Gene polymorphisms and serological markers of patients with active Crohn's disease in a clinical trial of antisense to ICAM-1.

Abstract

Serological profiles for anti-Saccharomyces cerevisiae antibodies (ASCA)/ perinuclear antineutrophil cytoplasmic antibodies (pANCA) and gene polymorphisms in tumour necrosis factor (TNF)-alpha and intercellular adhesion molecule-1 (ICAM-1) are associated with occurrence and/or outcome in Crohn's disease. The aim of the study was to characterize the ASCA/pANCA profile, soluble ICAM-1 expression and single nucleotide gene polymorphisms (SNPs) in TNF-alpha and ICAM-1 genes. Crohn's patients with moderate disease activity were enrolled in a clinical trial of Alicaforsen (ISIS 2302). Peripheral blood samples were collected prospectively for serum studies and for potential analysis of gene polymorphisms. A multivariate analysis was performed to compare treatment effect with the biomarkers studied. Serological testing for ASCA/pANCA was obtained for 257 patients at baseline: 37% were ASCA(+)/pANCA(-) (Crohn's pattern), 9% had both markers, 15% were ASCA(-)/pANCA(+) and 39% had neither marker. When the data were analysed by multiple regression analysis, a trend was found within the Alicaforsen-treated groups for greater rates of remission in the ASCA(+)/pANCA(-) subgroup versus all other serological profiles (25 versus 14%, P = 0.068), but not versus the placebo remission rate (18.8%). Gene polymorphisms were assessed in 64 patients, 21 from the placebo group. ICAM-1 assessment revealed no over-representation. However, three unique TNF-alpha SNPs were identified that correlated significantly with remission; sites 290 (P = 0.0253), -2735 (P = 0.0317) and -3090 (P = 0.0067). Although the overall clinical trial was negative, we have identified a trend towards clinical remission with Alicaforsen therapy in a subgroup of patients with Crohn's disease expressing ASCA(+)/pANCA(-). Furthermore, we have identified three TNF-alpha SNPs that may also predict a positive therapeutic outcome.

• Authors: B R Yacyshyn, A Schievella, K L Sewell, J A Tami
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 141 Issue 1 Pg. 141-7 (Jul 2005) ISSN: 0009-9104 [Print] England
• PMID: 15958080 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antibodies, Antineutrophil Cytoplasmic
• Antibodies, Fungal
• Biomarkers
• Gastrointestinal Agents
• Oligodeoxyribonucleotides, Antisense
• Phosphorothioate Oligonucleotides
• Thionucleotides
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• alicaforsen

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antibodies, Antineutrophil Cytoplasmic (blood)
• Antibodies, Fungal (blood)
• Biomarkers (blood)
• Crohn Disease (blood, drug therapy, genetics)
• Gastrointestinal Agents (therapeutic use)
• Humans
• Intercellular Adhesion Molecule-1 (blood, genetics)
• Middle Aged
• Oligodeoxyribonucleotides, Antisense (therapeutic use)
• Phenotype
• Phosphorothioate Oligonucleotides
• Polymorphism, Genetic
• Saccharomyces cerevisiae (immunology)
• Severity of Illness Index
• Solubility
• Thionucleotides (therapeutic use)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (genetics)