AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Lupus erythematosus (LE) is a heterogeneous connective-tissue disease associated with polyclonal B-cell activation and is believed to result from the interplay of genetic, environmental, and hormonal factors. The spectrum of disease involvement can vary from limited cutaneous involvement to devastating systemic disease.

From a dermatologic standpoint, the type of skin involvement can prove to be a good barometer of the pattern of underlying systemic activity. LE-specific skin diseases are recognized in 3 categories, including (1) acute cutaneous lupus erythematosus (ACLE), (2) subacute cutaneous lupus erythematosus (SCLE), and (3) chronic cutaneous lupus erythematosus (CCLE). Clinical characteristics of each group are unique, although histopathologically, only subtle differences are identified. The focus of this article is ACLE.

ACLE refers to a typical malar eruption in a butterfly pattern localized to the central portion of the face and/or a more generalized maculopapular eruption representing a photosensitive dermatitis. ACLE has a strong association with the systemic disease (see Image 4) for which patients present to rheumatologists and internists.

Pathophysiology

The etiology of LE is believed to be multifactorial, involving genetic, environmental, and hormonal factors. An association with human leukocyte antigen DR2 and human leukocyte antigen DR3 has been identified. Concordance in monozygotic twins and familial associations support a genetic basis in ACLE. In patients who are predisposed genetically, exposure to natural ultraviolet radiation is a frequent precipitating factor for LE.

Certain viruses (eg, Epstein-Barr virus, cytomegalovirus, HIV) have been implicated in precipitating or exacerbating LE.

Chemicals such as L-canavanine, which is present in alfalfa sprouts, have been known to induce systemic lupus erythematosus (SLE)–like illness. Drugs implicated in inducing an LE-like illness (eg, procainamide, isoniazid, hydralazine) are uncommonly associated with cutaneous manifestations.

Immunopathology

Data concerning direct immunofluorescence in ACLE are sparse. In one study, the results of 5 of 5 (100%) skin biopsies were reported as positive for the lupus band test. The lupus band test refers to the presence of immunoglobulins (Igs) and C3 complement components along the dermal-epidermal junction. All 3 immunoglobulin classes (immunoglobulin G [IgG], immunoglobulin M [IgM], immunoglobulin A [IgA]) and a variety of complement components have been identified at the dermal-epidermal junction. Recent research has shown that 60% of patients with a malar eruption of LE have positive lupus band test results. In nonlesional skin, positive lupus band test results correlate strongly with an aggressive course of systemic disease.

Frequency

United States

The malar rash has been reported in 20-60% of patients in large LE cohorts, while limited data suggest that the maculopapular eruption of SLE is present in 35% of patients with SLE.

Mortality/Morbidity

Significant morbidity and potential mortality are associated with SLE, of which ACLE is a manifestation.

Race

Precise data concerning the prevalence of ACLE in specific racial groups are not available; however, since photosensitivity is observed more frequently in whites than in blacks, the same prevalence for ACLE may be inferred. Estimates suggest that 1 in 250 black women in the US and the Caribbean and 1 in 1000 Chinese persons have SLE. Although LE may be rare in most parts of Africa, data concerning this finding conflict. Data concerning ACLE are difficult to interpret, since a lack of conformity is found in the description of lesions, and biopsy data are lacking for skin lesions observed in patients with systemic disease.

Age

The malar rash is believed to be associated with a younger age of disease onset.

CLINICAL

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History

• The most common presentation of ACLE is a red macular eruption involving the malar area. The forehead, periorbital area, and neck also may be involved, representing a photodistribution. Occasionally, unilateral involvement may occur (see Image 1).
• Less commonly, ACLE presents as a generalized photosensitive eruption, while more rarely, patients present with widespread blistering simulating toxic epidermal necrolysis (TEN). TEN is believed to be a phototoxic reaction (see Image 2).
• ACLE can be transient, lasting for several days to weeks. Lesions wax and wane with sun exposure over a period of several hours; however, some patients experience prolonged disease activity. Resolution of lesions may result in postinflammatory hyperpigmentation, especially in patients with darkly pigmented skin. Usually, the lesions are nonscarring.
• Patients with ACLE frequently experience superficial ulceration of the oral and nasal mucosae. These lesions may produce extreme discomfort in some patients, although the lesions may be entirely painless in others. The posterior surface of the hard palate is the site affected most frequently; however, the gingival, buccal, and lingual mucosae also may be involved.
• Note that ACLE may coexist with other LE-specific skin diseases. Localized ACLE lesions have been observed in 20% of SCLE patients; however, occurrence of ACLE with CCLE is unusual (see Image 3).

Physical

• Primary lesions include the following:
• • Confluent erythema and edema
  • Erythematous macules and papules that eventually become confluent
  • Bullous lesions resembling TEN
  • Morbilliform macules and papules in a generalized photo-distributed pattern
• Distribution of lesions
• • Malar eminence (representing the wings of the butterfly) and the nasal bridge (representing the body of the butterfly) typically are involved. Other sites of involvement include the forehead, periorbital area, and sides of the neck. Occasionally, a generalized photo-induced eruption may occur.
  • Associated findings include superficial ulceration primarily involving the posterior surface of the hard palate. Occasionally, buccal and gingival mucosae and the tongue may be involved.

Causes

In patients who are disposed genetically to developing SLE, the disease can be triggered by viruses (eg, EBV) and exposure to ultraviolet light. Medications typically do not induce ACLE in patients with drug-induced LE.

DIFFERENTIALS

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Other Problems to be Considered

Acne rosacea

WORKUP

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Lab Studies

• Since ACLE and SLE are associated closely, it is safe to assume that the laboratory findings in SLE closely mirror the findings in ACLE.
• Antinuclear antibody (ANA) assay: ANA results invariably are positive in patients with SLE and, therefore, in patients with ACLE. The peripheral rim pattern is associated most strongly with LE, although other patterns commonly are present. ANA results are less likely to be positive in dermatomyositis, which mimics LE both clinically and histologically.
• Anti–double-stranded DNA antibody (anti-dsDNA) assay: Anti-dsDNA is specific for SLE and is present in 60-80% of patients with ACLE, often in high titers.
• Complement: Complement levels usually are depressed in patients with ACLE.
• Anti-Sm antibody assay: Anti-Sm antibody has a strong specificity for SLE; therefore, perform this assay to exclude underlying systemic involvement. This is particularly relevant in patients in whom anti-dsDNA results are negative.
• Low-specificity tests
• • U1 ribonucleoprotein antibody assay: Results are positive in mixed connective-tissue disease, which sometimes manifests as a malar eruption.
  • CBC count: Anemia, leukopenia, and/or thrombocytopenia may be seen in patients with ACLE who have systemic involvement.
  • Erythrocyte sedimentation rate: Although a nonspecific marker, marked elevations in levels indicate possible systemic involvement.
  • Urinalysis: Proteinuria, hematuria, and urine casts are indicative of underlying nephritis.
  • Creatinine and BUN levels: Elevation indicates renal compromise.

Procedures

• Skin biopsy: Diagnosis is supported by histopathologic examination of the skin. Further substantiation is obtained by performing immunofluorescence examination of skin lesions.

Histologic Findings

The most striking change in ACLE is the presence of edema involving upper dermis and focal liquefactive degeneration of the basal cell layer. Cellular dermal infiltrate is sparse and consists of lymphocytes. In extreme cases, dissolution of the basal layer occurs secondary to extensive vacuolization, forming a subepidermal bulla.

TREATMENT

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Medical Care

• Systemic corticosteroids (prednisone 0.5-1 mg/kg/d) usually are the mainstay of therapy for systemic disease. Skin changes tend to respond in tandem with the systemic response to treatment. A rheumatologist usually undertakes systemic treatment. When administering systemic corticosteroids, address adverse effects such as diabetes mellitus, hypertension, osteonecrosis, the stigmata of Cushing syndrome, and the risk of osteoporosis.
  • Perform a baseline bone densitometry scan, and if normal, repeat the scan at 6 months.
  • Ideally, perform 24-hour urine collection to check calcium levels, since steroids enhance renal excretion of calcium, thereby increasing the patient's susceptibility to developing renal stones. If the results are normal, administer cholecalciferol (400-800 IU/d) and calcium (1500 mg/d).
  • If evidence of hypercalciuria is present, administer thiazide diuretics until levels return to normal.
  • If osteoporosis is present, refer the patient to an osteoporosis specialist for consideration of treatment with bisphosphonates.
• Additional immunosuppressive agents, such as azathioprine (0.5-3 mg/kg/d), cyclophosphamide (1-5 mg/kg/d, typically 50-200 mg/d), and thalidomide (100-200 mg/d), are used as adjuvant therapy to treat systemic disease because of steroid-sparing effects.
• Hydroxychloroquine also has been shown to have steroid-sparing effects and is administered as first-line therapy to most patients with systemic disease. The effects of hydroxychloroquine on skin lesions are especially beneficial.
• Intravenous IgG (IVIG; 0.5-1 g/kg/d for 4 d) recently has become important in controlling recalcitrant disease.

Consultations

• Refer patients with clinical and serologic evidence of LE to a rheumatologist for further treatment.
• Refer patients with red blood cell casts, significant proteinuria (>0.5 g/mL/24h), and a diastolic blood pressure of more than 90 mm Hg to a nephrologist.

Diet

Dietary restrictions may be necessary in the presence of renal compromise.

Activity

Advise patients to avoid activities involving excessive exposure to the sun.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Immunosuppressives

Used for immunosuppression and, ultimately, for disease control.

Drug Name	Cyclophosphamide (Cytoxan, Neosar)
Description	Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose	500-750 mg/m2 IV qmo
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Name	Thalidomide (Thalomid)
Description	Immunomodulatory agent that may suppress excessive production of tumor necrosis factor a (TNF-a) and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. In patients <50 kg (110 lb), start at low end of dose regimen.
Adult Dose	100-300 mg/d PO qd with water, preferably hs and at least 1 h pc
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine; women must use 2 additional methods of contraception or abstain from intercourse because of teratogenic effects
Pregnancy	X - Contraindicated in pregnancy
Precautions	Perform pregnancy test within 24-h period prior to initiating therapy (weekly during first month, followed by monthly tests in women with regular menstrual cycles or q2wk with irregular menstrual cycles); bradycardia may occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must register with STEPS provider registry established by manufacturer

Drug Name	Hydroxychloroquine (Plaquenil)
Description	Inhibits chemotaxis of eosinophils, locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Adult Dose	310 mg PO qd or bid for several wk depending on response; 155-310 mg/d for prolonged maintenance therapy
Pediatric Dose	3-5 mg base/kg/d PO qd or divided bid; not to exceed 7 mg/kg/d
Contraindications	Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones
Interactions	Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic (6 mo) ophthalmologic examinations; test periodically for muscle weakness

Drug Name	Immune globulin IV (Sandoglobulin, Gammagard, Gamimune, Gammar-P)
Description	Neutralize circulating myelin antibodies through anti-idiotypic antibodies; down regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Adult Dose	2 g/kg IV over 2-5 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies
Interactions	Increases toxicity of live virus vaccine (MMR); therefore, do not administer within 3 mo of vaccine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA before IVIG (use IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

FOLLOW-UP

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Further Outpatient Care

• Since ACLE typically mirrors systemic disease, further treatment is determined by the treatment modality selected for controlling systemic disease.

Deterrence/Prevention

• Advise patients to avoid exposure to ultraviolet light.

Complications

• Progression to LE-specific bullous dermatosis (aggravated by sun exposure) may occur, producing a TEN-type picture.
• No definite correlation has been identified between ACLE and nephritis; however, localized lesions of ACLE are believed to tend to wax and wane, paralleling the underlying systemic disease.
• Postinflammatory hyperpigmentation may occur in dark-skinned patients following resolution.

Prognosis

• The relationship between ACLE and systemic disease is demonstrated in Image 4.
• The malar eruption tends to wax and wane with systemic activity; however, whether the presence of malar rash indicates a worse overall outlook for patients has not been determined.

Patient Education

• Educate patients about the nature of skin, which acts as a barometer of disease activity. Control of the cutaneous manifestations depends ultimately on overall control of the disease.
• Instruct patients regarding the effects of ultraviolet light in exacerbating the disease.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Arthritis Center. Also, see eMedicine's patient education article Lupus (Systemic Lupus Erythematosus).

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to diagnose ACLE or systemic disease appropriately

MULTIMEDIA

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Media file 1:  Erythema involving the malar area, forehead, and neck. Note sparing of some of the creases.
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Media type:  Photo

Media file 2:  Toxic epidermal necrolysis–like eruption.
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Media type:  Photo

Media file 3:  Relationship of acute cutaneous lupus erythematosus (ACLE) to chronic cutaneous lupus erythematosus (CCLE) and subacute cutaneous lupus erythematosus (SCLE).
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Media type:  Graph

Media file 4:  Relationship of acute cutaneous lupus erythematosus (ACLE) to systemic disease. LE is lupus erythematosus. CCLE is chronic cutaneous lupus erythematosus. SCLE is subacute cutaneous lupus erythematosus.
	View Full Size Image
Media type:  Graph

REFERENCES

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• Sontheimer RD, Provost TT. Cutaneous Manifestations of Rheumatic Diseases. Baltimore, Md:. Williams & Wilkins;1996:1-56.
• Sontheimer RD. Skin manifestations of rheumatologic diseases. In: Freedberg IM, Eisen AZ, Wolff K, eds. Fitzpatrick's Dermatology in General Medicine. 5th ed. New York: McGraw-Hill;1999:1993.
• Su WP, Alegre VA. Bullous lesions in cutaneous lupus erythematosus. Changgeng Yi Xue Za Zhi. Mar 1991;14(1):15-21. [Medline].
• Vlachoyiannopoulos PG, Karassa FB, Karakostas KX, et al. Systemic lupus erythematosus in Greece. Clinical features, evolution and outcome: a descriptive analysis of 292 patients. Lupus. Oct 1993;2(5):303-12. [Medline].
• Watanabe T, Tsuchida T. Classification of lupus erythematosus based upon cutaneous manifestations. Dermatological, systemic and laboratory findings in 191 patients. Dermatology. 1995;190(4):277-83. [Medline].
• Werth VP. Clinical manifestations of cutaneous lupus erythematosus. Autoimmun Rev. Jun 2005;4(5):296-302. [Medline].
• Wysenbeek AJ, Block DA, Fries JF. Prevalence and expression of photosensitivity in systemic lupus erythematosus. Ann Rheum Dis. Jun 1989;48(6):461-3. [Medline].
• Wysenbeek AJ, Guedj D, Amit M, Weinberger A. Rash in systemic lupus erythematosus: prevalence and relation to cutaneous and non-cutaneous disease manifestations. Ann Rheum Dis. Jun 1992;51(6):717-9. [Medline].
• Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol. Sep 1996;135(3):355-62. [Medline].

Article Last Updated: Nov 21, 2006