Acute Cutaneous Lupus Erythematosus (ACLE) 

Updated: May 10, 2017
Author: Fnu Nutan, MD, FACP; Chief Editor: William D James, MD 

Overview

Practice Essentials

Acute cutaneous lupus erythematosus (ACLE) is the most common form of cutaneous lesions of lupus associated with systemic lupus erythematosus (SLE). It can predict the recurrence of systemic disease or prognosis of the disease is some cases. Serological investigations are indicated along with the clinical picture to confirm the diagnosis. Sun protection, smoking cessation, and local therapy are first-line treatment, followed by oral therapy. Additionally, therapies used to treat the systemic disease help in controlling ACLE lesions. Per the new Systemic Lupus International Collaborating Clinics (SLICC) group, four of the 11 criteria used for SLE classification are mucocutaneous in nature and include ACLE (also including subacute cutaneous lupus erythematosus [SCLE]), chronic cutaneous lupus erythematosus (CCLE), oral ulcers, and nonscarring alopecia.[1]

Background

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. (See Etiology.)

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 classified into three categories, (1) acute cutaneous lupus erythematosus (ACLE), (2) subacute cutaneous lupus erythematosus (SCLE), and (3) chronic cutaneous lupus erythematosus (CCLE). (See the diagram below.) Clinical characteristics of each group are unique, although histopathologically, only subtle differences are identified. The focus of this article is ACLE.[2, 3] (See Etiology, History, Physical Examination, and Workup.)

Relationship of acute cutaneous lupus erythematosu 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.

See Cutaneous Clues to Accurately Diagnosing Rheumatologic Disease, a Critical Images slideshow, to help recognize cutaneous manifestations of rheumatologic diseases.

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. See the image below. The condition has a strong association with the systemic disease for which patients present to rheumatologists and internists. (See History and Physical Examination.) Of patients with a new diagnosis of cutaneous lupus erythematosus, 24% have already been diagnosed with systemic lupus erythematosus (SLE) and about 18% will subsequently be diagnosed with SLE.[4]

Erythema involving the malar area, forehead, and n Erythema involving the malar area, forehead, and neck. Note sparing of some of the creases.

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. (See Prognosis, History, and Physical Examination.)

Etiology

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. In addition, certain viruses (eg, Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus [HIV]) have been implicated in precipitating or exacerbating lupus erythematosus in genetically predisposed individuals.

Smoking has been associated with lesions of cutaneous lupus erythematosus, and continued smoking is associated with more severe disease and decreased response to medications. Alcohol consumption has not been reported to affect cutaneous lupus erythematosus. Sex hormones are thought to play a role, as in other female-predominant autoimmune diseases.[5]

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) typically do not induce acute cutaneous lupus erythematosus (ACLE).

See also Bullous Lupus Erythematosus, Discoid Lupus Erythematosus, Drug-Induced Lupus Erythematosus, and Subacute Cutaneous Lupus Erythematosus.

Immunopathology

Data concerning direct immunofluorescence in ACLE 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 reveals the presence of immunoglobulins and C3 complement components along the dermoepidermal junction. All three immunoglobulin classes (IgG, IgM, 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.

Epidemiology

In the United States, the malar rash has been reported in 20-60% of patients in large lupus erythematosus cohorts, while limited data suggest that the maculopapular eruption is present in 35% of patients with systemic lupus erythematosus (SLE). The malar rash is believed to be associated with a younger age of disease onset. The incidence of cutaneous lupus erythematosus in Sweden and the United States has been estimated at 4 cases per 100,000 inhabitants.[6]

Race-related demographics

Precise data concerning the prevalence of acute cutaneous lupus erythematosus (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 United States and the Caribbean and 1 in 1,000 Chinese persons have SLE. Although lupus erythematosus 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.

Prognosis

Significant morbidity and potential mortality are associated with systemic lupus erythematosus (SLE), of which acute cutaneous lupus erythematosus (ACLE) is a manifestation.

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.

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.

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 patient education information, see the Arthritis Center, as well as Lupus (Systemic Lupus Erythematosus).

 

Presentation

History

Acute cutaneous lupus erythematosus (ACLE) can be classified into the following three categories:

  • Localized ACLE
  • Generalized ACLE
  • Toxic epidermal necrolysis (TEN)–like ACLE

Primary lesions in ACLE therefore include the classic facial malar rash, confluent erythema and edema, erythematous macules and papules that eventually become confluent, morbilliform macules and papules in a generalized photo-distributed pattern, bullous lesions resembling TEN, and erythema multiforme–like lesions (Rowell syndrome).[7]

The facial rash of ACLE includes the malar area and the cheeks and always spares the nasolabial folds. Other sites of involvement include the forehead, periorbital area, and sides of the neck, essentially all the areas that are exposed to the sun.

Generalized ACLE, although less common, presents as a erythematous morbilliform rash on exposed parts of the body, such as the extensor surfaces of the hand. Classically, it spares the knuckles.

Sometimes, vesicles and bullae on erythematous skin resembling Stevens-Johnson syndrome (SJS)/TEN can be seen because the inflammatory infiltrate is so severe.[8]

Superficial oral ulcers of the posterior surface of the hard palate are seen most commonly. Occasionally, buccal and gingival mucosae and the tongue may be involved.

Note that ACLE may coexist with other lupus erythematosus–specific skin diseases. In about 20% of cases, ACLE and subacute cutaneous lupus erythematosus (SCLE) coexist. However, the occurrence of ACLE with chronic cutaneous lupus erythematosus (CCLE) is unusual.

Erythema multiforme–like lesions may be seen with ACLE and SCLE and is often referred to as Rowell syndrome when associated with immunologic serum abnormalities such as a speckled antinuclear antibody (ANA) pattern and positive rheumatoid factor.[9]

Physical Examination

The most common presentation of acute cutaneous lupus erythematosus (ACLE) is a red macular eruption involving the malar area (see image below). The forehead, periorbital area, and neck also may be involved, representing a photodistribution. Occasionally, unilateral involvement may occur.

Erythema involving the malar area, forehead, and n Erythema involving the malar area, forehead, and neck. Note sparing of some of the creases.

Less commonly, ACLE presents as a generalized photosensitive eruption, while more rarely, patients present with widespread blistering simulating Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN). SJS/TEN-like cutaneous lupus erythematosus is due to extensive epidermal necrosis, which is believed to be a phototoxic reaction and may be triggered by intensive ultraviolet exposure, and must be differentiated from drug-induced TEN occurring in a patient with lupus erythematosus. The combination of recent lupus exacerbation; photodistribution; annular lesions; absent or mild focal erosive mucosal involvement; and histological changes including junctional vacuolar alteration, solitary necrotic keratinocytes at lower epidermal levels, dense periadnexal and perivascular lymphocytic infiltrates, and mucin favor lupus erythematosus over SJS or TEN.[10]

The term acute syndrome of apoptotic pan-epidermolysis (ASAP) has been proposed for the TEN-like cutaneous injury pattern that can occur in settings of lupus erythematosus, where Fas-Fas ligand interactions are implicated in the massive keratinocyte apoptosis.[11] See the image below.

Toxic epidermal necrolysis–like eruption. Toxic epidermal necrolysis–like eruption.

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.

An unusual reported cutaneous presentation is the presence of erythematous, slightly scaly, pruritic papules and plaques on the elbows.[12]

Complications

Unlike discoid lupus lesions, lesions of acute cutaneous lupus erythematosus (ACLE) do not scar with healing. Transient hyperpigmentation is seen during the healing phase. Oral lesions heal without scarring. Very rarely, hypopigmentation can be seen post healing of the malar rash.

 

DDx

Diagnostic Considerations

Dermatomyositis, one differential to consider in the diagnosis of acute cutaneous lupus erythematosus (ACLE), mimics lupus erythematosus clinically and histologically. However, antinuclear antibody (ANA) assay results invariably are positive in patients with systemic lupus erythematosus (SLE) and in those with ACLE, but they are less likely to be positive in those with dermatomyositis.

Acne rosacea should also be considered in the differential diagnosis of ACLE.

Differential Diagnoses

 

Workup

Approach Considerations

Because acute cutaneous lupus erythematosus (ACLE) and systemic lupus erythematosus (SLE) are associated closely, it is safe to assume that the laboratory findings in SLE closely mirror the findings in ACLE.

Diagnostic data from laboratory tests are supported by histopathologic examination of the skin. Further diagnostic substantiation is obtained by performing immunofluorescent examination of skin lesions.

The most striking histologic 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.[13]

Laboratory Studies

As previously mentioned, antinuclear antibody (ANA) assay results invariably are positive in patients with systemic lupus erythematosus (SLE) and, therefore, in patients with acute cutaneous lupus erythematosus (ACLE). 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 deoxyribonucleic acid (DNA) antibody (anti-dsDNA) assay is specific for SLE and is present in 60-80% of patients with ACLE, often in high titers.

Complement levels usually are depressed in patients with ACLE.

Anti-Sm antibody assay 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.

Ro (SS-A) antibodies are often correlated with cutaneous involvement in subacute cutaneous lupus erythematosus (SCLE). However, almost a third of Ro antibody–positive patients with ACLE present with kidney involvement, particularly young female patients.[14]

A positive rheumatoid factor and speckled ANA pattern may be seen in association with Rowell syndrome.[9]

Low-specificity tests include the following:

  • U1 ribonucleoprotein antibody assay - Results are positive in mixed connective-tissue disease, which sometimes manifests as a malar eruption

  • Complete blood cell (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 blood urea nitrogen (BUN) levels - Elevation indicates renal compromise

 

Treatment

Approach Considerations

Systemic corticosteroids 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.

Additional immunosuppressive agents, such as methotrexate, azathioprine, cyclophosphamide, and thalidomide, are used as adjuvant therapy to treat systemic disease because of steroid-sparing effects.[15, 16]

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. A 2017 meta-analysis found that antimalarials were 2.5 times more effective in lesions of acute cutaneous lupus erythematosus (ACLE) compared with other lupus cutaneous skin lesion types.[17] However, an inherent bias could be that patients with ACLE are on other systemic treatments for the associated systemic lupus erythematosus (SLE).

Intravenous IgG and rituximab have been used in controlling recalcitrant disease.[18, 19, 20, 21, 22]

Mycophenolate mofetil has shown poor results in disease refractory to multiple treatment modalities.[23]

One case reports describes the effectiveness of plasmapheresis for refractory toxic epidermal necrolysis (TEN)–like ACLE.[24]

Topical tacrolimus 0.1% ointment has shown to provide at least temporary benefit, especially in acute, edematous, nonhyperkeratotic lesions of cutaneous lupus erythematosus, in a small multicenter, randomized, double-blind, vehicle-controlled trial.[25]

In 2011, Díez et al described the positive clinical, histopathologic, and immunohistological effect of pulsed-dye laser on cutaneous lupus erythematosus lesions, with clinical improvement in 8 (88.9%) of 9 patients, reduction of the dermal lymphocytic infiltrate, basal layer damage, mucin deposition, and intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) expression.[26]

In 2017, transplantation of in vivo–harvested epidermal cell suspension was reported to successfully treat depigmentation associated with malar rash.[27]

Photoprotection

Cutaneous lupus erythematosus lesions may be induced and exacerbated by ultraviolet radiation exposure, and patients with cutaneous manifestations of lupus erythematosus are generally considered photosensitive. Patients with ACLE require extensive education about avoidance of sun exposure, photoprotection through physical barriers such as protective clothing, and daily application of broad-spectrum sunscreens.[28]

Diet and activity

Dietary restrictions may be necessary in the presence of renal compromise. In terms of activity, advise patients with ACLE to avoid activities involving excessive exposure to the sun. Advice to stop smoking is essential.

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.

Precautions in Corticosteroid Use

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. If osteoporosis is present, refer the patient to an osteoporosis specialist for consideration of treatment with bisphosphonates.

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.

Investigational Drugs

An investigational drug, belimumab, is currently undergoing phase III clinical trials for the potential treatment of systemic lupus erythematosus (SLE). It is a neutralizing B-lymphocyte stimulator monoclonal antibody that inhibits the biologic activity of the soluble form of essential B cells.[29] 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 Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores in seropositive patients (antinuclear antibody [ANA] ≥1:80 or anti-dsDNA >30 IU) and the physician global assessment score.

Epratuzumab is also 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 SLE. In an open-label, single-case study of 14 patients with SLE, patients received intravenous epratuzumab at 360 mg/m2 every 2 weeks for four 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.

Ustekinumab is a human monoclonal antibody that binds to interleukins 12 and 23, thereby preventing the activation of TH17 cells. It has been approved for the treatment of psoriasis and is also used for acute cutaneous lupus erythematosus (ACLE), hypertrophic cutaneous lupus, and chronic cutaneous lupus erythematosus (CCLE).[30] Currently, a phase IIA study for safety and efficacy of ustekinumab is underway. Multiple case reports are published regarding its benefit in CCLE.

 

Medication

Medication Summary

Systemic corticosteroids usually are the mainstay of therapy for systemic disease. Skin changes tend to respond in tandem with the systemic response to treatment.

Adjuvant therapy for systemic disease can be provided with methotrexate, azathioprine, cyclophosphamide, and thalidomide. Hydroxychloroquine, administered as first-line therapy to most patients with systemic disease, has particularly beneficial effects on skin lesions. Intravenous IgG has become important in controlling recalcitrant disease.[18]

Corticosteroids

Class Summary

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

Prednisone

Prednisone is a glucocorticoid (adrenocortical steroid) that is absorbed easily into the gastrointestinal (GI) tract. An immunosuppressant, it is used for the treatment of autoimmune disorders. Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN)-cell activity. It stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Immunosuppressives

Class Summary

These agents are used for immunosuppression and, ultimately, disease control.

Azathioprine (Imuran, Azasan)

Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, ribonucleic acid (RNA), and proteins. It may decrease the proliferation of immune cells, in that way lowering autoimmune activity. For dermatomyositis/polymyositis, respiratory and muscular symptoms respond, but skin lesion response has not been consistent.

Azathioprine is slow acting, with its therapeutic effect not being seen for 6-8 weeks. Metabolites accumulate slowly, and maximal immunosuppression is not reached until after 8-12 weeks. The drug is available in 25-, 50-, 75-, and 100-mg tablets or in a 100-mg vial.

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards. It is an alkylating agent, and the mechanism of action of its active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Thalidomide (Thalomid)

Thalidomide is an immunomodulatory agent that may suppress the excessive production of tumor necrosis factor-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. In patients weighing less than 50 kg (110 lb), start at low end of dose regimen.

Hydroxychloroquine (Plaquenil)

This agent inhibits chemotaxis of eosinophils and the 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 (Gammagard, Gamunex, Octagam, Gammaplex )

Immunoglobulin neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including interferon gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; and may increase cerebrospinal fluid IgG (10%).

Methotrexate (Otrexup, Rasuvo, Trexall)

Methotrexate was introduced in 1965. It is considered second-line therapy, especially in acute cutaneous lupus erythematosus (ACLE) and chronic cutaneous lupus erythematosus (CCLE). It is also used in lesions refractory to antimalarials and as a corticosteroid-sparing agent. Its mechanism of action includes action on adenosine, which is a purine nucleoside and has potent anti-inflammatory effects. It induces apoptosis in CD4+Tcells.

Dose ranges from 7.5-25 mg once per week orally, intravenously, or subcutaneously. Adverse effects include GI complaints, which can be alleviated with administration of folic acid prior to or after methotrexaste administration. Hepatotoxicity, nephrotoxicity, and bone marrow suppression are other known adverse effects.

Monoclonal Antibody

Class Summary

These drugs restore the potential to minimize self-immunity. Monoclonal antibodies can induce cytotoxicity after binding to specific antigens that may regulate cell cycle initiation. This then results in the inhibition of cell growth and differentiation.

Rituximab (Rituxan)

Rituximab is a 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. Rituximab is a murine/human chimeric anti-CD20 monoclonal antibody, US FDA approved for the treatment of refractory low-grade or follicular non-Hodgkin lymphoma and severe rheumatoid arthritis. It is available as an injectable solution of 10 mg/mL.