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The dominant antibody at mucous membranes and in exocrine secretions is IgA. It has been implicated in the pathogenesis of rheumatoid arthritis (RA), possibly due to immune complex formation.1,2 If IgA is important in RA pathogenesis one might predict that patients with abnormal levels would have different characteristics from the “normal” IgA population. Limited work published on patients with high IgA levels has suggested that there is an increase in erythrocyte sedimentation rate (ESR), microscopic haematuria, and both distal interphalangeal joint involvement and unilateral sacroiliitis, even though patients fulfil the American College of Rheumatology (ACR) criteria for RA and have no other evidence of spondyloarthropathy.3
Primary selective IgA deficiency is the most common hypogammaglobulinaemia in the general population, with a prevalence of around 1:500.4 It is associated with increased risk of autoimmune disease5 and, possibly, with RA.6 Primary IgA deficiency may result from impaired switching from class IgM to IgA.7 Secondary IgA deficiency may be caused by drugs such as d-penicillamine, sulfasalazine, and gold. The few descriptions of primary IgA deficiency and RA have been single case studies and a longitudinal study is needed to determine if these cases represent a subgroup.
METHODS AND RESULTS
Serum immunoglobulins were measured in 352 patients (aged 18–75) attending a rheumatology outpatient department over a six year period. All patients fulfilled the ACR criteria for diagnosis of RA.8 Patients with selective hypergammaglobulinaemia (>240 IU/ml) or primary selective IgA deficiency (<50 IU/ml) were identified as the two study cohorts. These were compared with patients with RA (n=277) with normal IgA levels. No patients had been treated with immunosuppressant drugs at the time of IgA determination. Measurements of disease activity and disability were made at 0, 6, 12, and 18 months. A long term follow up assessment (including Health Assessment Questionnaire9 and joint surgery) was made at about 12 years. Mortality was assessed after 15 years.
Of 352 patients, eight had a primary selective IgA deficiency, a point prevalence of 2.3%. A further three had a low IgA as part of combined immunoglobulin deficiency. Twenty two patients had a selective IgA hypergammaglobulinaemia, a point prevalence of 6.3%, with a further 28 having a high IgA combined with abnormal levels of IgG or IgM. The IgA deficient patients were more likely to have a first degree relative with RA than the overall RA population and none of this group had RA nodules compared with 29% of RA controls (table 1). There was a tendency for the high IgA group to have a higher ESR and C reactive protein over the first 18 months than the low IgA group and controls. The long term outcome data demonstrated no significant difference in joint damage, joint replacement surgery, or mortality.
As far as we know, this study is the first to examine long term outcome in patients with RA with abnormal IgA levels, and to investigate the prevalence of IgA deficiency. The latter has been associated with other autoimmune diseases, suggesting that it may predispose a person to autoimmune dysfunction. Although most cases of primary IgA deficiency are spontaneous, familial cases have been described. In our study, IgA deficient patients were more likely to have a history of RA in first degree relatives, suggesting inheritance of a predisposing factor. Though numbers were small, no similar published study was found. The lack of power caused by small sample sizes might have prevented us demonstrating more significant differences. None the less, the findings are of interest. As in previous work the high IgA group possibly had more active disease. However, there was little overall difference between the patients with abnormal IgA levels and the controls. These findings do not support a role for IgA as a key factor in the pathogenesis of RA, or its clinical presentation.
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