Chapter 31 Cutaneous Lupus Erythematosus
Cutaneous involvement in patients with lupus erythematosus (LE) is very common, and it is estimated that 85% of patients with SLE develop such changes during the course of their disease. In many cases, skin lesions are of special relevance because they frequently represent one of the initial symptoms of the disease and also may serve as an indicator for systemic disease activity. Moreover, skin manifestation in LE can be associated with a high degree of morbidity and severe impact on quality of life.1–3
Skin changes have been divided into two groups—those that are histologically specific for LE (LE-specific skin lesions) and those that do not express these characteristic features (LE-nonspecific skin lesions). The classification of the specific cutaneous LE (CLE) lesions is complex because similar types of skin involvement can occur in both SLE and patients with nonsystemic forms of LE. A widely accepted classification divides LE-specific skin disease into three major clinical subtypes according to their disease activity: acute CLE (ACLE), subacute CLE (SCLE), and chronic cutaneous LE (CCLE).4–6 However, clinical, histologic, and photobiologic evidence indicates several specific characteristics for LE tumidus. Therefore, it is now considered as a distinct entity, and is referred to as an intermittent subtype of LE (ICLE)7,8 (Box 31.1). The subtypes of CLE may be further specified according to the extent of their skin involvement (localized vs. generalized) and the localization of the inflammatory infiltrate in the skin (e.g., LE panniculitis, indicating LE-specific infiltration of the adipose tissue). It is important to note that in patients with SLE, different forms of LE-specific skin lesions can be present simultaneously. For example, a butterfly rash as a manifestation of localized ACLE and chilblain LE as a variant of CCLE may coincide in one and the same patient.9 On the other hand, nonspecific cutaneous manifestations such as Raynaud’s phenomenon, urticarial vasculitis, or calcinosis cutis may also occur in patients with different forms of CLE and SLE.10
The typical skin manifestations of ACLE are confluent symmetric erythema and edema, with a characteristic distribution in the central part of the face, commonly referred to as the malar dermatitis or butterfly rash (Fig. 31.1). It may present as a localized, occasionally transient form, or as a generalized more widespread variety (Box 31.2). Both forms of ACLE commonly occur in association with systemic disease and may develop several months before the onset of systemic organ involvement. ACLE lesions may be observed in 20 to 60 % of patients with SLE and represent one of the ACR diagnostic criteria for SLE.11,12
Localized ACLE typically commences as symmetric macules or papules on the cheeks and nose that later become confluent and last from several hours to weeks. This malar dermatitis frequently is misdiagnosed as sunburn. Occasionally, the lesions may be very discrete, demonstrating only erythema with little or no edema.
Generalized ACLE—also referred to as SLE rash, maculopapular rash of SLE, or photosensitive lupus dermatitis—is less common (5 to 10%) and often overlaps with the occurrence of systemic manifestations. It is characterized by a symmetrically distributed, maculopapular erythematous to violaceous and sometimes pruritic rash that often involves the trunk with accentuation of the UV-exposed areas, but may also be localized elsewhere including the hands or feet where knuckles are typically spared.13,14 In many cases induction, or exacerbation of the rash after exposure to ultraviolet light (UV) has been observed indicating photosensitivity as an important diagnostic clue and pathogenetic component. In some patients, even aggravation of the systemic disease after UV exposure has been reported.15,16 Exacerbation or aggravation of ACLE also may be observed after (viral) infections and drug intake (hydralazine, isoniazide, procainamide).17,18 An unusual very acute form of generalized ACLE characterized by toxic epidermal necrolysis (TEN)–like lesions is seen on rare occasions. The cause of this bullous variant of ACLE is disruption of the damaged epidermis from the underlying dermis as a result of exaggerated keratinocyte apoptosis and severe interface dermatitis.19–22
ACLE lesions usually heal without scarring, but sometimes they become hyperkeratotic and poikiloderma can result from dyspigmentation. The concurrent incidence of ACLE with SCLE may be observed but is unusual. Mucocutaneous manifestations in patients with SLE involving the oral and nasal cavity are very common in patients with SLE. Typically, they consist of painful ulcerations, especially on the lips and buccal and palatal mucosa, but may be localized elsewhere in the oral cavity (Fig. 31.2).23,24
The histopathologic changes in ACLE in early lesions are less characteristic than those seen in SCLE or DLE lesions. The lymphohistiocytic cellular infiltrate of the interface dermatitis is relatively modest and hydropic changes of basal keratinocytes only occasionally can be seen. Edema and fibrinoid deposits in the upper dermis as well as vasodilatation with extravasation of erythrocytes is a common feature. In severe forms, necrotic keratinocytes and epidermal necrosis resembling TEN may be observed. In the majority of patients with ACLE, band-like granular deposits of immunoglobulins and complement at the dermoepidermal junction of lesional as well as nonlesional skin known as the lupus band test (LBT) can be detected.25,26
The differential diagnosis of ACLE lesions includes erythema solare (sunburn), photoallergic and phototoxic drug eruptions, dermatomyositis, atopic eczema, seborrheic dermatitis, contact eczema, and rosacea.
Subacute cutaneous lupus erythematosus is associated with specific clinical, serologic, and genetic characteristics (Box 31.3), and was recognized as a distinct entity by Gilliam in 1977.6 SCLE frequently is associated with systemic symptoms such as arthritis and a pronounced photosensitivity but normally has a favorable prognosis. Patients with SCLE usually have circulating anti-Ro/SSA and anti-La/SSB antibodies and an increased association with the HLA B8, DR3 haplotype as well as a 308A TNF-α promoter polymorphism.27–29 Data from several studies further indicate that approximately half of patients with SCLE fulfill four or more ACR criteria for SLE.14
Initially, SCLE develops as erythematous papules or macules that expand and merge into hyperkeratotic papulosquamous or annular and sometimes polycyclic plaques. Thus, two types can be distinguished, including a papulosquamous variant consisting of psoriasis-like or eczema-like lesions and an annular variant consisting of slightly raised erythemas with central clearing (Figs. 31.3 and 31.4).2,30 Mixed types do occur. SCLE lesions typically are located on UV-exposed skin, including the lateral aspects of the face, the V of the neck (often with sparing of the area under the chin), the upper ventral and dorsal part of the trunk, and the dorsolateral aspects of the forearms. SCLE lesions never lead to scarring, but hypo- or de-pigmentation is common, resulting in vitiligo-like depigmentation.31 In some cases, the disease may be very mild with the appearance of a few distinct scaly plaques after sun exposure. Several drugs may induce SCLE, such as hydrochlorothiazide, terbinafine, diltiazem hydrochloride, ACE inhibitors, and griseofulvin, as well as leflunomide30,32–38 and biologic agents such as etanercept.39 Conversely, after starting etanercept therapy in a patient with rheumatoid arthritis and SCLE, the skin eruption of SCLE went into remission.40 Discontinuation of the medication does not always result in the clearance of skin lesions. There is some evidence for SCLE being a paraneoplastic syndrome in association with solid tumors.41 A substantial proportion of patients with SCLE is sensitive to UV-light and may exhibit mild systemic symptoms, such as arthralgias and musculoskeletal complaints, especially if the disease occurs in association with Sjögren’s syndrome. Autoimmune thyroiditis also may be observed in connection with SCLE.25,30,42
In the same patient with SCLE, other forms of LE-specific skin lesions may occur, including ACLE as well as CCLE. In addition, these patients can also develop LE-nonspecific skin disease such as Raynaud’s phenomenon, livedo reticularis, or leukocytoclastic vasculitis. There is some evidence that SCLE patients who develop either ACLE or LE-nonspecific skin lesions more often acquire systemic disease.14
Some patients with SCLE have been reported to develop erythema multiforme–like lesions, occasionally with involvement of the mucous membranes in the presence of anti-Ro/SSA and/or La/SSB antibodies, a speckled ANA pattern, and a positive rheumatoid factor. This variant also may be regarded as Rowell’s syndrome, which was originally described in patients with DLE, but apparently also occurs in association with other forms of CLE and SLE. The overlap in Rowell’s syndrome and SCLE in many features suggests that LE with erythema multiforme-like rashes represents SCLE with targetoid lesions rather than a distinct entity.20,43
The prognosis of SCLE in general appears to be good, although approximately 50% of the patients meet the ACR criteria for SLE. However, only a low percentage (∼15%) will develop manifestations of severe SLE.44
In newborns from mothers having anti-Ro/SSA autoantibodies, an SCLE-like rash has been observed, called neonatal lupus erythematosus (NLE). The annular erythematous lesions with central clearing predominantly are localized on the face especially the periorbital area. Although sensitivity to UV light has been reported, NLE lesions usually develop without sun exposure. Most infants with NLE have maternal anti-Ro/SSA autoantibodies. The skin lesions normally resolve within 6 months, correlating with the disappearance of the anti-Ro/SSA autoantibodies. In some children residual dyspigmentation and telangiectasias may persist.45,46 The histopathologic findings of NLE are identical to those seen in adult SCLE. In approximately 2%, heart involvement with congenital atrioventricular block may develop. Therefore, careful monitoring of SCLE patients during pregnancy is required. Serial echocardiograms of fetuses should be performed between 18 and 24 weeks of pregnancy.45,47
Histopathology of SCLE lesions usually reveals LE-specific findings, such as keratinocyte damage, epidermal atrophy, and interface dermatitis. In the epidermis, hydropic or eosinophilic degeneration of keratinocytes is commonly seen. The upper dermis typically contains an infiltrate of lymphohistiocytic cells in an interface, perivascular, and periadnexal pattern. In comparison to CCLE, lesions in SCLE have little hyperkeratosis, basement membrane thickening, follicular plugging, and lymphohistiocytic cellular infiltrate. Using histopathologic criteria, it is not possible to differentiate the annular from the papulosquamous form of SCLE.25 The lupus band test of lesional skin is positive in the majority of cases. A distinct pattern of granular IgG and IgM deposits in the epidermis rather than at the dermoepidermal junction has been described in SCLE.26 There is evidence that these epidermal deposits reflect the presence of in vivo bound anti-Ro/SSA autoantibodies.48
The differential diagnosis of SCLE lesions consists of photoallergic and phototoxic drug eruptions, as well as other forms of annular erythemas such as erythema annulare centrifugum, erythema gyratum repens, granuloma annulare, eczema, psoriasis, and tinea.