Discoid Lupus Erythematosus

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Background

Cutaneous lupus erythematosus (CLE) can be divided into 3 main subtypes: acute, subacute, and chronic, all of which demonstrate photosensitivity. Acute cutaneous lupus erythematosus (ACLE) most commonly presents as symmetric erythema overlying the malar cheeks and nasal bridge with sparing of the nasolabial folds (butterfly rash). However, it can also present as a diffuse morbilliform eruption with erythema and edema of the hands, with prominent sparing of the joints. Subacute cutaneous lupus erythematosus (SCLE) characteristically presents as annular or psoriasiform plaques in a photodistribution. Chronic cutaneous lupus erythematosus (CCLE) can be further divided into 3 main types: discoid lupus erythematosus (DLE), tumid lupus, and lupus panniculitis. Tumid lupus typically presents with juicy papules and plaques that heal without scarring, whereas lupus panniculitis involves the subcutaneous tissue, leading to painful subcutaneous nodules that heal with depression and atrophy.

DLE classically presents with erythematous-to-violaceous, scaly plaques with prominent follicular plugging that often results in scarring and atrophy (see the images below). DLE may occur in the absence of systemic disease, or it may occur in association with systemic lupus erythematosus (SLE).


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Discoid lupus erythematosus on the face.


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Chronic scarred lesion of discoid lupus erythematosus.

The risk of progression to SLE in patients with DLE was recently demonstrated to be higher than previously reported (16.7% progression within 3 years of diagnosis, as compared with previous data indicating that < 5-10% of patients with DLE progress to SLE).[1, 2] Overall, patients with DLE rarely fulfill 4 or more of the 11 American College of Rheumatology (ACR) criteria used to classify SLE.[3] Serologic abnormalities are uncommon.

Therapy with sunscreens, topical corticosteroids, and antimalarial agents is often effective. (See Clinical and Treatment.) However, immunosuppressive and/or immunomodulatory agents may be required for recalcitrant disease.

Patient education

Instruct patients in sun-avoidance techniques and the proper use of sunscreens, hats, and protective clothing. Advise patients to quit smoking. Discuss the possibility of systemic involvement with patients. Pamphlets from the Lupus Foundation of America, Inc. concerning skin disease and photosensitivity are useful adjuncts to verbally delivered information. For patient education information, see the Arthritis Center. Also see Prognosis and Treatment.

Etiology

Lupus erythematosus is a polygenic autoimmune disease linked to various HLA subtypes, immune signaling, and environmental factors, which ultimately leads to autoantibody production and T-cell dysfunction. However, the exact etiology of discoid lupus erythematosus (DLE) is not well understood. DLE likely occurs in genetically predisposed individuals, but the exact genetic connection has not been determined. It has been suggested that a heat-shock protein is induced in the keratinocyte following ultraviolet (UV) light exposure or stress, and this protein may act as a target for gamma (delta) T-cell–mediated epidermal cell cytotoxicity. Additionally, toll-like receptors may be involved in the pathogenesis.[4]

Epidemiology

Worldwide, the prevalence of systemic lupus erythematosus (SLE) ranges from 17-48 cases per 100,000 population. The highest prevalence of SLE occurs in persons aged 40-60 years, with SLE onset most often occurring in patients in their 20s and 30s. SLE is approximately 10 times more common in women than in men. In a 2009 study from Olmstead County, Minnesota, Durosaro et al demonstrated that the incidence of cutaneous lupus erythematosus (CLE) is comparable to that of SLE.[5]

Discoid lupus erythematosus (DLE) is responsible for 50-85% of cases of CLE and occurs 2-3 times more frequently in women than in men. DLE is slightly more common in African Americans than in whites or Asians. Although DLE may occur at any age, it most often develops in persons aged 20-40 years.

Prognosis

Although the prognosis of patients with discoid lupus erythematosus (DLE) is favorable regarding mortality, morbidity can be considerable. Patients may experience pain or burning of their lesions, and many experience disfigurement from the scars or atrophy that can develop. Scarring alopecia is particularly disturbing for patients. Prompt treatment of early lesions may help prevent or lessen the severity of scarring and atrophy.

Exacerbation is common with increased sun exposure, particularly in the spring and summer. Serious systemic disease is rare, but when it occurs, patients may develop life-altering sequelae. Malignant degeneration within DLE lesions is uncommon. However, prompt biopsy of suggestive lesions developing within chronic DLE lesions is warranted.[6]

History

Patients may report mild pruritus or occasional pain within the lesions, but most patients are asymptomatic. According to a recent epidemiologic study, approximately 16% of patients with discoid lupus erythematosus (DLE) may develop systemic involvement within 3 years of diagnosis.[2] Arthralgia or arthritis may occur.

Patients may manifest any sign or symptom of systemic lupus erythematosus (SLE); therefore, the history should include an assessment for serologic and/or hematologic abnormalities, arthritis, pleuritis, pericarditis, neurologic involvement, and renal involvement.

Malignant degeneration of chronic lesions of DLE leading to nonmelanoma skin cancer is rare. Dark-skinned individuals may be more prone to skin cancer because of the lack of pigmentation within the chronic lesion, combined with chronic inflammation and continued sun damage. Reported risk factors for the development of squamous cell carcinoma within lesions of chronic DLE include male sex, early age of onset, refractory disease, lip involvement, and tobacco use.[6]

Porphyria cutanea tarda (PCT) appears to be overrepresented in patients with cutaneous lupus erythematosus (CLE). Often, PCT is discovered when antimalarials are first administered. Lichen planus–like lesions may be due to an overlap between CLE and lichen planus or may occur as a result of antimalarial therapy.

Physical Examination

Discoid lupus erythematosus (DLE) lesions frequently are characteristic. The primary lesion is an erythematous papule or plaque with slight-to-moderate scale (see the images below). As the lesion progresses, the scale may thicken and become adherent. Pigmentary changes may develop, with hypopigmentation in the central, or inactive area, and hyperpigmentation at the active border.


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Discoid lupus erythematosus on the face.


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Chronic scarred lesion of discoid lupus erythematosus.

Lesions spread centrifugally and may merge. As lesions age, dilation of follicular openings occurs with a keratinous plug, termed follicular plugging or patulous follicles (see the image below). Resolution of the active lesion results in atrophy and scarring.


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Lesions of discoid lupus erythematosus in the conchal bowl demonstrate patulous follicles with follicular plugging.

At any time, individual lesions may have any or all of these features. Early lesions may be difficult to distinguish from those of subacute cutaneous lupus erythematosus (SCLE). DLE lesions are often photodistributed, but relatively unexposed skin may also be affected. The conchal bowls and scalp are both common areas of involvement. Permanent alopecia may result (see images below).


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Scarring alopecia of discoid lupus erythematosus.


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Widespread scarring alopecia.

Patients with DLE often are divided into 2 subsets: localized and widespread. Localized DLE occurs when the head and neck only are affected, while widespread DLE occurs when other areas are affected, regardless of whether disease of the head and neck is seen. Patients with widespread involvement often have hematologic and serologic abnormalities, are more likely to develop systemic lupus erythematosus (SLE), and are more difficult to treat.

Several unusual variants of chronic cutaneous lupus erythematosus (CCLE), other than DLE, have been reported. Mucosal surfaces may be affected by lesions that appear identical to DLE of the skin or by lesions that may simulate lichen planus. Palms and soles may be affected, but this occurs in less than 2% of patients (see the image below).[7]


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Palmar lesions of discoid lupus erythematosus.

DLE lesions may become hypertrophic or verrucous (see the image below). This subset is manifested by wartlike lesions, most often on the extensor arms. Hypertrophic lesions of chronic lupus erythematosus must be differentiated from warts, keratoacanthomas, or squamous cell carcinoma. These lesions are more difficult to treat.[8]

Lupus panniculitis, a form of CCLE that manifests with inflammation and destruction of the subcutaneous fat, may be accompanied by overlying typical DLE lesions and/or may occur in patients with SLE.[9]


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Hypertrophic lesions of chronic cutaneous lupus erythematosus on the dorsal hands. Characteristic lesions were observed elsewhere.

Other Tests

Deposition of immunoglobulin and/or complement at the dermoepidermal junction is a characteristic feature of lupus erythematosus referred to in most texts and articles. Tissue may be examined from skin lesions (lesional) or normal skin (nonlesional). Nonlesional biopsies may be from photoexposed or nonexposed surfaces. Testing of nonlesional, nonexposed skin is termed the lupus band test (LBT).

The use and interpretation of these tests vary according to the biopsy site. Approximately 90% of patients with discoid lupus erythematosus (DLE) manifest a positive direct immunofluorescence (DIF) test on lesional skin; however, the presence of immunoreactants in the basement membrane zone of lesional skin is not specific for lupus and can be seen in a variety of inflammatory skin diseases. Older lesions or very early lesions may be more likely to be negative on immunofluorescence microscopy.

Only patients with systemic lupus erythematosus (SLE) have a positive LBT, defined as the presence of multiple immunoreactants in the basement membrane zone. The LBT is neither sensitive nor specific and has mostly been replaced by advances in serologic testing.

Histologic Findings

The characteristic histopathologic alterations observed in discoid lupus erythematosus (DLE) include the following:

Often, an abundance of mucin is seen within the dermis. The histopathologic features differ depending on the type and age of the lesion.

Approach Considerations

Screening for systemic lupus erythematosus (SLE) should occur upon diagnosis of discoid lupus erythematosus (DLE). This should consist of a thorough history and physical examination, as well as standard laboratory screening including complete blood cell count, renal function tests, and urinalysis. Hematologic and serologic abnormalities may be present and an elevated sedimentation rate may occur in some patients. Additionally, rheumatoid factor may be positive and complement levels may be decreased. Abnormal renal function tests and/or urinalysis with proteinuria may reflect the presence of renal involvement.

Some patients with DLE (approximately 20%) manifest a positive antinuclear antibody (ANA) when tested with human substrates. HEp-2 cells currently are the most common substrate used in commercial laboratories.

Anti-Ro (SS-A) autoantibodies are present in approximately 1-3% of patients. Antinative deoxyribonucleic acid (DNA, either double-stranded or nDNA) or anti-Sm antibodies usually reflect SLE, and they may occur in some patients (< 5%).

Approach Considerations

The goals of management of discoid lupus erythematosus (DLE) are to improve the patient's appearance, to control existing lesions and limit scarring, and to prevent the development of further lesions. Advise patients that the development of serious systemic disease is possible, although rare. Regular repeat clinical evaluation accompanied by simple laboratory studies is usually sufficient to monitor for progression from primary cutaneous disease to systemic involvement.

Therapy begins with the use of sun-protective measures, including sunscreens, protective clothing, and behavior alteration. Cosmetic measures, such as cover-up makeup or wigs, may be suggested for appropriately selected patients. Makeup used for camouflage includes Covermark and Dermablend.

Standard medical therapy includes topical or intralesional corticosteroids and antimalarials. Topical calcineurin inhibitors have also been used in patients with cutaneous lupus erythematosus (CLE). In addition, topical retinoids have been reported to be helpful. Topical imiquimod was reported to be effective in 1 patient. Systemic corticosteroids are typically avoided given that the dose and duration of therapy needed to maintain control of cutaneous disease often results in substantial steroid-related adverse effects. Therefore, for recalcitrant disease, immunosuppressants and immunomodulators, including methotrexate, mycophenolate mofetil, and thalidomide, amongst others, should be considered.

Activity

Since chronic CLE is exacerbated by sunlight and other UV exposure, advise patients to take precautions by limiting exposure to sunlight to the early morning or late afternoon, when the sun is less intense. Even during these times, photoprotective measures should be practiced. Advise patients to avoid artificial light sources, such as tanning beds.

Consultations

Consultation with the following specialists may be helpful:

Antimalarial Therapy

Antimalarial therapy seems to lessen the progression to systemic lupus erythematosus (SLE) and to lower the risk of thrombovascular disease.[10, 11] Alternative therapies include auranofin, thalidomide,[10, 12, 13, 14] oral or topical retinoids, and immunosuppressive agents.[15, 16] Thalidomide is regularly used in antimalarial-resistant patients. In most patients, the antimalarial should be continued during thalidomide therapy, unless a complication due to the antimalarial occurs. In addition, lenalidomide may be useful in some patients.[17]

Hydroxychloroquine is the first-line systemic agent for discoid lupus erythematosus (DLE), whereas chloroquine is considered second-line antimalarial therapy in the United States. Quinacrine may be added to either hydroxychloroquine or chloroquine for additional benefit in some patients. Owing to the ability of both hydroxychloroquine and chloroquine to deposit in the retina and cause irreversible retinopathy, these 2 agents should not be used concomitantly because of the increased risk of ocular toxicity when used in combination.[18]

Traditionally, antimalarials have been considered to be less effective in patients who smoke; however, it is also possible that DLE is worse in these patients. A recent study demonstrated that cigarette smoking did not have a significant impact on response to hydroxychloroquine in patients with DLE. Rather, disseminated DLE and the presence of concomitant systemic lupus erythematosus (SLE) were both significantly associated with decreased therapeutic efficacy.[19]

Nonetheless, efforts regarding smoking cessation are advisable in patients who smoke or who are exposed to secondary smoke.[20, 21, 22] Furthermore, a recent study demonstrated that patients with cutaneous lupus erythematosus (CLE) who smoked had more severe cutaneous disease, had inferior quality of life, and were more frequently treated with a combination of hydroxychloroquine and quinacrine than were nonsmokers.[23]

Ocular toxicity is a well-known risk as both hydroxychloroquine and chloroquine can deposit in the retina with subsequent irreversible retinopathy. Thus, these 2 medications should not be used in combination. The American Academy of Ophthalmology recently changed their guidelines to include baseline ocular examinations prior to the initiation of hydroxychloroquine or chloroquine and then annual examinations after 5 years of therapy, as ocular toxicity is a cumulative effect.[18] In practice, ocular examinations are typically recommended at baseline (within 3 months of initiating the antimalarial agent) and annually thereafter.

Quinacrine is known to cause a reversible yellow discoloration of the skin and can rarely induce cytopenias. Thus, a complete blood cell count should be monitored routinely.

Corticosteroid and Immunomodulator Therapy

Topical corticosteroids are selected for the type of lesion under treatment and for the site of involvement. For example, solutions, lotions, oil, or foams are preferred for the scalp, weaker agents are used on the face, and superpotent agents are used under occlusion for hypertrophic lesions.

Intralesional injection of corticosteroids (typically, the authors use triamcinolone acetonide 3 mg/mL) is useful as adjunctive therapy for individual lesions. Potential for atrophy relates to the amount of corticosteroid injected in any one area; therefore, dilute concentrations are preferred. In addition, the treating physician must take care to limit the total dose of the injections at any given clinic visit to avoid systemic toxicity from the steroids; for example, if a patient is given 10 mL of triamcinolone 3 mg/mL, this means that the patient has received a total of 30 mg, and toxicity is the same as if it had been delivered orally or by intramuscular injection.

Among immunosuppressives, methotrexate, mycophenolate mofetil, and azathioprine may be considered.[24, 25] Two reports have documented the value of mycophenolate mofetil for treatment of cutaneous lesions of lupus erythematosus, including one study that used mycophenolate mofetil in antimalarial-resistant subjects.[26, 27]

In the authors’ experience, systemic corticosteroids are rarely effective and frequently lead to steroid-related adverse effects at the doses needed to manage cutaneous disease.

Excision and Laser Therapy

Excision of burned-out, scarred lesions is possible; however, reactivation of inactive lesions has been reported in some patients.

Laser therapy may be useful for lesions with prominent telangiectasias; however, one must consider the risk of reactivation with this form of therapy. An open trial in a small group of patients has demonstrated the efficacy of pulsed dye laser therapy for discoid lupus erythematosus (DLE) lesions. However, before using this therapy in patients, at a minimum, a test area should be treated to make certain that the DLE does not flare.[28]

Long-Term Monitoring

Follow patients with discoid lupus erythematosus (DLE) at regular intervals. Response to therapy varies from several weeks to several months. At each visit, question the patient about new symptoms that may reflect systemic disease. At regular intervals, perhaps annually in otherwise asymptomatic patients, perform routine laboratory studies for assessment, including complete blood cell count, renal function tests, and urinalysis. Repeat antibody testing is needed only if a change in symptomatology is noted.

Medication Summary

Hydroxychloroquine and chloroquine phosphate have shown beneficial effects in treating discoid lupus erythematosus (DLE). Alternative therapies, anecdotal reports, and small, open-label trials (as reported by Callen[29] ) suggest that the following agents may be useful in some patients:

Hydroxychloroquine (Plaquenil)

Clinical Context:  Hydroxychloroquine is used for the treatment of DLE and SLE. It inhibits chemotaxis of eosinophils and 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.

Chloroquine (Aralen)

Clinical Context:  Chloroquine inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions.

Quinacrine (Mepacrine)

Clinical Context:  Quinacrine inhibits complement-dependent antigen-antibody reactions.

Class Summary

Antimalarial agents may have immunomodulatory properties. Hydroxychloroquine is the drug of choice when a systemic agent is needed for discoid lupus erythematosus (DLE). Chloroquine is second-line antimalarial therapy. Quinacrine may be added to either hydroxychloroquine or chloroquine.[36] Chloroquine and hydroxychloroquine should not be used in combination due to the increased risk of ocular toxicity. The antimalarial drugs may prevent the development of systemic lupus erythematosus (SLE) in patients with DLE, and they might decrease the risk of cardiovascular disease.[10]

Dapsone

Clinical Context:  Dapsone's mechanism of action is similar to that of sulfonamides, in which competitive antagonists of para-aminobenzoic acid (PABA) prevent the formation of folic acid, inhibiting bacterial growth. The anti-inflammatory action may relate to suppression of neutrophil function by inhibition of the halide-myeloperoxidase system.

Class Summary

Leprostatic agents may modulate the immune system.

Auranofin (Ridaura)

Clinical Context:  Gold is taken up by macrophages, which, in turn, inhibit phagocytosis and lysosomal membrane stabilization. Gold alters immunoglobulins, decreasing prostaglandin synthesis and lysosomal enzyme activity.

Class Summary

Gold compounds have proven effective in the treatment of inflammation with autoimmune etiology.

Methotrexate (Rheumatrex, Trexall)

Clinical Context:  Methotrexate reversibly inhibits dihydrofolate reductase; it limits the availability of 1-carbon fragments necessary for the synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. Methotrexate is extensively used to treat cancer, rheumatoid arthritis, and psoriasis and is used as a steroid-sparing agent in various autoimmune conditions.

Thalidomide (Thalomid)

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

Azathioprine (Imuran, Azasan)

Clinical Context:  Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, ribonucleic acid (RNA), and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity.

Mycophenolate (CellCept, Myfortic)

Clinical Context:  Mycophenolate inhibits inosine monophosphate dehydrogenase and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. It inhibits antibody production.

Class Summary

Immunomodulators affect factors that regulate the immune system.

Triamcinolone (Kenalog-10)

Clinical Context:  Triamcinolone can be administered intralesionally in a concentration of 3-5 mg/mL. The amounts injected should be recorded. Systemic adverse effects are uncommon with low doses. Atrophy is possible and is dose dependent.

Class Summary

Corticosteroids are anti-inflammatory agents that suppress the immune system at several levels, including through the inhibition of inflammatory cells and the production of antibodies.

Acitretin (Soriatane)

Clinical Context:  Acitretin is a retinoic acid analog similar to etretinate and isotretinoin. Etretinate is the main metabolite, and acitretin has demonstrated clinical effects close to those seen with etretinate. The mechanism of action is unknown.

Isotretinoin (Claravis, Sotret, Amnesteem)

Clinical Context:  Isotretinoin is a synthetic 13-cis isomer of naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A. Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization.

A US Food and Drug Administration (FDA)–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to decrease the risk of pregnancy and unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Class Summary

Retinoids have the ability to regulate cell proliferation and the immune system.

Author

A Brooke W Eastham, MD, Resident Physician, Department of Dermatology, Harvard Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: UpToDate Honoraria author/editor; JAMA Dermatology Honoraria Associate editor and intermittent author; Elsevier Royalty Book author/editor; Stock holdings in various trust accounts include some pharmaceutical companies and device makers I do not control these accounts, but have directed our managers to divest pharmaceutical stocks as is fiscally prudent I inherited these trust accounts; XOMA Honoraria Consulting

Ruth Ann Vleugels, MD, MPH, Assistant Professor of Dermatology, Harvard Medical School; Associate Physician, Department of Dermatology, Brigham and Women's Hospital; Associate Physician, Department of Immunology and Allergy, Children's Hospital Boston

Disclosure: Nothing to disclose.

Specialty Editors

Craig A Elmets, MD, Professor and Chair, Department of Dermatology, Director, UAB Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine

Disclosure: Astellas Consulting fee Review panel membership; Massachusetts Medical Society Salary Employment; UpToDate Salary Employment

David F Butler, MD, Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

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  37. Eastham AB, Vleugels RA. Cutaneous lupus erythematosus. JAMA Dermatol. Mar 2014;150(3):344. [View Abstract]

Discoid lupus erythematosus on the face.

Chronic scarred lesion of discoid lupus erythematosus.

Discoid lupus erythematosus on the face.

Chronic scarred lesion of discoid lupus erythematosus.

Lesions of discoid lupus erythematosus in the conchal bowl demonstrate patulous follicles with follicular plugging.

Scarring alopecia of discoid lupus erythematosus.

Widespread scarring alopecia.

Palmar lesions of discoid lupus erythematosus.

Hypertrophic lesions of chronic cutaneous lupus erythematosus on the dorsal hands. Characteristic lesions were observed elsewhere.

Discoid lupus erythematosus on the face.

Chronic scarred lesion of discoid lupus erythematosus.

Lesions of discoid lupus erythematosus in the conchal bowl demonstrate patulous follicles with follicular plugging.

Palmar lesions of discoid lupus erythematosus.

Scarring alopecia of discoid lupus erythematosus.

Widespread scarring alopecia.

Hypertrophic lesions of chronic cutaneous lupus erythematosus on the dorsal hands. Characteristic lesions were observed elsewhere.