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A Randomized, Placebo-Controlled Trial of the PPARγ Ligand Rosiglitazone for Active Ulcerative Colitis
GASTROENTEROLOGY 2007;132:2585–2587
Late Breaking Abstracts Submitted to DDW 2007 These abstracts were presented at Digestive Disease Week® in Washington, DC, May 19 –24, 2007
Background: Thiazolidinedione ligands (TZDs) for the gamma subtype of peroxisome proliferator-activated receptors (PPAR␥), widely used to treat type 2 diabetes mellitus, have been proposed to have anti-inflammatory properties in the colon. However, their efficacy in humans with active ulcerative colitis is uncertain. Methods: This multicenter, randomized, double-blind, placebocontrolled clinical trial compared the efficacy of rosiglitazone (Avandia) 4 mg orally twice daily with placebo twice daily for 12 weeks in 105 patients with mild to moderately active ulcerative colitis refractory to or intolerant of 5-aminosalicylic acid. Disease activity was measured with the Disease Activity Index (DAI), with mild to moderate activity defined as a score of 4 –10, inclusively. The primary end point was clinical response (reduction in the DAI by 2 points or more) at week 12. Secondary outcomes included clinical response defined as reduction in the DAI by 3 points or more, clinical remission (DAI ⱕ 2), endoscopic remission (DAI ⬍ 2 and mucosal appearance ⫽ 0), and quality of life (increase in Inflammatory Bowel Disease Questionnaire score by 16 points or more). Patients who did not complete 12 weeks of follow-up were defined as treatment failures for all outcomes. Analyses were performed according to the principle of intention to treat. Results: After 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo had achieved clinical response (P ⫽ .03). Patients treated with rosiglitazone had higher rates of the secondary definition of response (reduction in the DAI by 3 points or more) and clinical remission but not endoscopic remission (Table 1). Improvement in endoscopic appearance (P ⫽ .01), stool frequency (P ⫽ .04),
Table 1. 12-Week Outcomes
Clinical response: 2-point decrease Clinical response: 3-point decrease Clinical remission Endoscopic remission
Rosiglitazone (n ⫽ 52)
Placebo (n ⫽ 53)
P value
44%
23%
.03
37%
13%
.01
17% 8%
2% 2%
.01 .34
bleeding (P ⫽ .21), and physicians’ global assessment (P ⫽ .03) were more common in the rosiglitazone arm. Clinical improvement was evident as early as 4 weeks (P ⫽ .049). Quality of life was significantly improved at week 8 (P ⫽ .01) but not at week 4 (P ⫽ .48) or 12 (P ⫽ .14). Serious adverse
events were rare. Conclusions: Rosiglitazone is efficacious in the treatment of mild to moderately active ulcerative colitis refractory to or intolerant of 5-aminosalicylic acid and is a novel second-line therapy.
HLA-DQ2 Homozygotes Are Associated With a 31-Fold Increased Risk of EMA Positivity in a Large Sample of Sera (n ⴝ 4152) From Patients at Risk for Celiac Disease M. Pietzak* and T. Schofield‡ *Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California; and ‡Prometheus Laboratories, San Diego, California Background: To assess the relative risk for celiac disease, as defined by endomysial antibody (EMA) positivity, by haplotype group. Methods: Blood samples from 4152 patients at risk for celiac disease, who had gastrointestinal symptoms or were relatives of patients with celiac disease (unique identifiers removed), were analyzed at a commercial laboratory. EMA immunoglobulin A was detected by indirect immunofluorescence using monkey esophagus. Highresolution sequence-specific oligonucleotide probe typing of celiac disease– associated HLA-DQ haplotypes was performed on DNA isolated from whole blood. Polymerase chain reaction amplification was performed with biotinylated primers in 2 multiplex reactions for the DQA1 and DQB1 loci. The amplified product was hybridized with 35 DQA1- and 37 DQB1-specific probes, and reactivity patterns were interpreted with LiRAS software (Innogenetics NV, Gent, Belgium) to determine the alleles present. Results: The 7 most common haplotype patterns are presented in Table 1. Patients homozygous for HLADQA1*05-DQB1*02 or carrying HLA-DQA1*05-DQB1*02 and HLA-DQA1*0201DQB1*02 (homozygous, DQ2H) comprised 5.4% of the sample, and 31.1% were EMA positive. Patients carrying only one of these haplotypes (heterozygous, DQ2h) comprised 38.3% of the sample, and 7.9% were EMA positive (OR DQ2H:DQ2h, 5.28; IC95, 3.77–7.38; P ⬍ .0001). Patients who expressed half DQ2 and half DQ8 heterodimers comprised 5.2% of the sample, and 13.4% were EMA positive. Interestingly, 40.8% of the sample was negative for both DQ2 and DQ8, and there were no EMA-positive patients in this group. Conclusions: To our knowledge, this is the largest series reported of celiac genetics in a US population at risk for celiac disease. We found that the rate of EMA positivity in DQ2 homozygous samples was about 30 times—and in DQ2 heterozygous samples about 8 times—the estimated prevalence of 1% for celiac disease in the United States. These data suggest that testing for HLADQ2 and -DQ8 haplotypes can effectively stratify patients at risk for celiac disease (those with gastrointestinal symptoms or relatives) into clinically meaningful risk groups. Targeting these high-risk HLA groups may also aid in the design of potential peptide immunotherapies to replace or augment the glutenfree diet.
PillCam COLON Capsule Endoscopy Compared With Colonoscopy in Detection of Colon Polyps and Cancers: Interim Analysis of a Prospective Multicenter Trial N. Schoofs,* A. Van Gossum,* J. Devière,* M. Munoz Navas,‡ I. Fernandez-Urien,‡ T. Ponchon,§ M. Lapalus,§ G. Gay,储 M. Delvaux,储 H. Neuhaus,¶ M. Philipper,¶ G. Costamagna,# M. Riccioni,# C. Spada,# C. Fraser,** A. Postgate,** A. Fitzpatrick,** F. Hagenmuller,‡‡ and M. Keuchel‡‡ *Gastroenterology, Erasme Hospital, Brussels, Belgium; ‡Gastroenterology,
Table 1. Allele
n (%)
Alleles detected
EMA positive, n (%)
DQ2 H DQ2 H DQ2 h DQ2 h DQ8 H DQ8 h DQ2-, DQ8-
141 (3.4) 84 (2.0) 901 (21.7) 494 (11.9) 38 (0.9) 584 (14.1) 1694 (40.8)
HLA-DQA1*05-DQB1*02 ⫹ HLA-DQA1*0201-DQB1*02 HLA-DQA1*05-DQB1*02 ⫹ HLA-DQA1*05-DQB1*02 HLA-DQA1*05-DQB1*02/03 ⫹ not DQ8 HLA-DQA1*0201-DQB1*02 ⫹ not DQ8 HLA-DQA1*03-DQB1*02 ⫹ HLA-DQA1*03-DQB1*02 HLA-DQA1*03-DQB1*02 ⫹ not DQ8 or DQ2 Not DQ2 ⫹ Not DQ8, Not DQ8 ⫹ Not DQ2
46 (32.6) 24 (27.4) 97 (10.8) 1 (0.2) 4 (10.4) 11 (2.9) 0 (0.0)
AGA INSTITUTE
A Randomized, Placebo-Controlled Trial of the PPAR␥ Ligand Rosiglitazone for Active Ulcerative Colitis J. D. Lewis,* G. R. Lichtenstein,* J. J. Deren,* S. Chuai,* J. H. Ellenberg,* L. Nessel,* G. D. Wu,* B. E. Sands,‡ S. B. Hanauer,§ J. A. Katz,储 B. Lashner,¶ and D. H. Present# *University of Pennsylvania, Philadelphia, Pennsylvania; ‡Massachusetts General Hospital, Boston, Massahcusetts; §University of Chicago, Chicago, Illinois; 储University Hospitals of Cleveland, Cleveland, Ohio; ¶Cleveland Clinic, Cleveland, Ohio; #Mt Sinai School of Medicine, New York, New York
Late Breaking Abstracts Submitted to DDW 2007 These abstracts were presented at Digestive Disease Week® in Washington, DC, May 19 –24, 2007
Background: Thiazolidinedione ligands (TZDs) for the gamma subtype of peroxisome proliferator-activated receptors (PPAR␥), widely used to treat type 2 diabetes mellitus, have been proposed to have anti-inflammatory properties in the colon. However, their efficacy in humans with active ulcerative colitis is uncertain. Methods: This multicenter, randomized, double-blind, placebocontrolled clinical trial compared the efficacy of rosiglitazone (Avandia) 4 mg orally twice daily with placebo twice daily for 12 weeks in 105 patients with mild to moderately active ulcerative colitis refractory to or intolerant of 5-aminosalicylic acid. Disease activity was measured with the Disease Activity Index (DAI), with mild to moderate activity defined as a score of 4 –10, inclusively. The primary end point was clinical response (reduction in the DAI by 2 points or more) at week 12. Secondary outcomes included clinical response defined as reduction in the DAI by 3 points or more, clinical remission (DAI ⱕ 2), endoscopic remission (DAI ⬍ 2 and mucosal appearance ⫽ 0), and quality of life (increase in Inflammatory Bowel Disease Questionnaire score by 16 points or more). Patients who did not complete 12 weeks of follow-up were defined as treatment failures for all outcomes. Analyses were performed according to the principle of intention to treat. Results: After 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo had achieved clinical response (P ⫽ .03). Patients treated with rosiglitazone had higher rates of the secondary definition of response (reduction in the DAI by 3 points or more) and clinical remission but not endoscopic remission (Table 1). Improvement in endoscopic appearance (P ⫽ .01), stool frequency (P ⫽ .04),
Table 1. 12-Week Outcomes
Clinical response: 2-point decrease Clinical response: 3-point decrease Clinical remission Endoscopic remission
Rosiglitazone (n ⫽ 52)
Placebo (n ⫽ 53)
P value
44%
23%
.03
37%
13%
.01
17% 8%
2% 2%
.01 .34
bleeding (P ⫽ .21), and physicians’ global assessment (P ⫽ .03) were more common in the rosiglitazone arm. Clinical improvement was evident as early as 4 weeks (P ⫽ .049). Quality of life was significantly improved at week 8 (P ⫽ .01) but not at week 4 (P ⫽ .48) or 12 (P ⫽ .14). Serious adverse
events were rare. Conclusions: Rosiglitazone is efficacious in the treatment of mild to moderately active ulcerative colitis refractory to or intolerant of 5-aminosalicylic acid and is a novel second-line therapy.
HLA-DQ2 Homozygotes Are Associated With a 31-Fold Increased Risk of EMA Positivity in a Large Sample of Sera (n ⴝ 4152) From Patients at Risk for Celiac Disease M. Pietzak* and T. Schofield‡ *Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California; and ‡Prometheus Laboratories, San Diego, California Background: To assess the relative risk for celiac disease, as defined by endomysial antibody (EMA) positivity, by haplotype group. Methods: Blood samples from 4152 patients at risk for celiac disease, who had gastrointestinal symptoms or were relatives of patients with celiac disease (unique identifiers removed), were analyzed at a commercial laboratory. EMA immunoglobulin A was detected by indirect immunofluorescence using monkey esophagus. Highresolution sequence-specific oligonucleotide probe typing of celiac disease– associated HLA-DQ haplotypes was performed on DNA isolated from whole blood. Polymerase chain reaction amplification was performed with biotinylated primers in 2 multiplex reactions for the DQA1 and DQB1 loci. The amplified product was hybridized with 35 DQA1- and 37 DQB1-specific probes, and reactivity patterns were interpreted with LiRAS software (Innogenetics NV, Gent, Belgium) to determine the alleles present. Results: The 7 most common haplotype patterns are presented in Table 1. Patients homozygous for HLADQA1*05-DQB1*02 or carrying HLA-DQA1*05-DQB1*02 and HLA-DQA1*0201DQB1*02 (homozygous, DQ2H) comprised 5.4% of the sample, and 31.1% were EMA positive. Patients carrying only one of these haplotypes (heterozygous, DQ2h) comprised 38.3% of the sample, and 7.9% were EMA positive (OR DQ2H:DQ2h, 5.28; IC95, 3.77–7.38; P ⬍ .0001). Patients who expressed half DQ2 and half DQ8 heterodimers comprised 5.2% of the sample, and 13.4% were EMA positive. Interestingly, 40.8% of the sample was negative for both DQ2 and DQ8, and there were no EMA-positive patients in this group. Conclusions: To our knowledge, this is the largest series reported of celiac genetics in a US population at risk for celiac disease. We found that the rate of EMA positivity in DQ2 homozygous samples was about 30 times—and in DQ2 heterozygous samples about 8 times—the estimated prevalence of 1% for celiac disease in the United States. These data suggest that testing for HLADQ2 and -DQ8 haplotypes can effectively stratify patients at risk for celiac disease (those with gastrointestinal symptoms or relatives) into clinically meaningful risk groups. Targeting these high-risk HLA groups may also aid in the design of potential peptide immunotherapies to replace or augment the glutenfree diet.
PillCam COLON Capsule Endoscopy Compared With Colonoscopy in Detection of Colon Polyps and Cancers: Interim Analysis of a Prospective Multicenter Trial N. Schoofs,* A. Van Gossum,* J. Devière,* M. Munoz Navas,‡ I. Fernandez-Urien,‡ T. Ponchon,§ M. Lapalus,§ G. Gay,储 M. Delvaux,储 H. Neuhaus,¶ M. Philipper,¶ G. Costamagna,# M. Riccioni,# C. Spada,# C. Fraser,** A. Postgate,** A. Fitzpatrick,** F. Hagenmuller,‡‡ and M. Keuchel‡‡ *Gastroenterology, Erasme Hospital, Brussels, Belgium; ‡Gastroenterology,
Table 1. Allele
n (%)
Alleles detected
EMA positive, n (%)
DQ2 H DQ2 H DQ2 h DQ2 h DQ8 H DQ8 h DQ2-, DQ8-
141 (3.4) 84 (2.0) 901 (21.7) 494 (11.9) 38 (0.9) 584 (14.1) 1694 (40.8)
HLA-DQA1*05-DQB1*02 ⫹ HLA-DQA1*0201-DQB1*02 HLA-DQA1*05-DQB1*02 ⫹ HLA-DQA1*05-DQB1*02 HLA-DQA1*05-DQB1*02/03 ⫹ not DQ8 HLA-DQA1*0201-DQB1*02 ⫹ not DQ8 HLA-DQA1*03-DQB1*02 ⫹ HLA-DQA1*03-DQB1*02 HLA-DQA1*03-DQB1*02 ⫹ not DQ8 or DQ2 Not DQ2 ⫹ Not DQ8, Not DQ8 ⫹ Not DQ2
46 (32.6) 24 (27.4) 97 (10.8) 1 (0.2) 4 (10.4) 11 (2.9) 0 (0.0)
AGA INSTITUTE
A Randomized, Placebo-Controlled Trial of the PPAR␥ Ligand Rosiglitazone for Active Ulcerative Colitis J. D. Lewis,* G. R. Lichtenstein,* J. J. Deren,* S. Chuai,* J. H. Ellenberg,* L. Nessel,* G. D. Wu,* B. E. Sands,‡ S. B. Hanauer,§ J. A. Katz,储 B. Lashner,¶ and D. H. Present# *University of Pennsylvania, Philadelphia, Pennsylvania; ‡Massachusetts General Hospital, Boston, Massahcusetts; §University of Chicago, Chicago, Illinois; 储University Hospitals of Cleveland, Cleveland, Ohio; ¶Cleveland Clinic, Cleveland, Ohio; #Mt Sinai School of Medicine, New York, New York