Treatment of Pemphigus With Gold FREE

PENNEYS ET AL¹ in 1973 first reported that gold could be used in the treatment of pemphigus. However, its use has decreased over the last 10 years. Instead, other treatment modalities, including azathioprine, cyclophosphamide, cyclosporine, high-dose intravenous steroids, and pulse intravenous cyclophosphamide, have been cited by investigators² as preferred steroid-sparing agents in the treatment of pemphigus. While concerns regarding its toxicity and efficacy are valid, the relative toxicity of gold compared with these immunosuppressive agents is low, particularly when considering reports of secondary malignancies occurring in patients treated with immunosuppressive drugs.³ We retrospectively reviewed 26 patients treated with gold over the last decade.

All patients seen in our institution with a diagnosis of pemphigus and treated with gold in the last decade were included. Patients were referred to our department from area dermatologists as well as primary care physicians. All but 4 patients were treated initially with oral corticosteroids. Gold was then added to decrease the daily corticosteroid requirement in patients who failed to tolerate a drug taper. There was some selection bias in that patients who were experiencing severe complications from use of steroid and required a more aggressive approach such as pulse cyclophosphamide, or those who were unable to come to our clinic weekly for injections, were excluded from gold therapy. The 4 patients who were treated with gold alone had moderate cutaneous and mucosal disease that was similar to that of the remaining patients. Reasons for not using concomitant steroids in those 4 patients included history of peptic ulcer disease, diabetes mellitus, and weight gain with past steroid usage. The severity of blistering at the onset of gold therapy varied from mild (<20 blisters and erosions) to severe (>100 blisters and erosions). During this period, our institution saw 58 patients with pemphigus, of whom 26 received gold therapy.

The diagnosis of pemphigus was made clinically and confirmed with biopsy specimens processed for routine examination and direct immunofluorescence testing in all patients. Six patients had circulating intercellular substance antibodies on indirect immunofluorescence testing as well. The mean age of the patients was 46 years (age range, 24-75 years), with 13 men and 13 women. Twenty-one (81%) had pemphigus vulgaris, 3 (12%) had pemphigus foliaceus, and 2 (7%) had pemphigus erythematosus.

Gold was administered in a manner similar to that described for rheumatoid arthritis. A 10-mg test dose of intramuscular gold thiomalate (Myochrysine) was administered if results of a screening complete blood cell count, routine chemistry workup, and urinalysis were normal. One week later, a 25-mg dose was given intramuscularly after a complete blood cell count and urinalysis were checked for gold toxicity. Subsequently, 50 mg/wk of gold was given intramuscularly weekly until control of disease was achieved. Tapering of prednisone therapy was attempted at the time of disease control. When the use of prednisone was discontinued, the frequency of gold therapy was gradually decreased to bimonthly and then to monthly injections for 4 months, after which it was discontinued. A complete blood cell count and urinalysis were performed to rule out toxicity prior to each injection of gold. Flares of pemphigus were treated by increasing the frequency of gold injections to every week and by suspending the prednisone taper. If an increased frequency of gold injections was insufficient to control the disease, the prednisone dosage was gradually increased.

Patients were examined at the time of each gold injection and the severity of disease was documented. Adjustments in prednisone dosage were based on disease severity and adverse effects were documented at each visit. Gold therapy was discontinued if significant toxic effects were observed, or if a cumulative dose of 1000 mg was reached without a beneficial effect.

A summary of our results is presented in Table 1. Twenty-six patients with pemphigus were treated with gold: 4 with gold alone and 22 with prednisone and gold. Twenty-two patients (85%) responded to therapy with gold. A response was defined as improvement of blistering and ability to significantly decrease prednisone dosage to less than 20 mg/d or complete discontinuation. Four patients (patients 3, 4, 15, and 16) were in complete remission (discontinued gold and prednisone therapy and free of disease) at the end of the study. Only 1 of these patients (patient 15) has had a mild relapse of disease, requiring only gold therapy to achieve control. Seven patients (patients 1, 5, 7, 8, 17, 19, and 22) discontinued use of prednisone and were free of disease at the end of the study, but were still receiving gold. Four of these patients (patients 1, 5, 7, and 8) have had mild recurrences that responded to short (<2-month) courses of prednisone. Five patients (patients 6, 10, 12, 13, and 20) responded to gold therapy but were still receiving prednisone and gold and had some degree of blistering at the end of the study. None of the disease exacerbations in patients who responded have been as severe as that at presentation. Patients 5 through 22 were able to decrease their daily prednisone dosage by half, suggesting that gold produced a lower steroid requirement to control disease. The average dosage of prednisone before gold therapy was initiated in patients 5 through 22 was 55 mg/d (range, 10-100 mg/d). The average dosage of prednisone in those who were still receiving steroids at the end of the study was 9 mg/d (range, 5-20 mg/d). No adjuvants other than gold were given during the course of the study.

Figure 1 and Figure 2 illustrate a typical response. Of the 4 patients who did not respond, 3 had discontinued therapy because of adverse effects. Two of these patients received less than 350 mg of gold; thus, they may not have had a chance to respond to gold therapy before toxic effects developed. Toxic effects were noted in 11 patients (42%), of whom 9 discontinued therapy. Therefore, 16 (62%) of 26 patients responded to gold therapy without having to discontinue treatment because of toxic effects. Indirect immunofluorescence results were available for 1 of the responders (patient 13), who had a decrease in antibody titer of 1:160 to less than 1:10 over 6 months.

In the time since Penneys and colleagues¹ first described the use of gold in treating patients with pemphigus, a series of investigators^{4 - 11} have reported its successful use in treating patients with mild to moderate disease. Recently, however, interest appears to have waned, with a paucity of reports on its use in pemphigus. Indeed, a recent review² of the management of bullous disorders cited adverse effects and the impression that gold is efficacious in only a small percentage of patients as reasons for its diminished use. However, gold may be safer than immunosuppressive agents, which have been associated with an increased risk of secondary malignancies and loss of fertility, particularly cyclophosphamide.³ While most studies have used gold intramuscularly to treat pemphigus, one report⁹ describes 3 patients who were treated with gold (auranofin) orally; however, its efficacy was poor. We chose not to use gold orally because of the lack of published studies demonstrating its efficacy.

The average duration of gold therapy in our patients was 12 months, with 1 patient receiving 108 months of gold therapy without adverse effects. Indeed, toxic effects are usually observed within the first 4 months of starting gold therapy (Table 2). Those who are able to tolerate gold for more than 4 months usually do not manifest toxicity thereafter. The time to halving of prednisone dosage was 3 months, which is longer than the expected 6-week lag time noted previously for initial responses.¹ This delay is longer than that which has been reported for other steroid-sparing agents, which may be unacceptable for seriously ill patients who manifest numerous adverse effects from steroid therapy. However, this delay may also account for patients who have been identified as unresponsive to the use of gold but have not been treated for an adequate period to assess a response. The mean time to achieve a prednisone dosage of less than 20 mg/d was 4 months. The time required for complete discontinuation of prednisone therapy, for the 11 patients in whom it could be stopped, was 6 months. The average dosage of prednisone at the end of the study in the 7 responders who were still receiving steroids was 9 mg/d. Twenty responders achieved a remission from disease, lasting an average of 8 months. These response times are favorable when compared with those of other steroid-sparing agents.

The long-term response rate of 62% in our patients is good when compared with other therapeutic modalities.¹² Eleven responders were able to discontinue prednisone therapy, which suggests a steroid-sparing effect; however, without adequate control patients receiving prednisone alone, it is difficult to confirm this effect. Unlike previous recommendations to administer up to 1 g before abandoning therapy, we found that a cumulative gold dose of only 359 mg was required before a substantial response was seen.⁵ While treatment with gold is frequently stopped prematurely because of perceived inefficacy, it may not be necessary to treat until a cumulative dose of 1 g has been reached before trying an alternative method of treatment.

While toxicity has been a concern, each of our patients with cutaneous, renal, or hematologic toxic effects returned to a normal status when the medication was discontinued. On the other hand, the need for laboratory monitoring prior to each gold dose must be emphasized as a method of detecting toxic effects early and stopping gold therapy if necessary. While pemphigus itself may cause eosinophilia, an increase in eosinophils during gold therapy has been reported to herald other complications and should lead to withholding the use of gold until it resolves.¹³ Cutaneous adverse effects, such as pruritus and drug eruptions, are common, as are proteinuria and nitritoid reactions.¹⁴ Gold therapy has been restarted after minor toxic effects such as dermatitis and mild proteinuria resolve, without a recurrence of adverse effects.^{1 ,14}

A recent report¹¹ recommends a combined dermatologist and rheumatologist approach to the treatment of pemphigus with gold. While all patients receiving high doses of corticosteroids should be followed up by a primary care physician to monitor cardiac, pulmonary, and renal status, we have not found it necessary to consult with rheumatologists as long as careful monitoring of the patient is performed. Rheumatologists are well versed in the treatment of rheumatoid arthritis with gold and may be helpful in assisting dermatologists when initiating gold therapy; however, the dermatologist will ultimately make most therapeutic decisions in patients with pemphigus based on an examination of the skin.

An often-cited criticism of studies^{7 ,12} investigating treatment regimens for pemphigus is that steroid-sparing effects are difficult to claim without adequately controlled trials. In all previous studies, historical controls were used. Indeed, only 4 of our patients were treated with gold alone, a number too small to compare with the steroid-treated group. Previous reports have also included few patients treated with gold alone; therefore, confirmation of gold's efficacy or steroid-sparing effect is still not possible. Prospective, controlled, multicenter trials are needed to confirm or disprove the efficacy of steroid-sparing agents in the treatment of pemphigus, as is currently being performed by the Medical Dermatology Society, Sacramento, Calif, in studying the efficacy of dapsone as a steroid-sparing agent in patients with pemphigus.

Accepted for publication March 21, 1998.

Presented at the First Annual Meeting of the Medical Dermatology Society, New Orleans, La, February 3, 1995.

We thank Paul Bergstresser, MD, and Richard Sontheimer, MD, for reviewing the manuscript and Margie Burrows for her excellent secretarial assistance.

Reprints: Amit G. Pandya, MD, Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9069.