This article is part of a series on immunologic testing guidelines. The series introduction, published in this issue, outlines the full methodology for obtaining data, grading the literature, combining the information from multiple sources, and developing recommendations. Briefly, MEDLINE and Healthstar were searched using a variety of search terms, and all relevant available literature was reviewed. All articles were critically reviewed using published standards for studies of diagnostic tests. Test use was categorized as primarily diagnostic or prognostic (which also included monitoring). Information was extracted from each article to allow for calculation of a weighted average for sensitivity and specificity; likelihood ratios (LRs) were then derived from these values (positive LR sensitivity / [1-specificity]; negative LR [1-sensitivity] / specificity). Recommendations for use of tests were based on the LRs, where a test was considered to be “very useful” for a given disease if the weighted average positive LR was 5 or negative LR was 0.2. A test was considered “useful” if the weighted average positive LR was 2 and 5 or negative LR was 0.2 and 0.5. A test was considered “not useful” if the positive LR was 2 or the negative LR was 0.5.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.10561

Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing.

https://www.amjmed.com/article/S0002-9343(96)00335-X/pdf

The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases

The aim of this study was to investigate the types and prevalence of disease-specific antinuclear antibodies (ANAs) and their relationship to rheumatic diseases in the general Japanese population. An immunofluorescence (IF) method was used for the first screening of ANA levels in serum samples obtained from 2181 residents of a small Japanese town. Individuals positive for IF-ANA were then further tested for disease-specific ANAs using eight enzyme immunoassays. Physical status and the presence of illness were determined by means of questionnaires and medical examinations. Based on the result of the IF-ANA assay, the rates of positive samples at 1:40 and 1:160 dilutions were 26.0 and 9.5%, respectively, with females have significantly higher positivity rates than males (P < 0.0001). Among 566 IF-ANA-positive individuals, 100 individuals were found to have 114 disease-specific ANAs. Anti-SSA/Ro, anti-centromere, and anti-U1RNP antibodies were detected in 58, 30, and 11 individuals, respectively, but anti-Sm, anti-Scl-70, and anti-Jo-1 antibodies were undetectable. Questionnaires and medical examinations revealed that among 60 disease-specific ANA-positive individuals that were available for testing, six had Sjogren’s syndrome (SS), five were suspected of having SS, and five had rheumatoid arthritis. Surprisingly, 34 (57%) of the disease-specific ANA-positive individuals were clinically healthy. Anti-SSA/Ro, anti-centromere, and anti-U1RNP antibodies were quite frequent among clinically healthy Japanese subjects, although anti-Sm, anti-Scl-70, and anti-Jo-1 antibodies were not. Of the 60 individuals who tested positive for disease-specific ANAs, 30% (18/60) actually manifested systemic rheumatic diseases, while 50% showed no detectable signs or symptoms of rheumatic diseases.

/pdf/prevalence-of-disease-specific-antinuclear-antibodies-in-363a0w38vq.pdf

Prevalence of disease-specific antinuclear antibodies in general population: estimates from annual physical examinations of residents of a small town over a 5-year period

Objective The objective of this paper is to conduct a systematic review and meta-analysis on the risk of developing elevated antiphospholipid (aPL) antibodies and related thromboembolic and/or pregnancy events following a viral infection. Method We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane Central Register of Controlled Trials through June 2016. Independent observational studies of elevated aPL antibodies in patients with a viral infection compared with controls or patients with lupus were included. Results We analyzed 73 publications for 60 studies. Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) were most commonly reported. Compared with healthy controls, patients with HIV were more likely to develop elevated anticardiolipin (aCL) antibodies (risk ratio (RR) 10.5, 95% confidence interval (CI) 5.6-19.4), as were those with HCV (RR 6.3, 95% CI 3.9-10.1), hepatitis B virus (HBV) (RR 4.2, 95% CI 1.8-9.5), and Epstein-Barr virus (EBV) (RR 10.9 95% CI 5.4-22.2). The only statistically significant increased risk for anti-β2-glycoprotein I (anti-β2-GPI) antibodies was observed in patients with HCV (RR 4.8 95% CI 1.0-22.3). Compared with patients with lupus, patients with HIV were more likely to develop elevated aCL antibodies (RR 1.8, 95% CI 1.3-2.6), and those with EBV, elevated anti-β2-GPI antibodies (RR 2.2, 95% CI 1.3-3.9). Thromboembolic events were most prevalent in patients with elevated aPL antibodies who had HCV (9.1%, 95% CI 3.0-18.1), and HBV (5.9%, 95% CI 2.0-11.9) infections, and pregnancy events were most prevalent in those with parvovirus B19 (16.3%, 95% CI 0.78-45.7). However, compared to virus-infected patients with negative aPL antibodies, the only statistically significant increased risk was observed in those with HCV and positive aPL. Conclusions Viral infection can increase the risk of developing elevated aPL antibodies and associated thromboembolic events. Results are contingent on the reported information.

Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis.

Antiphospholipid antibodies are commonly related to connective tissue disorders, the use of certain drugs, and infection. It is thought that antiphospholipid syndrome (APS) is associated primarily with connective tissue disorders. We describe a healthy young male who had an episode of APS that was associated with cytomegalovirus infection and who developed mesenteric and femoropopliteal thrombosis. He responded well to treatment with anticoagulants; 6 months after the onset of APS, IgM and IgG anticardiolipin antibody titers declined. We point out the importance of screening for infectious agents in cases of APS; if the agents are identified, APS may be transitory.

Antiphospholipid Syndrome Associated with Cytomegalovirus Infection: Case Report and Review

Following reports of associations between autoantibodies and living in the tropics, we have studied the seroprevalence and nature of anti-nuclear antibodies, anti-cardiolipin antibodies, antibodies to extractable nuclear antigens and anti-neutrophilic cytoplasmic antibodies in 351 West Africans with malaria, tuberculosis or hepatitis B, or in good health. Amongst healthy West Africans we found a seroprevalence of 7% for anti-nuclear antibodies with several staining patterns, and of 30.3% for anti-cardiolipin antibodies. Among patients with tuberculosis and malaria there was twice that frequency of anti-nuclear antibodies (predominantly speckled in pattern), and anti-neutrophil cytoplasmic antibodies (predominantly IgM) were demonstrated in a few cases. A possible association between IgG anti-cardiolipin antibodies and tuberculosis was observed (P < 0.05), but antibodies to double-stranded DNA were not elevated and no antibodies to extractable nuclear antigens were found in any of the patients or healthy individuals studied. Our findings suggest the need for caution in the interpretation of autoantibody tests in subjects from or living in the tropics, as well as in patients with tropical infections.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.1993.tb05950.x

Autoantibodies in malaria, tuberculosis and hepatitis B in a west African population

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects synovial joints. Activated B lymphocytes and plasma cells are present in the synovial tissue and are thought to contribute to the immunopathology of the rheumatoid joint. To investigate rheumatoid synovial B lymphocytes, we have generated B cell hybridomas from synovial tissue of an RA patient. Here we describe the immunoglobulin VH gene repertoire of eight IgM- and 10 IgG-secreting synovial-derived hybridomas. The VH4 gene family is highly represented (38.5%) in this panel of hybridomas compared with the frequency of VH4 gene expression in circulating B lymphocytes reported previously (19-22%) and with the VH4 gene frequency we observed in a panel of hybridomas derived in the same manner from the spleen and tonsil of normal individuals (19%). The increased frequency of VH4 gene expression was not due to the expansion of a single B cell clone in vivo as none of these hybridomas was clonally related. Two synovial-derived hybridomas secreted autoantibodies; one (VH3+) secreted an IgM-rheumatoid factor (RF) and the other (VH4+) secreted IgM with polyreactive binding to cytoskeletal proteins and cardiolipin. The antibodies secreted by the remaining synovial-derived hybridomas were not reactive with the autoantigens tested. The VH gene usage in a proportion (5/17) of synovial-derived hybridomas that expressed CD5 antigen provided preliminary evidence that CD5+ B cells in RA synovium have a similar increase of VH4 gene expression reported for CD5+ B cells from normal individuals and patients with chronic lymphocytic leukaemia.

Immunoglobulin heavy chain variable region gene utilization by B cell hybridomas derived from rheumatoid synovial tissue.

Rheumatoid arthritis (RA) in West Africa is atypical in a number of respects. In order to investigate this we evaluated the serological profile of a series of West African patients diagnosed as having RA. We found the presence of a wide range of autoantibodies including antinuclear antibodies (ANA), anticardiolipin antibodies and antineutrophil cytoplasmic antibodies but the pattern of these autoantibodies was similar to that reported in other studies. Our serological studies support the hypothesis that these patients do have RA and the presence of these autoantibodies is of interest with regards to implications for diagnosis.

Serological profile of rheumatoid arthritis in West Africa

/pdf/diagnostic-role-of-antikeratin-antibodies-in-ra-1694ti0bdq.pdf

R. N. Maini

Papers

Autoantibodies in malaria, tuberculosis and hepatitis B in a west African population

Immunoglobulin heavy chain variable region gene utilization by B cell hybridomas derived from rheumatoid synovial tissue.

Serological profile of rheumatoid arthritis in West Africa

Diagnostic role of antikeratin antibodies in RA.