Abstract
The management of rheumatoid arthritis (RA) is primarily based on the use of disease-modifying antirheumatic drugs (DMARDs), mainly comprising synthetic chemical compounds (that is, methotrexate or leflunomide) and biological agents (tumor necrosis factor inhibitors or abatacept). On the other hand, glucocorticoids (GCs), used for decades in the treatment of RA, are effective in relieving signs and symptoms of the disease, but also interfere with radiographic progression, either as monotherapy or in combination with conventional synthetic DMARDs. GCs exert most of their biological effects through a genomic action, using the cytosolic GC receptor and then interacting with the target genes within target cells that can result in increased expression of regulatory - including anti-inflammatory - proteins (transactivation) or decreased production of proinflammatory proteins (transrepression). An inadequate secretion of GCs from the adrenal gland, in relation to stress and inflammation, seems to play an important role in the pathogenesis and disease progression of RA. At present there is clear evidence that GC therapy, especially long-term low-dose treatment, slows radiographic progression by at least 50% when given to patients with early RA, hence satisfying the conventional definition of a DMARD. In addition, long-term follow-up studies suggest that RA treatment strategies which include GC therapy may favorably alter the disease course even after their discontinuation. Finally, a low-dose, modified night-release formulation of prednisone, although administered in the evening (replacement therapy), has been developed to counteract the circadian (night) rise in proinflammatory cytokine levels that contributes to disease activity, and might represent the way to further optimize the DMARD activity exerted by GCs in RA.
Highlights
Rheumatoid arthritis (RA) is a multifactorial, chronic inflammatory and immune-mediated syndrome that causes joint damage, but can in selected patients present with different tissue and organ involvement [1]
Today there is clear evidence that GC therapy, especially long-term, low-dose treatment, slows down radiographic progression by at least 50% when given to patients with early RA, satisfying the conventional definition of a disease-modifying antirheumatic drug (DMARD) [38]
GCs during long-term treatment of RA provide most of their effects through a genomic action using the cytosolic glucocorticoid receptor (cGR) and interacting with the target genes that can result in increased expression of regulatory – including anti-inflammatory – proteins or decreased production of proinflammatory proteins
Summary
Rheumatoid arthritis (RA) is a multifactorial, chronic inflammatory and immune-mediated syndrome that causes joint damage, but can in selected patients present with different tissue and organ involvement [1]. A dose of 20 mg/day prednisolone was used in clinical trials in 1960 (after GCs were available for treatment) to compare with aspirin, and while DMARD properties were well documented in RA patients, the conventional wisdom at that time was that low doses were not disease modifying (that is, did not decrease joint damage as assessed radiographically) [32,33]. Is possible to state there is clear evidence that low-dose, long-term GC therapy slows radiographic progression by at least 50% in treated early RA patients and GCs exert disease-modifying effects [50,51,52]. The clinical and biochemical improvement observed after GC therapy in patients with RA and polymyalgia rheumatica might be attributed to a direct dampening of proinflammatory factors as well as to the restoration of the steroid milieu, a sort of GC replacement therapy [61]
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