There have been numerous case reports regarding localized contact dermatitis to gold (Supplementary Table 2, http://links.lww.com/DER/A3), particularly involving the eyelids, ears, hands, and neck.21,36,45,53–63 This may take the form of a chronic papular eruption.64 Airborne dermatitis has also been reported, particularly involving the eyelids and neck.65–67 Granulomatous and lymphomatoid reactions have been described at sites of piercings with gold jewelry.53,68–75
Reported causes of localized contact dermatitis are often secondary to jewelry and occupational exposures. Bruze et al45 found that patients suspected to be gold allergic did not have an increased incidence of positive patch tests to gold sodium thiosulfate in comparison with patients with no known sensitization to gold. In 106 patients who were noted to have positivity to gold, however, sites of dermatitis in areas exposed to gold jewelry, such as the ears and fingers, were overrepresented. Fleming et al76 found that 2 of 8 patients with a positive patch test to gold had been suspected to have gold allergy before testing and noted resolution of their dermatitis with avoidance of gold jewelry. Trattner and David40 found that 2 of 34 patients improved upon avoidance of gold.
The long-lasting nature of gold reactions may present a diagnostic challenge. Sperber et al4 shared a case of papular dermatitis and persistent patch test reaction to gold sodium thiosulfate, where the eruption failed to improve after 2 months of gold avoidance. The authors were unable to ascertain whether the patient was having a persistent reaction to gold or an unidentified exposure to gold, or whether the dermatitis was secondary to a different etiology entirely, exemplifying the diagnostic challenges inherent to gold allergy.
In 1 double-blinded crossover trial of 24 patients with known contact allergy to gold, the patients were randomized into 2 groups where 1 group was topically provoked to gold (15-mg gold sodium thiosulfate applied to the shoulder for 48 hours) and 1 group to the control, then epicutaneously patch tested with 10 aqueous dilutions of gold sodium thiosulfate. Blood was drawn before exposure and after each patch testing read. After 6 weeks, the experiment was repeated and the group that had previously been provoked with gold was now provoked with the control and vice versa. Higher blood levels of gold were associated with a lower minimal eliciting concentration on patch testing.52
Several questionnaire studies have evaluated the frequency with which patients with gold-positive patch tests experienced symptoms from gold contact. Bruze et al45 found no difference between gold-positive and gold-negative patients (16.7% for the gold-positive patients compared with 15.9% for the gold-negative patients). On the other hand, Sabroe et al36 in a similar study noted a large difference of 53.8% for the gold-positive group compared with 12.6% for the gold-negative group.
Systemic contact dermatitis occurs when an individual who is sensitized to an allergen via the cutaneous route subsequently reacts to the same allergen or a cross-reacting allergen via a systemic route, including oral, intravenous, intramuscular, inhalational, transmucosal, or transcutaneous. One of the earliest such reports was a case of an extensive contact dermatitis in a patient reacting to a gold-ball orbital implant.79 Subsequently, many more studies have substantiated the role of gold exposure in causing systemic contact dermatitis.
Intramuscular gold has been demonstrated to cause flares of previous patch test reactions to gold, as well as flares of dermatitis, in the setting of allergen-specific cytokine release. Moller et al80,81 challenged 10 gold-allergic patients with an intramuscular dose of gold sodium thiomalate and observed a flare of 1-week-old gold patch test reactions in all of them. Five patients also experienced a morbilliform eruption, 1 patient had a flare of a previous contact dermatitis site, and 4 patients had a transient fever. Plasma levels of tumor necrosis factor α (TNF-α), interleukin-1ra, sTNF-R1, and C-reactive protein were increased, particularly in those with fever. A double-blinded study of 20 gold-allergic patients challenged with intramuscular gold sodium thiomalate and/or oral nickel found that 6 of 10 gold-allergic patients reacted to the intramuscular gold.82 None reacted to nickel. Plasma levels of TNF-R1, TNF-α, and IL-1 were increased in only those gold-allergic patients challenged with gold.
There have been several other small studies evaluating gold sensitivity and systemic contact dermatitis in patients with rheumatoid arthritis receiving gold sodium thiomalate therapy. In these cases, patients have generally been screened with gold sodium thiosulfate because this is thought to provide greater sensitivity on patch testing.85 Although Fleming et al85 did not find any gold sensitivity in 55 patients with rheumatoid arthritis, Moller et al86 found that patch test positivity to gold was quite common in a cohort of 77 patients with rheumatoid arthritis. It has been suggested that higher concentrations of gold sodium thiosulfate (ie, >0.5%) are required to detect gold allergy in patients with rheumatoid arthritis perhaps because of concomitant immunosuppressive medications or inherent immunosuppressive properties of the disease and that this may explain the discrepancy.87 Svensson et al87 evaluated 19 patients undergoing a first injection of gold sodium thiomalate for rheumatoid arthritis and found that 4 patients were patch test positive to gold. Contact allergy was corroborated by a statistically significant increase in serum TNF-α and IL-1 in gold-allergic patients but not in gold-negative patients. Only 1 of these patients became clinically symptomatic and developed malaise, vomiting, tachycardia, and a macular eruption over the abdomen 10 hours after injection.
A case of perianal itching that evolved into a generalized dermatitis was reported in a woman with a history of a gold dental crown who had recently started Aurocard, an over-the-counter gold-containing oral supplement indicated for the treatment of early heart failure.88 The authors diagnosed her with systemic contact dermatitis and also hypothesized that excretion of gold via the fecal route might have contributed to her initial perianal dermatitis because 85% to 95% of gold is excreted in the feces. She cleared upon discontinuation of the Aurocard.
Four patients who developed eyelid dermatitis after gold weights were implanted in the lids to assist with difficulties in closing the eye have also been described. Patch tests were positive for gold sodium thiosulfate, and the localized dermatitis resolved with removal of the weights.89
Gold-coated stents have been found to release ions into surrounding tissue because the metal has been found in vessels retrieved from patients with these stents.90 Gold-coated stents have also been associated with a 5-fold increased concentration of gold in blood compared with patients with stents not containing gold.51 A high prevalence of contact allergy to gold has been found in patients with gold stents,91 and multiple studies have shown that gold-containing stents are associated with an increased risk for in-stent restenosis.90,92–95
In a retrospective study of 484 patients who were given stents with or without gold coating, a correlation was found between contact allergy to gold, gold stent, and restenosis.93 Gold-allergic patients with gold stents were found to run a 3-fold higher risk for restenosis, and in the gold-stented patients, a significantly higher frequency of contact allergy to gold was seen on patch testing compared with a control group without stents (37% of gold-stented patients compared with 19% of controls, P < 0.01).93,94 There were no statistically significant differences in contact allergy to gold or nickel between nickel-stented patients and gold-stented patients, suggesting the presence of other sensitizing factors in addition to stent placement; however, the gold-coated stent demonstrated a trend toward statistical significance when other risk factors for contact allergy to gold were considered, such as dental gold and ear piercing (odds ratio, 1.43; 95% confidence interval, 0.95–2.16; P = 0.09). Overall, multivariate analysis showed a correlation between contact allergy to gold (gold-plated stents) and an increased frequency of restenosis (odds ratio, 2.3; 95% confidence interval, 1.0–5.1; P = 0.04).93
It has thus been hypothesized that gold implants give rise to ions, perhaps in the setting of mechanical damage to the surfaces in the stent in place, leading to increased gold concentration locally as well as in blood that can cause sensitization in those not previously sensitized by other means such as dental material. Through continuous release of ions, a contact allergic reaction may manifest as an endotheliitis within the vessel where the stent is located.93 Given the high rate of in-stent restenosis, the use of gold stents has been largely abandoned.
Dental implants have long been suspected to be a source of sensitization and contact allergy to gold. Gold may be found in the dental amalgam on the enamel side of the tooth as well as in the metal post for dental implants. Schaffran et al46 found that 34% of 71 asymptomatic patients with gold dental restorations had positive patch test reactions to gold as compared with 11% of those without gold dental restorations. Positive patch tests to gold in dental patients have also been corroborated in vitro through the lymphocyte proliferation test.96
Multiple studies have suggested that localized exposure to dental gold may result in systemic gold exposure. A correlation between the blood concentration of gold and the amount of dental gold has been described.50,57,97 One study reported immediate elevation of gold blood levels after the placement of dental gold, and this elevation remained for more than a decade.98 In addition, salivary gold levels also have been correlated to amount of dental gold.97
There is some direct and indirect evidence that gold dental implants may cause contact allergy. Aside from case reports,27,57,99 a statistically significant and dose-dependent relationship has been shown between contact allergy to gold and the number of dental gold restorations, although no statistically significant relationship was found with respect to oral lesions.100 In another series of 52 dental patients who patch tested positive to gold, 13 (25%) patients had a history of itching, irritation, or rash to gold jewelry and dental restorations.96 With regard to specifically oral lesions, Laeijendecker et al101 evaluated 200 patients with persistent oral lesions attributed potentially to gold allergy and found that 17 patients patch tested positive to gold trichloride. Moreover, 1 patient with allergic contact stomatitis and 1 patient with allergic contact dermatitis healed completely with gold replacement, although improvement was noted more frequently in patients with oral lichen planus.
Positive patch test reactions to dental materials have been associated with cheilitis, perioral dermatitis, burning mouth, stomatitis, ulceration, and lichenoid reaction.99,101–103 With regard to lichenoid reactions, both oral and cutaneous lichen planus eruptions have been associated with allergy to gold and other metals in dental work. Patients with oral lichenoid reactions have been reported to have higher frequencies of positive gold reactions compared with frequencies in the general dermatitis population reported by the NACDG in 1996 to 2003.32,33,104 In 51 patients with oral lichen planus, 20% had positive patch tests to gold, ranking it second only to mercury of 10 allergens.104 Ahlgren et al105 also found an increased frequency of patch test positivity to gold in patients with oral lichenoid lesions in comparison with patients undergoing evaluation of other dermatitis not affecting the oral region. In contrast, Martin et al106 did not find an association between oral gold and oral lichen planus. The authors did, however, find an increased risk for oral lichen planus in the presence of dissimilar metals in contact with each other in the mouth as well as amalgam corrosion.
Clinical relevance in these cases is uncertain. When 121 patients with facial and oral pathology underwent patch testing to dental materials, the most common allergens detected were gold, nickel, mercury, palladium, cobalt, and 2-hydroxyethyl methacrylate. Most of the reactions to mercury seemed relevant to the authors, whereas gold and nickel positives were of uncertain clinical relevance.102 In addition, a study of 206 patients with oral lichen planus and stomatitis found that 28 patients had positive patch test reactions to dental metals.107 Of note, fewer than 15% of the patients with lichen planus were thought to have a clinically relevant allergy. Only 4.9% of the patients demonstrated a positive reaction to gold possibly because of the use of a weaker concentration of gold sodium thiosulfate (0.25%) and the omission of a late reading.
Occupational exposure has been reported to occur in those who gild porcelain, enamel, and glass, where gold hydroxide, potassium, and sodium gold trichloride are often used.38 Potassium and sodium dicyanoaurate have also been reported to cause dermatitis in workers involved in gold plating.108 In addition, gold trichloride has been reported to cause dermatitis in photography.55 Occupational dermatitis often presents on exposed acral sites.109 Sperber et al4 shared a case of severe hand dermatitis in a jewelry saleswoman who had a positive patch test reaction to gold but not to nickel. She resolved completely after taking a leave of absence from her work. The authors also described a glass etcher with hand dermatitis who tested positive to gold. Her dermatitis was attributed to her gold-etching instrument, which resulted in the dispersion of gold particles while etching. She improved when she stopped etching glass. Airborne dermatitis has also been reported in those involved in gold smelting, gilding, and gold plating, particularly involving the eyelids and neck.65–67 Other workers who may be exposed to gold include gold miners, dentists, dental technicians, and those who work in gold recycling.38
In conclusion, gold seems to be a cause of contact dermatitis in specific clinical settings (Table 4). We recommend screening for gold allergy in cases of eyelid and/or facial dermatitis or when jewelry allergy is suspected. Screening should also be strongly considered when there is involvement of the ears, hands, and neck or a history of current exposure to gold dental materials. In addition, in the case of potential occupational exposure, patch testing to gold may be indicated.
Patch testing with gold can present unique challenges. Gold haptens may be irritating, so interpretation of results may require caution, especially in the setting of atopic dermatitis. When patch testing to gold, it is important to note that gold reactions may be delayed as many as 3 weeks after application and can be significantly long-lasting; thus, it is the opinion of the authors that routine patch testing to gold should be avoided. Currently, there is insufficient evidence to definitively recommend for or against a specific gold preparation for patch testing, although the most commonly tested form of gold in North America may be gold sodium thiosulfate 2% pet owing to its wide availability and decreased irritancy properties. To capture all gold patch test–positive patients, it may be necessary to test different gold salts in the same patient and, perhaps, different dilutions of each gold salt as well. Although this approach seems to increase sensitivity, specificity may decrease.
Determination of clinical relevance may be difficult because of the high rate of false or clinically irrelevant positives. Exposure is common, particularly in women and those with older dental restorations. We suggest obtaining a thorough history and maintaining a high index of suspicion for connubial and systemic sources of exposure.
Although the topic of gold contact allergy remains controversial, it is vital to both continue testing for gold allergy when appropriate and to report data regarding gold sensitivity. The story is not yet written, and we are hopeful that this article will renew dialogue about this provocative allergen. A multidisciplinary discussion and approach may help to elucidate the clinical relevance and role for patch testing to gold in the dermatologic community, with possible input from our colleagues—biochemical, metallurgical, and immunologic.
Altogether, gold has many unique characteristics, and the interpretation of clinical relevance remains challenging. There is a clear need for further research. Considerations include further testing to optimize gold-screening compounds such as testing with serial dilutions, different gold formulations, and different vehicles, as well as investigation into patch test sensitization, intradermal testing, the effects of systemic challenge, histopathologic and/or immunohistochemical findings, and the relationship between gold sensitivity and allergy to other metals. Randomized controlled trials and larger studies might be helpful in guiding evaluation of clinical relevance.
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