Gold is a precious metal that has been used as a treatment for rheumatoid arthritis (RA) for over 80 years — gold sodium thiomalate and aurothioglucose (the two gold compounds that have been used clinically) are classified as disease-modifying anti-rheumatic drugs (DMARDs) because they can slow or halt the progression of joint destruction in RA, rather than merely suppressing the symptoms of inflammation. The mechanism by which gold improves RA is not fully characterised, but the evidence suggests that it involves the modulation of the immune system (particularly the activity of macrophages and the production of pro-inflammatory cytokines), the inhibition of the NF-kappaB inflammatory pathway, and the direct effects of gold ions on the synovial fibroblasts and osteoclasts that are the primary mediators of joint destruction in RA. While the introduction of the biologic DMARDs (TNF inhibitors, IL-6 inhibitors, CTLA4-Ig) has reduced the clinical use of gold in RA, gold remains a valid treatment option for patients who cannot afford or tolerate the newer biologic agents — particularly in health systems where cost is a major determinant of treatment access.
The Pathogenesis of Rheumatoid Arthritis
Rheumatoid arthritis is a chronic autoimmune disease that is characterised by inflammation of the synovial lining of the joints, leading to the accumulation of inflammatory cells (macrophages, T lymphocytes, B lymphocytes, plasma cells), the proliferation of synovial fibroblasts, and the progressive destruction of articular cartilage and subchondral bone. The primary mediators of this joint destruction are the synovial fibroblasts (which proliferate abnormally and produce the matrix metalloproteinases that degrade cartilage) and the osteoclasts (which are activated by the inflammatory cytokines in the rheumatoid joint and which resorb the subchondral bone). The inflammatory cytokines that drive this process — particularly TNF-alpha, IL-1 beta, and IL-6 — are produced by the activated macrophages and T lymphocytes in the rheumatoid synovium and are the primary targets of the biologic DMARDs that have transformed the treatment of RA over the past 25 years.
Gold modulates the immune system at multiple points in the rheumatoid inflammatory cascade. It reduces the activity of macrophages (the primary producers of TNF-alpha and IL-1 in the rheumatoid joint), inhibits the production of pro-inflammatory cytokines by mononuclear cells, reduces the expression of adhesion molecules on endothelial cells (which are required for the recruitment of inflammatory cells into the joint), and inhibits the NF-kappaB transcription factor (the master regulator of the inflammatory gene expression program in macrophages and synovial fibroblasts). These immunomodulatory effects are complemented by direct effects on the effector cells of joint destruction — gold ions inhibit the activity of synovial fibroblasts and reduce their production of matrix metalloproteinases, and gold ions inhibit the formation and activity of osteoclasts (the bone-resorbing cells that are primarily responsible for the bone erosions that characterise rheumatoid arthritis).
Clinical Evidence
The clinical evidence for gold in RA is moderate in quality but consistently positive. A Cochrane systematic review of gold therapy in RA found that gold sodium thiomalate and aurothioglucose significantly reduced the number of swollen and tender joints, reduced morning stiffness, improved functional capacity, and reduced the erythrocyte sedimentation rate (a marker of systemic inflammation) compared to placebo. radiographic studies showed that gold therapy slowed the progression of joint damage in patients with RA, confirming its disease-modifying activity. The onset of action of gold is slow — it may take 3-6 months to achieve maximum benefit — but the effects are sustained for many years in patients who respond. The most common adverse effects of gold therapy are mouth ulcers (which are a dose-limiting toxicity in approximately 10-20% of patients), proteinuria (which is a warning sign of gold-induced nephropathy and requires monitoring), and in rare cases, bone marrow suppression (which requires immediate discontinuation of gold therapy). Approximately 50-70% of patients with RA respond to gold therapy, and the response is more likely in patients with early RA (within 2 years of onset) and in patients with rheumatoid factor positivity.
Practical Application
Gold therapy for RA is administered by intramuscular injection, typically as gold sodium thiomalate or aurothioglucose at doses of 10-50mg weekly for the first 20 weeks (a gradual escalation to full dose to reduce the risk of adverse effects), followed by maintenance doses of 50mg every 2-4 weeks for as long as the patient continues to respond. The most common adverse effects are mouth ulcers, skin rash, proteinuria, and (rarely) bone marrow suppression — all of which require monitoring and dose adjustment. Gold is contraindicated in pregnancy (it can cause fetal harm) and in patients with a history of renal disease, liver disease, or blood dyscrasias. For comprehensive RA management, gold pairs well with conventional DMARD therapy (methotrexate as the anchor drug), biologic DMARDs (for patients who do not respond to conventional DMARDs), omega-3 fatty acids (for the reduction of inflammatory prostaglandins and leukotrienes), and vitamin D (for the management of the osteoporosis that commonly accompanies long-term corticosteroid use in RA patients).
Leave a Reply