Chrysiasis: Gold Aggregates Around a Nevus and Osteoma Cutis.

ABSTRACT: Parenteral gold has historically been used to treat several conditions, including rheumatoid arthritis. Gold administration leads to a variety of cutaneous reactions, including chrysiasis, which is a permanent blue-grey hyperpigmentation of the skin due to dermal gold deposition. In this report, we describe the case of a patient who received parenteral gold injections 22 years before the onset of her chrysiasis for the treatment of rheumatoid arthritis. Biopsy of the macules showed dermal gold deposits aggregating around a melanocytic nevus, as well as around preexisting osteoma cutis. To the authors' knowledge, this is the first report in the literature describing a case of chrysiasis with gold deposits concentrated around a melanocytic nevus and an area of osteoma cutis.

Localized chrysiasis, aluminum salt deposition and dystrophic calcification a decade after gold injections.

Localized chrysiasis is rare and can occur in two settings: after localized or traumatic implantation of elemental gold or gold salts or after localized laser or light therapy in someone who has been previously exposed to systemic gold therapy. We report a unique case of localized chrysiasis with associated aluminum salt deposition and sclerosing lipogranulomas because of previous injections of aurothioglucose (Solganal®). The unique histopathologic findings seen in this case have not been previously reported.

Serum IgA and gold-induced toxic effects in patients with rheumatoid arthritis.

Serum Immunoglobulin concentrations were measured prospectively in 25 patients with rheumatoid arthritis at months 0, 1, 3, 6, and 12 of aurothloglucose treatment. Substantial lowering of IgA and IgM levels was found at month 3 and thereafter, and of IgG at month 12 only. When patients in whom drug-induced toxic effects developed at any time during treatment (toxic group) were compared with those who did not (nontoxic group), serum levels of IgA and to a lesser degree of IgG, but not of IgM, were found to be substantially lower in the toxic than in the nontoxic group, both at the onset and during treatment, except for IgG at month 12. When measured at the moment of toxic effect, only igA, but not IgG and IgM, was substantially lower than in serum samples of patients without toxic effects at that moment. The serum IgA concentration in patients with rheumatoid arthritis seems to be related to whether or not aurothioglucose-induced toxic effects occur.

Increased renal tubular cell excretion by patients receiving chronic therapy with gold and with nonsteroidal anti-inflammatory drugs.

Using rheumatoid arthritis patients who were receiving gold as models, we evaluated the renal effects of the chronic administration of very low doses of a nephrotoxic drug. The heavy metal gold has been shown to increase urinary enzyme excretion when it is given in usual doses for the treatment of rheumatoid arthritis. It is not clear whether the increased urine enzyme excretion caused by long-term drug therapy represents injury to the kidney or whether it is merely an effect of the drug. Urinary N-acetyl-beta-glucosaminidase and renal tubular cell excretion rates were measured in 19 patients who were receiving chronic treatment with gold and with nonsteroidal anti-inflammatory drugs for rheumatoid arthritis, in 10 patients who were receiving nonsteroidal anti-inflammatory drugs, and in 8 healthy control subjects. No subjects showed evidence of kidney disease. Both renal tubular cell and enzyme excretion rates were elevated in the gold-treated group. This showed that there was increased renal tubular cell turnover in this group, which suggests low level renal tubular injury and not merely an effect of the usual dose of gold.

Lymphadenopathy and lymph node infarction in the course of gold therapy.

Lymphadenopathy, as a complication of gold therapy, appears to be an uncommon occurrence. Lymph node infarction has not been previously documented in this setting. The unique pathologic features in this case may reflect: a phenomenon specific to gold; early examination of the infarcted node; or underlying leukocytoclastic angiitis secondary to gold toxicity. Polymorphonuclear leukocytic infiltration of an infarcted lymph node has apparently not been previously reported.

Auranofin versus placebo in the treatment of rheumatoid arthritis.

In a six-month, multicenter, double-blind study involving 340 patients, auranofin, 3 mg twice daily, was compared with placebo in the treatment of adult-onset rheumatoid arthritis. All patients were continued on a therapeutic regimen of salicylates and/or a newer nonsteroidal anti-inflammatory drug. Patients in both treatment groups who completed six months of therapy with coded medications showed significant improvement in the clinical features of rheumatoid arthritis (that is, number of tender and swollen joints, severity of pain, grip strength and duration of morning stiffness); however, the mean improvement was greater in the auranofin-treated group. Fifty-two percent of the auranofin-treated patients compared with 24 percent of the placebo-treated patients (p less than 0.05) were judged by their physician to have shown marked or moderate improvement. Only in the auranofin-treated patients was there significant improvement from baseline in the laboratory parameters of disease activity: erythrocyte sedimentation rate, IgA, IgG, and IgM. After at least three months of therapy, 30 percent (46 of 152) of the placebo-treated patients but only 9 percent (13 of 152) of the auranofin-treated patients (p less than 0.05) withdrew from coded medication due to insufficient therapeutic effect. Study medication was discontinued by 5 percent (eight of 152) of the auranofin-treated patients and 3 percent (four of 152) of the placebo-treated patients because of adverse therapy events (p = 0.24). This study demonstrates the efficacy of auranofin when added to salicylates and/or nonsteroidal anti-inflammatory drugs in the treatment of rheumatoid arthritis.

A 12-month comparative trial of auranofin and D-penicillamine in rheumatoid arthritis.

The oral gold salt auranofin, 6 mg per day, was compared with oral d-penicillamine, 500 mg per day, in a single-blind trial in 40 patients suffering with definite or classic rheumatoid arthritis. The patients were randomly allocated into the two therapeutic regimens (19 patients auranofin; 21 patients d-penicillamine) and monitored at a minimum of four-week intervals during the first year of treatment. Significant diminution in rheumatoid disease activity, as assessed by numerous clinical and laboratory parameters, was observed in both the auranofin- and penicillamine-treated groups. No significant differences existed for these parameters between the two groups, either initially or at the end of the trial period. Ten patients were lost from the trial over the 52-week period. Three subjects were withdrawn from the auranofin-treated group (increasing severity of rheumatoid arthritis at four weeks; severe diarrhea at four weeks; probable drug-related erosive gastritis at 40 weeks). Seven subjects were permanently withdrawn from the penicillamine-treated group (four, skin rashes four to eight weeks; one, heavy proteinuria at 24 weeks; one, therapeutic failure at 32 weeks; one, compliance failure at eight weeks), and treatment was temporarily withheld in three further patients because of thrombocytopenia (two) and proteinuria (one). We conclude that both drugs are effective in rheumatoid arthritis and that the lesser toxicity with auranofin will make it a valuable addition to our therapeutic armamentarium.

Gold therapy in patients with systemic lupus erythematosus.

Despite a progressively more favorable prognosis in systemic lupus erythematosus (SLE) a need remains for therapeutic agents with greater benefit and less toxicity than corticosteroids and immunosuppressive drugs. Therefore, we treated 16 patients with SLE but without renal diseases with auranofin, a drug with proved efficacy and safety in rheumatoid arthritis. A modest diminution in overall disease activity, as judged by the investigators, and a reduction in maintenance corticosteroid dosage was achieved. However, neither laboratory assessments nor more objective clinical measurements of SLE disease activity disclosed any improvement over baseline. One case each of proteinuria and thrombocytopenia was observed, most likely related to underlying disease and not the drug, suggesting that auranofin may be safe in patients with SLE. A controlled trial, utilizing a broader spectrum of patients with SLE, may be warranted.

Auranofin: dose-related risk to benefit.

Two separate, double-blind studies examined the most appropriate starting dose of auranofin, an orally administered gold compound, for the management of rheumatoid arthritis. One study indicated that neither of the two tested doses, 1 or 9 mg auranofin daily, was ideal; the 1 mg dose was insufficient therapeutically, whereas the 9 mg dose was associated with frequent lower gastrointestinal side effects. In the other study, which compared 2 and 6 mg auranofin daily, both doses resulted in similar clinical improvement and untoward effects, although the higher dose had greater efficacy sooner. Thus, it appears that 6 mg auranofin daily is the most appropriate starting dose.

Early experiences with auranofin in juvenile rheumatoid arthritis.

Pharmacologic management of juvenile rheumatoid arthritis is only one of several modalities necessary for effective control. The stepping stones to proper management include a planned long-range program, physical therapy with swimming, good health habits, and consultation with other health professionals who are part of the management team. Pharmacologic therapy includes nonsteroidal anti-inflammatory drugs initially, occasionally corticosteroids, and slow-acting antirheumatic drugs, including injectable gold when therapeutic response is inadequate. Early experiences with oral gold are reported here. Auranofin (triethylphosphine gold) was administered to 21 patients with juvenile rheumatoid arthritis during a segment I, open ended, open-label, noncontrolled trial designed to establish safety and preliminary efficacy. Initial dosage was 0.1 mg/kg per day; incremental increases to 0.2 mg/kg per day were allowed (with usual increase to 0.15 mg/kg per day). Aspirin (80 mg/kg per day) or tolmetin (20 to 40 mg/kg per day), or naproxen (400 to 600 mg/m2 per day) were allowed as rapidly acting antiinflammatory agents. Stable measurable plasma concentrations of gold were attained in all patients during the study. More than half the patients sustained clinically significant improvement (greater than 25 percent) with regard to the number and severity of joints with swelling, pain on motion, and tenderness. In nine of the 19 patients, the total number of joints with active arthritis decreased by at least 25 percent. All articular disease indices measured indicated improvement of group mean changes between the initial and final visit. Eleven of 16 patients with an elevated erythrocyte sedimentation rate showed decreases of at least 25 percent. The group given higher dosages had a greater proportion of responders in regard to decreases in erythrocyte sedimentation rate (nine of 11 patients). Four of six patients whose serums contained rheumatoid factor showed decreases in the titers. Discontinuation of auranofin was necessary in two patients: one because of headache and one because of hematuria and anemia associated with a severe flare-up of polyarticular disease. The results from this trial reveal sufficient patient improvement to plan a double-blind trial of auranofin in children with juvenile rheumatoid arthritis.

Auranofin: experience to date.

Auranofin, an oral gold-containing medication for the treatment of rheumatoid arthritis, has unique chemical, pharmacologic, and kinetic characteristics. Clinical improvement is achieved with lower blood gold levels than with parenteral gold compounds. More than 3,000 patients with rheumatoid arthritis in 27 countries have been treated with auranofin to date. In many patients, experience with auranofin extends beyond three years, and in some it exceeds four years. Available information indicates that auranofin (3 mg twice a day) is superior to placebo therapy, with similar efficacy and greater safety than gold sodium thiomalate.

Auranofin. A preliminary review of its pharmacological properties and therapeutic use in rheumatoid arthritis.

Auranofin is the first orally active gold compound for the treatment of rheumatoid arthritis. Like other chrysotherapeutic agents, its exact mechanism of action is unknown, but it probably acts via immunological mechanisms and alteration of lysosomal enzyme activity. Although long term clinical experience with auranofin is limited, its efficacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothioglucose, hydroxychloroquine and D-penicillamine are required before definitive statements can be made regarding the relative efficacy of auranofin and these agents. While patients have demonstrated clinical remission of rheumatoid arthritis in response to auranofin therapy, radiological studies have been inconclusive regarding its effect on the occurrence or progression of erosive lesions. Auranofin is relatively well tolerated in most patients, but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are potentially serious side effects which may occur during therapy. Whereas mucocutaneous side effects are more frequent with injectable gold compounds, gastrointestinal reactions are the most common adverse effect seen with auranofin. The frequency of side effects has been similar with auranofin and sodium aurothiomalate, but they are generally less severe with auranofin. While some of the side effects are controlled by a reduction in dosage, temporary or permanent withdrawal of auranofin may be necessary. Auranofin is clearly a useful addition to the limited list of agents with disease-modifying potential presently available for the treatment of rheumatoid arthritis. It will doubtless generate much interest as its final place in therapy becomes better defined through additional well-designed studies and wider clinical experience.

Chrysiasis resulting from gold therapy in rheumatoid arthritis: identification of gold by x-ray microanalysis.

A patient with blue-gray discoloration of the skin of her face, neck, and hands is described. She was a patient with rheumatoid arthritis who had received a large total cumulative dose of gold. Light microscopy of skin biopsy tissue from the forehead revealed deposits of heavy metal in macrophages. On electron microscopy, the particles were found in the lysosomes of the cell. X-ray microanalysis confirmed the presence of gold. This condition, which is called chrysiasis, may be incorrectly diagnosed as cyanosis.

Auranofin: a unique oral chrysotherapeutic agent.

Auranofin is a chemically unique gold coordination complex with demonstrated antiarthritic properties on oral administration. Its pharmacokinetic and immunologic profiles are distinct from injectable gold compounds. When auranofin is added to a regimen of salicylates and/or a nonsteroidal antiinflammatory drug for the treatment of RA, significant additional therapeutic benefit is observed. Published studies indicate that auranofin given 6 mg per day approaches the efficacy of parenteral gold salts in the treatment of rheumatoid disease. Noticeable improvement in clinical and laboratory parameters of disease activity has been observed by the third month of auranofin therapy. Further benefit occurs in some patients during the remainder of the first year of treatment. In the more than 3,000 patients treated with auranofin, the most frequently reported side effects were gastrointestinal (mainly diarrhea) and mucocutaneous. Most side effects were mild in nature and the withdrawal rate due to all adverse reactions averaged 11%. Auranofin differs from injectable gold by producing more gastrointestinal but fewer mucocutaneous reactions. The severity of these reactions is less with auranofin and causes fewer withdrawals from therapy.

Longitudinal changes of serum insulin concentration and insulin antibody features in persistent insulin autoimmune syndrome (Hirata's disease).

In a 56-year-old woman with granulomas of gold thioglucose in her hips, who developed insulin autoimmune syndrome, the relationships among the frequency or severity of hypoglycemic attacks, serum insulin (IRI) concentration, and characteristics of insulin antibodies were investigated during the clinical course with steroid treatment and two resection operations for the gold-thioglucose granulomas. When hypoglycemia was severe, the total IRI level was elevated, and Scatchard analysis showed that a high-affinity (k1), low-capacity (b1) population of antibodies had a relatively low affinity constant and very high binding capacity compared with the same population of antibodies in insulin-treated diabetic patients. When the attacks were relieved by steroid treatment and/or granuloma resection operation, the total IRI level was decreased and the high-affinity (k1), low-capacity (b1) population of antibodies showed a higher affinity constant and a lower binding capacity than those during the attacks. This indicated that the antibodies changed their characteristics to release insulin into the serum. The k1/b1 population of insulin antibodies with the lower affinity constant and higher binding capacity may easily release human insulin into the serum, leading to hypoglycemia. The longitudinal change of the k1/b1 population suggests a clonal change of the B cells producing the insulin antibody in insulin autoimmune syndrome.

Prospective studies of thyroid function in patients receiving gold therapy.

Gold inhibits the Type I deiodinase that provides the bulk of circulating T3 in humans. We prospectively studied thyroid function in patients receiving increasing parenteral cumulative gold doses. Eight consecutive euthyroid patients with rheumatoid or psoriatic arthritis who were initiating intramuscular gold therapy were enrolled. Serum thyroid hormone levels (total T4, T3, and rT3) and TSH were measured for each subject at various levels during gold therapy. For analysis, the free T4 and free T3 indices, TSH concentrations, and T4/T3 ratios were correlated with cumulative gold dose. Neither individual nor pooled linear regressions showed a significant correlation between cumulative gold dose and any of the thyroid function parameters. Thyroid function is not affected in patients receiving up to 1500 mg of gold compounds. The most likely explanation for this is that gold principally accumulates in the Kupffer cells and renal cortex and these cells do not express Type I deiodinase.

Beta-thioglucose inhibits gold thioglucose lesions in the ventromedial hypothalamus.

Gold thioglucose (GTG) has been known to be an obesity causing agent for over 40 years. GTG works by affecting dendrites in the mouse ventromedial hypothalamus (VMH) producing a permanent VMH lesion and subsequent hyperphagia and obesity. We have investigated the effect of beta-thioglucose (BTG), a glucose antimetabolite, on GTG-induced lesions in the VMH of mice. Twenty-eight female CF-1 mice were used in this study. Seven micron sections were made of the mouse VMH, mounted on glass slides, and stained with hematoxylin and eosin. A previous report of BTG action on GTG-induced lesions has not supported a competitive inhibition between these two drugs. Our data demonstrate that at 1/2 hour, 6 hours, and 12 hours post BTG, BTG completely inhibited GTG-induced lesions in the VMH.

Gold-induced colitis: a case report and review of the literature.

A case of severe colitis requiring subtotal colectomy following administration of 35 mg Solganal b for intractable arthritis is described. Abdominal pain and watery diarrhea developed six weeks after the last dose of gold. Colonoscopy revealed mucosal edema and ulceration of the entire colon. Supportive measures failed and the patient required subtotal colectomy. Review of the literature revealed 29 cases, ranging in severity from limited ileal involvement to fulminant panenteritis. Most of the patients responded to intravenous fluids, steroids, and antibiotics, but four required surgery. The case described is notable for the delay in appearance of abdominal symptoms following the cessation of gold therapy. The mechanism of injury is unknown. Abdominal complaints in a patient who has received gold therapy, especially parenteral, merit strict attention, even if occurring several weeks after the final dose, and the diagnosis of gold colitis should be entertained.

Chronic interstitial nephritis associated with gold therapy.

A patient suffered chronic interstitial nephritis after receiving large quantities of gold salts for rheumatoid arthritis. Gold deposits were seen with transmission electron microscopy and confirmed by microprobe x-ray analysis both within renal tubular epithelial cells and interstitial macrophages and free within the renal interstitium. Clinical resolution of renal failure followed discontinuation of therapy with gold salts. Probable mechanisms of injury to renal tubular epithelial cells include uptake of gold by tubular epithelial cells and incorporation of gold into mitochondria, with subsequent cellular injury; interstitial deposits probably occur after necrosis of tubular epithelial cells, with release of gold into the interstitium and resultant inflammation. Thus, chronic interstitial nephritis can be added to the patterns of renal injury seen after gold therapy for rheumatoid arthritis.