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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.

SUBMITTER: Meyer P

PROVIDER: S-EPMC6306983 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Project description:OBJECTIVE:Because of its association with joint destruction, anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) is considered to be more severe than ACPA-negative RA. Clinically relevant joint destruction is now infrequent thanks to adequate disease suppression. According to patients, important outcomes are pain, fatigue, and independence. We evaluated whether ACPA-positive RA patients diagnosed during or after 2000 have more severe self-reported limitations and impairments, including restrictions at work, than ACPA-negative RA patients. METHODS:A total of 492 ACPA-positive and 450 ACPA-negative RA patients who fulfilled the 2010 criteria and were included in the Leiden Early Arthritis Clinic cohort during or after 2000 were compared for self-reported pain, fatigue, disease activity, general well-being (measured by numerical rating scales), physical function (measured by the Health Assessment Questionnaire), and work restrictions, including absenteeism at baseline and during the 4-year followup. Linear mixed models were used. RESULTS:At disease presentation, ACPA-negative patients had more severe pain, fatigue, self-reported disease activity scores, and functional disability (P < 0.05), although absolute differences were small. During followup, ACPA-negative patients remained somewhat more fatigued (P = 0.002), whereas other patient-reported impairments and limitations were similar. Thirty-eight percent of ACPA-negative and 48% of ACPA-positive patients reported absenteeism (P = 0.30), with median 4 days missed in both groups in the last 3 months. Also, restrictions at work among employed patients and restrictions with household work were not statistically different at baseline and during followup. CONCLUSION:In current rheumatology practice, ACPA-positive RA is not more severe than ACPA-negative RA in terms of patients' relevant outcomes, including physical functioning and restrictions at work. This implies that efforts to further improve the disease course should be proportional to both disease subsets.

Project description:To determine the molecular and functional properties of human rheumatoid factors (RF), we established stable hybridomas and Epstein-Barr virus-transformed B cell lines from the synovial fluid or peripheral blood of three patients with rheumatoid arthritis and one patient with systemic lupus erythematosus. 17 cell lines were obtained that produced high-titer immunoglobulin M (IgM) RF that reacted exclusively with rabbit but not human IgG or IgG of other mammalian species. Certain anti-rabbit IgG RF also had specificity for other mammalian antigens (Ag), including cytoskeletal proteins and intracellular proteins found in HeLa cells, as well as for Ag present in an extract prepared from the cell wall of group A streptococci. 13 of the 17 RF contained lambda-type light (L) chains, of which 12 were classified serologically as members of the lambda-L chain variable region (V lambda) subgroup, designated V lambda III. The heavy chain V region (VH) and V lambda sequences of nine of these IgM lambda RF were determined at the cDNA level. Five VH genes in three VH families were used by these antibodies (Ab), including VH1 (dp21/1-4b and dp10 [51p1]/hv1051), VH3 (dp38/3-15 and dp77/13-21), and VH4 (dp70/4-4b). The deduced V gene-encoded amino acid sequences of the lambda chains of these IgM lambda RF confirmed their serological classification as lambda III, and they were further classified as members of the relatively uncommon V lambda III subgroup, designated V lambda IIIb. Based on cDNA analyses, nine were the product of three different V lambda III b germline genes. Two such genes, designated hsiggll150 and hsiggll295, were cloned and sequenced from genomic DNA. Unique combinations of these VH and V lambda III b genes could be related to distinctive patterns of reactivity among the IgM lambda RF. Although the VH and V lambda regions of these Abs were expressed primarily as germline-encoded sequences, four of nine multireactive Abs had extensive V region mutation, indicative of an Ag-driven process. The finding that lambda IIIb L chains are preferentially found among anti-rabbit IgG RF, and that some of these Ab have specificity for other protein, cellular, and bacterial Ag, provides new insight into the pathogenesis of RA and related diseases.

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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.

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