Simon Lichtiger

Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease

BACKGROUND The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohns disease are unknown. METHODS In this randomized, double-blind trial, we evaluated the efficacy of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate-to-severe Crohns disease who had not undergone previous immunosuppressive or biologic therapy. Patients were randomly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; 2.5 mg of oral azathioprine per kilogram daily plus a placebo infusion on the standard schedule; or combination therapy with the two drugs. Patients received study medication through week 30 and could continue in a blinded study extension through week 50. RESULTS Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P=0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone (P<0.001 for the comparison with combination therapy and P=0.006 for the comparison with infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, as compared with 28 of 93 patients (30.1%) receiving infliximab (P=0.06) and 18 of 109 patients (16.5%) receiving azathioprine (P<0.001 for the comparison with combination therapy and P=0.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group. CONCLUSIONS Patients with moderate-to-severe Crohns disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy. (ClinicalTrials.gov number, NCT00094458.)

Cyclosporine in severe ulcerative colitis refractory to steroid therapy.

BACKGROUND There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago. In an uncontrolled study, 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy. METHODS We conducted a randomized, double-blind, controlled trial in which cyclosporine (4 mg per kilogram of body weight per day) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy. A response to therapy was defined as an improvement in a numerical symptom score (0 indicated no symptoms, and 21 severe symptoms) leading to discharge from the hospital and treatment with oral medications. Failure to respond to therapy resulted in colectomy, but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine. RESULTS Nine of 11 patients (82 percent) treated with cyclosporine had a response within a mean of seven days, as compared with 0 of 9 patients who received placebo (P < 0.001). The mean clinical-activity score fell from 13 to 6 in the cyclosporine group, as compared with a decrease from 14 to 13 in the placebo group. All five patients in the placebo group who later received cyclosporine therapy had a response. CONCLUSIONS Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis.

Ustekinumab Induction and Maintenance Therapy in Refractory Crohn's Disease

BACKGROUND In patients with Crohns disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. METHODS We evaluated ustekinumab in adults with moderate-to-severe Crohns disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. RESULTS The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. CONCLUSIONS Patients with moderate-to-severe Crohns disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).

The Risk of Retention of the Capsule Endoscope in Patients with Known or Suspected Crohn's Disease

OBJECTIVES:Capsule endoscopy (CE) allows visualization of the mucosa of the entire small bowel and is therefore a potentially important tool in the evaluation of patients with known or suspected Crohns disease (CD). However, small bowel strictures, which are not uncommon in Crohns, are considered to be a contraindication to CE for fear of capsule retention. Our goal was to determine the risk of capsule retention in patients with suspected or known CD.METHODS:We retrospectively reviewed the records of 983 CE cases performed at three private gastroenterology practices between December 2000 and December 2003, and selected those with suspected or proven Crohns.RESULTS:A total of 102 cases were identified in which CE was used in patients with suspected (N = 64) or known (N = 38) CD. Only one of 64 patients (1.6%) with suspected CD had a retained capsule. However, in five of 38 (13%) patients with known Crohns, the capsule was retained proximal to a stricture. Of the five cases of retained capsules, three strictures were previously unknown. In four cases, the obstructing lesions were resected without complications, leading to complete resolution of the patients underlying symptoms. One patient chose not to undergo surgery and has remained without an episode of small bowel obstruction for over 38 months.CONCLUSIONS:Capsule retention occurred in 13% (95% CI 5.6%–28%) of patients with known CD, but only in 1.6% (95% CI 0.2%–10%) with suspected Crohns. A retained capsule may indicate unsuspected strictures in Crohns that may require an unexpected, but therapeutic, surgical intervention. Patients and physicians should be aware of these potential risks when using CE in CD.

Efficacy of cyclosporine in treatment of fistula of Crohn's disease.

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

Adverse Events Associated With the Use of Cyclosporine in Patients With Inflammatory Bowel Disease

BACKGROUND:Intravenous cyclosporine (IV CsA) is an effective therapy for patients with inflammatory bowel disease (IBD). However, data regarding its adverse events in these patients are limited.METHODS:A retrospective chart review of the initial 111 consecutive patients with IBD treated with IV CsA followed by a predetermined duration of oral therapy.RESULTS:One hundred eleven patients (64 UC, 47 CD; mean age 33 yr, range 16–68) received IV CsA at 4 mg/kg/day, then oral CsA at 8 mg/kg/day, with dose adjustment based on serum creatinine. The mean treatment duration was 9.3 months (range 1 wk to 34 months). Major adverse events occurred in 17 (15.3%) patients. Nephrotoxicity (serum creatinine ≥1.4 mg/dL [123 μmol/L] or a rise by at least 33% over baseline not responding to dose adjustment) sufficiently severe to warrant discontinuation of therapy occurred in 6 (5.4%) patients. Serious infection occurred in 7 (6.3%) patients, seizures in 4 (3.6%) patients, anaphylaxis in 1 (0.9%) patient, and death in 2 (1.8%) patients. Minor adverse events (transient effects with complete resolution either spontaneously or with dose adjustment) comprised: paresthesias (51%), hypomagnesemia (42%), hypertension (39%), hypertrichosis (27%), headache (23%), minor nephrotoxicity (defined as above but with restoration of normal serum creatinine with dose adjustment; 19% of patients), abnormal liver function tests (19%), minor infections (15%), hyperkalemia (13%), and gingival swelling (4%).CONCLUSIONS:In our initial experience, limited duration CsA therapy was frequently associated with adverse events although the majority of these were minor and responded to dose adjustment. Although not all severe adverse events can be clearly attributed to CsA use alone, its high incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required.

Erythrocytic sedimentation rate as a measure of clinical activity in inflammatory bowel disease.

To assess the reliability of the erythrocytic sedimentation rate (ESR) as a measure of clinical activity in inflammatory bowel disease, we analyzed the correlations of ESR with a global assessment of clinical activity in 77 patients with varying extents of Crohns disease and ulcerative colitis. Analysis of all 141 ESR determinations in all 77 patients showed a highly significant correlation between mean ESR and clinical activity score (r = 0.54, p less than 0.001). Analysis of 133 ESR determinations in these 77 patients when their disease activity was either mild, moderate, or severe showed some significant differences among certain disease categories. The highest mean ESRs were in patients with the most extensive colon involvement (Crohns colitis 40.7 +/- 3.3, universal ulcerative colitis 31.0 +/- 3.9), whereas the lowest mean ESRs were in patients with the most limited disease (ulcerative proctitis and proctosigmoiditis 19.2 +/- 2.1). The rate of increase in ESR with progressively increasing clinical activity from mild to moderate was the same in all disease categories, with the exception of Crohns disease limited to the small bowel (ileitis or jejunoileitis), in which the ESR was relatively unchanged in a small sample of patients. By the time clinical activity became severe, however, patients in all disease categories manifested similarly high ESRs, with the exception of ulcerative proctitis in which the ESR remained low in the single patient tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Dilation of colonic strictures by intralesional injection of infliximab in patients with Crohn's colitis

Background: Intestinal stenosis is a frequent complication of Crohns disease, often leading to repeated bowel obstruction and surgery. The prevalence of small bowel stenosis has ranged from 20% to 40% and from 7% to 15% in patients with colonic disease. Although balloon dilation is the initial preferred approach, many patients eventually restenose and require surgical resection or stricturoplasty. Infliximab, a chimeric IgG1 kappa monoclonal antibody against TNF‐alpha, has been effective in the treatment of enteric as well as fistulous complications of Crohns disease. Repeated systemic administration has been successful for active inflammatory disease yet has been reported to be ineffective in the treatment of strictures. Although the TREAT registry has shown systemic infliximab to be safe in the long term, there is concern regarding infectious as well as neoplastic complications. Methods: This report describes 3 patients refractory to all medical therapy including systemic infliximab. Results: In all 3 patients, dilation of a colonic stricture was accomplished by injection of infliximab, via the sclerotherapy technique, into the distal and medial portions of the stricture. Conclusions: Infliximab was shown to be effective in the treatment of strictures in 3 patients.

Early clinical experience with adalimumab in treatment of inflammatory bowel disease with infliximab‐treated and naïve patients

Background  Adalimumab, at an induction dose of 160/80 mg followed by 40 mg every other week is approved for treatment of refractory Crohns disease (CD) and for patients with loss of response to infliximab.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase2b Study of Ustekinumab, a Human Monoclonal Antibody to IL-12/23p40, in Patients With Moderately to Severely Active Crohn's Disease: Results Through Week 22 From the Certifi Trial

Early Use of Azathioprine Has a Steroid Sparing Effect on Recently Diagnosed Crohns Disease Patients Miquel Sans, Antonio Lopez-San Roman, Maria Esteve, Fernando Bermejo, Valle GarciaSanchez, Yolanda Torres, Eugeni Domenech, Marta Piqueras, Montserrat Aceituno, Maria Gomez-Garcia, Carlos Taxonera, Javier P. Gisbert, Ana Gutierrez, Fernando Gomollon, Daniel Ginard, Antonio Bernal, Antonio Z. Gimeno-Garcia, Carmen Munoz, Fermin Mearin, Miguel Minguez, Manuel Barreiro-de Acosta, Xavier Calvet, Juan Buenestado, Olga Merino, Maria Barrachina, Luis Bujanda, Miriam Manosa, Maria M. Calvo, Esther Garcia, Miguel A. Montoro, Jose Manuel Herrera Justiniano, Montserrat Andreu, Vicent Hernandez, Joaquin Hinojosa, Julian Panes