Diagnostic utility of, and influence of tobacco usage and genetic predisposition on, immunoglobulin A, rheumatoid factor and anti-citrullinated peptide auto-antibodies in South African rheumatoid arthritis patients

Abstract

Background: The immunoglobulin A isotypes of anti-cyclic citrullinated peptide antibodies (ACPA) and rheumatoid factor (RF) are associated with disease severity and progression in Caucasian rheumatoid arthritis (RA) patients, as well as with genetic predisposition and tobacco use.

Objectives: To compare levels of ACPA-IgA and RF-IgA with those of ACPA-IgG and cRF in a cohort of black South African RA patients and healthy controls.To investigate the relationship between IGA autoantibodies and disease severity, genetic predisposition and tobacco use.

Methods: RF-IgA and ACPA-IgA were determined in a cohort of predominantly black South African RA patients (n=75) in relation to serodiagnostic and prognostic potential, as well as tobacco use and genetic predisposition. Healthy control subjects were included to determine sensitivity, specificity and predictive values.ACPA-IgG/IgA and RF-IgA were determined by enzyme immunoassay and hs-CRP and cRF by nephelometry. Cotinine levels were determined by ELISA.

Results: The frequencies of ACPA-IgA and RF-IgA were 31% and 88% respectively compared to 88% for both types of traditional autoantibody procedures. ACPA-IgA was significantly higher (p=0.007) in patients with short disease duration, while linear regression analysis revealed a positive relationship with baseline disease activity scores. Levels of ACPA-IgG and ACPA-IgA were significantly higher in tobacco users who carried the HLA shared epitope.

Conclusion: Although lacking in serodiagnostic superiority over cRF and ACPA-IgG, inclusion of RF-IgA and ACPA-IgA in autoantibody panels may provide insights into disease pathogenesis, interactions between tobacco usage and HLA genotype in the production of potentially disease-triggering ACPA-IgA antibodies.

Keywords: South Africa; Tobacco usage; anti-citrullinated peptide; genetic predisposition; immunoglobulin A; rheumatoid arthritis patients.

Figure 1

Venn diagram of positive reactivity patterns of ACPA-IgG, cRF, ACPA-IgA RF-IgA individually as well as cross-reactivity patterns between these biomarkers. The Venn diagram indicates that 31% (n=23) of RA patients had cRF and ACPA autoantibodies of both serotypes (IgG and IgA), while 48% (n=36) were positive for ACPA-IgG, cRF and RF-IgA, but not for ACPA-IgA.

Figure 2

Median values of ACPA, and ACPA-IgA in patients categorised according to HLA-SE homozygosity (SS) and heterozygosity (SX). Values were standardised (z-scores) to display on common y-axis (standardisation: x* = (x-m)/SD Where m is the mean of x, and SD is the standard deviation of x).

Figure 3A

Median ACPA-IgA values in RA tobacco users and non-users showing a trend towards higher ACPA-IgA titres in users of tobacco.

Figure 3B

Median ACPA-IgA values in tobacco users and non-users categorised according to Shared Epitope homozygosity (SS) and heterozygosity (SX).