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Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor.

ABSTRACT: INTRODUCTION:As a group, rheumatoid arthritis (RA) patients exhibit increased risk of infection, and those treated with anti-tumor necrosis factor (TNF) therapy are at further risk. This increased susceptibility may result from a compromised humoral immune response. Therefore, we asked if short-term effector (d5-d10) and memory (1 month or later) B cell responses to antigen were compromised in RA patients treated with anti-TNF therapy. METHODS:Peripheral blood samples were obtained from RA patients, including a subset treated with anti-TNF, and from healthy controls to examine influenza-specific responses following seasonal influenza vaccination. Serum antibody was measured by hemagglutination inhibition assay. The frequency of influenza vaccine-specific antibody secreting cells and memory B cells was measured by EliSpot. Plasmablast (CD19+IgD-CD27hiCD38hi) induction was measured by flow cytometry. RESULTS:Compared with healthy controls, RA patients treated with anti-TNF exhibited significantly decreased influenza-specific serum antibody and memory B cell responses throughout multiple years of the study. The short-term influenza-specific effector B cell response was also significantly decreased in RA patients treated with anti-TNF as compared with healthy controls, and correlated with decreased influenza-specific memory B cells and serum antibody present at one month following vaccination. CONCLUSIONS:RA patients treated with anti-TNF exhibit a compromised immune response to influenza vaccine, consisting of impaired effector and consequently memory B cell and antibody responses. The results suggest that the increased incidence and severity of infection observed in this patient population could be a consequence of diminished antigen-responsiveness. Therefore, this patient population would likely benefit from repeat vaccination and from vaccines with enhanced immunogenicity.

SUBMITTER: Kobie JJ

PROVIDER: S-EPMC3334662 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor.

Kobie James J JJ Zheng Bo B Bryk Peter P Barnes Michael M Ritchlin Christopher T CT Tabechian Darren A DA Anandarajah Allen P AP Looney R John RJ Thiele Ralf G RG Anolik Jennifer H JH Coca Andreea A Wei Chungwen C Rosenberg Alexander F AF Feng Changyong C Treanor John J JJ Lee F Eun-Hyung FE Sanz Ignacio I

Arthritis research & therapy 20111216 6

<h4>Introduction</h4>As a group, rheumatoid arthritis (RA) patients exhibit increased risk of infection, and those treated with anti-tumor necrosis factor (TNF) therapy are at further risk. This increased susceptibility may result from a compromised humoral immune response. Therefore, we asked if short-term effector (d5-d10) and memory (1 month or later) B cell responses to antigen were compromised in RA patients treated with anti-TNF therapy.<h4>Methods</h4>Peripheral blood samples were obtaine ...[more]

PMID: 22177419

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Project description:OBJECTIVE:Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. METHODS:A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (triangle upDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. RESULTS:Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the triangle upDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99). CONCLUSION:Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.

Project description:BackgroundStudies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings have been inconsistent across studies. Among Japanese patients, only a few SNPs have been investigated. We report here the first genome-wide association study (GWAS) to identify genetic biomarkers of anti-TNF response among Japanese RA patients, using response at 2 time-points for a more reliable clinical phenotype over time.MethodsDisease Activity Scores based on 28 joint counts (DAS28) were assessed at baseline (before initial therapy), and after 3 and 6 months in 487 Japanese RA patients starting anti-TNF therapy for the first time or switching to a new anti-TNF agent. A genome-wide panel of SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline at both 3 (ΔDAS-3) and 6 months (ΔDAS-6) as the response phenotype, a longitudinal genome-wide association analysis was conducted using generalized estimating equations (GEE) models, adjusting for baseline DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (ΔDAS-3 or ΔDAS-6) as phenotype; all other variables were the same as in the GEE models.ResultsIn the GEE models, borderline significant association was observed at 3 chromosomal regions (6q15: rs284515, p = 6.6x10(-7); 6q27: rs75908454, p = 6.3x10(-7) and 10q25.3: rs1679568, p = 8.1x10(-7)), extending to numerous SNPs in linkage disequilibrium (LD) across each region. Potential candidate genes in these regions include MAP3K7, BACH2 (6q15), GFRA1 (10q25.3), and WDR27 (6q27). The association at GFRA1 replicates a previous finding from a Caucasian dataset. In the cross-sectional analyses, ΔDAS-6 was significantly associated with the 6q15 locus (rs284511, p = 2.5x10(-8)). No other significant or borderline significant associations were identified.ConclusionThree genomic regions demonstrated significant or borderline significant associations with anti-TNF response in our dataset of Japanese RA patients, including a locus previously associated among Caucasians. Using repeated measures of response as phenotype enhanced the power to detect these associations.

Dataset Information

Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor.

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Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor.

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