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REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS IN DERMATOLOGY
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DERMATOLOGIC THERAPY
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REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS IN DERMATOLOGY Laurence Le Cleach, MD, HelPne Bocquet, MD, and Jean-Claude Roujeau, MD
The times are gone when dermatologic therapy was mainly based on esoteric topical preparations. Today, dermatologists frequently prescribe effective systemic treatments for many skin disorders: Anti-infectious agents (antibacterial, antiviral, antifungal) are used in the management of skin infections, and systemic steroids and immunosuppressive agents are used in the management of autoimmune blistering disorders, systemic lupus, or dermatomyositis. This article focuses on those treatments that are more specific to skin diseases, including long-term use of tetracyclines in the treatment of acne, antimalarials, dapsone, thalidomide, oral retinoids, methotrexate, and cyclosporine.
Other indications include rosacea, syphilis, and nongonococcal urethritis. Interactions
Many drugs decrease the absorption of tetracyclines, including antacids, cholestyramine or colestipol, calcium, iron, or magnesium supplements. Long-term use of tetracyclines may reduce the reliability of estrogen-containing oral contraceptives. Concurrent administration of oral retinoids or vitamin A with tetracyclines increases the risk of benign intracranial hypertension (pseudotumor ~ e r e b r i ) . ~ ~ Side Effects
TETRACYCLINES
Tetracyclines are the oral broad-spectrum antibiotics used most frequently by dermatologists. Several double-blind trials revealed that tetracyclines were more effective than placebo in the treatment of acne vu1garis.l Although all tetracyclines are effective for long-term therapy of inflammatory acne of mild to moderate severity, tetracycline and minocycline are the most commonly used.
In long-term therapy with low doses, the overall incidence of side effects is 10% to 20%.1, 23 The most common (observed with all tetracyclines) are mild gastrointestinal symptoms and oral or vaginal candidiasis. Use in pregnant women, infants, and children up to eight years of age may cause permanent discoloration of teeth and enamel hypoplasia. Oral and skin hyperpigmentation may oc-
From the Service de Dermatologie, HBpital Henri Mondor, Universitk Paris XII, Crkteil, France
DERMATOLOGIC CLINICS VOLUME 16 * NUMBER 2 * APRIL 1998
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cur with all tetracyclines but is more frequent with minocycline. The incidence of pigmentation in acne patients treated with minocycline ranges from 4% to 23 The risk increases with the duration of therapy and may reach 20% after 4 years9 Discoloration persists after discontinuing the drug. Q-switched ruby laser therapy can improve it. Photosensitivity reactions have been reported with all tetracyclines. The risk is higher with demeclocycline and doxycycline, lower with minocycline. Benign intracranial hypertension (pseudotumor cerebri) is a rare side effect of all tetracyclines, occurring usually within 4 weeks of initiating therapy. Vestibular disturbance manifesting as dizziness, lightheadedness, or unsteadiness is not rare. It was reported in up to 75% of patients in short series and in 3.4% in a large series of long-term users of min~cycline.~~ Recently many reports in the medical literature have pointed to severe idiosyncratic hypersensitivity reactions attributed to minocycline.2, 27, 32 These reactions were reported under various denominations and most often combined a severe skin eruption, eosinophilia, hepatitis, and interstitial pneumonitis. Lupus-like syndromes and serum sicknesslike reactions have also been attributed to minocycline. Although rare (about 1 per 100,000 users) these hypersensitivity reactions were responsible for a few deaths and were considered severe enough to induce editorial recommendations that ”minocycline should not be the first line oral drug for the treatment In our own experience five of of acne.”12,20 seven severe hypersensitivity reactions occurred in black persons.2Because such a racial predisposition had already been observed for hypersensitivity reactions to other drugs, we recommend avoiding minocycline for therapy of acne in black persons. 4-AMINOQUINOLINE-DERIVED ANTIMALARIALS
Chloroquine and hydroxychloroquine are used frequently by dermatologists for their anti-inflammatory and photoprotective prope r t i e ~ Accepted .~ indications are: curative treatment of discoid (chronic) lupus erythematosus (DLE) and prophylaxis of relapse of systemic lupus erythemato~us.~~ Antimalarials are also considered useful in the prevention of polymorphous light eruption and the
treatment of porphyria cutanea tarda, cutaneous sarcoidosis, urticaria1 vasculitis, dermatomyositis, and benign cutaneous lymphocytic infiltrate^.^^
Interactions
Both chloroquine and hydroxychloroquine may increase plasma concentration and toxicity of peni~illamine.~~
Side Effects
Overdosage of chloroquine or hydroxychloroquine can be lethal, with severe cardiac toxicity occurring after acute ingestion of more than 2 g of chloroquine (20 tablets).55 Risk of overdosage is a major concern when chloroquine and hydroxychloroquine are used in children (doses of chloroquine phosphate as small as 300 mg may be fatal), but does not justify a c~ntraindication.~~ At therapeutic doses, mild gastrointestinal symptoms are the most frequent complications, occurring in up to 10% of patients. Skin and mucous membrane pigmentations are also frequent. Skin reactions lead to discontinuation of treatment in up to 3% of patients. Myopathy occurs in about 1%of patients in long-term treatrnent.ll Of more concern for long-term treatment is the potential occurrence of ocular toxicity: corneal opacities, keratopathy, or retinopathy. Retinopathy is dose-dependent, and the risk is negligible for daily doses below 3.5 mg/kg with chloroquine and 6 mg/kg for hydroxychloroq~ine.~ Complete remission of skin lesions of DLE often requires daily doses slightly above these ”safe” doses. In these cases regular ophthalmologic examination is recommended. The risk of occurrence of retinopathy has been estimated to be 3% to 10%.7z71 Early involvement of the retina can be detected by Amsler grid or color vision tests at a time when vision is not yet impaired and when discontinuation of treatment prevents the occurrence of symptomatic lesions. Because the occurrence of the most deleterious complications can be prevented by the strict observation of dosage and regular ophthalmologic examinations, long-term antimalarial treatment of DLE is generally considered safe and the benefit-to-risk ratio acceptable.
REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS
DAPSONE
Chemically related to sulfonamides, dapsone (diaminodiphenylsulfone, DDS) is still used as an antibacterial agent for the treatment of leprosy and the prophylaxis of HIV-related Pneurnocys tis cavinii pneumonia. Dermatologists prescribe dapsone in the treatment of dermatitis herpetiformis and of many other conditions, mostly those characterized by infiltration of tissues by neutrophils.60In large series, 95% to 97% of cases of dermatitis herpetiformis were controlled by dapsone,16usually with daily doses of 100 to 200 mg. Dapsone has a sizeable efficacy, with remissions in more than 50% of cases in linear IgA bullous diseases of adults and children, erythema elevatum diutinum, and Sneddon-Wilkinson disease. Other potential indications (vesiculo-bullous lupus erythematosus, pemphigus foliaceus, cutaneous vasculitis, pyoderma gangrenosum, polychondritis, granuloma annularis, Sweet syndrome)60are only based on anecdotal case reports. interactions
Rifampin decreases the activity of dapsone; conversely, trimethoprim increases the blood level and the risk of adverse effects. It is recommended to avoid concommitent therapy with drugs that may be associated with hemolysis or blood d y s c r a s i a ~ . ~ ~ Side Effects
Side effects leading to withdrawal of dapsone occur in 20% to 30% of patients and are considered severe in 6% of treated patients. Hemolysis and methemoglobinemia are nearly constant and dose-dependent. With a daily dose of 100 to 150 mg, the hemoglobin level is reduced by 2 g/dL as a mean. That degree of anemia is well tolerated by young patients, but the long-term effects of hemolysis have not been well studied. Hemolytic crisis may be life-threatening in patients with congenital deficiency of glucose 6 phosphate dehydrogenase. Severity of hemolysis should be checked by blood count 1 to 2 weeks after beginning therapy, 1 month later, and then at 3-month intervals later on. Methemoglobinemia may induce cyanosis and dyspnea when reaching more than 10% of the total amount of hemoglobin, a level
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often obtained with daily doses of dapsone of 200 mg or more. The most dangerous side effect is agranulocytosis. From data of the adverse drug reactions monitoring system in Sweden, it has been calculated that agranulocytosis occurs in 1 in 240 to 1 in 425 patients treated with dapsone for dermatitis herpetiformis.28Because the death rate of agranulocytosis reaches 9% to 10Y0,3~ the risk of death from agranulocytosis can be expected to be 1 in 3000 treated patients. Many other side effects have been attributed to dapsone. Peripheral neuropathies are considered rare,7O but in one series of 161 patients with dermatitis herpetiformis, six had nerve toxicity. Skin eruptions may be severe, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis and of the so-called “dapsone ~ y n d r o m e , ”a~ ~ hypersensitivity reaction associating fever, papular eruption, lymph node enlargement, eosinophilia, and hepatitis. These severe reactions have also induced some fatalities. Their incidence is unknown. From that compilation of side effects, it is clear that dapsone has a poor safety profile and should be avoided in those diseases in which its efficacy has not been well demonstrated. Even in dermatitis herpetiformis, when its efficacy is dramatic, dapsone should probably be used only in those patients who are not capable of adhering to a gluten-free diet. When dapsone is prescribed, blood examination should be performed at regular intervals, including complete blood count, methemoglobinemia, and liver function tests at regular intervals at the beginning of therapy.
THALlDOMiDE
Initially launched as a sedative and hypnotic agent, thalidomide decreases the production of tumor necrosis factor alpha.46,66 Immunomodulation could contribute to the anti-inflammatory effects of the drug in many disorders. Controlled trials have confirmed the effectiveness of thalidomide in erythema nodosum leprosum, severe aphthous stomatit i ~ , 5mucosal ~ ulcers of patients infected with HIV,66and Jessner lymphocytic infiltrate of the skin.24O.pen studies have suggested some efficacy in discoid lupus erythematosus, prurigo nodularis, recurrent erythema multi-
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forme, Langerhans' cell histiocytosis, and chronic graft-versus-host disease.66 Thalidomide is not commercially available in most countries, including the United States and Canada.
Interactions
Thalidomide increases the activity of barbiturates, chlorpromazine, and reserpine. It may raise the blood level and toxicity of acetaminophen. In vitro, it antagonizes histamine, serotonin acetylcholine, and prostaglandins.66
Side Effects
Thalidomide was withdrawn from the drug market in the 1960s after the disaster of birth defects. More than 10,000 babies with phocomelia (abnormally short legs and arms) were born from mothers who had taken thalidomide in the first month of pregnancy.8,46 The mechanisms of birth defects remain unknown. The incidence of these defects is not known precisely, but in the German experience in the 1960s it seemed that almost all women exposed to thalidomide in the third or fourth week of gestation had malformed newborns. The risk is so high that the prescription of thalidomide to fertile women must be restricted to highly controlled situations in which patients understand the risks (including the possibility of contraceptive failure) and agree to change their behavior to minimize that risk.50Only then are the benefits of the drug in improving severe diseases considered as overweighing the risk. Many other side effects of thalidomide are more difficult to control than the risk of teratogenesis. Sedation is nearly constant at high doses. Hypothyroidism has been occasionally reported, but its incidence is not known. With appropriate measures to prevent teratogenesis, peripheral neuropathy became the most common side effect of treatment with thalidomide. The incidence of thalidomiderelated neuropathy is variably estimated from 0.5% to more than 70?'0.~~It presents as a sensitive axonal neuropathy. The prognosis is characterized by slow regression after drug withdrawal with frequent persistent paresthesia. The following recommendations can pro-
vide the safest possible clinical use of that In fertile women, thalidomide should be prescribed only for severe conditions and after failure of other treatments. Patients should be fully informed of all risks and sign a written consent. Women should have a negative pregnancy test at initiation of therapy. Women should accept reliable contraceptive methods during the full length of treatment. All patients should have neurologic examinations and appropriate electrophysiologic measurements before treatment and at regular intervals. Follow-up visits and examinations should be performed at monthly intervals. SOTRETINOIN
The efficacy of isotretinoin as a systemic treatment of severe acne was demonstrated more than 15 years ago,48,63at daily doses ranging from 0.1 to 1 mg/kg per day for a cumulative dosage of 120 to 150 mg/kg.38,40 Severe cystic acne is the only accepted indication for isotretinoin. The drug may be helpful in selected severe cases of rosacea and hidradenitis suppurativa. Interactions
Concurrent use of many topical preparations, including topical acne preparations, may enhance the drying cutaneous effect of isotretinoin. Systemic tetracyclines increase the risk of benign intracranial hypertension (pseudotumor ~ e r e b r i ) . ~ ~ Side Effects Isotretinoin treatment of acne is associated with numerous side effects. Dry lips and cheilitis are nearly constant. Other mucocutaneous side effects occur in 30% to 60% of patients and include skin dryness, blepharoconjunctivitis, facial erythema, and dermatitis. These side effects are dosedependent. They are usually tolerable at a daily dosage of 0.5 mg/kg but can be difficult to tolerate at higher dosage. Other cutaneous side effects are less fre-
REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS
quent, such as increased risk of staphylococcal infections, transient exacerbation of acne, photosensitivity, alopecia, and folliculitis of the scalp. Systemic side effects are not rare. Myalgia and arthralgia are often reported by patients, and tendinitis may occur. Many patients complain of headache. Rarely, and usually in cases of simultaneous therapy with tetracycline antibiotics, intracranial hypertension can occur (pseudotumor cerebri). Like all retinoids, isotretinoin impairs lipoprotein metabolism. Moderate increases in the level of blood cholesterol occur in about 10% of patients as well as moderate rises in triglyceride level in 50%.22,39 Because isotretinoin is used for a few months only, these alterations in lipid metabolism are generally considered incapable of inducing a significant increase in the risk of cardiovascular disorders. Slight elevations of aminotransferases can occur in less than 5% of patients, and hepatotoxicity is not a major problem of isotretinoin. The most dangerous side effect of isotretinoin is teratogenicity. Several studies of human pregnancies with fetal exposure to isotretinoin showed that about 30% of newborns had major malformation^.^^ Characteristic abnormalities involve the face (microtia/anotia), the heart, and the central nervous system. These defects are similar to those induced in animals by retinoids or vitamin A. The risk of embryopathy has prompted extensive programs of information for physicians and patients. Unfortunately, these programs have failed in totally preventing the exposure of pregnant women to isotretinoin. A recent study detected 402 pregnancies among 124,216 women exposed to isotretinoin. That number of pregnancies was 8% of the expected number in the general population of similar age d i s t r i b ~ t i o n .Such ~ ~ a figure clearly demonstrates the impossibility of reducing the teratogenic risk to zero for a drug that is widely prescribed in a population of teenagers and young adults. Prescribers should remain aware that isotretinoin, the most efficient drug against severe acne to date, is also a dangerous product. The drug should not be used in women of childbearing age for acne of moderate severity and only for severe cystic acne or after failure of other well-conducted therapies.38In women, pregnancy tests should be performed before the prescription of the drug, and effective contraceptive methods should be used for the whole duration of therapy, beginning
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1 month before and lasting 1 month after the treatment. ETRETINATE AND AClTRETlN
Etretinate and acitretin are used in the management of psoriasis, lichen planus, and keratinization disorders.ls The efficacy of etretinate and acitretin is moderate to good in chronic plaque psoriasis and better in exfoliative dermatitis and pustular psoriasis.18,72 The interactions and side effects of etretinate and acitretin are essentially the same as those of isotretinoin.26The major difference in appreciating what risks can be accepted is the expected duration of treatment. Isotretinoin is prescribed for a few months in acne, whereas treatment of psoriasis should be scheduled for the long term. Teratogenicity is the principal problem.36 Because of the accumulation and long elimination half-life of etretinate and because of some biochemical transformation of acitretin to etretinate in vivo, pregnancy is contraindicated for 2 years after the discontinuation of treatment even if therapy has been short.ls Fertile women should be clearly advised of that risk and understand the need for prolonged contraception. The second main problem concerns the effects on blood lipids. Etretinate and acitretin increase the triglyceride level and induce a shift of cholesterol from the high density lipoproteins (HDL) to the low density lipoproteins (LDL). About 20% to 30% of patients treated with etretinate or acitretin develop hypertriglyceridemia or an increase in LDL/ HDL ratio.26,68 The direct demonstration that retinoids increase the risk of atherosclerosis is still lacking, but high LDL/HDL ratios are well demonstrated risk factors for the development of ischemic heart disease.68 In addition to these two main side effects, there are some concerns about hepatotoxicity, which seems uncommon (acute hepatitis and liver cirrhosis each occurred in 1% of 956 patients on long-term therapy with etretinate62),and about mucocutaneous side effects that are very frequent at low doses and nearly constant at high doses but that are most often tolerable and improve with dosage reduction.26 Before starting a treatment with acitretin or etritinate, a serum pregnancy test should be performed in women. Blood lipid and aminotransferase levels should be determined in
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all patients. These measurements should be repeated after two weeks and then monthly. METHOTREXATE
Proposed for psoriasis since 1969,5‘jmethotrexate is also used alone or in addition to systemic corticosteroids in dermatomyositis, pemphigus, and systemic lupus. The treatment begins with weekly doses of 7.5 to 10 mg orally or by intramuscular injections and is progressively increased to the usual effective dose of 15 to 25 mg per week. Several studies on large numbers of patients have shown that the rates of complete remission were in the range of 50%. In addition, about 30% of patients had a “good” partial res ~ o n s e .56,~‘j9~ ,
Interactions Alcohol and hepatotoxic medications increase the risk of liver damage in relation to methotrexate therapy of psoriasis. Nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates may increase toxicity by displacing methotrexate from its protein-binding sites and by inhibiting renal elimination of the Other folic acid antagonists (pyrimethamine or trimethoprim) may also increase toxic effects. Concurrent use of other bone marrow depressants should be avoided. Methotrexate may enhance the activity of oral anticoagulants. Side Effects
Side effects of methotrexate treatment of psoriasis are frequent. In the largest series, 70% of patients reported at least one side effect.56,69 These side effects result in withdrawal of the drug in 20% to 30% of cases. The most frequent are nausea, asthenia, and headache. Hematologic toxicity is not exceptional, and several studies (mainly in patients with rheumatoid arthritis) showed a risk of pancytopenia in the range of 1%to 2%.25That risk is more important in cases of dehydration and in cases of associated therapy with other antimetabolites, including folic acid antagonists. Acute skin toxicity (epidermal necrolysis, reactivation of sunburns, ulcerative stomatitis) is much rarer in the therapy of psoriasis than with high doses. Hypersensi-
tivity pneumonitis is also more rarely reported in psoriasis than in rheumatoid arthritis. Severe gastrointestinal complications with ulcerations, bleeding, or perforations are rare. Methotrexate is usually considered noncarcinogenic. Methotrexate alone does not increase the risk of skin carcinoma in patients treated for psoriasis.64Patients treated with methotrexate, however, may have an increased risk of developing skin carcinoma from PUVA therapy? Moreover, two cases of Epstein Barr virus-induced reversible lymphomas have been related to meth~trexate.~~ Hepatotoxicity is the side effect of methotrexate that has been the most extensively discussed in the dermatologic literature, with numerous studies providing contradictory results. In one series, 25% of patients treated for more than 5 years with methotrexate developed liver ~ i r r h o s i s A . ~ ~recent series including 55 patients treated for 8 years as a .~~ mean found 4% with liver ~ i r r h o s i sAnother recent study compared the liver biopsies performed in the same patients at several-year intervals, the first after a cumulative dose of methotrexate of 2.7 g and the second after a mean cumulative drug dose of 5 g. In that study there were no changes in the rate of liver fibrosis (22% on the first biopsy, 20% on the second one) or in the rate of cirrhosis (0% in both).4 The risk of cirrhosis induced by methotrexate is probably modulated by associated factors including obesity, alcohol intake, and exposure to other potentially hepatotoxic drugs. Guidelines have recommended that patients should have a liver biopsy soon after the beginning of treatment, after a cumulative dosage of 1.5 g, and at regular intervals after additional 1.5 g cumulated Such guidelines are based on the observation that important histologic changes can be found even in the absence of alteration in the liver function tests or in noninvasive investigations of the liver. These recommendations had been challenged by some dermatologists who consider that the risk of cirrhosis is low in patients who do not have additional risk factors and that the morbidity associated with liver biopsy is not negligible. Large series of liver biopsies showed a mortality in the order of 1 per 1000 patients (0.3 to 1.7 per 1000).19,42 The risk of dying from repeated liver biopsies may rise very close to the risk of dying from liver cirrhosis in the context of methotrexate therapy for patients without additional risk factors.
REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS
CYCLOSPORIN Several double-blind placebo-controlled therapeutic trialslO,41 and many open studies6, 35, 44, 51 have demonstrated the efficacy of cyclosporin in psoriasis and severe atopic dermatitis. Interactions
Many drugs including cimetidine, diltiazem, erythromycin, androgens, estrogens, ketoconazole, and itraconazole have been reported to increase the plasma concentration and the potential toxicity of cyclosporin. Hepatic enzyme inducers (rifampin, barbiturates, phenytoin, carbamazepine, primidone, and griseofulvin) may decrease the plasma concentration of cyclosporin. Additive toxicity may result from concurrent use of nephrotoxic medications, including NSAIDs, or of other immunosuppressants. Side Effects
The overall incidence of side effects reported in large series is 30% to 55%. In longterm studies (more than 6 months duration) 6% to 18% of patients interrupted the treat44 Most side ment because of side effe~ts.3~. effects are mild: headache, paresthesias, hirsutism, and influenza-like symptoms. Three side effects are of real concern: high blood pressure, nephrotoxicity, and potential promotion of cancer. High blood pressure was reported to occur in 5% to 26% of patients in short-term trials. Some studies suggested that the occurrence of high blood pressure was more frequent in patients receiving higher doses but such relationship was not found in most studies.13,35 High blood pressure usually responds to calcium channel blockers, mainly nifedipine or isradipine, which do not interfere with cyclosporin metab01ism.l~If blood pressure is not controlled by this treatment, cyclosporin doses should be decreased or discontinued. Blood pressure then returns to normal. Nephrotoxicity is the most frequent severe side effect. In a recently published long-term 46% of patients had a serum creatinine more than 30% above the baseline value at least once. In some instances, in relation to higher doses, the creatinine level was
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more than 100% above the baseline. In 6% of patients, the creatinine level remained increased after discontinuation of therapy. Renal toxicity from cyclosporin is attributed to a vasoconstrictive effect on kidney arteries. Prolonged vasoconstriction may lead to permanent alteration of blood vessels and to chronic fibrosis of the interstitium. Kidney biopsies found morphologic alterations in 21% of 192 patients receiving high doses of cyclosporin for autoimmune disorder~.'~ Because of the risk of chronic and irreversible alteration of the kidney, it has been recommended that cyclosporin should never be used for more than 2 years in patients with psoriasis. The last concern is the potential promotion of cancer. It has been well documented that the profound immunosuppression needed for organ transplantation was a risk factor for the development of Kaposi's sarcoma, squamous cell carcinoma of the skin, and lymphoma. In transplant recipients the risk of occurrence of non-Hodgkin lymphoma has been calculated to be about 30 times higher than in the general p ~ p u l a t i o nThe . ~ ~extent of the risk seems directly proportional to the degree of immunosuppression. Because it is more potent than conventional immunosuppressants, cyclosporin appeared associated with a higher incidence of proliferative disorders in organ transplant recipient^.^^ Most lymphomas occurring after cyclosporin therapy were B cell lymphomas with markers of Epstein Barr virus infe~tion.~ In organ transplant recipients, cyclosporin is usually given in addition to other immunosuppressants, and the doses are much higher than those used in the management of psoriasis. To date, only three cases of lymphoma have been reported in patients with psoriasis 34 Several cases of treated with cy~losporin.~~, transient lymphoproliferation have also been 52 Such observations clearly dem~bserved.~, onstrate that there is a risk of lymphoproliferation with the doses of cyclosporin used in patients with psoriasis, even if that risk is definitely lower than for organ transplant recipients. References 1. Akers WA, Allen AM, Burnett JW, et al: Systemic antibiotics for treatment of acne vulgaris. Arch Dermatol 111:1630, 1975 2. Bknkton N: Lancet 1997 3. Beveridge T, Krupp P, McKibbin C: Lymphomas and
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lymphoproliferative lesions developing under cyclosporin therapy. Lancet 1:788, 1984 4. Boffa M, Chalmers R, Haboubi N, et al: Sequential liver biopsies during long-term methotrexate treatment for psoriasis: A reappraisal. Br J Dermatol 133:774, 1995 5. Brown M, Ellis C, Billing J, et al: Rapid occurrence of nodular cutaneous T-lymphocyte infiltrates with cyclosporine therapy. Arch Dermatol 1241097, 1988 6. Christophers E, Mrowietz U, Henneicke H, et al: Cyclosporine in psoriasis: A multicenter dose-finding study in severe plaque psoriasis. J Am Acad Dermato1 2686, 1992 7. Cox NH, Paterson W D Ocular toxicity of antimalarials in dermatology: A survey of current practice. Br J Dermatol 131:878, 1994 8. DArcy PF, Griffin JP:Thalidomide revisited. Adverse Drug React Toxic01 Rev 13:65, 1994 9. Eisen D Minocycline-induced oral hyperpigmentation. Lancet 349:400, 1997 10. Ellis C, Fradin M, Messana J, et al: Cyclosporine for plaque-type psoriasis: Results of a multidose, doubleblind trial. N Engl J Med 324277, 1991 11. Estes ML, Ewing-Wilson D, Chou SM, et al: Chloroquine neuromyotoxicity, clinical and pathological perspective. Am J Med 82447, 1987 12. Ferner RE, Moss C: Minocycline for acne, first line treatment should be with tetracycline or oxytetracycline. BMJ 312:128, 1996 13. Feutren G, Abeywickrama K, Friend D, et al: Renal function and blood pressure in psoriatic patients treated with cyclosporin A. Br J Dermatol 122:S57, 1990 14. Feutren G, Mihatsch M: Risk factors for cyclosporineinduced nephropathy in patients with autoimmune diseases. N Engl J Med 326:1654, 1992 15. Frederiksson T, Petterson V Severe psoriasis, oral therapy with a new retinoid. Dermatologica 157238, 1978 16. Fry L, Seach PP: Dermatitis herpetiformis: An evaluation of diagnostic criteria. Br J Dermatol 90:137, 1974 17. Garioch JJ, Lewis HM, Sargent SA, et al: 25 years’ experience of a gluten-free diet in the treatment of dermatitis herpetiformis. Br J Dermatol 131:541, 1994 18. Geiger JM, Saurat JH: Acitretin and etretinate: How and when they should be used. Dermatol Clin 11:117, 1993 19. Gilmore I. Murrav-Lvon I. Williams R. et al: Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: An audit by the British Society of Gastroenterology and the Royal College of Physicians of London. Gut 36:437, 1995 20. Gottlieb A: Commentary: Safety of minocycline for acne. Lancet 349:374, 1997 21. Gough A, Chapman S, Wagstaff K, et al: Minocycline induced auto-immune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 312:169, 1996 22. Goulden V, Layton AM, Cunliffe WJ: Long-term safety of isotretinoin as a treatment for acne vulgaris. Br J Dermatol 131:360, 1994 23. Goulden V, Glass D, Cunliffe WJ: Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol 134:693, 1996 24. Guillaume J-C, Moulin G, Dieng MT, et al: Crossover study of thalidomide vs placebo in Jessner ’s lymphocytic infiltration of the skin. Arch Dermatol 131:1032, 1995 25. Gutierrez-Urena S, Molina J, Garcia C, et al: Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 39:272, 1996 i
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26. Halioua B, Saurat JH: Risk benefit ratio in the treatment of psoriasis with systemic retinoids. Br J Dermatol 36:S135, 1990 27. Hare1 L, Amir J, Livini E, et al: Serum-sickness-like reaction associated with minocycline therapy in adolescents. Ann Pharmacother 30:481, 1996 28. Homsten P, Keisu M, Wiholm BE: The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988. Arch Dermatol 126:919, 1990 29. Johnson DA, Cattau EL, Kuritsky JN, et al: Liver involvement in the sulfone syndrome. Arch Intem Med 146875,1986 30. Kame1 0, Van De Rijn M, Weiss L, et a1 Reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 328:1317, 1993 31. Kaufman D, Kelly J, Levy M, et al: The drug etiology of agranulocytosis and aplastic anemia. New York, Oxford University Press, 1991, p 148 32. Knowles SR, Shapiro L, Shear N S Serious adverse reactions induced by minocycline: Report of 13 patients and review of the literature. Arch Dermatol 132:934, 1996 33. Koo J, Kadonaga J, Wintroub B, et al: The development of B-cell lymphoma in a patient with psoriasis treated with cyclosporine. J Am Acad Dermatol 26:836, 1992 34. Krupp P, Monka C: Side-effect profile of cyclosporin A in patients treated for psoriasis. Br J Dermatol 122547, 1990 35. Laburte C, Grossman R, Abi-Rached J, et al: Efficacy and safety of oral cyclosporine A (CyA; Sandimmun) for long-term treatment of chronic severe plaque psoriasis. Br J Dermatol 130:366, 1994 36. Lammer EJ, Chen DT, Hoar RM, et al: Retinoic acid embryopathy. N Engl J Med 313:837, 1985 37. Lassus A, Geiger JM, Nyblom M, et al: Treatment of severe psoriasis with etretin (RO 10-1670). Br J Dermatol 117333, 1987 38. Layton AM, Cunliffe WJ: Guidelines for optimal use of isotretinoin in acne. J Am Acad Dermatol 2752, 1992 39. Layton AM, Knaggs H, Taylor J, et al: Isotretinoin for acne vulgaris 10 years later: A safe and successful treatment. Br J Dermatol 129:292, 1993 40. Lehucher-Ceyrac D, Weber-Buisset MJ: Isotretinoin and acne in practice, a prospective analysis of 188 cases over 9 years. Dermatology 186123, 19939 41. Mahrle G, Schulze HJ, Farber L, et al: Low-dose short-term cyclosporine versus etretinate in psoriasis: Improvement of skin, nail and joint involvement. J Am Acad Dermatol 32:78, 1995 42. McGill D, Rakela J, Zinsmeister A, et al: A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology 99:1396, 1990 43. Mitchell AA, Van Bennekom CM, Louik C: A pregnancy prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 333:101,1995 44. Mrowietz U, Farber L, Henneicke-Von Zepelin H, et al: Long-term maintenance therapy with cyclosporine and posttreatment survey in severe psoriasis. Results of a multicenter study. J Am Acad Dermatol 33:470, 1995 45. Nyford A: Benefits and adverse drug experiences during long-term methotrexate treatment of 248 psoriatics. Dan Med Bull 25:208, 1978 46. Ochonisky S, Revuz J: Thalidomide use in dermatology. Eur J Dermatol4:9, 1994
REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS 47. Pameix-Spake A, Bastuji-Garin S, Lobut J, et al: Mi-
nocycline as possible cause of severe and protracted hypersensitivity drug reaction. Arch Dermatol 131:490, 1995 48. Peck GL, Olsen TG, Yoder FW: Prolonged remissions of cystic and conglobata acne with 13-cis-retinoic acid. N Engl J Med 300329, 1979 49. Penn I, Brunson ME: Cancers after cyclosporine therapy. Transplant Proc 20:S885, 1988 50. Powell RJ, Gardner-Medwin M M Guideline for the clinical use and dispensing of thalidomide. Postgrad Med J 70:901, 1994 51. Powles A, Baker B, Valdimarsson, et al: Four years of experience with cyclosporine A for psoriasis. Br J Dermatol 122s 13, 1990 52. Puig L, Puig J, De Moragas J: Transient monoclonal gammapathy associated with cyclosporin treatment of psoriasis. Br J Dermatol 133:141, 1995 53, Rasmussen JE: Antimalarials, are they safe to use in children? Pediatr Dermatol 1:89, 1983 54. Revuz J, Guillaume J-C, Janier M, et al: Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Arch Dermatol 126:923, 1990 55. Riou B, Barriot P, Rimailho A, et al: Treatment of chloroquine poisoning’ Med 318:1f 1988 56. Roenigk H, Fowler-Bergfeldw, Curtis G: Methotrexate for psoriasis in weekly oral dose. Arch Dermatol 99236, 1969 57. Roenigk H, Auerbach R, Maibach H, et a1 Methotrexate in psoriasis: Revisited guidelines. J Am Acad Dermatol 19:145, 1988 58. Shuttleworth D, Marks R, Griffin P, et al: Epidermal dysplasia and cyclosporine therapy in renal transPlant Patients: A comparison With azathioprine. Br J Dermatol 120:551, 1989 59. Stainforth Fr,Layton AM, Taylor JP, et a1 Isotretinoin for the treatment of acne vulgaris: Which factors may predict the need for more than one course? Br J Dermatol 129297, 1993
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60. Stem RS: Systemic dapsone. Arch Dermatol 129:301, 1993 61. Stern RS, Laird N The carcinogenic risk of treatments for severe psoriasis. Cancer 73:2759, 1994 62. Stem RS, Fitzgerald E, Ellis CN, et al: The safety of
63. 64. 65.
66.
67. 68. 69, 70, 71, 72. 73.
etretinate as long-term therapy for psoriasis: Results of the etretinate follow-up study. J Am Acad Dermato1 33:44, 1995 Strauss JS, Rapini RP, Shalita AR, et al: Isotretinoin therapy for acne, results of a multicenter dose-response study. J Am Acad Dermatol 10:490, 1984 Stern RS, Zierler S, Parrish J: Methotrexate used for psoriasis and risk of noncutaneous or cutaneous malignancy. Cancer 50:869, 1982 The Canadian Hydroxychloroquine Study Group: A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med 324:150, 1991 Tseng Pak Gf Washenik Kf et Rediscovering thalidomide: A review of its mechanism of action, side effects and potential uses. J Am Acad Dermatol 35:969, 1996 USPDI Drug information for the health care professional. The United States Pharmacopeial Convention, Rockville, Maryland, 1997 Vahlquist A: Long term safety of retinoid therapy. J Am Acad Dermatol 2 7 9 9 , 1992 van Dooren-Greebe R, ~ ~A, Mulder i J, etj a1 Methotrexate revisited: Effects of long-term treatment in psoriasis. Br J Dermatol 130:204, 1994 Waldinger TP, siegle RJ, Weber W, et a1 D~~~~~~ induced peripheral neuropathy. Arch Dermatol 120:356, 1984 weiss JS: Antimalarial medications in dermatology: A review. Dermatol Clin 9:377, 1991 White SI, Marks JM, et a1 Etretinate in pustular psoriasis of palms and soles. Br J Dermatol 113:581, 1985 Zachariae H, Kragballe K, Sogaard H: Methotrexate induced liver fibrosis: Studies including serial liver biopsies during continued treatment. Br J Dermatol 102:407, 1980 3’
Address reprint requests to Jean-Claude Roujeau, MD Service de Dermatologie HBpital Henri Mondor 94010 Creteil Cedex, France
~
DERMATOLOGIC THERAPY
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REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS IN DERMATOLOGY Laurence Le Cleach, MD, HelPne Bocquet, MD, and Jean-Claude Roujeau, MD
The times are gone when dermatologic therapy was mainly based on esoteric topical preparations. Today, dermatologists frequently prescribe effective systemic treatments for many skin disorders: Anti-infectious agents (antibacterial, antiviral, antifungal) are used in the management of skin infections, and systemic steroids and immunosuppressive agents are used in the management of autoimmune blistering disorders, systemic lupus, or dermatomyositis. This article focuses on those treatments that are more specific to skin diseases, including long-term use of tetracyclines in the treatment of acne, antimalarials, dapsone, thalidomide, oral retinoids, methotrexate, and cyclosporine.
Other indications include rosacea, syphilis, and nongonococcal urethritis. Interactions
Many drugs decrease the absorption of tetracyclines, including antacids, cholestyramine or colestipol, calcium, iron, or magnesium supplements. Long-term use of tetracyclines may reduce the reliability of estrogen-containing oral contraceptives. Concurrent administration of oral retinoids or vitamin A with tetracyclines increases the risk of benign intracranial hypertension (pseudotumor ~ e r e b r i ) . ~ ~ Side Effects
TETRACYCLINES
Tetracyclines are the oral broad-spectrum antibiotics used most frequently by dermatologists. Several double-blind trials revealed that tetracyclines were more effective than placebo in the treatment of acne vu1garis.l Although all tetracyclines are effective for long-term therapy of inflammatory acne of mild to moderate severity, tetracycline and minocycline are the most commonly used.
In long-term therapy with low doses, the overall incidence of side effects is 10% to 20%.1, 23 The most common (observed with all tetracyclines) are mild gastrointestinal symptoms and oral or vaginal candidiasis. Use in pregnant women, infants, and children up to eight years of age may cause permanent discoloration of teeth and enamel hypoplasia. Oral and skin hyperpigmentation may oc-
From the Service de Dermatologie, HBpital Henri Mondor, Universitk Paris XII, Crkteil, France
DERMATOLOGIC CLINICS VOLUME 16 * NUMBER 2 * APRIL 1998
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cur with all tetracyclines but is more frequent with minocycline. The incidence of pigmentation in acne patients treated with minocycline ranges from 4% to 23 The risk increases with the duration of therapy and may reach 20% after 4 years9 Discoloration persists after discontinuing the drug. Q-switched ruby laser therapy can improve it. Photosensitivity reactions have been reported with all tetracyclines. The risk is higher with demeclocycline and doxycycline, lower with minocycline. Benign intracranial hypertension (pseudotumor cerebri) is a rare side effect of all tetracyclines, occurring usually within 4 weeks of initiating therapy. Vestibular disturbance manifesting as dizziness, lightheadedness, or unsteadiness is not rare. It was reported in up to 75% of patients in short series and in 3.4% in a large series of long-term users of min~cycline.~~ Recently many reports in the medical literature have pointed to severe idiosyncratic hypersensitivity reactions attributed to minocycline.2, 27, 32 These reactions were reported under various denominations and most often combined a severe skin eruption, eosinophilia, hepatitis, and interstitial pneumonitis. Lupus-like syndromes and serum sicknesslike reactions have also been attributed to minocycline. Although rare (about 1 per 100,000 users) these hypersensitivity reactions were responsible for a few deaths and were considered severe enough to induce editorial recommendations that ”minocycline should not be the first line oral drug for the treatment In our own experience five of of acne.”12,20 seven severe hypersensitivity reactions occurred in black persons.2Because such a racial predisposition had already been observed for hypersensitivity reactions to other drugs, we recommend avoiding minocycline for therapy of acne in black persons. 4-AMINOQUINOLINE-DERIVED ANTIMALARIALS
Chloroquine and hydroxychloroquine are used frequently by dermatologists for their anti-inflammatory and photoprotective prope r t i e ~ Accepted .~ indications are: curative treatment of discoid (chronic) lupus erythematosus (DLE) and prophylaxis of relapse of systemic lupus erythemato~us.~~ Antimalarials are also considered useful in the prevention of polymorphous light eruption and the
treatment of porphyria cutanea tarda, cutaneous sarcoidosis, urticaria1 vasculitis, dermatomyositis, and benign cutaneous lymphocytic infiltrate^.^^
Interactions
Both chloroquine and hydroxychloroquine may increase plasma concentration and toxicity of peni~illamine.~~
Side Effects
Overdosage of chloroquine or hydroxychloroquine can be lethal, with severe cardiac toxicity occurring after acute ingestion of more than 2 g of chloroquine (20 tablets).55 Risk of overdosage is a major concern when chloroquine and hydroxychloroquine are used in children (doses of chloroquine phosphate as small as 300 mg may be fatal), but does not justify a c~ntraindication.~~ At therapeutic doses, mild gastrointestinal symptoms are the most frequent complications, occurring in up to 10% of patients. Skin and mucous membrane pigmentations are also frequent. Skin reactions lead to discontinuation of treatment in up to 3% of patients. Myopathy occurs in about 1%of patients in long-term treatrnent.ll Of more concern for long-term treatment is the potential occurrence of ocular toxicity: corneal opacities, keratopathy, or retinopathy. Retinopathy is dose-dependent, and the risk is negligible for daily doses below 3.5 mg/kg with chloroquine and 6 mg/kg for hydroxychloroq~ine.~ Complete remission of skin lesions of DLE often requires daily doses slightly above these ”safe” doses. In these cases regular ophthalmologic examination is recommended. The risk of occurrence of retinopathy has been estimated to be 3% to 10%.7z71 Early involvement of the retina can be detected by Amsler grid or color vision tests at a time when vision is not yet impaired and when discontinuation of treatment prevents the occurrence of symptomatic lesions. Because the occurrence of the most deleterious complications can be prevented by the strict observation of dosage and regular ophthalmologic examinations, long-term antimalarial treatment of DLE is generally considered safe and the benefit-to-risk ratio acceptable.
REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS
DAPSONE
Chemically related to sulfonamides, dapsone (diaminodiphenylsulfone, DDS) is still used as an antibacterial agent for the treatment of leprosy and the prophylaxis of HIV-related Pneurnocys tis cavinii pneumonia. Dermatologists prescribe dapsone in the treatment of dermatitis herpetiformis and of many other conditions, mostly those characterized by infiltration of tissues by neutrophils.60In large series, 95% to 97% of cases of dermatitis herpetiformis were controlled by dapsone,16usually with daily doses of 100 to 200 mg. Dapsone has a sizeable efficacy, with remissions in more than 50% of cases in linear IgA bullous diseases of adults and children, erythema elevatum diutinum, and Sneddon-Wilkinson disease. Other potential indications (vesiculo-bullous lupus erythematosus, pemphigus foliaceus, cutaneous vasculitis, pyoderma gangrenosum, polychondritis, granuloma annularis, Sweet syndrome)60are only based on anecdotal case reports. interactions
Rifampin decreases the activity of dapsone; conversely, trimethoprim increases the blood level and the risk of adverse effects. It is recommended to avoid concommitent therapy with drugs that may be associated with hemolysis or blood d y s c r a s i a ~ . ~ ~ Side Effects
Side effects leading to withdrawal of dapsone occur in 20% to 30% of patients and are considered severe in 6% of treated patients. Hemolysis and methemoglobinemia are nearly constant and dose-dependent. With a daily dose of 100 to 150 mg, the hemoglobin level is reduced by 2 g/dL as a mean. That degree of anemia is well tolerated by young patients, but the long-term effects of hemolysis have not been well studied. Hemolytic crisis may be life-threatening in patients with congenital deficiency of glucose 6 phosphate dehydrogenase. Severity of hemolysis should be checked by blood count 1 to 2 weeks after beginning therapy, 1 month later, and then at 3-month intervals later on. Methemoglobinemia may induce cyanosis and dyspnea when reaching more than 10% of the total amount of hemoglobin, a level
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often obtained with daily doses of dapsone of 200 mg or more. The most dangerous side effect is agranulocytosis. From data of the adverse drug reactions monitoring system in Sweden, it has been calculated that agranulocytosis occurs in 1 in 240 to 1 in 425 patients treated with dapsone for dermatitis herpetiformis.28Because the death rate of agranulocytosis reaches 9% to 10Y0,3~ the risk of death from agranulocytosis can be expected to be 1 in 3000 treated patients. Many other side effects have been attributed to dapsone. Peripheral neuropathies are considered rare,7O but in one series of 161 patients with dermatitis herpetiformis, six had nerve toxicity. Skin eruptions may be severe, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis and of the so-called “dapsone ~ y n d r o m e , ”a~ ~ hypersensitivity reaction associating fever, papular eruption, lymph node enlargement, eosinophilia, and hepatitis. These severe reactions have also induced some fatalities. Their incidence is unknown. From that compilation of side effects, it is clear that dapsone has a poor safety profile and should be avoided in those diseases in which its efficacy has not been well demonstrated. Even in dermatitis herpetiformis, when its efficacy is dramatic, dapsone should probably be used only in those patients who are not capable of adhering to a gluten-free diet. When dapsone is prescribed, blood examination should be performed at regular intervals, including complete blood count, methemoglobinemia, and liver function tests at regular intervals at the beginning of therapy.
THALlDOMiDE
Initially launched as a sedative and hypnotic agent, thalidomide decreases the production of tumor necrosis factor alpha.46,66 Immunomodulation could contribute to the anti-inflammatory effects of the drug in many disorders. Controlled trials have confirmed the effectiveness of thalidomide in erythema nodosum leprosum, severe aphthous stomatit i ~ , 5mucosal ~ ulcers of patients infected with HIV,66and Jessner lymphocytic infiltrate of the skin.24O.pen studies have suggested some efficacy in discoid lupus erythematosus, prurigo nodularis, recurrent erythema multi-
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forme, Langerhans' cell histiocytosis, and chronic graft-versus-host disease.66 Thalidomide is not commercially available in most countries, including the United States and Canada.
Interactions
Thalidomide increases the activity of barbiturates, chlorpromazine, and reserpine. It may raise the blood level and toxicity of acetaminophen. In vitro, it antagonizes histamine, serotonin acetylcholine, and prostaglandins.66
Side Effects
Thalidomide was withdrawn from the drug market in the 1960s after the disaster of birth defects. More than 10,000 babies with phocomelia (abnormally short legs and arms) were born from mothers who had taken thalidomide in the first month of pregnancy.8,46 The mechanisms of birth defects remain unknown. The incidence of these defects is not known precisely, but in the German experience in the 1960s it seemed that almost all women exposed to thalidomide in the third or fourth week of gestation had malformed newborns. The risk is so high that the prescription of thalidomide to fertile women must be restricted to highly controlled situations in which patients understand the risks (including the possibility of contraceptive failure) and agree to change their behavior to minimize that risk.50Only then are the benefits of the drug in improving severe diseases considered as overweighing the risk. Many other side effects of thalidomide are more difficult to control than the risk of teratogenesis. Sedation is nearly constant at high doses. Hypothyroidism has been occasionally reported, but its incidence is not known. With appropriate measures to prevent teratogenesis, peripheral neuropathy became the most common side effect of treatment with thalidomide. The incidence of thalidomiderelated neuropathy is variably estimated from 0.5% to more than 70?'0.~~It presents as a sensitive axonal neuropathy. The prognosis is characterized by slow regression after drug withdrawal with frequent persistent paresthesia. The following recommendations can pro-
vide the safest possible clinical use of that In fertile women, thalidomide should be prescribed only for severe conditions and after failure of other treatments. Patients should be fully informed of all risks and sign a written consent. Women should have a negative pregnancy test at initiation of therapy. Women should accept reliable contraceptive methods during the full length of treatment. All patients should have neurologic examinations and appropriate electrophysiologic measurements before treatment and at regular intervals. Follow-up visits and examinations should be performed at monthly intervals. SOTRETINOIN
The efficacy of isotretinoin as a systemic treatment of severe acne was demonstrated more than 15 years ago,48,63at daily doses ranging from 0.1 to 1 mg/kg per day for a cumulative dosage of 120 to 150 mg/kg.38,40 Severe cystic acne is the only accepted indication for isotretinoin. The drug may be helpful in selected severe cases of rosacea and hidradenitis suppurativa. Interactions
Concurrent use of many topical preparations, including topical acne preparations, may enhance the drying cutaneous effect of isotretinoin. Systemic tetracyclines increase the risk of benign intracranial hypertension (pseudotumor ~ e r e b r i ) . ~ ~ Side Effects Isotretinoin treatment of acne is associated with numerous side effects. Dry lips and cheilitis are nearly constant. Other mucocutaneous side effects occur in 30% to 60% of patients and include skin dryness, blepharoconjunctivitis, facial erythema, and dermatitis. These side effects are dosedependent. They are usually tolerable at a daily dosage of 0.5 mg/kg but can be difficult to tolerate at higher dosage. Other cutaneous side effects are less fre-
REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS
quent, such as increased risk of staphylococcal infections, transient exacerbation of acne, photosensitivity, alopecia, and folliculitis of the scalp. Systemic side effects are not rare. Myalgia and arthralgia are often reported by patients, and tendinitis may occur. Many patients complain of headache. Rarely, and usually in cases of simultaneous therapy with tetracycline antibiotics, intracranial hypertension can occur (pseudotumor cerebri). Like all retinoids, isotretinoin impairs lipoprotein metabolism. Moderate increases in the level of blood cholesterol occur in about 10% of patients as well as moderate rises in triglyceride level in 50%.22,39 Because isotretinoin is used for a few months only, these alterations in lipid metabolism are generally considered incapable of inducing a significant increase in the risk of cardiovascular disorders. Slight elevations of aminotransferases can occur in less than 5% of patients, and hepatotoxicity is not a major problem of isotretinoin. The most dangerous side effect of isotretinoin is teratogenicity. Several studies of human pregnancies with fetal exposure to isotretinoin showed that about 30% of newborns had major malformation^.^^ Characteristic abnormalities involve the face (microtia/anotia), the heart, and the central nervous system. These defects are similar to those induced in animals by retinoids or vitamin A. The risk of embryopathy has prompted extensive programs of information for physicians and patients. Unfortunately, these programs have failed in totally preventing the exposure of pregnant women to isotretinoin. A recent study detected 402 pregnancies among 124,216 women exposed to isotretinoin. That number of pregnancies was 8% of the expected number in the general population of similar age d i s t r i b ~ t i o n .Such ~ ~ a figure clearly demonstrates the impossibility of reducing the teratogenic risk to zero for a drug that is widely prescribed in a population of teenagers and young adults. Prescribers should remain aware that isotretinoin, the most efficient drug against severe acne to date, is also a dangerous product. The drug should not be used in women of childbearing age for acne of moderate severity and only for severe cystic acne or after failure of other well-conducted therapies.38In women, pregnancy tests should be performed before the prescription of the drug, and effective contraceptive methods should be used for the whole duration of therapy, beginning
425
1 month before and lasting 1 month after the treatment. ETRETINATE AND AClTRETlN
Etretinate and acitretin are used in the management of psoriasis, lichen planus, and keratinization disorders.ls The efficacy of etretinate and acitretin is moderate to good in chronic plaque psoriasis and better in exfoliative dermatitis and pustular psoriasis.18,72 The interactions and side effects of etretinate and acitretin are essentially the same as those of isotretinoin.26The major difference in appreciating what risks can be accepted is the expected duration of treatment. Isotretinoin is prescribed for a few months in acne, whereas treatment of psoriasis should be scheduled for the long term. Teratogenicity is the principal problem.36 Because of the accumulation and long elimination half-life of etretinate and because of some biochemical transformation of acitretin to etretinate in vivo, pregnancy is contraindicated for 2 years after the discontinuation of treatment even if therapy has been short.ls Fertile women should be clearly advised of that risk and understand the need for prolonged contraception. The second main problem concerns the effects on blood lipids. Etretinate and acitretin increase the triglyceride level and induce a shift of cholesterol from the high density lipoproteins (HDL) to the low density lipoproteins (LDL). About 20% to 30% of patients treated with etretinate or acitretin develop hypertriglyceridemia or an increase in LDL/ HDL ratio.26,68 The direct demonstration that retinoids increase the risk of atherosclerosis is still lacking, but high LDL/HDL ratios are well demonstrated risk factors for the development of ischemic heart disease.68 In addition to these two main side effects, there are some concerns about hepatotoxicity, which seems uncommon (acute hepatitis and liver cirrhosis each occurred in 1% of 956 patients on long-term therapy with etretinate62),and about mucocutaneous side effects that are very frequent at low doses and nearly constant at high doses but that are most often tolerable and improve with dosage reduction.26 Before starting a treatment with acitretin or etritinate, a serum pregnancy test should be performed in women. Blood lipid and aminotransferase levels should be determined in
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Le CLEACH et a1
all patients. These measurements should be repeated after two weeks and then monthly. METHOTREXATE
Proposed for psoriasis since 1969,5‘jmethotrexate is also used alone or in addition to systemic corticosteroids in dermatomyositis, pemphigus, and systemic lupus. The treatment begins with weekly doses of 7.5 to 10 mg orally or by intramuscular injections and is progressively increased to the usual effective dose of 15 to 25 mg per week. Several studies on large numbers of patients have shown that the rates of complete remission were in the range of 50%. In addition, about 30% of patients had a “good” partial res ~ o n s e .56,~‘j9~ ,
Interactions Alcohol and hepatotoxic medications increase the risk of liver damage in relation to methotrexate therapy of psoriasis. Nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates may increase toxicity by displacing methotrexate from its protein-binding sites and by inhibiting renal elimination of the Other folic acid antagonists (pyrimethamine or trimethoprim) may also increase toxic effects. Concurrent use of other bone marrow depressants should be avoided. Methotrexate may enhance the activity of oral anticoagulants. Side Effects
Side effects of methotrexate treatment of psoriasis are frequent. In the largest series, 70% of patients reported at least one side effect.56,69 These side effects result in withdrawal of the drug in 20% to 30% of cases. The most frequent are nausea, asthenia, and headache. Hematologic toxicity is not exceptional, and several studies (mainly in patients with rheumatoid arthritis) showed a risk of pancytopenia in the range of 1%to 2%.25That risk is more important in cases of dehydration and in cases of associated therapy with other antimetabolites, including folic acid antagonists. Acute skin toxicity (epidermal necrolysis, reactivation of sunburns, ulcerative stomatitis) is much rarer in the therapy of psoriasis than with high doses. Hypersensi-
tivity pneumonitis is also more rarely reported in psoriasis than in rheumatoid arthritis. Severe gastrointestinal complications with ulcerations, bleeding, or perforations are rare. Methotrexate is usually considered noncarcinogenic. Methotrexate alone does not increase the risk of skin carcinoma in patients treated for psoriasis.64Patients treated with methotrexate, however, may have an increased risk of developing skin carcinoma from PUVA therapy? Moreover, two cases of Epstein Barr virus-induced reversible lymphomas have been related to meth~trexate.~~ Hepatotoxicity is the side effect of methotrexate that has been the most extensively discussed in the dermatologic literature, with numerous studies providing contradictory results. In one series, 25% of patients treated for more than 5 years with methotrexate developed liver ~ i r r h o s i s A . ~ ~recent series including 55 patients treated for 8 years as a .~~ mean found 4% with liver ~ i r r h o s i sAnother recent study compared the liver biopsies performed in the same patients at several-year intervals, the first after a cumulative dose of methotrexate of 2.7 g and the second after a mean cumulative drug dose of 5 g. In that study there were no changes in the rate of liver fibrosis (22% on the first biopsy, 20% on the second one) or in the rate of cirrhosis (0% in both).4 The risk of cirrhosis induced by methotrexate is probably modulated by associated factors including obesity, alcohol intake, and exposure to other potentially hepatotoxic drugs. Guidelines have recommended that patients should have a liver biopsy soon after the beginning of treatment, after a cumulative dosage of 1.5 g, and at regular intervals after additional 1.5 g cumulated Such guidelines are based on the observation that important histologic changes can be found even in the absence of alteration in the liver function tests or in noninvasive investigations of the liver. These recommendations had been challenged by some dermatologists who consider that the risk of cirrhosis is low in patients who do not have additional risk factors and that the morbidity associated with liver biopsy is not negligible. Large series of liver biopsies showed a mortality in the order of 1 per 1000 patients (0.3 to 1.7 per 1000).19,42 The risk of dying from repeated liver biopsies may rise very close to the risk of dying from liver cirrhosis in the context of methotrexate therapy for patients without additional risk factors.
REACTIONS AND INTERACTIONS OF SOME COMMONLY USED SYSTEMIC DRUGS
CYCLOSPORIN Several double-blind placebo-controlled therapeutic trialslO,41 and many open studies6, 35, 44, 51 have demonstrated the efficacy of cyclosporin in psoriasis and severe atopic dermatitis. Interactions
Many drugs including cimetidine, diltiazem, erythromycin, androgens, estrogens, ketoconazole, and itraconazole have been reported to increase the plasma concentration and the potential toxicity of cyclosporin. Hepatic enzyme inducers (rifampin, barbiturates, phenytoin, carbamazepine, primidone, and griseofulvin) may decrease the plasma concentration of cyclosporin. Additive toxicity may result from concurrent use of nephrotoxic medications, including NSAIDs, or of other immunosuppressants. Side Effects
The overall incidence of side effects reported in large series is 30% to 55%. In longterm studies (more than 6 months duration) 6% to 18% of patients interrupted the treat44 Most side ment because of side effe~ts.3~. effects are mild: headache, paresthesias, hirsutism, and influenza-like symptoms. Three side effects are of real concern: high blood pressure, nephrotoxicity, and potential promotion of cancer. High blood pressure was reported to occur in 5% to 26% of patients in short-term trials. Some studies suggested that the occurrence of high blood pressure was more frequent in patients receiving higher doses but such relationship was not found in most studies.13,35 High blood pressure usually responds to calcium channel blockers, mainly nifedipine or isradipine, which do not interfere with cyclosporin metab01ism.l~If blood pressure is not controlled by this treatment, cyclosporin doses should be decreased or discontinued. Blood pressure then returns to normal. Nephrotoxicity is the most frequent severe side effect. In a recently published long-term 46% of patients had a serum creatinine more than 30% above the baseline value at least once. In some instances, in relation to higher doses, the creatinine level was
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more than 100% above the baseline. In 6% of patients, the creatinine level remained increased after discontinuation of therapy. Renal toxicity from cyclosporin is attributed to a vasoconstrictive effect on kidney arteries. Prolonged vasoconstriction may lead to permanent alteration of blood vessels and to chronic fibrosis of the interstitium. Kidney biopsies found morphologic alterations in 21% of 192 patients receiving high doses of cyclosporin for autoimmune disorder~.'~ Because of the risk of chronic and irreversible alteration of the kidney, it has been recommended that cyclosporin should never be used for more than 2 years in patients with psoriasis. The last concern is the potential promotion of cancer. It has been well documented that the profound immunosuppression needed for organ transplantation was a risk factor for the development of Kaposi's sarcoma, squamous cell carcinoma of the skin, and lymphoma. In transplant recipients the risk of occurrence of non-Hodgkin lymphoma has been calculated to be about 30 times higher than in the general p ~ p u l a t i o nThe . ~ ~extent of the risk seems directly proportional to the degree of immunosuppression. Because it is more potent than conventional immunosuppressants, cyclosporin appeared associated with a higher incidence of proliferative disorders in organ transplant recipient^.^^ Most lymphomas occurring after cyclosporin therapy were B cell lymphomas with markers of Epstein Barr virus infe~tion.~ In organ transplant recipients, cyclosporin is usually given in addition to other immunosuppressants, and the doses are much higher than those used in the management of psoriasis. To date, only three cases of lymphoma have been reported in patients with psoriasis 34 Several cases of treated with cy~losporin.~~, transient lymphoproliferation have also been 52 Such observations clearly dem~bserved.~, onstrate that there is a risk of lymphoproliferation with the doses of cyclosporin used in patients with psoriasis, even if that risk is definitely lower than for organ transplant recipients. References 1. Akers WA, Allen AM, Burnett JW, et al: Systemic antibiotics for treatment of acne vulgaris. Arch Dermatol 111:1630, 1975 2. Bknkton N: Lancet 1997 3. Beveridge T, Krupp P, McKibbin C: Lymphomas and
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Address reprint requests to Jean-Claude Roujeau, MD Service de Dermatologie HBpital Henri Mondor 94010 Creteil Cedex, France
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