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Chrysiasis
Chrysiasis
Chrysiasis
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Chrysiasis
SpecialtyDermatology Edit this on Wikidata

Chrysiasis is a dermatological condition induced by the parenteral administration of gold salts, usually for the treatment of rheumatoid arthritis.[1]: 859–60  Such treatment has been superseded as the best practice for treating the disease because of "numerous side effects and monitoring requirements, their limited efficacy, and very slow onset of action".[2]

Similar to silver, a gold preparation used parenterally for a long period may rarely produce a permanent skin pigmentation – especially if the skin is exposed to sunlight or artificial ultraviolet radiation.

The skin's pigmentation (in this condition) has been described as uniformly gray, grayish purple, slate gray, or grayish blue, and is usually limited to exposed portions of the body. It may involve the conjunctivae over the scleras but usually not the oral mucosa. Location of pigment predominantly in the upper dermis leads to the blue component of skin color through the scattering phenomenon. It is much less likely to be deposited in the nails and hair.

Chrysiasis was said to have been much more common when medicines containing traces of gold were used for treatment of tuberculosis (commonplace forms of treatment nearly fifty years ago). Treatments containing gold traces were also used to treat cases of rheumatoid arthritis – but because the dose used for tuberculosis was higher than for arthritis, it has not afflicted many subscribing to such treatments.

Gold can be identified in the skin chemically by light microscopy, electron microscopy, and spectroscopy.

There is no way to reverse or treat chrysiasis.[citation needed]

See also

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Notes

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References

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Chrysiasis

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Chrysiasis is a rare, permanent dermatological condition characterized by blue-gray to grayish-purple pigmentation of the skin, particularly in sun-exposed areas, due to the deposition of gold particles in the following prolonged parenteral administration of gold salts. This discoloration arises from chrysotherapy, a historical treatment involving gold compounds like aurothioglucose or gold sodium thiomalate, most commonly used for since the 1930s, though its use has declined sharply since the 1990s with the advent of safer alternatives such as . The condition was first described in 1928 in a patient receiving gold for pulmonary , with early preparations like sanocrysin introduced in 1924. Clinically, chrysiasis typically manifests months to years after cumulative gold doses exceed 1–1.5 grams, starting with discoloration around the eyes and progressing to involve the face, neck, arms, and other photoexposed sites; it spares covered areas and is exacerbated by ultraviolet radiation, which mobilizes deposited . The pigmentation results from particles accumulating in macrophages and elastic fibers without causing inflammation, and it is more pronounced in fair-skinned individuals. Ocular chrysiasis, a related manifestation, involves asymptomatic deposits in the , , or lens, detectable via slit-lamp examination and occasionally causing glare but rarely vision impairment. Diagnosis relies on a history of therapy, clinical appearance, and confirming refractile particles under electron microscopy, with differentials including (silver-induced) or pigmentation. There is no curative treatment for chrysiasis, as the deposits are irreversible, though the pigmentation may partially fade over years if gold exposure ceases; patients are advised to avoid to prevent worsening. Emerging options like pulsed therapy (e.g., 595 nm wavelength) have shown promise in lightening discoloration and improving , as demonstrated in cases with multiple sessions yielding noticeable improvement after 13–16 months. Due to its rarity today, chrysiasis serves as a historical reminder of the risks associated with once-standard -based therapies for autoimmune diseases.

Signs and symptoms

Cutaneous manifestations

Cutaneous manifestations of chrysiasis are characterized by a permanent blue-gray to slate-gray pigmentation of the skin, resulting from the deposition of particles following prolonged parenteral . This discoloration arises due to the interaction of these particles with , producing a visible hue through in the . The pigmentation is most prominent in sun-exposed areas, reflecting the role of exposure in enhancing particle aggregation and visibility. The condition typically begins with a subtle discoloration around the periorbital region, which intensifies and spreads over months to years of , evolving into a deeper or slate-gray tone. It commonly affects the face, particularly starting periorbitally, and extends to the , dorsal hands, forearms, and other photo-exposed sites such as the upper trunk and arms. The severity correlates with cumulative doses exceeding 20 mg/kg or approximately 1.3–1.5 g, with the pigmentation becoming more widespread and intense in areas of greater sun exposure. Histologically, gold deposits are located in the upper (papillary) and reticular , often within macrophages, elastic fibers, endothelial cells, and extracellularly as particulate aggregates, contributing to the observed color via the where shorter blue wavelengths are scattered. In typical cases, mucous membranes, nails, and hair remain unaffected, distinguishing the pattern from more generalized pigmentary disorders. Rarely, with high cumulative doses or additional UV provocation, generalized chrysiasis may involve non-sun-exposed areas, leading to broader dermal pigmentation. This skin changes must be differentiated from , which presents similar discoloration but stems from silver exposure.

Ocular manifestations

Ocular manifestations of chrysiasis primarily involve the deposition of particles in various eye structures, most commonly observed during long-term chrysotherapy for conditions such as . These deposits are typically detected through slit-lamp biomicroscopy and are generally benign, with no reported impact on or . While typically , rare cases may involve mild glare or haze in bright conditions. Corneal chrysiasis is the most prevalent ocular finding, appearing as fine, scattered yellow-brown or reddish-purple granular deposits in the deep corneal stroma, often centrally or peripherally located. These deposits are visible in up to 97% of patients receiving continuous therapy, particularly after a cumulative dose exceeding 1 gram of elemental . The pigmentation correlates directly with the total administered dose, becoming more pronounced with prolonged treatment, and arises from gold particles diffusing into the corneal tissue via the aqueous humor. Conjunctival involvement occurs less frequently but can present as golden-brown pigmentation in the . Such pigmentation is confluent and diffuse in affected areas. Lens chrysiasis, occurring in approximately 36–55% of patients on long-term , is characterized by fine, dust-like yellowish deposits on the anterior lens capsule or along anterior suture lines, observed in patients with high cumulative exposure. These particulate deposits do not alter lens transparency or function and remain . Overall, ocular deposits in chrysiasis are and do not require intervention, though their presence serves as a marker of systemic accumulation. The incidence is higher in patients on parenteral salts, with deposits persisting indefinitely after cessation.

Causes and risk factors

Gold therapy indications

, also known as chrysotherapy, was initially developed in the early for the treatment of (TB), following Robert Koch's 1890 observation that cyanide inhibited the growth of in vitro. This led to the widespread use of , such as potassium aurocyanide, in TB patients during the 1910s and 1920s, often at high doses that carried significant toxicity risks, including early reports of cutaneous side effects resembling chrysiasis. By the 1920s, gold salts shifted to primary use as disease-modifying antirheumatic drugs (DMARDs) for (RA), particularly in cases of progressive joint inflammation unresponsive to other therapies. Introduced clinically by Jacques Forestier in , injectable became a cornerstone of RA management for over five decades, aiming to slow disease progression and reduce synovial inflammation. Less commonly, gold therapy was applied to , , systemic (SLE), and certain other autoimmune or inflammatory conditions, though evidence for efficacy in these areas was more limited compared to RA. Historical applications also extended briefly to other infectious diseases beyond TB, but these were largely abandoned due to inconsistent results and emerging antibiotics. The principal gold salts employed were water-soluble injectable forms administered intramuscularly, including sodium aurothiomalate (Myochrysine) and aurothioglucose (Solganal), each containing approximately 50% elemental by weight. These were preferred over oral agents like auranofin for their established in treating . In , gold salts exert immunomodulatory effects by inhibiting macrophage and , while suppressing pro-inflammatory cytokine production such as (TNF), interleukin-1 (IL-1), and IL-6, thereby mitigating autoimmune-driven joint damage.

Dosage and incidence

Chrysiasis develops in a substantial proportion of patients on long-term parenteral therapy for , with one clinical study of 40 Caucasian patients treated with intramuscular sodium aurothiomalate reporting visible cutaneous pigmentation in 31 cases (78%). The condition's incidence correlates directly with cumulative gold exposure, with visible changes emerging above a threshold of approximately 20 mg/kg body weight (equivalent to about 1.3–1.5 g for an average adult), and severity escalating at higher doses exceeding 1,500–2,000 mg, where rates in exposed cohorts can approach 50–80%. Parenteral routes, particularly intramuscular injections of gold salts like sodium aurothiomalate, are associated with greater risk than oral administration due to higher systemic absorption and tissue deposition, making intramuscular therapy the preferred method for despite the elevated chrysiasis potential. Historically, even higher cumulative doses administered for treatment amplified the likelihood compared to standard regimens. Pigmentation typically manifests insidiously months to years after ongoing , once the total cumulative dose surpasses 1–1.5 g, allowing initial gold particle deposits in the . In contemporary practice, therapy has been supplanted by alternatives such as , rendering chrysiasis exceedingly rare; its primary era of use spanned the to . The blue-gray discoloration of chrysiasis is more conspicuous in individuals with lighter skin tones owing to greater contrast against baseline pigmentation, while no gender predominance has been observed. Risk may be heightened by chronic UV exposure or use of photosensitizing agents, though these are secondary to cumulative dose.

Pathophysiology

Mechanism of pigmentation

Chrysiasis pigmentation results from the parenteral administration of salts, which dissociate into ions that are subsequently reduced to metallic particles and deposited in the and other tissues. These particles primarily accumulate in the reticular and papillary , where they bind to components including elastic fibers and , as well as endothelial cells.04707-9/fulltext) These particles often form aurosomes within lysosomes. The gold particles, typically measuring 10–100 nm in diameter, are phagocytosed by macrophages or persist in the , rendering them resistant to physiological clearance mechanisms. This deposition occurs without eliciting a typical inflammatory response, as the particles become inert following accumulation. The characteristic blue-gray discoloration arises from the Tyndall phenomenon, whereby the gold nanoparticles in the upper scatter visible light; shorter wavelengths (blue) are preferentially scattered and reflected, while longer wavelengths (red) are absorbed, producing the observed hue. Gold exhibits systemic distribution, accumulating in highest concentrations in the organs such as the liver, kidneys, and spleen, as well as the skin; dermal involvement is promoted by vascular access and UV-induced alterations in tissue.

Role of light exposure

(UV) radiation from sunlight mobilizes particles deposited in the and stimulates production, thereby enhancing the visibility and intensity of pigmentation in sun-exposed areas. This process results in a characteristic or purple discoloration that is most prominent on the face, , and hands, as UV alters the optical properties of the , making it more apparent through the . Studies have shown that even low cumulative doses of can lead to chrysiasis when combined with significant sun exposure, suggesting that UV accelerates the manifestation of pigmentation beyond what deposition alone would cause. UV radiation penetrates the and influences dermal changes, including increased production stimulated by deposits. Sun exposure not only deepens the color but may contribute to higher concentrations in exposed , contributing to localized . This interaction underscores why pigmentation is typically confined to photo-exposed regions, with non-exposed areas remaining unaffected despite systemic distribution. Q-switched lasers, such as (694 nm) or alexandrite (755 nm) types used for treating pigmented lesions like solar lentigines or tattoos, can induce localized chrysiasis by fragmenting intracellular gold particles in patients with a history of . The high-energy pulses fragment and reduce the size of gold particles, altering them to smaller nanoparticles and causing immediate dark blue-gray at the treatment sites due to changed light scattering properties. This complication can occur even years or decades after gold therapy cessation, as dormant deposits remain susceptible to laser-induced changes. Case reports illustrate this risk: a 60-year-old developed macules on her cheeks 26 years after intramuscular injections when treated with Q-switched alexandrite laser for facial pigmentation, resolving only after subsequent long-pulsed laser interventions. Similarly, a 49-year-old with experienced -gray macules on her hands, , and seven months post-Q-switched for solar lentigines, following a cumulative dose of 4.3-13 g over 10 years. These examples highlight the need for screening therapy history before laser procedures. Avoiding sun exposure serves a preventive role by halting the progression of pigmentation, as minimizing UV contact prevents further mobilization of gold and melanin stimulation around gold deposits. However, this measure does not reverse existing deposits, which are permanent, emphasizing the importance of early recognition and protection strategies like broad-spectrum sunscreen in affected individuals.

Diagnosis

Clinical evaluation

The clinical evaluation of suspected chrysiasis commences with a detailed patient history to identify prior exposure to gold salts. Patients are questioned regarding treatment with parenteral gold compounds, such as sodium aurothiomalate (Myocrisin) or gold thioglucose (Solganal), typically administered for rheumatoid arthritis (RA) or other inflammatory conditions like psoriatic arthritis. Key elements include the total cumulative dose, duration of therapy, and any associated symptoms, as pigmentation risk increases with doses exceeding 20 mg/kg of elemental gold. Additionally, the history assesses for ongoing RA activity or other potential gold toxicities, such as proteinuria or dermatitis, to contextualize the presentation. Physical examination focuses on inspecting sun-exposed for the hallmark blue-gray to slate-gray pigmentation, which develops insidiously and may go unnoticed by the patient. The discoloration preferentially affects photo-exposed areas, including the face, neck, dorsal hands, and forearms, with periorbital regions often exhibiting the earliest and most pronounced mauve-to-blue hue that progresses over time. The pigmentation spares covered areas and lacks associated , tenderness, or textural changes, aiding in its recognition during routine dermatologic assessment. Differential diagnosis is essential to distinguish chrysiasis from similar pigmentary disorders. Argyria, caused by silver deposition, typically produces more diffuse, generalized blue-gray discoloration not limited to sun-exposed sites. Amiodarone-induced pigmentation often manifests as yellow-brown to violaceous hues in photo-exposed skin among patients on long-term antiarrhythmic therapy. Hemosiderin deposits, seen in conditions like , yield localized brown pigmentation due to iron accumulation. These distinctions rely on correlating the history of exposure with the distribution and color of pigmentation. If ocular symptoms such as or visual haze are reported, slit-lamp biomicroscopy is indicated to evaluate for corneal and conjunctival deposits, appearing as yellow-brown glistening particles in the stroma without affecting in most cases. No routine laboratory tests are required for diagnosis, as chrysiasis is presumptively established through history and examination; any testing prioritizes excluding active or unrelated toxicities.

Histological confirmation

Histological confirmation of chrysiasis involves targeted tissue sampling and specialized or to detect deposits, distinguishing it from other causes of pigmentation. A , typically obtained via punch or shave technique from a clinically pigmented area such as the face or sun-exposed , is the primary method for verification. On hematoxylin and (H&E) , light microscopy reveals golden-brown granules within the , often aggregated in macrophages and located in the reticular and papillary layers in a perivascular distribution. For ultrastructural analysis, (TEM) of the sample identifies electron-dense particles, primarily within lysosomes of macrophages and occasionally associated with elastic fibers. These particles appear faceted and are confirmed as through ancillary techniques. Spectroscopic methods provide definitive elemental identification. Energy-dispersive X-ray microanalysis (EDXMA), often integrated with TEM, detects the characteristic spectral peaks of in the deposits. Alternatively, on homogenized tissue samples quantifies concentration, correlating with pigmentation severity and cumulative therapy dose. Ocular involvement is assessed non-invasively, as is rarely performed due to risks. Slit-lamp biomicroscopy visualizes deposits as fine, polychromatic granules in the , anterior stroma, or . In patients with a history of and symptomatic pigmentation, histological and spectroscopic confirmation correlates with the severity of pigmentation, as the amount of deposited relates to cumulative dose and clinical presentation.

Management

Prevention strategies

Preventing chrysiasis involves careful patient selection, dose management, and protective measures during gold therapy for conditions like . Patients at higher risk, such as those with occupations involving significant sunlight exposure or fair skin that may accentuate pigmentation, should be considered for alternative disease-modifying antirheumatic drugs (DMARDs) like or biologics to avoid initiating gold therapy altogether. Careful monitoring of cumulative gold exposure is essential, as pigmentary changes typically emerge after doses exceeding 1–1.5 g (approximately 20 mg/kg for an average adult) but can occur at lower doses. Regular toxicity assessments, including complete blood counts and urine protein checks every 1-2 weeks initially and monthly thereafter, help detect early renal involvement or other adverse effects that could exacerbate pigmentation risks. For all patients on gold therapy, rigorous sun protection is recommended to reduce light-induced gold deposition in the skin, including daily use of broad-spectrum with SPF 50 or higher, protective , hats, and avoidance of midday sun exposure (10 a.m. to 4 p.m.). These measures can limit the exacerbation of dermal even after therapy begins. Prior to Q-switched treatments for skin lesions, clinicians should screen for a history of gold therapy, as even remote exposure (up to 26 years prior) can trigger localized chrysiasis at treatment sites. If early signs of pigmentation appear during therapy, gold administration should be discontinued promptly to halt progression, though deposits may persist indefinitely.

Treatment options

Chrysiasis results in permanent deposition of gold particles in the skin, rendering the pigmentation irreversible with no effective reversal agents available. Chelation therapy, such as with , has been attempted but proves ineffective for removing gold from cutaneous tissues, as the deposits are bound within macrophages and . Cosmetic management offers limited options for partial improvement in select cases. The 595 nm pulsed can provide lightening of the blue-gray pigmentation by targeting vascular components and superficial particles, though it requires multiple sessions and is not suitable for all presentations. Q-switched lasers should be avoided, as they can exacerbate pigmentation by fragmenting particles and promoting their dispersal. Supportive care focuses on mitigating cosmetic concerns and emotional impact. Camouflage makeup, using opaque formulations with , can effectively conceal facial pigmentation for daily use. Psychological support is recommended to address distress from visible changes, improving through counseling or support groups. Case reports demonstrate modest success with pulsed dye laser therapy; for instance, one patient with generalized chrysiasis achieved approximately 50% reduction in pigment intensity after several sessions, alongside resolution of associated telangiectasias. Another report noted substantial clinical lightening after nine treatments, eliminating the need for constant makeup application. The prognosis for chrysiasis is benign, with no associated systemic effects or functional impairments beyond aesthetic concerns; management thus emphasizes quality-of-life enhancements rather than cure.

History

Development of chrysotherapy

The development of chrysotherapy began in the late 19th century with Robert Koch's observation that gold cyanide inhibited the growth of Mycobacterium tuberculosis in vitro, sparking interest in gold compounds as potential antitubercular agents. This discovery prompted the synthesis of various gold salts, such as Sanocrysin, which was introduced in 1924 and entered clinical trials for tuberculosis in the 1920s, marking the initial therapeutic application of gold in medicine despite mixed efficacy and notable toxicity. Building on these antitubercular efforts, French rheumatologist Jacques Forestier extended gold therapy to () in 1929, hypothesizing that the compounds' anti-inflammatory effects observed in patients could benefit , a condition then thought to have infectious origins. Forestier popularized injectable gold salts, reporting symptomatic improvements in joint pain and swelling among patients, and introduced the term "chrysotherapy" to describe this approach. His work, disseminated through clinical studies in the early 1930s, shifted gold therapy from toward rheumatologic use, establishing it as a novel . By the 1930s and 1940s, chrysotherapy gained widespread adoption across and the as a cornerstone for managing progressive , with gold salts like aurothioglucose and sodium thiomalate becoming standard injectable therapies in . The U.S. approved Myochrysine ( sodium thiomalate) in the 1940s, reflecting regulatory endorsement amid growing enthusiasm for its potential to halt disease progression, even as adverse effects emerged. This era saw peak utilization, with thousands of patients treated annually, underscoring 's role as the primary second-line agent before corticosteroids and other immunosuppressants. The term "chrysiasis," derived from the Greek chrysos meaning "," was first applied to describe the permanent blue-gray skin pigmentation resulting from gold deposition, initially reported in 1928 by Hansborg et al. among tuberculosis patients receiving higher cumulative doses than those later used in RA. These early cases, often involving periorbital discoloration exacerbated by sun exposure, highlighted a rare but distinctive , yet did not deter the therapy's momentum during its formative decades.

Decline in use

During the and , clinical trials such as the multicentre controlled study by the Empire Rheumatism Council highlighted the efficacy of gold therapy in while underscoring significant toxicities, including , , and chrysiasis, with overall adverse events occurring in approximately 10-15% of patients and prompting more cautious administration with strict weekly monitoring protocols for injections and laboratory assessments. By the , these concerns further limited its routine use, as physicians adopted slower dose escalation and frequent toxicity surveillance to mitigate risks. The introduction of safer disease-modifying antirheumatic drugs (DMARDs), beginning with in the late 1980s and followed by biologics in the 1990s, dramatically reduced gold prescriptions for by over 90%, rendering it largely obsolete as a frontline . Current guidelines, such as the 2021 American College of Rheumatology recommendations, do not endorse gold salts as initial or standard treatment, reserving them only for rare cases of refractory disease after failure of multiple alternatives. This shift has resulted in new chrysiasis cases approaching zero, with most documented instances stemming from patients treated in the mid-20th century. Despite its decline, gold therapy is acknowledged for pioneering effective RA management and demonstrating disease-modifying potential before modern agents, though it was phased out in most countries by the early 2000s.

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