of inflammatory bowel disease.

Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps.

BACKGROUND & AIMS: Adenomatous polyps are by definition dysplastic and pathologically indistinguishable from the dysplasia-associated lesion or mass (DALM) described in 1981. Yet, adenomatous polyps in noncolitic colons are usually removed definitively endoscopically, whereas DALMs are regarded as harbingers of colon cancer, mandating colectomy. METHODS: Since 1988, all of our patients with chronic ulcerative or Crohn's colitis and dysplastic polyps and no coexistent dysplasia in flat mucosa underwent colonoscopic polypectomy. Biopsy specimens were obtained also adjacent to polypectomy sites, from strictures, and throughout the colon at 10-cm intervals. Follow-up colonoscopies and biopsies were performed within 6 months after polypectomy and yearly thereafter. RESULTS: Colonoscopy in 48 patients with chronic colitis (mean duration, 25.4 years) resected 70 polyps (60 in colitic and 10 in noncolitic mucosa). Polyps were detected on screening colonoscopies (29%) and on surveillance (71%). Pathology was tubular adenoma in all polyps from noncolitic mucosa and low-grade dysplasia (57), high-grade dysplasia (2), or carcinoma (1) in polyps from colitic mucosa. Subsequent colonoscopies (mean follow-up, 4.1 years) revealed additional polyps in 48% but no carcinomas. Surgical resection (6 patients) for recurrent polyps confirmed colonoscopic findings. No dysplasia or cancers in flat mucosa were found at surgery or on follow-up colonoscopies. CONCLUSIONS: In patients with chronic colitis who have no dysplasia in flat mucosa, colonoscopic resection of dysplastic polyps can be performed effectively, just as in noncolitic colons.

Review article: the efficacy of infliximab in Crohn's disease--healing of fistulae.

In the management of fistulae, the current therapeutic approach is the use of a combination of antibiotics and/or a combination of immunomodulatory agents. However, clinicians treating patients with fistulae, particularly those with fistulizing Crohn's disease, have little data from controlled clinical trials of these pharmacologic agents or regimens to substantiate their use in treating this complication. Therapy with the anti-tumour necrosis factor-alpha antibody, infliximab, has shown promise in treating patients with Crohn's disease and those with the disease complicated by fistulae. A recent clinical trial was designed specifically to evaluate infliximab in the treatment of fistulizing Crohn's disease. Study results demonstrated infliximab to be the first therapeutic agent to show statistical efficacy in fistulae closure in a placebo-controlled trial. Therapy with the chimeric monoclonal antibody was characterized by a rapid onset of closure and a lasting benefit of action. Two patient cases from the clinical trial are presented to exemplify the dramatic effectiveness of this novel therapeutic approach in modulating the immune response of patients with this debilitating complication of Crohn's disease.

Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.

BACKGROUND & AIMS: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit. METHODS: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied. RESULTS: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation. CONCLUSIONS: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.

Infliximab for the treatment of fistulas in patients with Crohn's disease.

BACKGROUND: Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. METHODS: The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas. RESULTS: Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue. CONCLUSIONS: Infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.