Lupus Erythematosus
Key Points
Lupus erythematosus (LE) is a multisystem, chronic autoimmune disease with a wide spectrum of presenting symptoms
Cutaneous manifestations appear in 72% to 85% of patients with SLE, and in 23% to 28% it can be the presenting sign of the disease
Acute cutaneous LE is characterized by a butterfly rash over both cheeks, seen in 87% of patients
Discoid LE is a chronic condition that presents as well-demarcated, scaly, erythematous macules or papules that gradually develop into indurated discoid plaques
LE is caused by dysfunction in the immune system, involving loss of self-tolerance through the production of autoantibodies
Sunlight can precipitate cutaneous disease de novo or it can aggravate existing lesions
Eyelid lesions often begin as erythematous scaly maculae or papules that gradually grow peripherally into larger discoid plaques and may be associated with blepharitis and madarosis
Management involves avoidance of UV exposure and topical steroids, tacrolimus, antimalarial drugs, or immunosuppressant agents
The prognosis for cutaneous LE depends on the specific clinical variant and on the presence and severity of any associated systemic manifestations
5% to 10% of patients with CLE will evolve to SLE over 5 years
Lupus erythematosus (LE) is a multisystem, chronic autoimmune disease with a wide spectrum of presenting symptoms ranging from mild manifestations in localized cutaneous LE (CLE) to severe, life-threatening systemic LE (SLE) with involvement of internal organs.1 In Europe, the prevalence of SLE is estimated to be 39.2 cases per 100,000 individuals, and the annual incidence rate is 1 to 3.8 per 100,000 individuals.2,3 Cutaneous manifestations appear in 72% to 85% of patients with SLE, and in 23% to 28% it can be the presenting sign of the disease.4 Moreover, isolated CLE, while rare, is still several times more common than SLE and can occur in the absence of systemic disease.5
CLE may present in various forms and it must be determined if it is isolated or a manifestation of SLE. The association with SLE varies depending upon the specific phenotype of CLE. The association has been reported at 100% in acute cutaneous lupus erythematosus (ACLE),6 to 50% in subacute cutaneous lupus erythematosus (SCLE),7 to only 5% for localized discoid lupus erythematosus (DLE).
In 1982, the American College of Rheumatology (ACR) developed a widely used classification of criteria for the diagnosis of SLE.8 The ACR classification included 11 clinical and laboratory criteria, including four cutaneous features (malar rash, discoid lesions, mucosal ulcers, and photosensitivity). However, skin features seen in CLE occur with a broader spectrum of clinical presentations beyond those listed in the ACR criteria for SLE.9 In 2012, the Systemic Lupus Collaborating Clinics (SLICC) revised the ACR criteria to comprise 17 clinical and immunological criteria, including some minor revisions of the cutaneous criteria, omitting photosensitivity, and adding nonscarring alopecia.10
Criteria for the diagnosis of the subtypes of CLE are still largely based on the classification system proposed by Gilliam in 1981.11 CLE was divided into LE-specific lesions and LE-nonspecific lesions.12 LE-nonspecific lesions included findings that are not usually characteristic of SLE and may be present in other diseases. These include Raynaud’s phenomenon, periungual telangiectasias, livedo reticularis, and leukocytoclastic vasculitis.12,13 The phenotypes included under the umbrella of LE-specific lesions encompass several subtypes defined by clinical features, the average duration of the cutaneous lesions, histologic findings, as well as laboratory abnormalities. These subtypes include acute, subacute, and chronic CLE.11 Chronic CLE included several subgroups: DLE, LE profundus (LEP), and chilblain LE (CHLE). In more recent years, new subtypes of CLE have been added, including LE tumidus (LET),14,15 although there is still no agreement whether this form should be considered as a subtype of CCLE or should be differentiated as a separate category of CLE.16,17
Acute Cutaneous Lupus Erythematosus
ACLE is characterized by a transient malar, or “butterfly” rash, over both cheeks, induced by sun exposure, seen in 87% of patients, and sometimes associated with fine surface scales and/or edema.1 A discoid rash can be seen in 20%, and oral ulcers in 33%. The condition may be associated with diffuse hair thinning.6 ACLE typically presents in the third decade of life12 and is frequently associated with active SLE.18,19 It can be associated with arthritis, renal disorders, or neurologic involvement in 20% to 60% of cases.
Subacute Cutaneous Lupus Erythematosus
SCLE occurs primarily in young to middle-aged women.17 It presents clinically with a photosensitive malar rash in 30% to 40% of cases, which can either be annular or papulosquamous or occasionally with features of both.12,20 The annular type is characterized by scaly annular erythematous plaques, which tend to coalesce.17 Lesions occur in sun-exposed areas of the throat, upper back, and the extensor surfaces of arms, generally with sparing of the face and scalp. About 50% of cases meet the criteria for SLE,21 but most of these patients usually have only mild systemic symptoms, and renal or neurologic involvement is seen in 4% to 20% of these patients.1
Chronic Cutaneous Lupus Erythematosus
Chronic cutaneous LE (CCLE) includes four subtypes that include DLE, LEP, CHLE, and LET. They differ by relatively minor clinical and histopathologic features. Unlike ACLE and SCLE, CCLE only rarely shows systemic involvement.22
Discoid lupus erythematosus (DLE) – Discoid lesions are the most common photosensitive rashes seen in CCLE, occurring in 90% of patients.1 They occur more frequently in females in their fourth and fifth decades of life.17 Localized DLE typically involves the head and neck, whereas generalized DLE occurs both above and below the neck. DLE lesions present as well-demarcated, scaly, erythematous macules or papules that gradually develop into an indurated discoid plaque.12,23 Hair follicles become involved resulting in scarring alopecia. Rarely, squamous cell carcinoma can occur within a DLE lesion.24
Lupus erythematosus profundus (LEP) – LEP, also known as lupus erythematosus panniculitis, presents as a painful firm, tender, subcutaneous nodules in areas of increased fat deposition, such as the upper arms and legs, face, and breasts. They run a chronic course with episodes of remission and exacerbation, finally healing as depressed, atrophic plaques.19,24 Occasionally, systemic or other forms of cutaneous LE may occur concurrently with LEP. Several cases have been associated with dermatomyositis.25
Chilblain lupus (CHLE) – Chilblain lupus is a rare form of CCLE that presents as painful, pruritic, infiltrative, violaceous erosions or ulcerations on skin areas exposed to cold, including the fingers, toes, nose, and ears. Involvement of the face is uncommon. Lesions tend to improve during warmer months. Two-thirds of patients may also have hypergammaglobulinaemia. Most cases are sporadic, but there have been familial cases inherited in an autosomal dominant manner.26 About 20% of these patients will eventually develop features of SLE.27
Lupus erythematosus tumidus (LET) – Lupus tumidus is another subtype of chronic CCLE. It occurs mostly in men and is characterized by photosensitive, elevated, erythematous, and edematous lesions on the face and neck.28 It is considered to be the most benign form of CLE, rarely associated with SLE. Skin lesions have an annular or semiannular appearance without scales, ulceration, or crust formation. Lesions heal without scarring or postinflammatory pigmentary changes.29 Drugs are considered to be minor risk factors for LET, reported to be associated with infliximab, adalimumab, etanercept, thiazide diuretics, and bortezomib.29
Etiology and Pathophysiology
Lupus erythematosus is caused by dysfunction in the adaptive and innate immune system, involving a loss of self-tolerance through the production of autoantibodies.30 Skin lesions in CLE can be induced by both UVB (290-320 nm) and UVA (320-400 nm) radiation.31,32,33 Sunlight can precipitate cutaneous disease de novo or it can aggravate existing lesions. Also, phototherapy (UVB) and tanning beds (UVA) have been reported to either induce or exacerbate SLE.
UV light has multiple effects on living tissue and molecular targets include DNA, RNA, proteins, and lipids. It can induce the binding of antibodies to selected nuclear antigens associated with LE and photosensitivity.31 UV radiation can also induce apoptosis in keratinocytes by a variety of mechanisms including ligand-independent activation of membrane death receptors, sensitization of keratinocytes to TNF-induced apoptosis, DNA damage, or through the mitochondrial pathway.31 Apoptotic cells accumulate in the epidermis of patients with cutaneous LE after UV irradiation,34,35 It has been proposed that the biochemical processes of apoptosis can generate novel antigens that can be targeted by autoantibodies.36,37 Proteins phosphorylated during apoptosis become targets for autoantibody production in patients with SLE, and these might be important in the initiation of autoimmune responses.31
This model of the pathogenesis of CLE originally proposed by Norris38 presupposes an abnormal susceptibility to UV light resulting in altered cytokine expression and induction of increased keratinocyte apoptosis, the presence of antibodies with appropriate specificities targeting keratinocyte components, and the presence of activated lymphocytes specific for autoantigens.31 Since this model was proposed, new data have been presented supporting this concept and uncovering genetic abnormalities in apoptosis induction or apoptotic cell clearance, as well as various cytokines linked to CLE. Details are beyond the scope of this chapter and are well discussed elsewhere.39,40,41,42,43
Erythema is a normal response to UV light and is mediated by a wide range of vasoactive mediators, neuropeptides, and cytokines released from keratinocytes, mast cells, endothelial cells, and fibroblasts.31 UV light can induce significant and persistent erythema in patients with CLE. UV light can also induce cutaneous inflammation through the release of inflammatory mediators, cytokines, and chemokines that attract inflammatory cells to the skin.44
Cigarette smoking may have phototoxic effects45 and is an important environmental trigger for CLE, linked with increased disease activity and a poor response to antimalarial therapy.46,47 In a series of 405 patients with CLE and SLE, 45.9% were smokers, and in LET the rate was 83%,
both significantly greater than the 33.2% of smokers in the matched general population.48
both significantly greater than the 33.2% of smokers in the matched general population.48
Twin studies in SLE have shown a much higher disease concordance in monozygotic twins (24%-57%) than in dizygotic twins, indicating there is a genetic predisposition to the disease.49,50,51,52,53 In a study of 183 CLE patients, Kunz et al54 identified polymorphisms in genes responsible for antigen presentation, regulation of apoptosis, RNA processing, and interferon response (HLA-DQA1, MICA, MICB, MSH5, TRIM39, and RPP21). There are likely genetic predispositions and environmental triggers that underlie the development of SLE and CLE. While no single gene or single environmental factor is associated in most individuals, genetic studies have shown a relationship between smoking and several genes, including TNFRSF1B, NAT2, and CYP1A1/GSTM1, with an increased risk of SLE in the presence of both factors.55,56
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