Objectives To evaluate in a cross-sectional study the relationship between the clinical/radiological disease outcome, the presence or absence of RA-associated HLA-DRB1* alleles and circulating levels of IL-1ra in patients with rheumatoid arthritis.
Methods 120 patients, stratified in sub-groups defined by disease duration, RF status and HLA-DRB1* typing were analysed for an association between disease course and circulating levels of IL-1ra. HLA-DRB1* allele typing was performed by standard methods, IL-1ra and other cytokines (IL-6, IL-8, sTNFR55/75) were measured using commercially available ELISA reagents. Patient’s characteristics assessed included inflammatory disease activity by clinical and standard laboratory measures. Radiographic disease progression was determined by the Steinbrocker method.
Results There was inverse correlation between circulating IL-1ra levels and radiographic outcome in the patient population with a disease duration < 5 years (Pearson correlation coefficient: – 0.23; p < 0.03). In most of the sub-populations analysed IL-1ra correlated strongly with the levels of IL-6, IL-8, and sTNFR 55/sTNFR75s. In Subgroups of patients defined by HLA-DRB1* typing, patients (n = 30) with clinical and radiographic evidence for a more severe disease course were positive for a double-dose of HLA-DRB1* 0404/0401 or positive for a combination of a HLA-DRB1* 040x allele with the HLA-DRB1* 0101 allele. These patients presented with significantly (p = 0.01) lower IL-1ra levels (mean: 384 pg/ml) than patients (n = 37) bearing none the RA-linked HLA-DRB1* alleles (mean: 1197 pg/ml). IL-1ra levels in healthy controls (n = 22; mean: 337 pg/ml) were comparable with IL-1ra deficient patients bearing a double gene dose. When only one of the suspected HLA-DRB1* alleles was present, IL-1ra levels were in the intermediate range (n = 42; mean: 626 pg/ml).
Conclusion IL-1ra deficiency appears to predispose patients to a more aggressive disease course of rheumatoid arthritis, whereas in other patients synovial IL-1ra production in response to increased IL-1 activity represents a physiological mechanism to restore the balance between pro-inflammatory and anti-inflammatory activity.
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