ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease

doi:10.1053/gast.2001.23966

Gastroenterology

Volume 120, Issue 6, May 2001, Pages 1347-1355

https://doi.org/10.1053/gast.2001.23966 Get rights and content

Abstract

Background & Aims: In the clinical trial, a lower response to infliximab was observed in some patients after multiple infusions, suggesting that clinical subgroups of Crohn's disease (CD) exist based on response to anti–tumor necrosis factor (anti-TNF). The aim of this study was to characterize these subgroups further by antineutrophil cytoplasmic antibody (ANCA) pattern and TNF genotype. Methods: Crohn's Disease Activity Index (CDAI) data from the North American patients in the clinical trial (n = 59) were evaluated as the response parameter. Speckled ANCA (sANCA) subjects were ANCA positive by ELISA with a speckling over the entire neutrophil on indirect immunofluorescence. Genotypes were determined for polymorphisms in the TNF/lymphotoxin α (LTA) region. Results: Response to infliximab as median change in CDAI was placebo (least response) < perinuclear ANCA (pANCA) < not pANCA or sANCA < sANCA (greatest response) (P_overall = 0.003; 4 weeks). The response of subjects with sANCA was significantly different from that of placebo at all time points; that of pANCA subjects was not. Homozygotes for the LTA NcoI-TNFc-aa13L-aa26 haplotype 1-1-1-1 did not respond (P_overall = 0.007). Conclusions: These observations suggest that sANCA may identify a CD subgroup with a better response to infliximab and that pANCA and homozygosity for the LTA 1-1-1-1 haplotype may identify subgroups with a poorer response.

GASTROENTEROLOGY 2001;120:1347-1355

Section snippets

Study populations

Analyses of genetic and marker antibodies were performed on 75 patients with CD who participated in a phase II placebo-controlled trial of infliximab at North American centers out of a total of 108 patients enrolled worldwide.¹ All studies have been approved by the Cedars-Sinai Medical Center Human Subject Institutional Review Board and by the institutional review board in each of the North American centers participating in the original clinical trial.¹

Study design and clinical assessment

Seventy-five patients with active CD who

Comparison of patients who did not initially respond to infliximab

Patients who did not respond after 4 weeks in the blinded part of the trial were given a subsequent infusion of infliximab in the open-label part of the trial. These patients form 2 groups, one composed of patients who received placebo during the blinded trial and the other of patients who received infliximab. A comparison of the clinical endpoints at 4 weeks after the second infusion between these 2 patient groups for the entire cohort is given in Table 2.

. Comparison of response to infliximab

Discussion

In this ancillary study to the randomized, placebo-controlled clinical trial of infliximab for the treatment of active CD, we observed that subgroups of CD patients with different response to infliximab therapy were associated with differences in ANCA pattern and genotype in the TNF region (specifically at the LTA locus, also known as TNF-β). With respect to ANCA pattern, the response of patients to infliximab therapy, measured by the 3 measures of response (i.e., rate of response, median

Acknowledgements

The authors thank Thomas F. Schaible and Kimberly DeWoody of Centocor Corporation, Malvern, Pennsylvania, for providing clinical data and some of the statistical analyses.

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^☆: Address requests for reprints to: Kent D. Taylor, Ph.D., Medical Genetics SSB-3, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. e-mail: [email protected]; fax: (310) 423-0237.

^☆☆: Supported by National Institute of Diabetes and Digestive and Kidney Diseases grant DK46763, and by the Board of Governors Chair of Medical Genetics (to J.I.R.) and the Feintech Family Chair in IBD (to S.R.T.) at Cedars-Sinai Medical Center.

^★: Dr. Targan is among the founders and current equity holders of Prometheus Laboratory, San Diego, California.

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Alimentary TractANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease☆,☆☆,★

Abstract

Section snippets

Study populations

Study design and clinical assessment

Comparison of patients who did not initially respond to infliximab

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

J Pediatr

Gastroenterology

Blood

Genomics

Gastroenterology

Mol Immunol

Gastroenterology

Hum Immunol

J Allergy Clin Immunol

Gastroenterology

Gastroenterology

Gastroenterology

A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor a for Crohn's disease

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Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease: Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5

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Gut

IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization inintestinal mucosal cells

J Immunol

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DNA sequence polymorphism at the human tumor necrosis factor (TNF) locus: numerous TNF/Lymphotoxin alleles tagged by two closely linked microsatellites in the upstream region of the lymphotoxin (TNFβ) gene

Proc Natl Acad Sci U S A

Alimentary Tract
ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease☆,☆☆,★