Other Systemic Drugs

Abstract

This chapter reviews systemic medications commonly used in dermatology that are not discussed elsewhere in this text. For each drug, a historical overview is provided followed by the mechanism of action, dosages, side effects, indications, contraindications, pregnancy considerations, and drug interactions. Systemic drugs used in dermatology may be subdivided into broad categories, such as immunosuppressive, cytotoxic, and antiproliferative. Medications covered include antimalarials, apremilast, azathioprine, bleomycin, clofazimine, colchicine, cyclophosphamide, cyclosporine, dapsone, hydroxyurea, leukotriene inhibitors, methotrexate, mycophenolate mofetil, saturated solution of potassium iodide, sirolimus (rapamycin), tacrolimus, and thalidomide. Information contained in this chapter is meant to serve as a springboard for the reader. It allows for a comparison of various systemic medications, taking into account side effects and contraindications. However, this chapter is merely a starting point as it is not a substitute for the in-depth knowledge and experience necessary to implement these systemic therapies, nor is it a complete library of systemic drugs used in dermatology.

Keywords

mechanism of action, medication side effects, use in pregnancy and lactation, drug interactions, dosages, indications and contraindications of systemic medications in dermatology, antimalarials, apremilast, azathioprine, bleomycin, clofazimine, colchicine, cyclophosphamide, cyclosporine, dapsone, hydroxyurea, leukotriene inhibitors, methotrexate, mycophenolate mofetil, saturated solution of potassium iodide (SSKI), sirolimus (rapamycin), tacrolimus, thalidomide

Introduction

This chapter is designed to be a broad overview of selected systemic therapies for dermatologic diseases. It provides an historical perspective for each drug, a discussion of its mechanism of action and side effects, and touches briefly on indications and clinical use. This information should serve as a starting point, allowing the reader to readily compare and contrast treatment options. It is not a substitute for the in-depth knowledge and experience necessary to implement these therapies, nor is it a complete library of systemic drugs used in dermatology. A number of systemic medications are reviewed in other chapters ( Table 130.1 ) and will not be discussed here.

Table 130.1

Systemic medications covered in other chapters.

IL-1R, interleukin-1 receptor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; JAK, Janus kinase.

SYSTEMIC MEDICATIONS COVERED IN OTHER CHAPTERS
Antihistamines	Ch. 18
Antimicrobials	Ch. 127
Biologic immunomodulators, including rituximab, secukinumab, TNF-α inhibitors, ustekinumab	Ch. 128
Cytokines, including G-CSF, GM-CSF, interferons	Ch. 128
Glucocorticosteroids	Ch. 125
Interleukin (IL)-1 and IL-1R antagonists, including anakinra, canakinumab, rilonacept	Chs 45 & 128
Intravenous immunoglobulin (IVIg)	Ch. 128
Ivermectin	Ch. 84
JAK inhibitors, e.g. tofacitinib	Ch. 128
Psoralens	Ch. 134
Psychotropic agents, including pimozide, atypical antipsychotic agents	Ch. 7
Retinoids, including acitretin, bexarotene, isotretinoin	Chs 8 , 36 & 126
Spironolactone	Ch. 36

Systemic drugs used in dermatology may be subdivided into broad categories, such as immunosuppressive, cytotoxic, and antiproliferative ( Table 130.2 ). Drugs in a single category act in a relatively similar fashion and generally have similar important side effects. For example, immunosuppressive drugs suppress the body’s ability to recognize or eliminate infections and neoplastic cells. Patients may be at increased risk for opportunistic infections and selected lymphoproliferative malignancies as well as squamous cell carcinomas. Given this increased risk for infection, patients with either an active infection or one that may reactivate (e.g. tuberculosis, hepatitis B viral infection) should be cautiously given these drugs.

Table 130.2

Categories of systemic drugs used in dermatology based upon mechanism of action.

CATEGORIES OF SYSTEMIC DRUGS USED IN DERMATOLOGY BASED UPON MECHANISM OF ACTION
Immunosuppressive/Anti-inflammatory	Cytotoxic	Antiproliferative	Miscellaneous
Apremilast Azathioprine Mycophenolate mofetil Cyclosporine Tacrolimus Thalidomide	Cyclophosphamide Bleomycin	Methotrexate * Hydroxyurea	Dapsone Antimalarials Saturated solution of potassium iodide (SSKI)

* Also immunosuppressive/anti-inflammatory.

Most of the drugs discussed herein lack Food and Drug Administration (FDA) approval for dermatologic indications. However, in most instances, their use is based on the mechanism of action of the drug and the presumed pathogenesis of the disease, although in some instances, it is based upon anecdotal observations. When choosing therapy for a patient, certain broad general principles apply. First, the physician should be aware of all common therapeutic modalities available that are likely to yield optimal results. Certain systemic medications will not be utilized frequently enough for a given clinician to become comfortable with their use; therefore, patients requiring more specialized drugs should be referred to colleagues experienced with their use. Patients should be advised of all reasonable therapeutic choices as well as the risk–benefit profile of each modality. Non-compliance is a relative contraindication for all medications discussed in this chapter.

Prior to initiation of several of these medications, based upon potential side effects, the patient should have a complete history and physical examination, with specific emphasis on organ systems that may be affected by the particular drug. Tuberculin skin testing and/or interferon-gamma release assays (IGRAs; e.g. QuantiFERON ^®-TB Gold test, T-SPOT ^®.TB) should be performed prior to using some of the immunosuppressive medications, specifically corticosteroids (particularly when a prolonged course is anticipated) and biologic immunomodulators (see Ch. 128 ). Suggested screening for hepatitis B and C viruses is outlined in Table 128.8 . Consultation with appropriate generalists or specialists in selected situations may be required prior to initiating therapy as well as for periodic screening for treatment complications. Table 130.3 outlines suggested monitoring guidelines for systemic medications discussed in this chapter. These tests may need to be performed more frequently in high-risk patients or in patients with abnormal results. Additionally, each outpatient visit should include an appropriate review of systems and physical examination.

Table 130.3

Monitoring guidelines for systemic medications, as recommended by the authors (i.e. not necessarily standards of care).

Before using any of these medications, the risk–benefit profiles and adverse effects should be thoroughly discussed with each patient. More frequent monitoring is needed in high-risk patients, when results are abnormal or when increasing doses. AAO, American Academy of Ophthalmology; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count with differential; CMP, comprehensive metabolic panel (includes liver function tests); G6PD, glucose-6-phosphate dehydrogenase; GFR, glomerular filtration rate; HDL, high-density lipoproteins; IGRAs, interferon-gamma release assays; PLT, platelet; TG, triglycerides; TPMT, thiopurine methyltransferase; UA, urinalysis; WBC, white blood count.

MONITORING GUIDELINES FOR SYSTEMIC MEDICATIONS
Drug	Initial screening	Follow-up monitoring	Special considerations
Antimalarials	Ocular: Slit lamp and fundoscopic examination: assessment of visual acuity and visual field testing Laboratory: CBC CMP G6PD (selected cases)	Ocular: Repeat testing every 6 months for 1 year and then yearly versus recent AAO guidelines – baseline examination within the first year of use then annual screening after 5 years of continuous therapy, unless high-risk patient or symptoms arise (see Table 130.4 ) Laboratory: CBC monthly for 3 months, then every 4–6 months CMP after 1 and 3 months, then every 4–6 months	G6PD testing before antimalarial therapy is controversial and is probably most important with the use of primaquine Urine or serum porphyrins should be measured when porphyria is clinically suspected
Antimalarials			Retinopathy risk is greatest for those on treatment for at least 5 years (especially with chloroquine) and if maximum daily safe maintenance dose has been exceeded
Azathioprine	CBC with PLT count CMP UA Consider pregnancy test for women of childbearing potential TPMT level, if available Tuberculin skin testing/IGRAs (should be considered depending on clinical situation)	CBC with PLT count every 2 weeks for 2 months, then every 2–3 months if stable AST/ALT every 2 weeks for 2 months, then every 2–3 months if stable	25% dose reduction is necessary if GFR 10–50 ml/min; 50% dose reduction if GFR <10 ml/min Frequency of laboratory studies is based on baseline TPMT determination (see Table 130.7 ); if TPMT is not known, hematologic parameters should be more closely monitored Discontinue therapy, at least temporarily, if WBC declines to <3500–4000 cells/mm ³or if hemoglobin <10 g/dl Yearly skin examination and age-appropriate cancer screening, including yearly gynecologic examination in women
Cyclophosphamide	CBC with PLT count CMP UA Pregnancy test for women of childbearing potential	CBC with PLT count every week for 2–3 months, then every 2 weeks if stable. After 3–6 months, may decrease to every 3 months if stable UA every week for 2–3 months, then every 2 weeks if stable. After 3–6 months may decrease to every 3 months if stable CMP monthly for 3–6 months, then every 3 months if stable	Discontinue temporarily or lower dose if WBC declines to <3500–4000 cells/mm ³or PLT count to <100 000 cells/mm ³ Stop treatment if red blood cells appear in urine; refer to urologist if hematuria persists Urine cytology after a cumulative dose of 50 g or after an episode of hemorrhagic cystitis; consider repeating yearly and/or after each 50 g Yearly physical examination and CBC as well as age-appropriate cancer screening
Cyclosporine	At least 2 baseline blood pressure readings At least 2 baseline serum creatinine levels CMP (must include BUN, magnesium, potassium and uric acid) CBC with PLT count UA with microscopic examination Fasting lipid profile (TG, cholesterol, HDL)	CBC with PLT count at 1 month, then every 2–4 months CMP (must include BUN, creatinine, uric acid, potassium, magnesium) every 2 weeks for 1–2 months, then monthly or every 3 months if stable UA with microscopic examination every month if abnormal; otherwise yearly Fasting lipid panel every 2–4 weeks for 1–2 months, then every 3 months if stable	Blood pressure must be monitored every 2 weeks for first 3 months and then monthly if stable Lower dose by 25–50% if serum creatinine remains elevated (over 2 weeks) by >25% of baseline Lower dose by 25–50%, or discontinue, if at any time serum creatinine is elevated by ≥50% of baseline Consider creatinine clearance if >6 months of therapy Skin examination at least yearly and age-appropriate cancer screening Consider trough whole drug cyclosporine level if non-compliance, poor absorption or drug interactions are suspected
Dapsone	CBC with PLT count CMP UA G6PD level	CBC with PLT count every 2 weeks for 2 months, then every 3–4 months; after 9–12 months of therapy, for patients on lower doses with stable normal laboratory values, consider twice-yearly testing Reticulocyte count if anemia develops CMP every 3–4 months UA every 3–4 months	Each visit should include an assessment of peripheral motor function and an assessment for the signs and symptoms of methemoglobinemia and peripheral neuropathy (e.g. motor strength, reflexes) Methemoglobin level if clinically indicated Increase monitoring frequency when dose is increased
Methotrexate	CBC with PLT count CMP Pregnancy test for women of childbearing potential Serologic tests for hepatitis A, B, C HIV testing if indicated	CBC with PLT and AST/ALT after initial 2.5–5 mg test dose CBC with PLT and AST/ALT every week for 2–4 weeks and after each dose escalation, then monthly for 2–4 months, and then every 3–4 months, if stable BUN and serum creatinine every 6–12 months See text for discussion of serum markers and non-invasive imaging studies used to assess hepatic fibrosis	Per recent psoriasis treatment guidelines (2009) , for patients without risk factors for hepatic fibrosis, liver biopsies may not be indicated or the frequency of liver biopsies may be markedly reduced (as compared to previous recommendations for liver biopsies baseline and then after every 1.5–2 g in low-risk patients). For high-risk patients, liver biopsies are done baseline and then after every 1 g, and in those with grade IIIA liver biopsy changes, every 6 months or as recommended by a hepatologist Consider creatinine clearance, especially in elderly patients
Mycophenolate mofetil	CBC with PLT count CMP Pregnancy test for women of childbearing potential	CBC with PLT count every 2 weeks for 2–3 months, then monthly for first year CMP after 1 month and then every 3–4 months	Discontinue or decrease dose if WBC declines to <3500–4000 cells/mm ³
Thalidomide	CBC with PLT count CMP Pregnancy test in women of childbearing potential Subjective review of sensory and motor neurologic function and neurologic examination	Consider CBC with PLT count and AST/ALT every 2–3 months Pregnancy test every week for 4 weeks, then monthly for women of childbearing potential with regular menses, or every 2 weeks for those with irregular menses and as clinically indicated Neurologic examination monthly for 3 months, then every 1–6 months	Measurements of sensory nerve action potential amplitudes (SNAP), if indicated by history prior to therapy Consider SNAP measurements every 6 months, or as indicated

The use of each drug during pregnancy and lactation is reviewed. Wherever possible, this has been referenced with the ninth edition of Drugs in Pregnancy and Lactation by Briggs and colleagues. Additionally, in 2015, under the Pregnancy and Lactation Labeling Rule (PLLR), the FDA abolished the letter rating system for drug safety in pregnant women and during lactation; the letters are to be replaced with narrative-based labeling . Drugs approved prior to 2015 have three years to comply with the new format while drugs approved thereafter must comply from the onset. This text will, when possible, include both when applicable. In general, one should be circumspect in prescribing systemic medications to women of childbearing potential. It is not adequate to merely ask the patient if she is utilizing birth control; the patient must be made acutely aware of the risks associated with medication use during pregnancy and risks of continuing therapy if she becomes pregnant. The prescribing physician also needs to be aware that birth defects have sometimes been ascribed to systemic medications despite lack of strong scientific evidence. Family planning consultation and communication with the patient’s obstetrician or primary care physician can prove helpful.

A few of the medications reviewed in this chapter, including mycophenolate mofetil and thalidomide and its derivatives, are subject to FDA-mandated Risk Evaluation and Mitigation Strategies (REMS). In addition to specifically designed medication guides for patients, there are educational programs for health care providers and restrictive computerized programs to ensure compliance and safe usage of the medications, especially as it pertains to pregnancy.

Lastly, several drugs discussed herein have parenteral formulations. Clinicians who administer parenteral medications in the ambulatory setting should be current in Advanced Cardiac Life Support (ACLS) training and keep emergency resuscitation supplies available.

Antimalarials

Quinine and its derivatives have been used since the 1600s to treat malaria. Quinine, derived from the bark of the cinchona tree in South America, was first used in dermatology by Payne in 1894 to treat discoid lesions in patients with lupus erythematosus (LE). The most common antimalarials are hydroxychloroquine (Plaquenil ^®), chloroquine (Aralen ^®), and quinacrine; the latter, which can lead to yellow skin discoloration, is only available in the US via compounding pharmacies and will not be discussed in detail.

The antimalarials are absorbed extensively into tissues and slowly released, leading to a half-life of 40–50 days. A steady state is achieved slowly, and it may take 3–4 months to see adequate clinical effects. Hydroxychloroquine is catabolized into two metabolites, desethylhydroxychloroquine and desethylchloroquine. Chloroquine is metabolized only into the latter. The initial metabolites then undergo further change into the primary amine form. Overall, 50% of each drug undergoes renal excretion .

Mechanism of Action

The mechanisms of action of antimalarials are complex and incompletely understood. Known endpoints include the following: stabilization of lysosomes within injured cells; inhibition of antigen presentation, cell-mediated immunity, and the synthesis of proinflammatory cytokines; and antithrombotic/antiplatelet effects . The photoprotective effect attributed to the antimalarials may result from their anti-inflammatory properties .

Dosages

Most conditions will respond to dosages between 200 and 400 mg/day of hydroxychloroquine or 250 mg/day of chloroquine, with a maximum safe chronic dose (from an ocular standpoint) being 5 mg/kg/day and 2.3 mg/kg/day, respectively, utilizing real body weight . After a suitable therapeutic response has been achieved, the response may be maintained with hydroxychloroquine 100–200 mg daily. If available, quinacrine (100 mg/day) can be added to 200 mg twice daily of hydroxychloroquine, to maximize the clinical benefit without increasing the risk of ocular toxicity. Lower doses of chloroquine (125 mg twice weekly) or hydroxychloroquine (100 mg three times weekly) must be used in patients with porphyria cutanea tarda, in order to minimize the risk of a toxic reaction (e.g. hepatotoxicity) in addition to a marked increase in urinary uroporphyrin output and flare of cutaneous disease ( Fig. 130.1 ).

If no response is noted after 3–4 months, the specific antimalarial has failed and should be discontinued; however, a different antimalarial can be tried. In patients with porphyria cutanea tarda, the antimalarial can slowly be increased to daily dosing if necessary and if laboratory monitoring of transaminases allows.

Monitoring guidelines are outlined in Table 130.3 and in the next section.

Major Side Effects

Antimalarials are highly concentrated in the iris and choroid, reaching levels 480 000 times that of plasma . However, irreversible retinopathy rarely occurs when dosages remain within the recommended range and patients are monitored by an ophthalmologist experienced with the ocular effects of antimalarials ( Table 130.4 ). As noted in Table 130.4 , the risk of retinopathy is much less with hydroxychloroquine than with chloroquine.

Table 130.4

Risk factors and types of retinopathy associated with antimalarial therapy.

The ocular examination should include white 10-2 threshold testing (automated visual field testing) plus one or more of the following, if available: spectral domain optical coherence tomography, multifocal electroretinogram, or fundus autofluorescence.

Adapted from references .

RISK FACTORS AND TYPES OF RETINOPATHY ASSOCIATED WITH ANTIMALARIAL THERAPY
	Hydroxychloroquine	Chloroquine
Risk factors
Dosing risk
Daily dose	>400 mg/day (>5 mg/kg/day, based upon real body weight)	>250 mg/d (>2.3 mg/kg/day based upon real body weight)
Total cumulative dose	>1000 g	>460 g
*Other risk factors*
Ocular	• History of retinopathy or maculopathy	• History of retinopathy or maculopathy
Systemic	• Renal or hepatic dysfunction • Use of tamoxifen	• Renal or hepatic dysfunction
Age	• Elderly	• Elderly
Types of retinopathy
Reversible ocular toxicity: • Corneal deposits leading to blurred vision, halos of colors around lights • Loss of accommodation/diplopia • Premaculopathy: no visual symptoms or loss of visual acuity, central and paracentral scotomata	• Observed in 5% of patients • Often reversible with discontinuation of therapy	• Observed in 90% of patients • Often reversible with discontinuation of therapy
Irreversible ocular toxicity (true retinopathy): • “Bull’s eye” pigment deposition • Central scotomata • Changes in visual acuity	• Incidence of 0.5% after 6 years of treatment • If develops, suspend treatment	• Incidence can reach 1% after 5 years of treatment • If develops, suspend treatment

Because of the risk of dose-related ocular toxicity, referral to an ophthalmologist is necessary for a baseline examination. The revised American Academy of Ophthalmology (AAO) guidelines recommend this baseline examination be performed within the first year of antimalarial use. With the exception of higher risk individuals (e.g. the elderly, history of maculopathy) and those patients with symptoms, annual screening then begins after five years of continuous use . This is in distinction to previous guidelines in which screening was performed every 6–12 months. The basis for the revised guidelines is the negligible risk of retinopathy during the first five years of therapy with commonly employed doses (see Table 130.4 ) . Of note, recent data regarding long-term usage suggest a significant potential for retinopathy after 10 years of continuous therapy .

Up to one-third of patients who receive antimalarials for over 4 months will develop a blue–gray to black hyperpigmentation on their shins ( Fig. 130.2 ), face, palate and/or nail beds ( Table 130.5 ). The discoloration fades after cessation of therapy, but may take months to years to resolve completely. Reversible bleaching of the hair roots (achromotrichia) occurs in up to 10% of patients, presumably due to interference with melanosomal function. Another 10–20% may develop an exanthem, ranging from urticaria to lichenoid reactions to exfoliative erythroderma. Of interest, morbilliform and urticarial exanthems have been observed with greater frequency in individuals with dermatomyositis as compared to those with LE.

Table 130.5

Side effects of systemic drugs used in dermatology.

CHF, congestive heart failure; Derm, dermatologic; G6PD, glucose-6-phosphate dehydrogenase; ENT, ear, nose and throat; GI, gastrointestinal; GU, genitourinary; Gyn, gynecologic; Heme, hematologic; ID, infectious diseases; Neuro, neurologic; Ob/Gyn, obstetrical/gynecologic; Ophtho, ophthalmologic; Psych, psychiatric; RA, rheumatoid arthritis; SCC, squamous cell carcinoma; TEN, toxic epidermal necrolysis.

SIDE EFFECTS OF SYSTEMIC DRUGS USED IN DERMATOLOGY
Drug	Common	Uncommon	Rare
Antimalarials	*Derm* : blue–gray to black discoloration; yellowing from quinacrine	*Derm* : bleaching of hair roots, exanthem (e.g. urticarial, lichenoid) GI : nausea, vomiting, elevated liver enzymes *Neuro* : irritability, nervousness	*Heme* : pancytopenia, hemolysis (G6PD-deficient, primarily with non-dermatologic antimalarials) *Ophtho* : reversible (early) and irreversible retinopathy, vision changes (see Table 130.4 )
Apremilast	*GI:* nausea, diarrhea *ENT:* nasopharyngitis *Metabolic:* weight loss	*Neuro:* headaches	*Psych:* depression and suicidal ideation
Azathioprine	*Derm* : non-melanoma skin cancers (NMSC) *Heme* : leukopenia, thrombocytopenia, immunosuppression	GI : nausea, vomiting ID : opportunistic infections	*Heme* : pancytopenia GI : pancreatitis, hepatitis *Malignancy* : lymphoma, cutaneous and gynecologic SCC Hypersensitivity syndrome
Cyclophosphamide	GI : nausea, vomiting GU : sterility (higher doses or long-term administration) *Heme* : leukopenia	*Derm* : diffuse hyperpigmentation, alopecia GU : dysuria, hemorrhagic cystitis, amenorrhea, azoospermia, sterility (with lower doses) *Heme* : anemia, thrombocytopenia ID : opportunistic infections	GI : hemorrhagic colitis, hepatotoxicity *Heme* : aplastic anemia *Malignancy* : bladder (esp. chronic oral administration), lymphoma, acute leukemia *Pulmonary* : pneumonitis, interstitial fibrosis Anaphylaxis
Cyclosporine	*Cardiac* : hypertension *Derm* : NMSC GU : renal dysfunction * *Metabolic* : hyperlipidemia *Neuro* : headache, tremor	*Derm* : hypertrichosis, gingival hyperplasia, sebaceous hyperplasia GI : nausea, diarrhea *Neuro* : paresthesia, hyperesthesia *Metabolic* : hyperkalemia ^†, hypomagnesemia, hyperuricemia	*Derm* : trichodysplasia spinulosa/viral-associated trichodysplasia ID : infections (unless combined with other immunosuppressives) *Musculoskeletal* : myalgias, myositis GI : hepatotoxicity *Malignancy* : lymphoma *Pulmonary* : dyspnea, bronchospasm
Dapsone	*Heme* : hemolysis, methemoglobinemia	GI : dyspepsia, anorexia	*Heme* : agranulocytosis *Neuro* : peripheral neuropathy Dapsone hypersensitivity syndrome
Hydroxyurea	*Heme* : anemia, megaloblastic changes	*Derm* : leg ulcers, alopecia *Heme* : leukopenia	*Derm* : hyperpigmentation, dermatomyositis-like lesions, NMSC GI : hepatitis GU : renal dysfunction *Heme* : thrombocytopenia *Malignancies* : acute leukemia
Methotrexate	*Heme* : leukopenia	*Derm* : photosensitivity, alopecia, oral ulcers GI : elevated liver enzymes, nausea, vomiting, anorexia, cirrhosis *Heme* : thrombocytopenia	*Derm* : necrosis of psoriatic plaques, accelerated rheumatoid (cutaneous) nodulosis *Heme* : pancytopenia, lymphoproliferative disorder (primarily in patients with RA) ID : infections *Pulmonary* : pneumonitis, fibrosis
Mycophenolate mofetil	GI : diarrhea, cramps, nausea, vomiting	*Heme* : anemia, leukopenia, thrombocytopenia ID : opportunistic infections	GU : dysuria, sterile pyuria *Neuro* : insomnia, dizziness, tinnitus
Saturated solution of potassium iodide (SSKI)	*Derm* : acneiform eruption GI : nausea, vomiting, diarrhea, abdominal pain *Metabolic* : reversible hypothyroidism	*Derm* : iododerma *Metabolic* : hyperkalemia	*Cardiac* : CHF, pulmonary edema *Derm* : flare of dermatitis herpetiformis GI : salivary gland enlargement *Metabolic* : irreversible hyperthyroidism, goiter, “iodism” Hypersensitivity reactions
Tacrolimus	*Cardiac* : hypertension *Derm* : NMSC GU : renal dysfunction * *Neuro* : paresthesias	ID : infections *Metabolic* : hyperkalemia ^†, hypomagnesemia	*Derm:* trichodysplasia spinulosa/viral-associated trichodysplasia *Metabolic* : diabetes mellitus, hyperuricemia *Malignancy* : lymphoma
Thalidomide	*Derm* : xerosis, pruritus GI : constipation *Neuro* : peripheral neuropathy, sedation *Ob/Gyn* : fetal abnormalities, amenorrhea	*Cardiac* : peripheral edema GI : xerostomia, increased appetite *Gyn* : primary ovarian failure *Heme* : thromboses *Psych* : headache, mood changes	*Derm* : exfoliative erythroderma, TEN *Heme* : leukopenia Hypersensitivity reaction (in HIV+)

* Not permanent during short-term treatment if guidelines are followed.

† Especially when used in conjunction with ACE inhibitors.

Antimalarials have been reported to worsen psoriasis in some patients, even though in the past they were commonly used to treat psoriatic arthritis. Psoriatic patients traveling to malaria-endemic areas may take these drugs prophylactically.

Laboratory abnormalities do not commonly occur, but it is the practice of the authors to monitor patients as outlined in Table 130.3 . An overdose of antimalarials can be fatal, and although pediatric usage is safe and effective, patients should be warned to keep the drug out of the reach of small children.

Indications

The most common dermatologic use for antimalarials is as second-line therapy for cutaneous LE, after topical or intralesional corticosteroids. Antimalarials are especially useful in patients with widespread discoid lesions and in those with the annular or papulosquamous lesions of subacute cutaneous LE (SCLE). Antimalarial use has also been credited with fewer thromboembolic events in patients with systemic LE (SLE) . Additional cutaneous disorders that may respond to antimalarial therapy are listed in Table 130.6 .

Table 130.6

Cutaneous disorders that can be treated with specific systemic drugs.

Their use is based on double-blind controlled trials or large clinical series. CTX, cyclophosphamide; MMF, mycophenolate mofetil; SSKI, saturated solution of potassium iodide.

CUTANEOUS DISORDERS THAT CAN BE TREATED WITH SPECIFIC SYSTEMIC DRUGS
Antimalarials	Azathioprine	CTX	Cyclosporine	Dapsone	Methotrexate	MMF	SSKI	Thalidomide
• Dermatomyositis ^# • Discoid lupus erythematosus (LE) * • GVHD (chronic) • Lichen planus and its variants, e.g. lichen planopilaris • LE tumidus • Lupus panniculitis • Polymorphic light eruption • Porphyria cutanea tarda ^† • Sarcoidosis • Subacute cutaneous LE • Livedoid vasculopathy • Antiphospholipid antibody syndrome • Morphea	• Atopic dermatitis • Chronic actinic dermatitis • Behçet disease • Bullous pemphigoid • Dermatomyositis • Mucous membrane (cicatricial) pemphigoid • Oral lichen planus • Pemphigus	• Cutaneous T-cell lymphoma * • Mucous membrane (cicatricial) pemphigoid • Pemphigus • Systemic LE (renal) • Systemic sclerosis (pulmonary) • Systemic vasculitides, including granulomatosis with polyangiitis (Wegener granulomatosis), polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome)	• Atopic dermatitis • Behçet disease • Chronic actinic dermatitis • Dermatomyositis (pulmonary) • GVHD (acute) • Psoriasis * • Pyoderma gangrenosum • Stevens–Johnson syndrome/toxic epidermal necrolysis • Urticaria	• Behçet disease • Bullous eruption of SLE • Cutaneous small vessel vasculitis • Dermatitis herpetiformis * • Erythema elevatum diutinum • Leprosy • Linear IgA bullous dermatosis • Mucous membrane (cicatricial) pemphigoid	• Bullous pemphigoid • Cutaneous T-cell lymphoma • Cutaneous LE • Dermatomyositis • Langerhans cell histiocytosis • Lymphomatoid papulosis • Palmoplantar pustulosis • Pityriasis rubra pilaris • Pityriasis lichenoides et varioliformis acuta • Psoriasis * • Systemic sclerosis	• Cutaneous LE • Dermatomyositis • GVHD (acute and chronic) • Oral lichen planus • Pemphigus • Systemic sclerosis (pulmonary)	• Erythema nodosum • Sporotrichosis	• Actinic prurigo • Aphthous stomatitis • Behçet disease • Erythema nodosum leprosum • GVHD (chronic) • Prurigo nodularis • Subacute cutaneous and discoid LE