Clinical and pathological significance of anti-lipocortin autoantibodies in rheumatoid arthritis

Podgorski, Mark Richard (1988) Clinical and pathological significance of anti-lipocortin autoantibodies in rheumatoid arthritis. University of Southampton, Doctoral Thesis.

Abstract

Corticosteroids induce the formation of novel proteins, the lipocortins, which inhibit phospholipase A₂ activity, and thus mediate the anti-inflammatory actions of corticosteroids. Clinical observations of reduced efficacy and prolonged requirements of oral corticosteroid treatment in some patients with rheumatic diseases, particularly rheumatoid arthritis (RA), have led to the hypothesis that antibodies directed against lipocortin(s) may impair corticosteroid therapeutic effects. An enzyme-linked immunosorbent assay (ELISA), using recombinant lipocortin-1 as substrate, with specificity for anti-lipocortin-1 autoantibodies (ALA), has been developed. RA patients have elevated (ALA) levels in association with prolonged daily oral prednisolone therapy of > 7.5 mg, independent of disease activity and of corticosteroid-related side effects. However, in systemic lupus erythematosus and RA patients complicated by Felty's syndrome, elevated ALA levels are unassociated with corticosteroid therapy, but instead correlate with features of active immunoregulatory disturbances. Patients with polymyalgia rheumatica and corticosteroid-dependent asthma, despite prolonged and high daily maintenance dose corticosteroid treatment, do not have elevated ALA levels. Commencement of oral corticosteroid therapy can lead to significant elevation of ALA levels in RA. However, high dose intravenous methylprednisolone therapy does not lead to induction of ALA; instead, initially elevated ALA levels fell significantly eight weeks post-treatment onset. Elevated ALA in RA patients, either due to oral corticosteroid treatment or vasculitis, were associated with impaired efficacy of intravenous methylprednisolone treatment. In order to assess a functional role of ALA in affecting CS actions in vivo, a standardised hydrocortisone stimulation test (HST) challenge was used in matched RA patient groups to determine if ALA impaired corticosteroid effects. Patients with high ALA levels had impaired HST-induced lymphopaenic responses, particularly amongst peripheral blood lymphocyte subsets that stained with the monoclonal antibodies CD8⁺ (T suppressor cells), CDW29⁺ (T helper/inducer cells), WR18⁺ (MHC class-II⁺ cells), when compared to RA patients with normal ALA levels. These findings support the concept that ALA are responsible, at least in part, for impaired responses to corticosteroids, both exogenous and endogenous, and thus contribute to perpetuating pathogenetic inflammatory mechanisms. (DX88266)

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