Adverse reactions with oral and parenteral gold preparations.

Auranofin (triethylphosphine gold), an oral gold preparation, has recently been made available, and along with injectable gold preparations, is of therapeutic value for rheumatoid arthritis. Serious gold toxicity is uncommon, and drug-related deaths rare. Many potential adverse reactions are similar, including dermatitis, stomatitis, thrombocytopenia, leucopenia, and proteinuria, generally with increased incidence in the injectable gold-treated patients. Oral gold is associated with benign lower gastrointestinal side effects, including diarrhoea, loose stools and abdominal cramps that are often dose-related and resolve spontaneously. The incidence of severe reactions such as thrombocytopenia, aplastic anaemia and exfoliative dermatitis is lower with oral gold than injectable preparations, and contributes to a superior risk-benefit ratio. The treatment of gold toxicity depends on the type and extent of organ involvement.

Pharmacology of auranofin: overview and update.

Auranofin, the only approved oral gold complex of value in suppressing rheumatoid arthritis, differs from injectable gold compounds molecularly and pharmacologically. Although comparably efficacious, the side-effect profiles of oral and intramuscular gold differ, and the withdrawal rate for adverse reactions is several-fold lower with auranofin. Considerably less elemental gold is available to the internal milieu with auranofin than with gold sodium thiomalate (3 mg/week vs. 25 mg/week), a difference reflected in lower blood, synovial fluid and tissue gold levels. Approximately 25% of the administered auranofin dose is absorbed orally, and 85% is recovered in feces. Serum gold levels are 300-400 micrograms/dl one week after injectable gold and 60-70 micrograms/dl daily with auranofin (6 mg/d). But, surprisingly, the fraction of gold associated with the red blood cell fraction is higher with auranofin. Blood gold levels do not correlate with clinical response to treatment or frequency or type of adverse reaction, regardless of the gold preparation used. Similar results obtain with penicillamine. Methotrexate blood levels are not related to the development of hepatic fibrosis. The mechanisms of gold action in rheumatoid arthritis are unknown, despite the laboratory definition of multiple antiinflammatory, immunologic and other effects. Sulfhydryl binding activity, an established property of injectable gold compounds and penicillamine of potential importance pharmacodynamically, is limited with auranofin.

Genetic linkage analysis of the carpal tunnel syndrome.

Two generations of a family with autosomal dominant carpal tunnel syndrome were studied for genetic linkage to 20 informative polymorphic blood markers. No linkage was demonstrated between the syndrome and the markers tested; exclusion of close linkage (lod score less than -2.0) was found for MNSs, ACP, GALT, GPT, GLO, Hp, Gc, and Pi.

Intra-articular corticosteroids. An updated assessment.

Local corticosteroid injections are a relatively safe and effective adjunct in managing rheumatoid arthritis, other connective tissue arthropathies, and soft tissue rheumatism. Rheumatoid synovitis may be suppressed for three months or longer using relatively insoluble microcrystalline preparations. No convincing evidence exists, however, that joint erosive changes are retarded, and steroid injections should be considered ancillary to rest, physical therapy, nonsteroidal anti-inflammatory agents, and disease modifying antirheumatic drugs. The few controlled studies in hip and knee osteoarthritis have demonstrated only modest, fleeting beneficial effects. Nonetheless, clinical experience suggests that intra-articular steroids often ameliorate acute exacerbations of knee osteoarthritis associated with significant effusions, symptomatic involvement of interphalangeal and other nonweight-bearing articulations, synovial cysts, and lumbar facet arthropathy. Judicious use of intrasynovial injections seldom produces significant adverse effects. Iatrogenic infectious arthritis follows one in 14,000-50,000 injections. Rapid acceleration of cartilage attrition is observed rarely. The concept of "corticosteroid arthropathy" is based largely on subprimate animal studies and several anecdotal case reports; limited investigation of primate (monkey) models has shown no significant long-term deleterious effect on cartilage.

Comparison of the kinetics of parenteral and oral gold.

The intramuscular (gold sodium thiomalate and aurothioglucose) and the orally (auranofin) administered gold compounds exhibit contrasting patterns of absorption, excretion and body tissue and fluid levels. The parenteral compounds are fully absorbed after injection but negligibly absorbed orally. Approximately 25% of the gold in auranofin is orally absorbed. Serum gold levels peak several hours after injection during conventional weekly treatment, attaining concentrations of 600-800 micrograms/dl, and then decline gradually, reaching 300-350 micrograms/dl before the next injection. Whole blood gold levels with auranofin vary from 10 to 90 micrograms/dl with doses of 1-9 mg/day. Blood gold levels plateau after 6-8 weeks with the injectable compounds and after 12 weeks with oral gold, reflecting the shorter blood half-life of gold sodium thiomalate (5.5 days) than of auranofin (17-26 days). A larger fraction of gold is within or attached to circulating blood cells, especially erythrocytes, with auranofin than with injectable gold. Fourty percent of the administered dose is excreted during injectable chrysotherapy, and 75-100% is recovered in excreta with auranofin. Parenteral gold is excreted primarily in urine (70%) while auranofin gold is recovered primarily in faeces (95%). Approximately 43% of intravenous radiolabelled gold sodium thiomalate is retained in the body at 60 days and 30% at 180 days; only 15% of radiolabelled auranofin remains at 10 days and less than 1% at 180 days. During injectable therapy, the total body burden of gold rises steadily; preliminary studies suggest minimal tissue accumulation with auranofin.

Comparative pharmacokinetics of parenteral and oral gold compounds.

The pharmacokinetics of intramuscular and oral gold compounds differ widely. Aurothioglucose and gold sodium thiomalate absorption is complete; 25% of auranofin (AF) is absorbed. Blood gold concentrations with conventional parenteral treatment generally peak between 600-800 microgram/dl the day of injection and decline gradually to about 300 micrograms/dl 7 days later. Levels range between 30 and 100 micrograms/dl, using 2-9 mg/d AF, and show little variation. A smaller percentage of gold is found in the cellular fraction of blood with I.M. than with oral gold. The blood half-life is approximately 6 days with gold sodium thiomalate, and 21 days with AF. Forty percent of the administered dose of injectable gold is excreted; depending upon dosage, 75-100% of oral gold is recovered in excreta, which is a combination of unabsorbed and excreted gold. Nearly 70% of parenteral gold is excreted in the urine and 30% in feces, while only 5% of AF is in urine and 95% in feces. The amount of gold retained following intravenous 195Au-labelled gold sodium thiomalate is 43% at 60 days and 25% at 250 days, but only 15% with oral radiolabeled AF 10 days after ingestion. Synovial fluid gold levels are much higher with parenteral than with oral gold but the blood-to-synovial fluid ratio is similar. Skin gold concentrations rise steadily with injectable but not oral treatment, but hair and nail accumulation is insignificant. Corneal, lens, and skin chrysiasis may develop with parenteral therapy, but has not been recognized with AF.

Bacterial monarthritis due to Neisseria meningitidis in systemic lupus erythematosus.

Two patients with systemic lupus erythematosus developed monarticular infectious arthritis, in which Neisseria meningitidis was recovered from knee synovial fluid. In one instance, the sole manifestation of meningococcal disease was a chronic, indolent, erosive monarthritis. In the second, a febrile, bacteremic illness presented with an acute, septic arthritis.

Temporal fat pad sign during corticosteroid treatment.

Hypercortisolism alters the distribution of body fat, causing truncal obesity, moon facies, buffalo hump, and other localized fatty deposits. In a patient with a mixed collagen vascular disease (overlap syndrome), who received high systemic doses of prednisone, prominent painless bitemporal masses developed in association with moon facies. Punch biopsy specimens of the lesion disclosed normal adipose tisue. This unappreciated feature of hypercortisolism is described, and other clinical manifestations of glucocorticoid excess involving fat tissue are reviewed briefly.

Complications of local corticosteroid injections.

Unusual complications associated with local microcrystalline corticosteroid injections were observed in four patients with diverse rheumatic disorders. Adverse reactions included (1) bilateral digital flexor tendon rupture following carpal tunnel injection for idiopathic median nerve compression syndrome; (2) bowstring deformity of a finger after local corticosteroid treatment of psoriatic digital flexor tendonitis; (3) carpal tunnel infection following dorsal arthrocentesis of a wrist in a patient with rheumatoid arthritis; and (4) pronounced flushing of the face, neck, and chest after intrasynovial corticosteroid injection in a patient with psoriasis and arthritis. This article considers some physiologic actions of corticosteroids possibly responsible for development of these untoward effects.