Types of Cutaneous Lupus

Cutaneous Lupus

Lupus is a chronic autoimmune disease. It is characterised by autoantibody production. This means your immune system produces antibodies to cells within the body. The normal function of the immune system is to protect and fight off viruses, bacteria and germs by producing proteins called antibodies autoimmune disease lupus erythematosus is associated with a broad range of cutaneous pathology. Skin manifestations known as cutaneous lupus erythematosus (CLE) are frequently the presenting sign of lupus erythematosus (LE), and in the case of certain cutaneous lupus erythematosus (CLE) subtypes, they can occur in the absence of systemic disease. CLE is two to three times more frequent than SLE [1]. Similar to proposed aetiologies for SLE, current theories discuss a multifactorial relationship leading to the development of cutaneous lupus including genetic susceptibility, autoimmune induction, and immune system damage.

 

How is CLE currently classified?

At present, dermatologists use the only universally accepted criteria for the classification of SLE, which was set forth by the ACR. This scheme of eleven clinical and lab criteria was developed by rheumatologists for the purpose of distinguishing SLE from other autoimmune diseases. The ACR guidelines require four of eleven criteria to be met for a diagnosis of SLE, however, four of the criteria are cutaneous in nature (malar rash, discoid lesions, mucosal ulcers, and photosensitivity), which, some authors argue, skews diagnosis patterns in patients with exclusively cutaneous involvement. A 2012 multicentre database analysis from the European Society of CLE (EUSCLE) found that 48% of patients with four or more ACR criteria had CLE without systemic symptoms and concluded that the ACR criteria were inadequate in distinguishing CLE from SLE [2]. A dermatology position paper on the ACR criteria specifically questioned the usefulness of photosensitivity in SLE, as lesions can be delayed in onset and thus potentially not attributed to sun exposure, and is similarly seen in diseases such as dermatomyositis [3]. A Swedish population based study found that 25% of CLE patients previously held an SLE diagnosis, and that 20% of newly diagnosed CLE patients received a diagnosis of SLE within three years. Notably, the authors used ICD-9 codes without knowledge of how these diagnoses were made. Furthermore, many of these patients with an SLE diagnosis had very mild systemic symptoms or limited skin disease [4]. Wieczorek et al observed that patients with CLE who progress to SLE typically meet the mildest of SLE criteria [5]. In 2012, the Systemic Lupus International Collaborating Clinics Classification Criteria (SLICC) was proposed as an updated method for diagnosing SLE, including the revised dermatologic criteria of ACLE, CCLE, oral ulcers, and nonscarring alopecia. This validated SLICC criteria is undergoing further comparative testing with the ACR SLE criteria in various populations [6]. In addition, there is ongoing controversy over the classification of the cutaneous manifestations of LE from a dermatologic vantage point.

Gilliam proposed a classification system that separated LE-specific lesions from LE-nonspecific lesions, based on histopathology. The various morphologies of CLE fall under the umbrella of LE-specific lesions, including acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE). CCLE encompasses discoid LE (DLE), LE profundus (LEP), chilblain LE (CHLE), and LE tumidus (LET) [7]. The Duesseldorf Classification in 2004 proposed a separate category for LET, entitled intermittent cutaneous LE (ICLE), although this division is not universally accepted [8]. LE-nonspecific lesions, on the other hand, include findings that are not characteristic of, but are frequently seen in SLE. Such lesions include Raynaud’s phenomenon, periungual telangiectasias, livedo reticularis, and leukocytoclastic vasculitis.

 

How can we differentiate the CLE subtypes?

Acute Cutaneous Lupus Erythematosus

Acute cutaneous lupus typically presents in the third decade of life and is frequently associated with active SLE [9] and [10]. There are localized and generalized forms of ACLE. The localized form is the frequently described malar, or “butterfly” rash, which refers to erythema that occurs over both cheeks, extends over the nasal bridge, and spares the nasolabial folds [11]. These lesions are classically transient, sun-induced, and non-scarring, although dyspigmentation can occur [12]. Patients may initially mistake this rash for a sunburn, and only seek medical attention when it persists for several days. A fine surface scale and/or edema may be associated with the erythema. Malar rashes have been reported to be present in up to 52% of SLE patients at the time of diagnosis, with clinical activity of the rash paralleling that of the systemic disease. This rash can be confused with acne rosacea and seborrheic dermatitis, however the former is associated with the formation of papules and pustules, and the latter occurs within the nasolabial folds [13].

The more rare generalized form occurs above and below the neck, and has been referred to as a ‘maculopapular rash of lupus’ or ‘photosensitive lupus dermatitis.’ This presents as an often pruritic, widespread eruption of symmetric macules and papules that is photosensitive and may resemble a drug rash. Patients may have associated mucosal ulcerations/apthae, as well as diffuse hair thinning [14]. Generalized ACLE may resemble dermatomyositis as both diseases involve the dorsum of the hands, however, dermatomyositis affects the distal interphalangeal, proximal interphalangeal, and metacarpophalangeal joints, while they are spared in ACLE [13]. Cuticular overgrowth, as well as erythema or dilated vessels and drop-out of vessels in the periungual area are frequently seen. Lesions resembling erythema multiforme in ACLE or SCLE patients have been termed Rowell’s syndrome [15]. Rarely, a severe acute form can resemble toxic epidermal necrolysis. Other differentials include drug-induced photosensitivity, pemphigus erythematosus, atopic dermatitis, contact dermatitis, and photocontact dermatitis.

Histologically, ACLE lesions show liquefactive degeneration of the basal layer, edema of the upper dermis, and a scattered interface, perivascular, and periadnexal lymphocytic infiltrate, all of which are generally less pronounced as compared to other CLE subtypes. Immunologically, a positive ANA is found in 95% of ACLE patients, as well as a high incidence of anti-dsDNA and anti-Sm antibodies [16]. Lesional direct immunofluorescence reveals granular immune deposits at the dermal-epidermal junction and perivascular deposits in the upper dermis, most commonly IgM [9].

 

Subacute Cutaneous Lupus Erythematosus

As with SLE, Subacute Cutaneous Lupus Erythematosus (SCLE) occurs primarily in young to middle aged women [11]. SCLE is highly photosensitive, with 70-90% of patients meeting the ACR definition of abnormal photosensitivity [17]. There are two morphologic variants of SCLE: annular and papulosquamous. A study of 58 SCLE patients found that 42% had annular SCLE and 39% exhibited papulosquamous SCLE, while 16% of patients showed features of both [18]. Other studies have found more papulosquamous SCLE [19] and [20]. The annular type is characterized by scaly annular erythematous plaques, which tend to coalesce and produce a polycyclic array [11]. The papulosquamous variant can resemble eczema or psoriasis, as well as pityriasis in some instances [12] and [21]. SCLE lesions occur in sun-exposed areas, including the upper thorax (‘V’ distribution), upper back, and the extensor surfaces of arms and forearms. The central face and scalp are usually spared, and lesions typically do not occur below the waist [11]. The cutaneous lesions are not indurated and heal without scarring, although vitiligo-like hypopigmentation may occur [22]. The differential diagnosis for SCLE also includes dermatomyositis, cutaneous T-cell lymphoma, tinea corporis, erythema annulare centrifugum, erythema gyratum repens, photolichenoid drug eruption, granuloma annulare, and pemphigus foliaceus. Many of these lesions have similar appearances, and histologic examination is often necessary for differentiation.

An estimated 50% of SCLE patients meet criteria for SLE [23]. Patients with SCLE usually have only mild systemic symptoms, most commonly arthritis and myalgias, while severe systemic symptoms, such as lupus vasculitis, CNS lupus, and nephritis occur in less than 10% [24]. Immunologically, 70% of SCLE patients are anti-Ro (SS-A) positive, and overlap between Sjogren’s syndrome and SCLE has been seen [12]. A multicenter study found 70-80% of SCLE patients were ANA positive, and only 5% had anti-dsDNA [16]. SCLE is frequently associated with the existence of human lymphocyte antigen (HLA)-DR3 [25]. Drug-induced SCLE is more common than in other subtypes, with terbinafine, tumour necrosis factor-α inhibitors, antiepileptics, and proton pump inhibitors the most frequently reported culprits found in a 2012 population-based match case control study [26]. Pathologic examination of SCLE lesions demonstrates hydropic degeneration of the basal keratinocytes, dermal edema, hyperkeratosis, follicular plugging, and a sparse superficial inflammatory infiltrate [10]. The presence of “dust-like particles” representing IgG deposits on DIF is a highly specific but not sensitive finding in SCLE [27].

 

Chronic Cutaneous Lupus Erythematosus

Chronic cutaneous lupus includes discoid LE (DLE), LE profundus (LEP), chilblain LE (CHLE), and LE tumidus (LET).

 

Discoid Lupus Erythematosus

Discoid lesions are the most common lesions of CCLE. DLE occurs more frequently in women in their fourth and fifth decade of life [11]. Patients with DLE generally have a more benign disease course as compared to patients with other CLE subtypes, with only a reported 5-10% developing SLE throughout their disease course [28,29]. Studies have shown that patients with generalized DLE are more likely to progress to systemic disease, compared to patients with localized DLE [9,30]. Localized DLE commonly involves the head and neck, and particularly the scalp and ears. Generalized DLE, which occurs both above and below the neck, is less common and typically involves the extensor forearms and hands [11]. Occasionally, DLE can occur on mucosal surfaces, including lips, and oral, nasal, and genital mucosa. DLE lesions appear as a well-demarcated, scaly, erythematous macule or papule, which gradually develops into an indurated discoid (coin-shaped) plaque with an adherent scale that is painful to remove. Plaques tend to extend into the hair follicle, resulting in scarring alopecia. Through time, these lesions typically become atrophic, with hyperpigmentation peripherally and depigmentation centrally. Sun exposure or trauma (Koebner phenomenon) can exacerbate disease. Squamous cell carcinoma can occur within a DLE lesion [31]. Discoid lesions are very distinct in appearance from other entities, however the early indurated erythematous plaques of DLE can resemble those of psoriasis, lymphocytoma cutis, cutaneuous T-cell lymphomoa, granuloma faciale, polymorphous light eruption eruption, and sarcoidosis [32]. Buccal mucosal DLE may mimic lichen planus, however the former has a radial brush-like appearance originating from a central area of erythema [22]. An uncommon variant of DLE, hypertrophic or veruccous DLE, refers to extremely thickened lesions occurring on the arms, hands, and face. These lesions have features in common with keratoacanthomas and hypertrophic lichen planus.

Histologic examination of a longstanding active DLE lesion reveals hyperkeratosis, dilated compact keratin-filled follicles, vacuolar degeneration of the basal keratinocytes, and an intensely inflammatory dermal infiltrate. Serologically, DLE patients have a lower incidence of ANA, dsDNA, Sm, U1RNP, and Ro/SSA antibodies, as compared to other CLE subtypes [32]. Ninety percent of DLE lesions have a positive lupus band test, with C3 and IgM as the most common immune deposits [14].

 

Lupus Erythematosus Profundus

LE profundus (LEP), or panniculitis, features painful firm subcutaneous nodules with occasionally overlying DLE occurring in areas of increased fat deposition, such as the upper arms and legs, face, and breasts. LEP tends to have a chronic course, characterized by remission and flares, and ultimately leaving atrophic scars [10]. Histology shows lobular panniculitis with a dense lymphocytic infiltrate. Biopsy is critical in these cases, as lesions have frequently been shown to closely resemble subcutaneous lymphoma [33]. Biopsy specimens should be reviewed by a dermatopathologist, as diagnosis can be difficult, occasionally requiring the use of cell markers and gene rearrangements.

 

Chilblain Lupus

Chilblain Lupus (CHLE) is a rare form of CCLE resembling frostbite. Lesions appear as painful, violaceous plaques and nodules in cold-exposed areas. Central erosions or ulcerations may occur on acral surfaces, such as fingers, toes, heels, nose, and ears. Chilblain lupus occurs when there is a temperature drop, and can be difficult to distinguish from frostbite. Pathology shows epidermal atrophy, interface vacuolization, and a perivascular mononuclear infiltrate. Twenty percent of patients with CHLE develop features of SLE at some point in their disease course [34].

 

Lupus Erythematosus Tumidus

Lupus tumidus is a subtype of CCLE characterized by extreme photosensitivity and a benign course occurring preferentially in men. Clinically, these lesions appear on the face as erythematous, edematous, urticaria-like polycylic plaques with sharp raised borders and smooth surfaces. Unlike classic DLE lesions, follicular plugging does not occur. Histologically, these lesions exhibit a dense perivascular and periadnexal infiltrate without involvement of the interface. DIF testing is typically negative, and 10% of patients are ANA positive [35]. Some authors have suggested a separate category for LET, entitled Intermittent Cutaneous Lupus Erythematosus (ICLE), but there is not agreement and there are some who feel this could also be a lupus-associated skin disease [22].

 

References

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