Asher Kornbluth

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.

Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee

Guidelines for clinical practice are aimed to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind placebo controlled studies are preferable, but compassionate-use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject regardless of specialty training or interests and are aimed to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the board of trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision analysis. The recommendations of each guideline are therefore considered valid at the time of composition based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at a time established and indicated at publication to assure continued validity. The recommendations made are based on the level of evidence found. Grade A recommendations imply that there is consistent level 1 evidence (randomized controlled trials), grade B indicates that the evidence would be level 2 or 3, which are cohort studies or case–control studies. Grade C recommendations are based on level 4 studies, meaning case series or poor-quality cohort studies, and grade D recommendations are based on level 5 evidence, meaning expert opinion.

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.

Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis : the ASCEND II trial

BACKGROUND AND AIMS:Preliminary data have shown that delayed release oral mesalamine (Asacol®) dosed at 4.8 g/day provided additional efficacy benefit compared to 1.6 g/day in patients with mildly to moderately active ulcerative colitis. Additionally, Asacol dosed at 2.4 g/day has been proved to be more effective than 1.6 g/day. Whether 4.8 g/day of mesalamine (dosed with an investigational 800 mg tablet) is more effective than Asacol 2.4 g/day (dosed with a 400 mg tablet) in patients with moderately active ulcerative colitis is unknown.METHODS:A randomized, double-blind, controlled trial (ASCEND II) was conducted to evaluate the efficacy of 4.8 g/day of mesalamine in adults with active ulcerative colitis. Three hundred eighty-six patients with mild to moderate ulcerative colitis were randomized for treatment with mesalamine 2.4 g/day (400 mg tablet) or 4.8 g/day (800 mg tablet) for 6 wk. The primary efficacy population was 268 patients with moderately active ulcerative colitis treated with 2.4 g/day (n = 139) or 4.8 g/day (n = 129). The primary endpoint was the proportion of patients in each treatment group that achieved overall improvement (“treatment success,” defined as either complete remission or a clinical response to therapy) from baseline at week 6.RESULTS:Seventy-two percent of patients receiving 4.8 g/day of mesalamine for moderate ulcerative colitis (89/124 patients) achieved treatment success at week 6, compared with 59% of those who received 2.4 g/day (77/130 patients) (p = 0.036). Both regimens were well tolerated. Adverse events and clinically significant changes in laboratory results were similar in both treatment groups.CONCLUSIONS:Patients with moderately active ulcerative colitis treated with 4.8 g/day of mesalamine (800 mg tablet) are significantly more likely to achieve overall improvement at 6 wk compared to patients treated with 2.4 g/day.

Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial

Background and aims The Crohns Disease Activity Index (CDAI) has been criticised due to heavy weighting on subjective clinical symptoms. C-reactive protein (CRP) and endoscopic lesions are objective measures of inflammation. We investigated the relationships between clinical disease activity, CRP normalisation and mucosal healing in Crohns disease (CD). Methods The Study of Biologic and Immunomodulator Naive Patients in CD trial compared infliximab to azathioprine and to infliximab plus azathioprine in 508 CD patients. Mucosal healing was defined as the absence of mucosal ulceration at the week 26 ileocolonoscopy in a patient who had evidence of ulceration at the baseline ileocolonoscopy. Results 188 patients who had evaluable ileocolonoscopy with evidence of mucosal ulceration at baseline, CDAI scores and CRP values at baseline and week 26 were analysed. Seventy-two of 136 patients (53%) who had a CDAI<150 at week 26 achieved mucosal healing, and 38 of 90 patients (42%) achieved both CRP normalisation (CRP<0.8 mg/dL) and mucosal healing while in clinical remission. The positive predictive value (PPV) and negative predictive value (NPV) of CDAI to detect mucosal healing using 150 as a cut-off for CDAI were 65% and 53%, respectively. The PPV and NPV of CDAI to detect mucosal healing and CRP normalisation using 150 as a cut-off for CDAI were 79% and 42%, respectively. Conclusions Half the patients under azathioprine and/or infliximab in clinical remission have endoscopic and/or CRP evidence of residual active CD, whereas other patients with endoscopic and CRP normalisation have persistent clinical symptoms. Clinical symptoms as scored by CDAI are not a reliable measure of the underlying inflammation.

Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis

OBJECTIVES:Tumor necrosis factor-α (TNF-α) is an important cytokine involved in the pathogenesis of inflammatory bowel disease. The monoclonal antibody to TNF-α, infliximab, is effective in treating Crohns disease. Preclinical studies suggest the importance of TNF-α in treating ulcerative colitis (UC). We report the effectiveness of infliximab for UC and examine factors predictive of response to medication.METHODS:Data from all UC patients receiving infliximab at four institutions were analyzed. Disease activity was determined by the Disease Activity Index.RESULTS:A total of 27 patients with active UC received inpatient (37%) and outpatient (63%) infliximab as single (52%) or multiple (two to 15) infusions (48%). Twelve patients (44%) achieved remission and six patients (22%) had partial response. Nine patients had no response; five subsequently underwent total colectomy. The median time to achieve response and remission was 4 days and the median duration 8 wk. Nine of the 18 patients who responded experienced 19 relapses; 18 of these relapses (95%) were successfully treated with repeat infusions. Steroid-refractory patients were less likely to respond to infliximab therapy than were steroid-responsive patients (33% vs 83%; p = 0.026). No other factors were predictive of response to infliximab. Two patients developed serious adverse events, including death in one case.CONCLUSIONS:Preliminary evidence suggest effectiveness of infliximab in the treatment of UC, including medically refractory severe disease. Individuals who are refractory to corticosteroids, however, may be unlikely to respond to infliximab. A randomized controlled trial is necessary to further investigate the efficacy of infliximab in patients with UC.

Small bowel tumours: yield of enteroscopy.

A total of 258 patients with obscure gastrointestinal bleeding were referred for small bowel enteroscopy, a procedure which allows endoscopic evaluation of most of the small intestine. A small bowel tumour was found in 5% of patients. In 50% of patients no diagnosis could be made, but when the cause of obscure bleeding was discovered small bowel tumours were the single most common lesion in patients younger than 50 years. Small bowel tumours causing gastrointestinal bleeding may remain undetected despite extensive diagnostic evaluation. We conclude that small bowel tumours are the most common cause of obscure gastrointestinal bleeding in patients less than 50 years of age. Small bowel enteroscopy is diagnostic of small bowel tumours even when all previous diagnostic studies, including enteroclysis and angiography, are negative.

Treatment of ulcerative colitis with fish oil n―3-ω-fatty acid : an open trial

We evaluated the efficacy of fish oil n--3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. An open trial of 10 patients with mild to moderate ulcerative colitis who had either failed (n = 9) or refused (n = 1) conventional therapy was performed. Patients received 15 MAX-EPA capsules containing a total of 2.7 g of eicosapentanoic acid in three divided doses daily for 8 weeks. The activity of ulcerative colitis and response to therapy was based upon daily stool diaries, sigmoidoscopy, and symptomatic response. All patients tolerated the fish oil and showed no alteration in routine blood studies. Seven patients had moderate to marked improvement; steroid dose could be reduced in four of the five patients on prednisone. Three patients had little or no improvement. No patient worsened. These results of our open study appear to justify a double-blind trial of this dietary supplement in ambulatory patients with ulcerative colitis.

Relapses of Inflammatory Bowel Disease During Pregnancy: In-Hospital Management and Birth Outcomes

BACKGROUND:There are few studies that describe the medical treatment and colitis response rates among patients with a severe relapse of inflammatory bowel disease (IBD) during pregnancy, and few studies of the effect of such a relapse on birth outcomes in these patients.OBJECTIVES:To describe the treatment and response rates of severe colitis in pregnancy, and to assess the effects of a severe relapse of colitis during pregnancy on birth outcomes.METHODS:We performed a case control study of pregnant patients with IBD hospitalized for a disease relapse at two large treatment centers between 1989 and 2001. Details of management of disease relapse and maternal and fetal outcomes were recorded.RESULTS:Eighteen patients (11 ulcerative colitis, 6 Crohns disease, 1 indeterminate colitis), mean age 28.6 yr (range 19–38) formed the study group; 41 age-matched pregnant IBD patients without disease relapse formed the control group. Study patients were hospitalized at a mean of 15.9-wk gestation (range 8–35) for a mean of 10.4 days (range 3–31). All 18 patients received IV hydrocortisone (mean dose 199 mg/day) and 7 patients (39%) either continued taking or were commenced on immunomodulators: IV cyclosporine (5 patients) and azathioprine/6-MP (3 patients). Fifteen patients (83%) had a clinical response to these medical treatments, 3 patients required colectomy. There were significant differences between study and control groups in gestation period (35.0 wk vs 38.7 wk, respectively, P = 0.0001) and birth weight (2,001 g vs 3,018 g, respectively, P < 0.0001).CONCLUSIONS:Treatment with IV hydrocortisone and IV cyclosporine appears effective at inducing remission of colitis but their use must continue to be confined to severely ill patients being treated at specialized centers. Severe relapses of colitis during pregnancy increase the risk of preterm birth and low birth weight.