Subacute cutaneous lupus erythematosus (SCLE) is a distinct entity with specific clinical and serologic features that was first described by Gilliam in 1977 (Gilliam, 1977), with expanded discussion in 1979 (Sontheimer et al., 1979) and 1982 (Gilliam and Sontheimer, 1982). Most patients with SCLE are sensitive to sunlight and have prominent cutaneous and musculoskeletal complaints but generally do not develop a severe systemic disease (Crowson and Magro, 2001; Cohen and Crosby, 1994; Tan et al., 1982). Furthermore, the majority of patients with this subtype produce anti-Ro/SSA antibodies, the presence of which supports, but is not necessary to make the diagnosis of SCLE.
Initially, SCLE patients show sharply demarcated, elevated, erythematous papules or small plaques covered with fine scales affecting shoulders, upper back, extensor aspects of the arms, and the V-area of the back or neck. The lesions expand and merge in some patients producing papu-losquamous lesions that can mimic those of psoriasis vulgaris. In other patients, the primary lesions expand and clear centrally to produce annular lesions that may merge into polycyclic arrays (Fig. 2) (Sontheimer, 1989; Bangert et al., 1984). While few patients with SCLE simultaneously exhibit both papulosqaumous and annular lesions, most have predominantly one type. Some groups have observed a predominance of the papu-losquamous lesions, whereas others have noted an abundance of the annular/polycyclic type (Herrero et al., 1988; Molad et al., 1987; Callen and Klein, 1988; Fabbri et al., 1990; David-Bajar, 1993; Chlebus et al., 1998; Cohen and Crosby, 1994). Both types of SCLE lesions heal without scarring but can leave long-lasting and permanent vitiligo-like pigmentary changes as a 'clue' for the clinical diagnosis (Milde and Goerz, 1994).
Occasionally, SCLE lesions may present with an appearance of erythema multiforme, which can simulate the appearance of Rowell's syndrome (erythema multiforme-like lesions occurring in patients with SLE in the presence of anti-La/SSB antibodies) (Sontheimer, 1985b; Rowell et al., 1963). In 1998, Lyon et al. (1998) reported two cases of delayed diagnosis of SCLE because of the clinical and histologic similarities between SCLE and erythema multiforme. Furthermore, several LE-non-specific skin manifestations have been described in patients with SCLE (Sontheimer, 1989; Parodi et al., 2000) including non-scarring alopecia, livedo reticularis, periungual teleangiect-asias, and Raynaud's phenomenon (Sontheimer,
1985a; Herrero et al., 1988; Molad et al., 1987; Callen and Klein, 1988; Callen et al., 1986; David et al., 1984; Sanchez-Perez et al., 1993). Cutaneous vasculitis of the lower extremities is a further frequent finding in anti-Ro/SSA-positive patients with SCLE described under the rubric of Sjogren's syndrome/LE overlap syndrome (Provost et al., 1988b). Calcinosis cutin may be seen rarely in patients with SCLE, and HPV-11-associated squamous cell carcinoma of the skin was also noted in one patient with this subtype (Cohen et al., 1992). In one case, annular/polycyclic SCLE lesions were reported over time to progress to plaques of morphea (Rao et al., 1990). In a study by Herrero et al. (1988), vesiculobullous changes were present in 38% of the SCLE population, which coincided histologically with focal areas of necrosis. In 1988 (DeSpain and Clark, 1988), one patient with SCLE was reported to initially present exfoliative ery-throderma which was also noted more recently by Mutasim (2003).
The group of chronic cutaneous lupus erythematosus (CCLE) includes several entities, such as discoid LE (DLE) and the more rare subtypes LE profundus (LEP) and chilblain LE (CHLE).
2.3.1. Discoid lupus erythematosus Discoid lupus erythematosus (DLE) is the most common subtype of the chronic cutaneous variants of LE and may present as a localized or disseminated form. The localized form, characterized by limited cutaneous involvement of the head and scalp, usually accounts for 70% of patients with DLE, and the disseminated form, characterized by the extension to areas below the neck for 30% of patients with DLE. Disseminated DLE, especially when involving the trunk, is in most cases associated with progression to SLE. Interestingly, approximately 30% of patients with SLE may develop DLE lesions during the course of their disease and, in about 5-10% of patients, DLE lesions may already be present at the onset of the disease (Cervera et al., 1993; Hymes and Jordon, 1989; Tebbe et al., 1997).
Clinically, the skin lesions of patients with DLE begin with flat or slightly elevated, demarcated, erythematous macules or papules with a scaly surface. Early lesions most commonly evolve into larger, coin-shaped ("discoid"), confluent, disfiguring plaques of varying size demonstrating a prominent adherent scale formation (Fig. 3) (Crowson and Magro, 2001). When the adherent scale is peeled back from more advanced lesions, follicle-sized keratotic spikes similar in appearance to carpet tacks can be seen projecting from the
Figure 3. Discoid lupus erythematosus (DLE). Facial erythematous plaques with active inflammation at the periphery and central atrophic scarring.
undersurface of the scale ('the carpet tack sign'). Teleangiectasia and hyperpigmentation can replace the active inflammation, and the lesions may give a poikilodermatous appearance. The DLE plaques are generally progressive, and resolution of the lesions leaves more or less evident atrophy and scarring, depending on the duration and severity of the lesions during the active phase. This may result in considerable mutilations, particularly when present in acral regions on the face, such as the tip of the nose and the ears, or in irreversible scarring alopecia on the scalp. A characteristic pitted, acneiform scarring is also a common feature of the perioral area.
Approximately 2% of patients with DLE show a hyperkeratotic type of lesion (Mascaro et al., 1997; Costner et al., 2003; Kuhn et al., 2000c) consisting of dull, red, and indurated lesions. These verru-cous, hyperkeratotic plaques can occur at any site of the body where classical DLE lesions develop, although the extensor aspects of the arms and limbs, the upper back, and the face are most frequently affected (Mascaro et al., 1997; Daldon et al., 2003). Recently, conjunctival hyperkeratotic lesions have been reported in a patient with a history of chronic blepharoconjunctivitis (Uy et al., 1999). When the palms and soles are involved, hyperkeratotic DLE produces localized or partially diffuse keratoderma, up to 1-3 mm thick, that makes mobility more difficult (Rothfield, 1993). Differential diagnosis of the hyperkeratotic type of DLE must take into consideration verrucous psoriasis, hyperkeratotic lichen planus, prurigo nod-ularis, keratoacanthoma, and squamous cell carcinoma (Romero et al., 1977; Perniciaro et al., 1995; Daldon et al., 2003; Vinciullo, 1986).
DLE lesions predominantly occur in sun-exposed areas of the skin and the appearance in unusual locations and on completely sun-protected areas may be evidence that these lesions can follow in the wake of any form of trauma to the skin (Koebner's phenomenon or isomorphic response) (Ueki, 2005). Mostly, the lesions appear on the face, particularly the cheeks and ears, the neck, and arms, but may also be found in inguinal folds, palmo-plantar, and the scalp (McCauliffe, 2001; Fabbri et al., 2003; Patel and Werth, 2002; Costner et al., 2003). At the latter location, DLE may even be the only cutaneous manifestation in 10% of cases and thus presents a classical differential diagnosis of scarring alopecia (Prystowsky and Gilliam, 1975). In some patients, DLE on the scalp progresses to the point of total, irreversible scarring alopecia and may be accompanied by secondary bacterial superinfection. Mucous membrane involvement can be found in 25% of patients with DLE, but does not necessarily reflect systemic manifestation or high disease activity (Burge et al.,
1989; Botella et al., 1999; Andreasen and Poulsen, 1964); however, it is included in the list of the 11 diagnostic Criteria of the American College of Rheumatology (ACR) for the diagnosis of SLE (Tan et al., 1982). The lesions usually begin as painful, erythematous patches, later maturing to a chronic plaque that has a sharply marginated, irregularly scalloped white border with radiating white striae. The centers of older lesions cause atrophy and may become depressed and, occasionally, undergo painful ulceration. Oral, mainly buccal, manifestations are most common, with the palate, alveolar processes, and tongue less frequently involved, but nasal, conjunctival, and anogenital mucous membranes may also be affected at times. Persistent erythema, epithelial thickening, fine kera-tosis, or erosions are also seen on the vermilion border of the lips and can present as a diffuse cheilitis, especially on the more sun-exposed lower lip, causing considerable discomfort and disfiguration. The nails can be involved as a very uncommon site of occurrence; however, periungual teleangiect-asias and erythema of the proximal nail fold are significant features that can occur in patients with DLE prone to developing systemic disease. Furthermore, focal lesions of DLE occurring over the nail fold can produce nail plate dystrophy (Kanwar et al., 1993).
2.3.2. Chilblain lupus erythematosus Chilblain lupus erythematosus (CHLE), distinguished by Hutchinson in 1888 (Hutchinson, 1888), is seen predominantly in females and strongly influenced by environmental factors (Breathnach and Wells, 1979; Rowell, 1987; Uter et al., 1988; Doutre et al., 1992; Helm and Jones, 2002). The pathogenesis of this rare subtype of CCLE is unknown, but microvascular injury secondary to exposure to cold, damp weather, or a drop in temperature and possible hyperviscosity from immunologic abnormalities may play a role (Yell et al., 1996; Mascaro et al., 1997). The risk of developing SLE is estimated to be approximately 20%, but only few studies of patients with CHLE have been reported (Viguier et al., 2001).
The lesions of CHLE are clinically characterized by symmetrically distributed, circumscribed, sometimes infiltrated, pruriginous or painful areas of livid and purple plaques. There is only a slight tendency to central regression, and the lesions, in their evolution, may ulcerate or present firmly adherent hyperkeratosis (Costner et al., 2003; Kuhn et al., 2000c). Mostly, the dorsal and lateral parts of the hands and feet, the ears, the nose, the elbows, the knees, or the calves are involved (Su et al., 1994; Helm and Jones, 2002). On toes and fingers, the lesions present on the back or on the pads (Fisher and Everett, 1996; Doutre et al., 1992), and fissuring of the knuckles as well as accompanying hyperhidrosis are common, producing a great deal of discomfort (Costner et al., 2003). Ulceration is frequent in digital pulp lesions, and they easily become necrotic on the soles (Mascaro et al., 1997). When located in the periungual zone, the nail plate may develop mild to severe dystrophy. A chronic form of CHLE occurs especially in older patients who have underlying vascular abnormalities, such as acrocyanosis, Raynaud's phenomenon, atherosclerosis, or erythrocyanosis. In such patients, this subtype of CCLE can last for several months and tends to recur annually, sometimes with hemorrhagic blisters, erosions, or ulcers.
2.3.3. Lupus erythematosus profundus Historically referred to as Kaposi-Irgang disease (Kaposi, 1883; Irgang, 1940), lupus erythematosus profundus (LEP) is a rare variant of CCLE characterized by inflammatory lesions in the lower dermis and subcutaneous tissue. This subtype generally affects middle-aged women; however, in a recent study it has been shown that in Asian patients LEP is more frequent in a younger age group compared with the Caucasian population (Ng et al., 2002). Patients with LEP present most commonly without any or only mild signs of systemic manifestations and it can only be found in 2% of patients with SLE. The course of LEP is usually chronic and characterized by periods of remission and exacerbation, and the major morbidity is usually disfigurement and disability related to pain (Mascaro et al., 1997; Kuhn et al., 2000c).
The lesions of LEP typically appear as single or multiple sharply defined, persistent, asymptomatic or sometimes painful subcutaneous plaques or nodules of varying sizes (Peters and Su, 1989; Costner et al., 2003). The overlying skin becomes attached to the firm lesions, producing a deep depression into the subcutis with a normal or erythematous, inflammatory surface. Dystrophic calcifications or ulcerations within older lesions of LEP, leaving atrophic scars or sometimes resembling lipatrophy, may occur and at times can be a prominent clinical feature of the disease requiring surgical excision. Trauma may often directly be related to the lesions of LEP (Tuffanelli, 1971). Most lesions of LEP are usually found on the trunk, buttocks, and proximal upper and lower extremities, but the shoulders and thighs are further sites of predominant involvement (Martens et al., 1999). This subtype may also develop on the scalp clinically simulating alopecia areata (Kossard, 2002) and in unusual areas on the face, such as the parotid region. Furthermore, periorbital edema as an initial symptom of LEP has also been described in several patients as the only clinical manifestation of the disease (Lodi et al., 1993; Magee et al., 1991; Franke et al., 1999).
LET has recently been defined as a distinct entity of cutaneous lupus erythematosus (CLE) and is now inclued in the new classification as the intermittent subtype. The importance of re-evaluating this form lies in the characteristic clinical picture, the histologic pattern, the remarkable photosensitivity, and in the course of the disease (Kuhn et al., 2004). In several aspects, LET differs from other variants of CLE. Scarring, the hallmark of DLE, does not occur in LET, even in patients with recurrent skin lesions. Follicular plugging and adherent hyperkeratotic scaling, which are further features of DLE, have also not been seen in any of the patients with LET. Hypopig-mentation, frequently evident in patients with SCLE after the active phase with erythema and scaling, has never been detected in LET (David-Bajar and Davis, 1997). Furthermore, association with systemic disease seems to be very rare in patients with LET, and has only been documented in very few cases (Jolly et al., 2004). Although joint symptoms occur temporarily, no signs of inflammatory joint disease or rheumatoid arthritis have been detected, and further systemic manifestations, such as renal, central nervous system, or lung involvement, have not yet been appreciated in any of the patients. Therefore, the prognosis in patients with LET is generally more favorable than in those with other forms of CLE (Kuhn et al., 2000a).
2.4.1. Lupus erythematosus tumidus LET is clinically characterized by succulent, urticaria-like, single or multiple plaques with a bright reddish or violaceous smooth surface (Fig. 4). The swollen appearance of the lesions and the absence of clinically visible epidermal involvement are the most important features of this subtype. The borders are sharply limited, and, in some cases, there is a tendency for the lesions to coalesce in the periphery, producing a gyrate configuration, or to swell in the periphery and flatten in the center (Mascaro et al., 1997). LET lesions can coexist with DLE lesions (Ruiz and Sanchez, 1999) and have been reported to mimic alopecia areata when present on the scalp (Werth et al., 1992). Some patients develop erythematous, annular lesions on the cheeks and upper extremities imitating the annular type of SCLE, and, recently, a patient with LET following the lines of Blaschko has been reported (Pacheco et al., 2002). However, other LE-non-specific manifestations such as calcinosis cutis and livedo reticularis, have never been detected in any of the patients.
The skin lesions in LET are primarily found on sun-exposed areas, such as the face, the upper back, the V-area of the neck, the extensor aspects of the arms, and the shoulders (Kuhn et al., 2000a). Therefore, it has long been suggested that this subtype of CLE is characterized by a remarkable photosensitivity (Goerz et al., 1990). Provocative phototesting confirmed that patients with LET are more photosensitive than those with other forms of CLE. In a study by our group (Kuhn et al., 2001b), characteristic skin lesions
Figure 4. Lupus erythematosus tumidus (LET). Single. rythematous, succulent, urticaria-like plaques on the forehead.
were induced by UV irradiation in 72% of the patients. However, because of the latency period in developing positive phototest reactions, it may be difficult for patients to link sun exposure to their disease.
The most frequent histologic features in LET lesions are a fairly well-circumscribed lymphocytic dermal infiltrate in a perivascular and periadnexal pattern and abundant interstitial mucin deposition (Kuhn et al., 2003). In a few cases, the epidermis is acanthotic, and the dermis shows edema in its upper part; however, in contrast to other forms of CLE, epidermal changes such as atrophy and follicular plugging, and vacuolar degeneration of the dermoepidermal junction or basement membrane thickening are absent. Therefore, some authors have not considered LET as a subtype of CLE or as a separate entity different from other variants of CLE, and it is likely that skin lesions described under different designations, such as "urticarial plaque lupus erythematosus,'' represent the same disease entity (Sontheimer and Provost, 1996). Further more, some skin conditions share a variety of similar features, demanding attention to rather subtle details and appreciation of the characteristic signs of LET as well as the course of the disease. In 2000, our group (Kuhn et al. 2000a) analyzed 40 patients with LET and defined diagnostic criteria for the classification of this disease, which have been confirmed by other investigators (Alexiades-Armenakas et al., 2003; Choonhakarn et al., 2004). Interestingly, most case reports of LET in the literature are published by European countries indicating that many more patients are seen in the Caucasian population (Sontheimer, 2000).
3. Non-specific cutaneous manifestations of lupus erythematosus
Skin lesions which are seen not only in patients with LE but are also found in association with other conditions are defined as non-specific cutaneous manifestations. These non-specific cutaneous manifestations are morphologically varied and include non-scarring alopecia, calcinosis cutis, rheumatoid nodules, and sclerodactyly (Table 2). Several skin diseases can also be found in the context of LE, such as acanthosis nigricans, anetoderma, cutaneous vascular diseases, e.g. Raynaud's phenomenon, erythema multiforme, lichen planus, and porphyria cutanea tarda (Costner et al., 2003; Provost, 2004). In addition, bullous skin lesions, and autoimmune disorders, urticaria vasculitis, papulonodular mucinosis, and annular erythema can be associated with various forms of LE and will be described in the following.
Non-specific cutaneous manifestations of lupus erythematosus
Alopecia (non-scarring) Annular erythema Bullous skin lesions Calcinosis cutis
Papulonodular mucinosis Rheumatoid nodules Sclerodactyly
Acanthosis nigricans Anetoderma
Bullous autoimmune disorders Cutaneous vascular diseases (e.g., urticaria vasculitis (Raynaud's phenomenon)
Erythema multiforme Lichen planus Porphyria cutanea tarda
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