Acute cutaneous lupus erythematosus

 

Lupus erythematosus 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. Lupus erythematosus–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 acute cutaneous lupus erythematosus.

Acute cutaneous lupus erythematosus 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. Acute cutaneous lupus erythematosus has a strong association with the systemic disease for which patients present to rheumatologists and internists.

Pathophysiology

The etiology of lupus erythematosus 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 acute cutaneous lupus erythematosus.

More than 25 genes have been identified as contributing to the mechanisms that predispose patients to lupus. They include alleles in the major histocompatibility complex region (multiple genes): IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFA1P3, SPP1, some fc gene receptors, and deficiency in several complement components, including C1qC4+C2. In patients who are predisposed genetically, exposure to natural ultraviolet radiation is a frequent precipitating factor for lupus erythematosus.^1,2

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

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 a lupus erythematosus–like illness (eg, procainamide, isoniazid, hydralazine) are uncommonly associated with cutaneous manifestations.

Immunopathology

Data concerning direct immunofluorescence in acute cutaneous lupus erythematosus are sparse. In one study, the results of 5 (100%) of 5 skin biopsy specimens were reported as positive for the lupus band test. The lupus band test refers to the presence of immunoglobulins and C3 complement components along the dermoepidermal 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 dermoepidermal junction. Research has shown that 60% of patients with a malar eruption of lupus erythematosus have positive lupus band test results. In nonlesional skin, positive lupus band test results correlate strongly with an aggressive course of systemic disease.³

History

The most common presentation of acute cutaneous lupus erythematosus 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, as shown below

Less commonly, acute cutaneous lupus erythematosus 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

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Acute cutaneous lupus erythematosus 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 acute cutaneous lupus erythematosus 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 acute cutaneous lupus erythematosus may coexist with other lupus erythematosus–specific skin diseases. Localized acute cutaneous lupus erythematosus lesions have been observed in 20% of subacute cutaneous lupus erythematosus patients; however, occurrence of acute cutaneous lupus erythematosus with chronic cutaneous lupus erythematosus is unusual.

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 systemic lupus erythematosus, the disease can be triggered by viruses (eg, EBV) and exposure to ultraviolet light. Medications typically do not induce acute cutaneous lupus erythematosus in patients with drug-induced lupus erythematosus

Laboratory Studies

• Since acute cutaneous lupus erythematosus (ACLE) and systemic lupus erythematosus (SLE) are associated closely, it is safe to assume that the laboratory findings in systemic lupus erythematosus closely mirror the findings in acute cutaneous lupus erythematosus.
• Antinuclear antibody (ANA) assay: ANA results invariably are positive in patients with systemic lupus erythematosus and, therefore, in patients with acute cutaneous lupus erythematosus. The peripheral rim pattern is associated most strongly with lupus erythematosus, although other patterns commonly are present. ANA results are less likely to be positive in dermatomyositis, which mimics lupus erythematosus both clinically and histologically.
• Anti–double-stranded DNA antibody (anti-dsDNA) assay: Anti-dsDNA is specific for systemic lupus erythematosus and is present in 60-80% of patients with acute cutaneous lupus erythematosus, often in high titers.
• Complement: Complement levels usually are depressed in patients with acute cutaneous lupus erythematosus.
• Anti-Sm antibody assay: Anti-Sm antibody has a strong specificity for systemic lupus erythematosus; 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 acute cutaneous lupus erythematosus 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 acute cutaneous lupus erythematosus 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

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) has become important in controlling recalcitrant disease.⁵
• Mycophenolate mofetil has shown poor results in disease refractory to multiple treatment modalities.⁶
• One case reports describes the effectiveness of plasmapheresis for refractory toxic epidermal necrolysis (TEN)–like acute cutaneous lupus erythematosus.⁷

Consultations

• Refer patients with clinical and serologic evidence of lupus erythematosus 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

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

Belimumab is investigational. It is a neutralizing B-lymphocyte stimulator monoclonal antibody that inhibits the biologic activity of the soluble form of essential B cells. Belimumab is currently undergoing phase III clinical trials for the potential treatment of systemic lupus erythematosus (SLE). Doses used in the phase II trials were randomized to 1, 4, or 10 mg/kg intravenously on days 1, 14, and 28, and then every 28 days for 76 weeks. The treatment significantly improved the SLE disease activity index (SLEDAI) scores in seropositive patients (ANA ≥1:80 or anti-dsDNA >30 IU) and physicians global assessment score.⁸

Epratuzumab is investigational. It is a humanized anti-CD22 monoclonal antibody that partially depletes B cells. Treatment is shown to decrease disease activity but not autoantibody levels in patients with moderately active systemic lupus erythematosus. In an open-label, single-case study of 14 patients with systemic lupus erythematosus, patients received intravenous epratuzumab at 360 mg/m² every 2 weeks for 4 doses, with analgesic/antihistamine premedication prior to each dose. Total British Isle Lupus Assessment Group (BILAG) scores were decreased by greater than or equal to 50% in all 14 patients at 6 weeks.

Corticosteroids

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

Prednisone (Sterapred)

Glucocorticoid (adrenocortical steroid) absorbed easily into GI tract. Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Immunosuppressives

Used for immunosuppression and, ultimately, for disease control.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. For dermatomyositis/polymyositis, respiratory and muscular symptoms respond but skin lesion response has not been consistent.
Slow acting with therapeutic effect not seen for 6-8 wk. Metabolites accumulate slowly, and maximal immunosuppression not reached until 8-12 wk. Available as 25-, 50-, 75-, and 100-mg tab or 100-mg vial.

Cyclophosphamide (Cytoxan, Neosar)

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.

Thalidomide (Thalomid)

Immunomodulatory agent that may suppress excessive production of tumor necrosis factor-alpha 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.

Hydroxychloroquine (Plaquenil)

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.

Immune globulin IV (Sandoglobulin, Gammagard, Gamimune, Gammar-P)

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%).

Monoclonal Antibody

Rituximab (Rituxan)

Murine/human chimeric anti-CD20 monoclonal antibody. CD20 is expressed early in pre-B cell development. Binding induces complement-dependent B-cell cytotoxicity along with antibody-dependent cellular toxicity.

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