Cutaneous Reactions to Drugs Used for Rheumatologic Disorders

Collagen Vascular Diseases

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Cutaneous Reactions to Drugs Used for Rheumatologic Disorders Donna E. Roth, MD, * Linda V. Spencer, MD, * and Edwin M. Ahrens, MDt

Cutaneous reactions to medications probably represent the most common manifestation of drug reactions. 10 While most cutaneous reactions are mild and do not require treatment, some may impose permanent disability or even be fatal. The diversity of cutaneous eruptions produced by drugs provides a challenge in searching for the mechanisms producing the reaction. Many eruptions are due to a form of allergic hypersensitivity, while others may be idiosyncratic, due to a metabolic abnormality, or represent a cumulative phenomenon. The challenge to the clinician is to recognize an eruption as a possible drug effect and then to identify the offending agent. When the cutaneous eruption is characteristic for a drug the patient is known to be taking, or when the patient is only taking one or two drugs, identifying the responsible drug is not problematic. However, the more typical situation is to be faced with a nonspecific eruption in a patient on multiple medications. This article discusses the diagnosis of drug-induced cutaneous reactions by reviewing specific drugs commonly used in rheumatologic therapy.

NONSTEROIDAL ANTI-INFLAMMATORY AGENTS The nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications in the United States. 15 They are useful in controlling the pain and inflammation associated with a variety of inflammatory and degenerative disorders. There are several chemical classes of these compounds, all of which inhibit prostaglandin synthesis to various From the Department of Dermatology, University of Louisville School of Medicine, Louisville, Kentucky *Residents in Dermatology

t Assistant Clinical Professor Medical Clinics of North America-Vo!' 73, No. 5, September 1989

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degrees through effects on the cyclo-oxygenase pathway of arachidonic acid metabolism. Other actions contributing to their anti-inflammatory effect include interference with leukocyte function, thereby reducing chemotaxis, superoxide production, and protease production. Diverse cutaneous reactions to these agents have been reported. The mechanisms of these reactions are not understood, and it is possible that they may involve alteration of the inflammatory pathway.98 Some types of reactions are observed more commonly with a specific class, but others may be seen with agents of differing chemical structure. The four agents currently available in the United States which are most frequently reported to cause cutaneous reactions are piroxicam, sulindac, meclofenamate sodium, and phenylbutazone. 15. 98 It is doubtful that this reflects the true incidence of adverse cutaneous reactions, since reactions to older agents such as aspirin are well documented and no longer warrant reporting in the literature. NSAIDs that frequently induced adverse cutaneous reactions but are no longer on the market include benoxaprofen and zomepirac sodium. These agents will not be discussed in this review. Table 1 lists NSAIDs currently available in the United States. Table 1. Nonsteroidal Anti-inflammatory Drugs: Chemical Classification CHEMICAL CLASSIFICATION

Salicylates

GENERIC NAME

BRAND NAME

Acetylates Aspirin Nonacetylated Diflunisal Salsalate Choline magnesium trisalicylate

Trilisate

Acetic acids

Indomethacin Sulindac Tolmetin Diclofenac

Indocin Clinoril Tolectin Voltaren

Propionic acids

Ibuprofen Naproxen Fenoprofen Ketoprofen Suprofen Flurbiprofen

Motrin, Advil, Rufen, Nuprin Naprosyn Nalfon Orudis Suprol Ansaid

Anthranilic acids

Mefenamate Meclofenamate sodium

Ponstel Meclomen

Pyrazolones

Phenylbutazone Oxyphenbutazone

Azolid, Butazolidin Oxalid, Tandearil

Oxicams

Piroxicam

Feldene

Various Dolobid Disalcid

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SALICYLATES

Acetylated Salicylates: Aspirin Aspirin is the prototype of the nonopiate analgesics and the NSAIDs and has been widely available since it was first introduced by Bayer in 1899. It is particularly useful in the treatment of rheumatoid arthritis and the arthritis and serositis of systemic lupus erythematosus (SLE). Aspirin is the monoacetyl ester of salicylic acid. It is rapidly hydrolyzed to salicylic acid which is then metabolized via several hepatic enzyme pathways to salicyluric acid, glucuronic acid, gentisic acid, and other products. These enzyme systems may become saturated at high doses, allowing a small further increase in aspirin dose without lengthening the frequency of administration to markedly elevate serum salicylate levels. Excretion is primarily renal. The most common adverse cutaneous effects of aspirin are acute urticaria (Fig. 1), exacerbation of chronic urticaria, and purpura. 10 Salicylates have been estimated to cause up to 10 per cent of acute urticaria and were found to cause worsening of chronic urticaria in 22 per cent of patients in one study. 70 Many aspirin-sensitive patients also develop urticaria secondary to the other NSAIDs, as wellas to preservatives such as sodium benzoate

Figure 1. Extensive urticaria secondary to aspirin.

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and azo dyes such as tartrazine. Other common effects of aspirin are easy bruisability and purpura due to irreversible effects on platelet function. Uncommon cutaneous reactions to aspirin include aphthous stomatitis caused by chewable aspirin, fixed drug eruptions, generalized pruritus, erythema multiforme, erythema nodosum, aspirin-induced pustular psoriasis, and dyshidrosis. 5. 10. 11 Nonacetylated Salicylates: Di8unisal (Dolohid), Salsalate (Disalcid), and Choline Magnesium Trisalicylate (Trilisate) A major advantage of the nonacetylated salicylates is their lack of effect on platelet aggregation, allowing them to be used in patients with bleeding disorders or undergoing surgery. They also have longer half-lives, thus permitting once- or twice-daily dosage schedules. Up to 5 per cent of patients develop cutaneous complications, most often generalized pruritus, or exanthem, or urticaria. 105 Diflunisal has been reported to cause StevensJohnson syndrome 15 and an orallichenoid eruption. 36 ACETIC ACIDS

Indomethacin (Indocin) Indomethacin is an indole derivative with analgesic and antipyretic properties. Extensive protein binding contributes to its relatively long halflife of 5 to 10 hours. It is demethylated and deacetylated in the liver and excreted in the urine and bile. Indocin has a remarkably low incidence of cutaneous reactions. 5. 10, 15, 98 Erythematous maculopapular eruptions, especially in the elderly, appear to be the most frequent side effect. Urticaria and angioedema have been reported, particularly in aspirin-sensitive patients. Exacerbation of psoriasis has occurred. It has been hypothesized that the inhibition of cyclooxygenase leads to an accumulation of arachidonic acid. This leads to an increased formation of certain leukotrienes that play a role in the pathogenesis of psoriasis. 1 Other reported reactions to indomethacin include pruritus, periorbital edema,85 cutaneous vasculitis,64 toxic epidermal necrolysis,75 mouth ulcers,19 and photosensitivity. 98 Sulindac (Clinoril) Sulindac is an indene analogue of indomethacin with similar antiinflammatory, analgesic, and antipyretic properties but less gastrointestinal and central nervous system (CNS) toxicity. Its active metabolite has a halflife of about 16 hours, allowing twice-daily dosing. It is metabolized in the liver and excreted primarily in the urine with variable excretion in the bile. A wide variety of cutaneous reactions to sulindac have been reported. The most serious reactions are erythema multiforme and toxic epidermal necrolysis (Fig. 2), which have been reported numerous times and have resulted in at least three deaths.41, 47, 57, 77 A morbilliform eruption is more commonly seen, and pruritus may occur alone or in association with other cutaneous reactions. A potentially fatal syndrome of sulindac-induced tox-

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Figure 2. Widespread bullae with loss of epidermis in toxic epidermal necrolysis.

icity characterized by fever and involvement of one or more organ systems may be heralded by a cutaneous eruption. 15, 47, 77 Other reported adverse cutaneous effects include exfoliative erythroderma, photosensitivity, urticaria, serum sickness, petechiae, stomatitis, fixed drug eruptions, facial and oral erythema, and a pernio-like reaction. 15, 98 Tolmetin (Tolectin) Tolmetin is a pyrrole-acetic acid derivative that is effective in rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. It has a relatively short plasma half-life of 1 hour and is excreted in the urine. An unusual number of anaphylactoid reactions have been reported in association with tolmetin. 10,67 These reactions may be accompanied by pruritus or urticaria. 15 One case of severe toxic epidermal necrolysis was reported to the Adverse Drug Reaction Reporting System (ADRRS).98 Diclofenac (Voltaren) Diclofenac was most recently introduced in the United States. It is indicated for rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. It is a chlorophenyl amino derivative of benzene acetic acid that may be given orally, rectally, or intramuscularly. It is metabolized in the liver and excreted in the bile and urine, but does not require dosage adjustments in patients with renal or hepatic impairment. It appears to have a low rate of cutaneous reactions. Like other NSAIDs, it may precipitate urticaria or angioedema. Pruritus and rash were reported in 0.4 per cent of patients in one large study.l05 There have been several reports of hepatitis with diclofenac, often associated with pruritus, rash, fever, and eosinophilia, suggesting an immunoallergic reaction. Other reported adverse cutaneous reactions include generalized pustular psoriasis, hepatic porphyria, and Stevens-Johnson syndrome. 71

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PROPIONIC ACIDS

Ibuprofen (Motrin, Advil, Rufen, Nuprin) Ibuprofen is a phenylpropionic acid derivative that is effective for the symptomatic relief of osteoarthritis, rheumatoid arthritis, and gout. It is the most frequently dispensed NSAID in this drug class and in 1984 was made available without a prescription. It is rapidly absorbed, and has a half-life of 2 hours. It is excreted in the urine as unchanged drug and two inactive metabolites. Cutaneous reactions to ibuprofen are rare. 10 Pruritus and a nonspecific dermatitis appear to be the most common reactions. 10. 15 Urticaria may occur, with or without angioedema.1O, 98 Perioperative highdose ibuprofen was reported to result in markedly compromised wound repair, causing flap necrosis and graft dehiscence. This was attributed to ibuprofen's anti-inflammatory properties, and theoretically could be caused by any of the NSAIDs.83 Maculopapular drug eruptions have been reported ~n patients with SLE. 27,93 Erythema multiforme, toxic epidermal necrolysis, leukocytoclastic vasculitis, fixed drug eruption, exacerbation of psoriasis, oral lichen planus, and a pemphigoid-like bullous eruption limited to the legs have also been reported. 12, 15, 36, 53, 98 Naproxen (Naprosyn) Naproxen is effective in the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and gout. The mean plasma half-life is 13 hours, making twice-daily dosage possible. The drug is highly bound to plasma protein and excreted in a conjugated form in the urine. Cutaneous reactions are estimated to occur in approximately 5 per cent of patients taking naproxen.1O Pruritus is the most common reaction, occurring in 14 per cent of patients in one study.72 Urticaria and angioedema may be seen. There have been several reports of pseudoporphyria secondary to naproxen, a distinctive cutaneous reaction not seen with other N SAIDs. 40, 44, 66, 89 This eruption is clinically and histologically identical to porphyria cutanea tarda, but is not associated with any abnormalities of porphyrinheme biosynthesis. Vesicles and bullae occur in sun-exposed areas, particularly the backs of the hands. These heal with mild scarring and formation of milia (Fig. 3). Increased skin fragility may lead to cutaneous erosions apd ulcerations which are slow to heal. Rare cutaneous reactions include photosensitivity,90 cutaneous vasculitis, erythema multiforme, vesicobullous eruptions, fixed drug eruptions, purpura, and hyperhidrosis. 10, 98 Fenoprofen (Nalfon) Fenoprofen is an arylacetic acid derivative that is indicated for treatment of rheumatoid arthritis and osteoarthritis. It is highly protein bound and has a half-life of approximately 3 hours. It is excreted almost exclusively in the urine in a conjugated form. Cutaneous reactions to fenoprofen are rare and most commonly take the form of pruritus, urticaria, and/or angioedema. A vesicobullous eruption was reported to the ADRRS.98

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Figure 3. Naproxen-induced pseudoporphyria causing multiple bullae which heal with mild scarring and milia formation.

Ketoprofen (Orudis) Ketoprofen is indicated for the treatment of rheumatoid arthritis and osteoarthritis. It is rapidly absorbed and 99 per cent protein bound. After hepatic conjugation with glucuronic acid, it is excreted through the kidney as metabolites and unchanged drug. The elimination half-life is highly variable and dependent on whether the drug has been administered previously.31 The most common adverse cutaneous effect is pruritus with or without a rash which may be eczematous, maculopapular, purpuric, or bullous. The eruption may generalize to an exfoliative dermatitis. Urticaria may develop, as is common to the NSAIDs. Photosensitivity may be seen. Contact allergy has been reported. 21 Unusual reactions include alopecia, hyperhidrosis, and onycholysis. Suprofen (Suprol) Suprofen is more potent as an analgesic than as an anti-inflammatory agent. It has a relatively short half-life of 1 to 3 hours and is renally excreted. The most common cutaneous effects are dermatitis and pruritus. Severe contact dermatitis following application of a topical suprofen cream has been reported. 23 Flurbiprofen (Ansaid) Flurbiprofen is a new anti-inflammatory drug that is a potent inhibitor of prostaglandin synthetase. 2 It is effective in the treatment of inflammatory and degenerative arthritides. It is highly protein bound and excreted in the urine. Up to 6 per cent of patients develop a skin rash. 31 Urticaria, angioedema, pruritus, and photosensitivity may occur. Toxic epidermal necrolysis and exfoliative dermatitis have been reported to the drug company. Rare side effects include alopecia, nail disorders, xerosis, and hyperhidrosis. A lichenoid eruption in the mouth secondary to flurbiprofen has been reported. 36 ANTHRANILIC ACIDS

Meclofenamate sodium (Meclomen) Meclofenamate is a halogenated anthranilic acid derivative that inhibits both prostaglandin synthesis and blocks prostaglandin receptor sites. It is

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indicated for symptomatic treatment of rheumatoid arthritis and osteoarthritis. Its short half-life of 2 hours increases to 3.3 hours after multiple doses. Approximately two thirds of the drug is excreted in the urine and one third in the feces. Cutaneous reactions occur in 3 to 9 per cent of patients. The most common reaction reported to the ADRRS was an exanthem usually accompanied by pruritus. 98 Immunologically confirmed bullous pemphigoid associated with a Coombs' -positive hemolytic anemia and diarrhea has been reportedly induced by meclofenamate. 92 Exacerbation of psoriasis has been documented, presumably by the same mechanism as indomethacin-induced psoriasis. 1 Erythema multiforme, exfoliative dermatitis, vasculitis, purpura and/or petechiae, a vesiculobullous eruption, fixed drug eruption, and photosensitivity have also been reported. 15. 98

PYRAZOLONES

Phenylbutazone (Azolid, Butazolidin) and Oxyphenbutazone (Oxalid, Tandearil) The pyrazolones, phenylbutazone and its major metabolite oxyphenbutazone, are effective anti-inflammatory, analgesic, and antipyretic agents, but their usefulness is limited by their potential to cause agranulocytosis and aplastic anemia. Generally they are used only for brief periods during acute flares of rheumatoid arthritis, gout, ankylosing spondylitis, and osteoarthritis. They are metabolized in the liver and highly bound to plasma proteins. Excretion is primarily in the urine. Adverse cutaneous reactions occur frequently. Approximately 3 per cent of patients develop pruritus followed by a generalized morbilliform eruption which resolves on withdrawal of the drug. 5 Erythema multiforme, toxic epidermal necrolysis, and exfoliative dermatitis have also been well documented, some cases with a fatal outcome. 5, 10, 15 Fixed drug eruptions are common, particularly with oxyphenbutazone. 5 , 10, 15 Mouth ulcers may be seen with or without an associated blood dyscrasia. 5 Urticaria and angioedema may appear, especially in aspirin-sensitive patients. Less common reactions include pustular psoriasis, 1 nonthrombocytopenic purpura, vasculitis, hemorrhagic bullous eruption of the hands, erythema nodosum, acne necrotica, photosensitivity, an SLE-like syndrome, and allergic vasculitis, including temporal arteritis and polyarteritis nodosa. 5, 10

OXICAMS

Piroxicam (Feldene) This enolic acid derivative is effective in relieving the signs and symptoms of rheumatoid arthritis, osteoarthritis, and acute musculoskeletal disorders.6 It is metabolized by hydroxylation and subsequent conjugation with glucuronic acid and excreted primarily in the urine. With repeated once-daily doses, steady state plasma levels are attained in 7 to 12 days.

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Cutaneous reactions have been reported to occur in 2.4 per cent of patients. B2 A distinctive photosensitivity developing within a few days of the start of piroxicam therapy is well documented. 68. BB. 9B The eruption is almost always vesiculobullous, but may be macular, papular, or lichenoid. It is usually accompanied by edema and a sensation of itching, burning, or stinging. A dyshidrosiform eruption of the hands may be associated (Fig. 4). lB, 6B Three of 11 patients in one report became persistent light reactors.6B Like other NSAIDs, piroxicam may cause urticaria and/or angioedema. Several cases of piroxicam-induced erythema multiforme have been reported, and morbilliform eruptions often accompanied by pruritus are not uncommon. 98 Henoch-Schonlein purpura32 and fatal pemphigus vulgaris 65 have also been ascribed to piroxicam use. CORTICOSTEROIDS Corticosteroids have potent anti-inflammatory activity and are used extensively in the treatment of connective tissue disease, vasculitis, and other inflammatory disorders. Long-term use is limited by their Significant adverse side effects, including iatrogenic Cushing's syndrome, hypertension, diabetes mellitus, and osteoporosis. Cushing's syndrome is manifested in the skin by atrophy, increased fragility, and impaired wound healing. Easy bruisability and wide, violaceous striae also may be seen. Virilism, menstrual irregularities, and hypertension occur less commonly in iatrogenic Cushing's than in spontaneous Cushing's syndrome because of the lack of adrenocorticotropic hormone (ACTH) elevation. Nevertheless, these complications may be seen in the patient on corticosteroids. Fine vellus

Figure 4. Piroxicam-induced bullous photosensitivity associated with a dyshidrosiform eruption of the hands.

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hairs become darker and thicker. Steroid-induced acne most often develops 2 to 3 weeks after initiation of high-dose steroid therapy. The lesions are typically monomorphous papules and closed comedones which are resistant to standard acne therapy but resolve when the corticosteroids are withdrawn. Xerosis and keratosis pilaris have been reported in a group of renal transplant patients. 50 Withdrawal of either systemic or potent topical corticosteroids may lead to an exacerbation of psoriasis, especially of the pustular type. 1 Subcutaneous injection of corticosteroids may lead to atrophy of the fatty tissue. Adipose tissue hypertrophy or even lipomata may develop at the periphery of atrophic lesions. 21 Impaired host defense secondary to corticosteroid therapy causes an increased incidence and severity of bacterial, viral, and fungal infections. Reactivation of tuberculosis in patients receiving glucocorticoids is well documented and may result in cutaneous involvement. Warts are often multiple, resistant to treatment, and do not spontaneously regress. Herpes simplex infections are commonly more widespread and take longer to resolve. Herpes zoster is seen more frequently in patients on corticosteroids, and is more likely to disseminate. Fungal infections seen commonly in patients taking corticosteroids include dermatophytoses as well as lesions caused by more unusual organisms. Tinea versicolor is seen in 9 per cent of patients on prednisone for inflammatory bowel disease. 17 Cutaneous involvement with disseminated candidiasis is reported more frequently in patients receiving chemotherapy for hematologic malignancies but may be seen in rheumatologic patients. 26 Lesions usually appear as multiple erythematous or purpuric nodules. Candida tropicalis is the organism most commonly recovered. 26 Maduromycosis secondary to Allescheria boydii developed in a patient with SLE after receiving steroids for 9 months. 81 The next category of drugs are the remission-inducing or slow-acting drugs. 6. 85 Most are also anti-inflammatory by nature. They are used in uncontrolled, active disease unresponsive to anti-inflammatory agents. They should be used early enough in the course of disease to prevent irreversible destruction. Because they are slow to act (4 to 6 months), analgesic and anti-inflammatory therapy should be continued until a response is obtained. 86 The use of one of these agents with anti-inflammatory drugs such as phenylbutazone and oxyphenbutazone or concurrent use of two remission-inducing drugs should be avoided to prevent excessive bone marrow suppression. 86 ANTIMALARIALS

Quinacrine, chloroquine, and hydroxychloroquine all have a 4-aminoquinolone nucleus, are water soluble, and are readily absorbed orally.lO They appear to act by stabilizing membranes and inhibiting DNA and RNA replication. 31. 49 They readily bind metabolically active tissues (liver, lung, spleen, kidney, adrenals, and skin), plasma proteins, and the pigmented epithelium of the eye. lO . 31 The steady state half-life is 6 to 7 days and

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excretion is via the kidneys. The slow excretion reflects the firm tissue binding of these drugs. 6 They are used in the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, LE, and other connective tissue diseases. They have not been adequately studied in Reiter's disease and ankylosing spondylitis. 6 They may be effective in psoriatic arthropathy, but are known to exacerbate psoriatic skin lesions. 6 The antimalarials are thought to be the least hazardous of the remissioninducing drugs. Therapy is stopped in 3 to 7 per cent of patients due to adverse reactions. 6 Common dermatologic side effects include pigmentary changes and a variety of eruptions. Quinacrine classically causes a yellow discoloration of skin, nails, sclerae, and secretions in many patients (36 per cent in one study).24 All the antimalarials may cause an ecchymotic blue-black pigmentation of the face and photoexposed areas, palate, nails, and pretibial area. The nail beds can show diffuse involvement or transverse bands of pigmentation. Slow resolution can occur after the drugs are stopped. 24 Histologically, there is increased epidermal melanin and hemosiderin. A reversible bleaching of scalp and facial hair may occur with all three antimalarials. This is usually seen in red-headed patients. 49 Reversible graying of scalp, eyebrow, eyelash, and beard hair has been reported on higher dose antimalarials in the past.24 When quinacrine was in wide use, a lichenoid drug reaction accounted for 30 per cent of eruptions. It was reported to evolve after 2 to 6 months of use. Clinical features include prominent intertriginous involvement, frequent hypertrophic lesions, palmar and plantar lesions, and hair loss. Chloroquine has been reported to cause a similar eruption. 31 All of the antimalarials may cause a worsening of psoriatic skin lesions. The flare is seen after 3 weeks of therapy. 51 Exfoliative erythroderma may occur in psoriatic patients, and a recent review of the literature found an 8.5 per cent incidence of drug-induced erythroderma in this population. 95 Pruritus is reported to occur in 3 per cent of patients on quinacrine and up to 5 per cent of patients on chloroquine. 24 Uncommon side effects include urticaria, fixed drug reaction, erythema annulare centrifugum, and exacerbations of porphyria cutanea tarda. 10 Nonmucocutaneous adverse reactions include retinopathy which develops in less than 1 per cent of patients and is related to daily doses of Plaquenil in excess of 0.75 to 1 g.6, 24. 43, 99 Other side effects include hemolytic anemia in glucose-6-phosphate dehydrogenase deficient individuals, headaches, gastrointestinal and neurologic symptoms, neuromyopathy, and acute intermittent porphyria. 6

GOLD The gold salts include two parenteral preparations, aurothiomalate (Myochrysine) and aurothioglucose (Solganol), and an oral preparation, auranofin (Ridaura). The mechanisms of action are thought to be multiple and include inhibition of histamine and lysosomal enzymes,28 inhibition of complement activation, interference with prostaglandin synthesis,7, 74, 78 and

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the inhibition of chemotactic and phagocytic responses of macrophages31 and neutrophils as well as neutrophil degranulation in vitro. 100 Additional immunologic effects include a decrease in rheumatoid factor titer and serum immunoglobulin levels31 (although this could be secondary to decreased disease activity) and inhibition of lymphocyte mitogen stimulation in vitro. Auranofin has exhibited inhibition of antibody-dependent, cell-mediated toxicity and complement lysis and a dose-dependent inhibition of DNA, RNA, and protein synthesis in vitro. 61. 94, 100 Of the two intramuscular preparations, the oil-based aurothioglucose is preferred since it is as effective as the aqueous-based aurothiomalate and has a lower frequency of adverse reactions, most notably the anaphylactoid or "nitritoid-type" reactions thought to be due to the aurothiomalate vehicle. 6. 79 Absorption is complete after intramuscular injection with a serum half-life of 6.5 days.31, 100 Gold binds to serum albumin and is then deposited in all cells with the highest concentrations in those sites that exhibit toxicity-the liver, kidneys, and skin. 5 Excretion is via the kidneys, and gold can be detected in the urine for many months after discontinuing therapy. 5, 31 Total body accumulation cannot be predicted from tissue concentrations. Twenty-five per cent of an oral dose of auranofin is absorbed, and serum gold concentration is approximately one third that seen after intramuscular dosing, but is more predictable. The half-life is 21 days but retention and accumulation of gold is much less than with intramuscular preparations. Auranofin binds to serum albumin, red blood cells, and lymphocytes. Elimination is via the gastrointestinal tract where most of its side effects are seen. Auranofin has fewer side effects and is safer and easier to use. 100 Gold is used in the treatment of adult and juvenile rheumatoid arthritis and psoriatic arthritis. Mucocutaneous reactions occur early and are very common with gold. They may be preceded or accompanied by an elevated eosinophil count. 79 They are estimated to occur in 35 per cent of patients on parenteral gold and in 18 per cent of patients on oral gold, requiring cessation of therapy in 11 per cent and 2 per cent of patients, respectively.103 Mucocutaneous symptoms are very common with 84 per cent of patients complaining of generalized pruritus which usually resolves despite continued use. Patients also complain of a metallic taste although there are no visible changes. 74. 80 The most common eruption is nonspecific, pruritic, eczematous, and maculopapular. 74, 79, 80, 100 Gold therapy should be discontinued at this point to avoid progression to an exfoliative erythroderma. 5 Another gold reaction is a lichen-planus like eruption occurring in 32 per cent of patients. It may differ from classic lichen planus by the presence of many widespread lesions, the lack of oral involvement, and atypical histologic findings (Fig. 5).74, 80 A pityriasis rosea-like dermatitis has been estimated to develop in 11 per cent of patients (Fig. 6), and is characterized by classic salmon-colored ovoid macules with a fine branny scale in a fir tree distribution. 74, 80 Mucosal side effects may be mild with ageusia, metallic taste, cheilitis, and discrete ulcers, or severe with a diffuse mucositis involving all mucosal surfaces. lO,31 Mucositis is usually accompanied by cutaneous changes. Chrysiasis is an uncommon gray-blue photodistributed pigmentation

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Figure 5. A lichenoid-type drug reaction to gold on the wrists and thighs.

of the skin and sclerae. It is seen most often in Caucasian women, is dosedependent, and probably irreversible. Pigmentation is inducible in nonpigmented, photoprotected skin with ultraviolet irradiation. Patients with chrysiasis have more gold particles in dermal melanophages than patients on gold therapy without chrysiasis. Gold deposition in sun-exposed skin is greater than in unexposed skin, suggesting preferential uptake by sunexposed skin. Melanin synthesis is also stimulated by the gold deposition and is partially responsible for the pigmentation as seen in hyperpigmentation due to other heavy metals. 56 A case of onychochrysiasis with yellow banding and thickening of the nails has been reported. These are probably analogous to Mees' arsenical stripes. 25 Corneal chrysiasis also occurs after large doses, but is not a contraindication to continuing therapy. lOO

Figure 6. Pityriasis rosea-like gold dermatitis. (Courtesy of Neal Penneys, MD.)

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Rare but reported side effects are urticaria, alopecia, erythema nodosum, flares of pemphigus, exfoliative dermatitis, toxic epidermal necrolysis,100 acneiform eruptions, erythema multiforme, vasculitis, photosensitivity reactions,5 and reactivation of a metallic gold contact allergic dermatitis. 10 Purpura may also occur due to thrombocytopenia and may be an indication for the use of dimercaprol to increase gold excretion. 5 Most of these eruptions are self-limited and regress after stopping gold therapy. Symptomatic therapy may be sufficient, and topical or systemic steroids may be helpful. Chelation therapy with dimercaprol or penicillamine is rarely indicated. Histocompatibility antigen (HLA)-Bw35 has been associated with the development of mucocutaneous lesions in patients on gold therapy, 74 although this has been refuted in other reports. 4. 33, 83 Several reports confirm the relative safety of the use of auranofin in patients who have previously had a cutaneous reaction to parenteral preparations. Of 22 patients who had mucocutaneous reactions requiring the cessation of parenteral gold, only four had mucocutaneous reactions to auranofin, and only one patient had to stop therapy.103 Noncutaneous side effects include the development of proteinuria that has been associated with the HLA-DR3 phenotype. 33. 83 Agranulocytosis, aplastic anemia, or thrombocytopenia may be life-threatening. 100 Encephalitis, hepatitis, neuritis, and pulmonary infiltrates are also reported. 31 D-PENICILLAMINE

D-Penicillamine is a hydrolytic product of penicillin. It chelates heavy metals, depolymerizes macromolecules, solubilizes cysteine, alters collagen maturation, and interferes with immune responses. 10. 22 It affects immune complex levels, possibly by aT-cell effect. 6 Absorption from the gut is good, and peak blood levels occur at about 1 hour. 6, 31 It is stable in the body and excreted by the kidneys. D-Penicillamine is used in treating adult and juvenile rheumatoid arthritis and progressive systemic sclerosis,6, 10 and appears to be as effective as gold and cytotoxic agents. 6 It has not been shown to be effective in ankylosing spondylitis and other HLA-B27associated arthropathies (psoriatic arthropathy, Reiter's syndrome). 6 Mucocutaneous toxicity has been reported in 28 per cent of patients, although this may be lower since, in general, lower doses are being used than previously.35 Toxic reactions can be divided into disorders of immunologic function and of connective tissue. 10 Most commonly seen are early acute hypersensitivity-type reactions with an "ampicillin-like" maculopapular rash, urticaria, and pruritus. 22 These eruptions may be a manifestation of cross-reactivity to penicillin. 31 Fever, leukopenia, eosinophilia, and thrombocytopenia may accompany the eruption. This usually develops in the first month of use. Desensitization by administering small doses or concurrent parenteral steroids may permit reintroduction and continued use of penicillamine. 10 Lichen planus-like lesions are also common and develop after 4 to 16 months of use. Cutaneous and/or oral lesions may be present and resolve

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1 to 3 months after discontinuing therapy.87 Dysgeusia, hypogeusia, mucosal ulceration, erythema nodosum, alopecia, and hirsutism have also been reported. 22, 35, 37 Less common disorders of immunologic function secondary to penicillamine include the development of pemphigus (Fig. 7), with a twofold predominance of the usually rare pemphigus foliaceus variant over pemphigus vulgaris. 10,49,59 It develops 6 to 12 months after commencing therapy and is usually mild, but may be fatal. Mouth ulcers may occur. 109 Resolution usually occurs 3 to 6 weeks after discontinuing penicillamine. lO, 59 HLA testing of seven patients with penicillamine-induced pemphigus showed HLA-BI5 in 71 per cent of these patients as compared to 6 per cent in a normal population. Thissuggests that penicillamine may unmask a genetic predisposition to develop pemphigus. 109 Drug-induced lupus may also occur months to years after initiating penicillamine and manifests as a recurrence of joint symptoms with a positive antinuclear antibody (ANA).86 Cutaneous lupus has also been reported to occur after initiating penicillamine therapy.7 Another uncommon occurrence is the appearance of dermatomyositis or polymyositis during therapy.63 Epidermolysis bullosa has also been reported to occur during penicillamine therapy. Cutaneous vasculitis is a rare immunologic reaction to penicillamine. 10 Disorders of collagen and elastin occur due to the lathyrogenic effect of the inhibition of copper-dependent lysyl oxidase that prevents crosslinkages. It is probably dose-related. Most commonly, it manifests as easy bruisability and purpuric plaques. Later, the skin becomes atrophic, fragile, and wrinkled and healing is slow. lO Rarely, elastosis perforans serpiginosalike lesions have been seen (Fig. 8).46 There has been one report each of

Figure 7. Penicillamine-induced pemphigus. (Courtesy of Neal Penneys, MD.)

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Figure 8. Elastosis perforans serpiginosa. (Courtesy of Philip Bailen, MD.)

reversible cutis laxa58 and Ehlers-Danlos-like syndrome69 in infants exposed to penicillamine in utero. There has also been a report of morpheaform plaques developing after 14 months of penicillamine therapy that did not resolve after 1 year of therapy. 14 Hypogeusia commonly occurs after 6 weeks of use and improves after another 6 weeks despite continued therapy. 86 Noncutaneous side effects include fever, myasthenia gravis, Goodpasture's syndrome, obliterative bronchiolitiS, gastrointestinal complaints, diffuse interstitial lung disease, acute hypersensitivity pneumonitis, cholestatic hepatitis,52 membranous glomerulopathy, thrombocytopenia, leukopenia, agranulocytosis, and aplastic anemia. 31 . 86 Skin findings can be seen due to some of these disorders and their complications.

CYTOTOXIC AGENTS There are three categories of cytotoxic agents: (1) the alkylating agents (cyclophosphamide and chlorambucil); (2) the purine analogs (azathioprine); and (3) the folic acid antagonists (methotrexate).86 The immunosuppressive effect is probably via a reduction in pools of immunocompetent lymphocytes. Paradoxical enhancement of the immune response is thought to occur due to a decrease in T suppressor cell that is greater than the T helper cell reduction. 86 These agents have been shown to be effective in rheumatoid arthritis, SLE, polyarteritis and other vasculitides, Wegener's granulomatosis, polymyositis, psoriatic arthritis, and other nonrheumatologic disorders. 86 Phase-specific agents exhibit cytotoxicity during a discrete phase of the mitotic cycle and are thus selective for rapid dividing cell systems. These agents include methotrexate (S-phase specific) and vincristine (Mcphase

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specific).86 Cycle-specific agents are toxic to both proliferating and intermitotic cells but with a preferential effect on proliferating cells. Cyclophosphamide and chlorambucil are included in this group. Finally, cycle nonspecific agents exhibit uniform toxicity to all cells regardless of replicative status, as with X-irradiation. Nonphase specific agents exhibit immunosuppression only at doses close to toxic levels. Primary immune responses are more likely to be inhibited than secondary ones, and many immunosuppressants are less active in an established immune reaction. Both humoral and cellular immunity are limited, although the extent of inhibition of each depends on the agent used. 86 The disadvantages of these agents include nonselective cytotoxicity most evident in the rapidly dividing skin and mucosa, bone marrow, gastrointestinal epithelium, gonadal germinal centers, and fetal tissue. 86 An impaired response to a wide variety of antigens accounts for a generalized immune deficiency syndrome that leaves patients open to infections. Gramnegative bacteremia and Streptococcus pneumoniae infections are common, as are infections with opportunistic pathogens (Pneumocystis, Listeria, Cytomegalovirus, and Toxoplasma). Direct and indirect mucocutaneous involvement can be seen as a result of these infections. The induced immunodeficiency is probably responsible for the increased rate of malignancies, especially lymphomas, found in these patients. Methotrexate. Methotrexate binds folic acid reductase with a greater affinity than dihydrofolic acid and therefore prevents thymidine synthesis. Oral and parenteral absorption is good. Most of the drug is bound to plasma proteins. Excretion is mostly via the kidneys, and therefore caution should be used in patients with renal insufficiency or those patients concurrently taking drugs that undergo tubular excretion. Methotrexate remains in human tissue for up to several months. 31 It is used most often in rheumatoid arthritis, psoriasis, psoriatic arthropathy, and polymyositis. Mucocutaneous effects are few except for stomatitis86 and transient alopecia. 3 High-dose methotrexate is associated with exfoliative erythema, and hypersensitivity reactions such as urticaria, angioedema, and transient erythematous eruptions. 3, 38, 83 Photosensitivity has been reported with methotrexate. 38, 83 Radiation recall is a flare of acute radiation dermatitis after exposure to cytotoxic agents. This has been reported with low-dose methotrexate therapy.60 Reactivation of ultraviolet B or psoralen plus ultraviolet A erythema has also occurred in psoriatic patients on methotrexate. 60 Radiation enhancement can also occur with methotrexate given as chemotherapy. 3, 38. 83 Other toxicities of concern are leukopenia, thrombocytopenia, aplastic anemia, hepatotoxicity and cirrhosis, hypersensitivity pneumonitis, pulmonary fibrosis, and megaloblastic anemia. 6 Azathioprine. Azathioprine is a purine analogue that is rapidly converted to 6-mercaptopurine, is incorporated into RNA, and blocks formation of adenylate and guanylate by feedback inhibition. It is eventually oxidized by xanthine oxidase; therefore if allopurinol is used simultaneously, the dose of azathioprine must be decreased to one fourth or one third the usual dose. 6,31 It is as efficacious as other cytotoxic agents with less toxicity.lO It has direct anti-inflammatory and immunosuppressive action and inhibits the proliferation of promyelocytes, thereby decreasing the number of

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mononuclear and granulocytic cells available. Azathioprine suppresses T cells to a greater extent than it suppresses B cells. It is used predominantly for rheumatoid arthritis, psoriatic arthropathy, LE, and polymyositis. 6, 86 Cutaneous side effects are uncommon and include alopecia, urticaria, dermatitis, and stomatitis. 10, 31 There is an increased risk of developing cutaneous neoplasms such as squamous cell carcinoma and keratoacanthomas.lO· 39 Noncutaneous effects include hematologic abnormalities (leukopenia, thrombocytopenia, and rarely aplastic anemia), hepatotoxicity, and an increased risk of infection and neoplasia, especially reticulum cell sarcoma. Drug fever, nausea, pancreatitis, and hypersensitivity-type interstitial pneumonitis may also occur. 6 Cyclophosphamide. Cyclophosphamide is a cyclic alkylating mustard prodrug that must be metabolized by liver microsomal enzymes. 6 Peak levels occur 1 hour after oral or intravenous dosing. There is no innate anti-inflammatory activity. 10 It is the single most effective cytotoxic immunosuppressant, has a marked lympholytic effect, and inhibits proliferation of B lymphocytes to a greater extent than T lymphocytes. It is used for severe rheumatoid arthritis, Reiter's syndrome, Wegener's granulomatosis, SLE, polymyositis, and autoimmune blood disorders.6 Adverse reactions are frequent and severe. Alopecia is dose-related and represents an anagen effluvium. There is an increased susceptibility to viral and fungal skin infections. Uncommon cutaneous reactions include exanthems, stomatitis, hypersensitivity reactions, 54 and oral ulcers.1O Reversible black pigmentation of the nails and skin has been described. 38, 83, 89 Other adverse reactions include nausea, vomiting, acute hemorrhagic cystitis, abnormal urine cytology, bone marrow suppression, severe and opportunistic infections, and an increased risk of neoplasia, especially leukemia. 86 Chlorambucil. Chlorambucil is another alkylating agent with properties similar to cyclophosphamide. It is well absorbed orally and has a plasma half-life of 1 hour. 31 It has a longer induction time than cyclophosphamide but may have less toxicity especially to the hematologic and urinary systems. It is used to treat Behc;et's syndrome, SLE, and Wegener's granulomatosis. 6 Dermatitis has also been reported. 31 CYCLOSPORINE Cyclosporine, an extract of the soil fungus Tolypocladium inflatum, is a neutral hydrophobic cyclic peptide. It is not cytotoxic but works by inhibiting the activation and proliferation of effector T lymphocytes by blocking the synthesis of IL-l and IL_2.76 It does not affect suppressor T lymphocytes or B lymphocyte function. 6, 31 There is a reversible suppression of humoral immunity and of cell-mediated immunity without leukopenia or bone marrow toxicity.76 As with the cytotoxic agents, it is more effective in inhibiting primary immune responses than secondary. Twenty to 50 per cent of an oral dose is bioavailable, with peak levels occurring at 2 to 4 hours. 31 It is metabolized by the hepatic cytochrome P450 system; therefore, ketoconazole and cimetidine will increase and phenytoin and rifampin will

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decrease levels of cyclosporine. 76 Cyclosporine is used in many settings besides transplantation including rheumatologic disorders such as psoriatic arthropathy, polymyositis/dermatomyositis, arthralgias in LE, and Behr;et's disease. 1.3, 16, 42, 7.3, 76, 108 Mucocutaneous side effects include gingival hypertrophy; onset is early with rapid progression and is associated with poor oral hygiene. 76, 104 Hirsutism has also been reported. 6 A burning sensation in the skin, alopecia, and angioedema have been reported in lupus patients receiving cyclosporine. 42 The greatest toxicity is seen in the kidneys, and for this reason serum trough levels must be closely followed. Elevated liver function tests, nausea, vomiting, diarrhea, anorexia, neurologic side effects, fatigue, breast adenomas, thrombotic events, and the development of lymphoma have all been reported with cyclosporine therapy. 16,31,76

RETINOIDS Both etretinate and the third-generation aromatic retinoid arotinoid (Ro 13-6298) have been found to have an effect on psoriatic arthropathy. 6, 29 Etretinate has also been used for arthropathies associated with Reiter's syndrome. 55 One prospective study of etretinate use of psoriasis identified a subgroup of seven patients with longstanding arthropathy. Four of these seven were improved as judged by increased mobility, decreased pain, stiffness, and less need for anti-inflammatory medication after 6 months of use. Psoriatic skin lesions were improved in all patients. 45 Length of remission after therapy is not known. It has been suggested that a decrease in elevated polyamines while on etretinate may play a role in decreasing joint symptoms. 45 Acetretin, with a much shorter half-life, may be a good alternative to etretinate when it becomes available. Very common mucocutaneous side effects are chapped lips, dry nasal mucosa, and peeling of palms, soles, and fingertips. Frequent adverse effects include hair loss, skin fragility, bruising, thirst, epistaxis, sticky or clammy skin, eye irritation, and nail changes. 62 Systemic effects include bone and joint pain, skeletal hyperostoses, hyperlipidemia, hepatic effects, and changes in dark visual acuity. 62 Arotinoid (Ro 13-6298) is a very potent agent with antitumor, anticollagenase, and antikeratinizing activities. It has been shown to have antiinflammatory and anti-arthritic activity in adjuvant arthritis in the rat. In 1982, a pilot study of Ro 13-6298 in 12 patients with moderate or severe psoriatic arthropathy was reported. Eleven of these patients were resistant to other treatment modalities. Seven to 14 days after initiating treatment, nine patients improved, with the remaining three better after a few weeks. There was a decrease in joint signs and symptoms allowing decreased use of analgesics and NSAIDs. The three slow responders had some residual symptoms. Ten of the 12 patients remained on therapy (1.5 to 5 months). One patient relapsed after 3 months, and one remained improved 6.5 months after cessation of therapy. Side effects noted were cheilitis in three patients and pruritus in one patient. No hair loss or skin fragility was noted.

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Skin lesions present were seen to clear at 3 to 6 weeks, and sedimentation rates decreased while on therapy.29 Future development of safer, more efficacious retinoids may play a greater role in the control of rheumatologic disorders.

TREATMENT Identification and elimination of the offending agent are the mainstays of treatment. Drugs that were begun within 3 weeks of the onset of the cutaneous eruption are the most likely offenders. The pattern of skin reaction will help identify which agent is most likely to have produced the eruption. Once the responsible drug is eliminated, most eruptions will resolve within 1 month. Some cutaneous reactions, such as induced autoimmune or connective tissue disorders, may take many months to resolve or may not resolve at all. Antihistamines such as diphenhydramine or hydroxyzine help relieve itching and may suppress urticaria. Topical skin care depends on the type of reaction. Acutely inflamed skin requires wet compresses or colloidal oatmeal baths (Aveeno) followed by topical steroids in a nonocclusive base. Very mild topical steroids such as 1 to 2.5 per cent hydrocortisone lotion should be used on the thin skin of the face, axillae and crural areas. Dry, chronically inflamed skin may benefit from topical steroids in a cream or ointment base together with the generous use of emollients. Treatment of any secondary infection is important. Erythromycin orally for 7 days is frequently used for this indication. The use of systemic steroids is controversial. They help suppress severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and exfoliative erythroderma, but may predispose to secondary infections and actually increase morbidity and mortality. Acquaintance with the cutaneous effects of medications may allow earlier recognition and treatment and prevent significant adverse sequelae.

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9. Ashton H, Beveridge GW, Stevenson CJ: Therapeutics XI. Immunosuppressive drugs. Br J Dermatol 83:326, 1970 10. Bailin PL, Matkaluk RM: Cutaneous reactions to rheumatological drugs. Clin Rheum Dis 8:493-516, 1982 11. Baker H, Moore-Robinson M: Cutaneous responses to aspirin and its derivatives. Br J Dermatol 82:319-320, 1970 12. Ben-Chetrit A, Rubinow A: Exacerbation of psoriasis by ibuprofen. Cutis 38:45, 1986 13. Bendtzen K, Tvede N, Anderson V, et al: Cyclosporin for polymyositis. Lancet 1:792793, 1984 14. Bernstein RM, Hall MA, Gostelow BE: Morphea-like reaction to D-penicillamine therapy. Ann Rheum Dis 40:42-44, 1981 15. Bigby M, Stern R: Cutaneous reactions to nonsteroidal anti-inflammatory drugs. J Am Acad Dermatol 12:866-876, 1985 16. Biren CA, Barr RJ: Dermatologic applications of cyclosporine. Arch DermatoI122:10281032, 1986 17. Boardman PL, Hart FC: Side effects of indomethacin. Ann Rheum Dis 26:127,1967 18. Braunstein BL: Dyshidrotic eczema associated with piroxicam photosensitivity. Cutis 35:485-486, 1985 19. Brockelhurst JC, Humphreys GS: The use of indomethacin in old age. Geront Clin 7:270, 1965 20. Burrish G, Kaatz B: Sulindac-induced anaphylaxis. Ann Emerg Med 10:154-155, 1981 21. Davies DM: Textbook of Adverse Drug Reactions, ed 3. New York, Oxford University Press, 1987, p 54 22. Davis P, Bleehan SS: D-penicillamine in the treatment of rheumatoid arthritis and progressive systemic sclerosis. Br J Dermatol 94:705-711, 1976 23. Dooms-Goosens A, Dooms M, Van Lint L, et al: Skin sensitizing properties of arylalcanoic acids and their analogues. Contact Derm 5:324-328, 1979 24. Dubois EL: Antimalarials in the management of discoid and systemic lupus erythematosus. Semin Arthritis 8:33-57, 1978 25. Fam AG, Paton TW: Nail pigmentation after parenteral gold therapy for rheumatoid arthritis: "Gold nails." Arthritis Rheum 27:119-120, 1984 26. File TM, Marina OA, Flowers FP: Necrotic skin lesions associated with disseminated candidiasis. Arch Dermatol 115:214-215, 1979 27. Finch WR, Strottman MP: Acute adverse reactions to ibuprofen in SLE. JAMA 241:26162618, 1979 28. Finkelstein AE, Roisman FR, Ladizesky MG, et al: Auranofin and lysosomal enzymes in rheumatoid arthritis. J Rheumatol 9:46-53, 1982 29. Fritsch P, Rauschmeier W, Neuhofer J: Response to psoriatic arthropathy to Arotinoid (Ro 13-6298): A pilot study. In Cunliffe J, Miller AJ (eds): Retinoid Therapy. Lancaster, England, MP Publishers, 1982, pp 329-333 30. Fritsch P, Rauschmeier W, Zussner C: Treatment of Reiter's disease with etretinate. In Saurat L (ed): Retinoids: New Trends in Research and Therapy. Basel, Karger, 1985, pp 384-390 31. Gilman AG, Goodman LS, Rail TW, et al: The Pharmacologic Basis of Therapeutics, ed 7. New York, MacMillan, 1985 32. Goebel KM, Mueller-Brodman W: Reversible overt nephropathy with Henoch-Schonlein purpura due to piroxicam. Br Med J 284:311-312, 1982 33. Gran JT, Husby G, Thorsby E: HLA DR antigens and gold toxicity. Ann Rheum Dis 42:63-66, 1983 34. Gran JT: HLA-Bw35 and mucocutaneous toxicity in rheumatoid arthritis patients treated with gold. Arthritis Rheum 29:303, 1986 35. Halverson PG, Kozin F, Bernhard GC, et al: Toxicity of penicillamine, a serious limitation to therapy in rheumatoid arthritis. JAMA 240:1870-1871, 1978 36. Hamburger J, Potts AJC: Non-steroidal anti-inflammatory drugs and oral lichenoid reactions. Br Med J 287:1258, 1983 37. Hill HFH: Treatment of rheumatoid arthritis with penicillamine. Semin Arthritis Rheum 6:361-388, 1977 38. Hood AF, Haynes HA: Mucocutaneous complications of cancer chemotherapy. In Fitzpatrick TB, Eisen AZ, Wolff K, et al (eds): Update: Dermatology in General Medicine. New York, McGraw-Hill, 1983, pp 80-97

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39. Hood AF: Cutaneous complications of immunosuppressive agents. Dermatol Clin 1:591606, 1983 40. Howard AM, Dowling J, Varigos G: Pseudoporphyria due to naproxen. Lancet 1:819820, 1985 41. Husain Z, Runge L, Jabbs J, et al: Sulindac-induced Stevens-Johnson syndrome: Report of three cases [letter]. J Rheumatol 8:176--179, 1981 42. Isenberg DA, Snaith ML, AI-Khader AA, et al: Cyclosporin relieves arthralgias, causes angioedema. N Engl J Med 303:754, 1980 43. Johnson MW, Vine AK: Hydroxychloroquine therapy in massive total doses without retinal toxicity. Am J Ophthal 104:139-144, 1987 44. Judd LE, Henderson DW, Hill DC: Naproxen-induced pseudoporphyria, a clinical and ultrastructural study. Arch Dermatol 122:451-454, 1986 45. Kaplan RP, Russell DH, Lowe NH: Etretinate therapy for psoriasis: Clinical responses, remission times, epidermal dNA and polyamine responses. J Am Acad Dermatol 8:95102, 1983 46. Kirsch N, Hukill PB: Elastosis perforans serpiginosa induced by penicillamine. Electron microscopic observations. Arch Dermatol 113:630-635, 1977 47. Klein SM, Khan MA: Hepatitis, toxic epidermal necrolysis and pancreatitis in association with sulindac therapy. J Rheum 10:512-513, 1983 48. Kohn SR: Fatal penicillamine-induced pemphigus foliaceous-like dermatosis. Arch Dermatol 122:17, 1986 49. Koranda FC: Antimalarials. J Am Acad Dermatol 4:650-655, 1981 50. Koranda FC, Dehmel EM, Kahn G, et al: Cutaneous complications in immunosuppressed renal homograft recipients. JAMA 229:419-424, 1974 51. Kuflik EG: Effect of antimalarial drugs on psoriasis. Cutis 26:153-155, 1980 52. Kumar A, Bhat A, Gupta DK, et al: D-penicillamine-induced acute hypersensitivity pneumonia and cholestatic hepatitis in a patient with rheumatoid arthritis. Clin Exp RheumatoI3:337-339, 1985 53. Laing VB, Sheretz EF, Flowers FP: Pemphigoid-like bullous eruption related to ibuprofen. J Am Acad Dermatol 19:91-94, 1988 54. Lakin JD, Cahill RA: Generalized urticaria to cyclophosphamide: Type I hypersensitivity to an immunosuppressive agent. J Allergy Clin ImmunoI56:160-171, 1976 55. Lassus A, Eskelinen A, Saila K, et al: In Saurat L (ed): Retinoids: New Trends in Research and Therapy. Basel, Karger, 1985, pp 391-396 56. Leonard PA, Moatamed F, Ward JR, et al: Chrysiasis: The role of sun exposure in dermal hyperpigmentation secondary to gold therapy. J Rheumatol 13:58-64, 1986 57. Levit L, Pears on R: Sulindac-induced Stevens-Johnson toxic epidermal necrolysis syndrome. JAMA 243:1262-1263, 1980 58. Linarer A, Zarranz JJ, Rodriguez-Alarcon J, et al: Reversible cutis laxa due to maternal D-penicillamine treatment. Lancet 2:43, 1979 59. Livden JK, Naevdal A, Milde EJ: Pemphigus in rheumatoid arthritis treated with penicillamine. Scand J Rheumatol 10:95-96, 1981 60. Logan RA, McFadden JP, Eady RAJ: Reaction of cutaneous radionecrosis associated with methotrexate therapy for psoriasis. Clin Exp Dermatol 13:350-352, 1988 61. Lorber A, Jackson WH, Simon TM: Effects of chrysotherapy on cell-mediated immune response. J Rheumatol 9(suppl 8):37-45, 1982 62. Lowe NJ, Lazarus V, Matt L: Systemic retinoid therapy for psoriasis. J Am Acad Dermatol 19:186--191, 1988 63. Lund HI, Nielsen M: Penicillamine-induced dermatomyositis. Scand J Rheumatol 12:350-352, 1983 64. Marsh FP, Almeyda JR, Levy IS: Non-thrombocytopenic purpura and acute glomerulonephritis after indomethacin therapy. Ann Rheum Dis 30:501-505, 1971 65. Martin RL, McSweeney GW, Schneider J: Fatal pemphigus vulgaris in a patient taking piroxicam [letter]. N Engl J Med 309:795-796, 1983 66. Mayou S, Black MM: Pseudoporphyria due to naproxen. Br J Dermatol 114:519-520, 1986 67. McCall C: Tolmetin anaphylactoid reaction. JAMA 243:1263, 1980 68. McKerrow KJ, Greig DE: Piroxicam-induced photosensitive dermatitis. J Am Acad Dermatol 15:1237-1241, 1986

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69. Mjolnerod OK, Rasmussen K, Dommesud SA, et al: Congenital connective tissue defect probably due to D-penicillamine treatment in pregnancy. Lancet 1:673-675, 1971 70. Moore-Robinson M, Warin R: Effects of salicylates in urticaria. Br Med J 4:262-264, 1967 71. Morris BAP, Remtulla SS: Erythema multiforme major following use of diclofenac. Can Med Assoc J 133:665, 1985 72. Myhal D, Camerlain M, Menard H, et al: Naproxen: Long-term study in rheumatoid arthritis and placebo pulse. J Clin Pharmacol 15:327-334, 1975 73. Nussenblatt RB, Palestine AG, Chan C, et al: Effectiveness of cyclosporin therapy for Beh<;et's disease. Arthritis Rheum 28:671-679, 1985 74. Nusslein HG, Jahn H, Losch G, et al: Association of HLA-Bw35 with mucocutaneous lesions in rheumatoid arthritis patients undergoing sodium aurothiomalate therapy. Arthritis Rheum 27:833-836, 1984 75. O'Sullivan M, Hanly J, Molloy M: A case of toxic epidermal necrolysis secondary to indomethacin. Br J Rheum 22:47-49, 1983 76. Page EH, Wexler DM, Guenther LC: Cyclosporin A. J Am Acad Dermatol 14:785-791, 1986 77. Park G, Spector R, Headstream T, et al: Serious adverse reactions associated with sulindac. Arch Intern Med 142:1292-1294, 1982 78. Penneys NS, Ziboh V, Gottlieb NL, et al: Inhibition of prostaglandin and human epidermal enzymes by aurothiomalate in vitro: Possible actions of gold in pemphigus. J Invest Dermatol 63:356-361, 1974 79. Penneys NS: Gold therapy: Dermatologic uses and toxicities. J Am Acad Dermatol 1:315-320, 1979 80. Penneys NS, Ackerman AB, Gottlieb NL: Gold dermatitis: A clinical histopathological study. Arch Dermatol 109:372-376, 1974 81. Pillay VKG, Wilson DM, Ing TS, et al: Fungus infection in steroid-treated systemic lupus erythematosus. JAMA 205:63-265, 1968 82. Pitts N: Efficacy and safety ofpiroxicam. Am J Med 72(suppI2A):77-87, 1982 83. Proper SA, Fenske NA, Burnett SM, et al: Compromised wound repair caused by perioperative use of ibuprofen. J Am Acad Dermatol 18: 1173-1179, 1988 84. Reinertsen J: Unusual pernio-like reaction to sulindac [letter]. Arthritis Rheum 24:1215, 1981 85. Rothermich NO: An extended study of indomethacin, I. Clinical pharmacology. JAMA 195:53, 1966 86. Rodnan GP, Schumacher HR: Primer on the Rheumatic Diseases, ed 8. Atlanta, Arthritis Foundation, 1983, pp 192-196 87. Seehafer JR, Rogers RS, Fleming R, et al: Lichen planus-like lesions caused by penicillamine in primary biliary cirrhosis. Arch Dermatol117:140-142, 1981 88. Serrano G, Bonillo J, Aliaga A, et al: Piroxicam-induced photosensitivity. J Am Acad Dermatol11:113-120, 1984 89. Shah PC, Rao KRP, Ashok RP: Cyclophosphamide-induced nail pigmentation. Br J Dermatol 98:675-680, 1978 90. Shelley ED, Shelley WB, Burmeister V: Naproxen-induced pseudoporphyria presenting a diagnostic dilemma. Cutis 40:314-316, 1987 91. Shelley WB, Elpern DJ, Shelley ED: Naproxen photosensitization demonstrated by challenge. Cutis 38:169-170, 1986 92. Sheperd AN, Ferguson J, Bewick M, et al: Mefanamic acid-induced bullous pemphigoid. Postgrad Med J 62:67-68, 1982 93. Shoenfeld Y, Livni E, Shaklai M, et al: Sensitization to ibuprofen in SLE [letter]. JAMA 244:547-548, 1980 94. Simon L, Mills J: Nonsteroidal anti-inflammatory drugs. N Engl J Med 302:1179-1185, 1237-1243, 1980 95. Simon TM, Kunishima DH, Vibert GJ, et al: Cellular antiproliferative action exerted by auranolin. J Rheumatol 6(suppl 5):91-97, 1979 96. Slagel GA, James WD: Plaque nil-induced erythroderma. J Am Acad Dermatol 12:857862, 1985 97. Smith F, Lindberg P: Life-threatening hypersensitivity to sulindac. JAMA 244:269-270, 1980

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98. Stern RS, Bigby M: An expanded profile of cutaneous reactions to nonsteroidal antiinflammatory drugs. JAMA 252:1433-1437, 1984 99. Terrell WL, Haik KG, Haik GM: Hydroxychloroqlline slllfate and retinopathy. South Med J 81:1327-1328, 1988 100. Thomas 1: Gold therapy and its indications in dermatology: A review. J Am Acad Dermatol 16:845-854, 1987 101. Todd PA, Heel RC: Suprofen: A review of its pharmacodynamic and pharmacokinetic properties, and analgesic efficacy. Drugs 30:514-538, 1985 102. Todd PA, Sorkin EM: Diclofenac sodium: A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 35:244-285, 1988 103. Tumati B, Veneziani M, Bellelli A, et al: Mucocutaneous toxicity of gold salts by parenteral administration-rechallenge with auranofin. J Rheumatol 14:177, 1987 104. Tyldesley WR, Rotter E: Gingival hyperplasia induced by cyclosporin A. Br Dent J 157:305-309, 1984 105. Ubenhaver ER: Diflunisal in the treatment of the pain of osteoarthritis: Summary of clinical studies. Pharmacotherapy 3(suppl 2):55-60, 1983 106. Wilkins RF: Worldwide clinical safety experience with diclofenac. Semin Arthritis Rheum 15(suppI1):105-110, 1985 107. Wintroub BU, Stern RS, Arndt KA: Cutaneous reactions to drugs. In Fitzpatrick TB, Eisen AZ, WolffK, et al (eds): Dermatology in General Medicine. New York, McGrawHill, 1987, pp 1353-1366 108. Zabel P, Leimenstoll G, Gross WL: Cyclosporin for acute dermatomyositis. Lancet 1:343, 1984 109. Zone J, Ward J, Boyce E, Schupback C: Penicillamine-induced pemphigus. JAMA 247:2705-2707, 1982 Division of Dermatology Department of Medicine Universitv of LOllisville School or'Medicine 310 East Broadway, Suite 200 Louisville, KY 40202