How to cite this article: Méndez-Flores S, Tinoco-Fragoso F, Hernández-Molina G. Cutaneous lupus erythematosus, a multidimensional entity. Rev Med Inst Mex Seguro Soc. 2015 Nov-Dec;53(6):764-72.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/26506497

REVIEW ARTICLES

Received: August 20^th 2014

Accepted: April 28^th 2015

Cutaneous lupus erythematosus, a multidimensional entity

Silvia Méndez-Flores,^a Fátima Tinoco-Fragoso,^a Gabriela Hernández-Molina^b

^aDepartamento de Dermatología

^bDepartamento de Inmunología y Reumatología

Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Distrito Federal, México

Communication with: Gabriela Hernández-Molina

Telephone: (55) 5485 0766

Email: gabyhm@yahoo.com

Skin lesions caused by systemic lupus erythematosus are among the most frequent manifestations of this disease. These lesions show great variability in both their clinical and histological expression, making their understanding and study difficult. Patients presenting with cutaneous lupus do not necessarily have serious systemic complications, but they do have significant morbidity from impact on quality of life given the extent of the lesions, chronic tendency, and the risk of scarring; hence the importance of establishing a fast and effective treatment. This paper addresses the different varieties of specific injuries attributed to lupus erythematosus, correlation with systemic activity, quality of life, and the treatments available.

Keywords: Skin diseases, Cutaneous lupus erythematosus, Skin manifestations.

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Introduction

Lupus erythematosus (LE) is an autoimmune disease, whose clinical spectrum is broad and diverse, from the signals to the prognosis of the disease. At one extreme are patients who develop life-threatening manifestations meeting criteria of systemic lupus erythematosus, and at the other, patients with cutaneous lupus erythematosus. However, skin involvement occurs in 70-85% of patients with systemic lupus erythematosus at some point during the course of disease.¹ Although cutaneous manifestations rarely endanger the patient's life, they do contribute to morbidity in terms of personal and psychosocial well-being as well as to professional disability, leading to high medical and social costs, and it is the dermatological disease with the third greatest psychosocial impact.²

Pathogenesis

The pathogenesis of cutaneous lupus is multifactorial and not yet fully studied. However, it has been described that a genetic predisposition is essential.³ The HLA-A1-D8-DR3 haplotype is strongly associated with subacute lupus erythematosus (SALE).⁴ The gene for alpha M integrin (ITGAM) has also been demonstrated to play a role in the pathogenesis of discoid lupus erythematosus (DLE).⁵ Factors have been recognized such as drug use, smoking, and even some viral infections. However, in the development of these manifestations, photosensitivity has a central role. It is known that ultraviolet radiation can cause aberrant induction of apoptosis in keratinocytes, with subsequent secondary release of proinflammatory and auto-antigenic components.⁶ Furthermore, there is a relationship between anti-Ro antibodies and the development of skin and heart disease, as well as neonatal lupus. In regard to cutaneous lupus, these antibodies have also been associated with photosensitivity. It has been shown that UV radiation can induce expression of Ro/SSA antigens on the cell surface and subsequent binding of anti-Ro antibodies to the surface of keratinocytes. However, its role is still a controversial topic.⁷

Classification

Skin manifestations have a highly variable clinical expression, which hinders their classification, and erroneous clinical diagnosis occurs often. Since 1981 Gilliam and Sontheimer’s classification⁸ has been used, which uses histopathological changes to define two main groups: specific and non-specific cutaneous skin manifestations. The first includes all specific skin lesions of the disease that translate, from a histological point of view, to the presence of interface dermatitis (presence of necrotic keratinocytes, vacuolar degeneration of the basal layer, perivascular infiltration of lymphocytes, and pigment incontinence). Any of these lesions on their own can establish a diagnosis of cutaneous lupus erythematosus. Within this group, in turn, three major subgroups are distinguished: acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus erythematosus. These subgroups are defined by clinical features and some histological changes, and, in turn, different clinical variants are identified within each subgroup (Table I). On the other hand, non-specific cutaneous manifestations consist of a large number of polymorphic skin lesions that are not exclusive to lupus erythematosus, as they can be seen in the context of other autoimmune diseases and do not by themselves establish the diagnosis of lupus. Interface dermatitis is not observed in the histology of these lesions, as is typical of the specific skin lesions.⁹

Table I Gilliam and Sontheimer's classification: specific and nonspecific CLE manifestations.4

A) Histologically specific lesions of lupus erythematosus (LE):

Acute cutaneous LE (ACLE):

Localized

Generalized

Toxic epidermal necrolysis type

Subacute Cutaneous LE (SACLE)

Annular

Pappular-scaly

Mixed pattern

Chronic cutaneous LE (CCLE)

Classic discoid LE: a) localized, b) generalized

Hypertrophic LE (Verrucous)

Deep LE (Lupus Panniculitis)

LE with mucosal involvement

LE tumidus

LE chilblain

Overlaying LE- lichen planus

(B) Histologically nonspecific lesions, but associated with LE:

Vascular skin disease

Vasculitis

Vascular disease:

Degos disease

White atrophy

Periungual telangiectasias

Livedo reticularis

Thrombophlebitis

Raynaud's phenomenon

Erythromelalgia

(Non-scarring) alopecia

Lupus hair

Telogen effluvium

Alopecia areata

Sclerodactyly

Rheumatoid nodules

Calcinosis cutis

Nonspecific blistering lesions of LE

Pemphigoid LE, epidermolysis bullosa acquisita type

Pemphigoid LE, dermatitis herpetiformis urticaria type

Papulonodular mucinosis

Anetoderma/cutis laxa/elastolisis of the middle dermis

Acanthosis nigricans (type B insulin resistance)

Erythema multiforme (Rowell syndrome)

Finally, there is a third group of skin lesions that are difficult to classify, defined as those lesions for which there is, so far, no unanimous agreement as to which of the above groups should include them.¹⁰ In this review we focus on the description of specific cutaneous lesions of cutaneous lupus erythematosus.

Specific cutaneous manifestations

a) Chronic cutaneous lupus erythematosus

Within this subgroup, the most common variety is discoid lupus erythematosus (DLE). In turn, these patients are divided into those with lesions limited to the head and neck (localized DLE), and those who also develop lesions in other locations (generalized DLE). Discoid lupus erythematosus is characterized by well-demarcated papules or plaques, often rounded, erythematous, covered by a thick scale that is attached, of varying intensity. Sometimes with dermoscopy it is possible to observe the horn-like plugs formed by small clusters of keratin within the follicular ostium 11 (Figure 1). These lesions follow a torpid development, leaving areas of depigmentation, telangiectasia, and atrophy in their central areas. The clinical appearance can easily point to the diagnosis, but microscopic findings allow confirmation. The histological alterations include hydropic or vacuolar degeneration of the basal layer, a degree of atrophy of the epidermis, and an infiltrate composed of lymphocytes, positioned in patches around vessels and annexes. Sunlight can exacerbate lesions or even induce them in some patients.^11,12 The distinction between localized discoid lupus (lesions confined to the head) and generalized discoid lupus (widespread lesions that can affect any part under the neck) is of interest when they differ in their clinical behavior and prognosis. The generalized form is more common in males, up to 30% of cases may have antinuclear antibodies or any accompanying hematologic abnormality, and patients may develop lesions on the palms and soles, a location that generates significant functional disability.¹² In hypertrophic discoid lupus erythematosus, the thick and adhering scale is replaced by a massive hyperkeratosis giving the lesion a look similar to a wart or even squamous cell carcinoma, which is usually accompanied by other lesions typical of discoid lupus erythematosus, facilitating diagnosis.¹⁰ Deep lupus erythematosus or lupus panniculitis is a rare variant of chronic cutaneous lupus erythematosus, characterized by inflammation of the adipose tissue resulting, from the microscopic point of view, in lobular panniculitis. It most often affects women in middle age, and it classically begins or worsens after a trauma. Clinically, it presents as poorly-defined subcutaneous nodules, covered in erythematosus-like skin, sometimes painful, indistinguishable from any other panniculitis. The location tends towards the proximal region of the extremities, face, and, less frequently, trunk and scalp, leaving foveae once the active inflammatory process abates. This is why the lesions can leave disfiguring sequelae that are difficult to treat¹³ (Figure 2).

Figure 1 Localized discoid lupus

Figure 2 Deep lupus (lupus panniculitis)

b) Subacute cutaneous lupus erythematosus   

This term describes a group of specific skin lesions of lupus erythematosus characterized by the appearance of maculopapular and erythematous plaques with fine scales at the periphery that may coalesce to form polycyclic or circinate plaques. They usually affect the upper anterior chest, back, neck, forearms, and back of hands, respecting the knuckles (i.e. in sun-exposed areas). This event is characterized by recurrence, triggered by sun exposure, and heals without scarring (Figure 3).

In turn, clinical sub-varieties are described according to clinical presentation. The main ones include:

Figure 3 Annular subacute cutaneous lupus erythematosus

• Annular subacute cutaneous lupus erythematosus, which is usually manifested by circinate plaques, with scales in the periphery and central scarring, so it takes on a ring-like morphology (Figure 3).
• Psoriasiform cutaneous lupus erythematosus, which is characterized by thick, adherent, chalky scales, covering the entire surface of the plaque, giving the appearance of psoriasis vulgaris (Figure 4).

Figure 4 Psoriasiform subacute cutaneous lupus erythematosus

70% of patients with subacute cutaneous lupus erythematosus are carriers of anti-Ro/SSA and anti-La/SSB antibodies, compared to anti-double-stranded DNA, anti-Sm, anti-RNP antibodies, which are rare. There is a proportion of patients carrying HLA-A1-D8-DR3 who present a predominance of polymorphism in the TNF-alpha gene. All this has indicated that the term subacute cutaneous lupus erythematosus describes not only a certain type of skin lesions, but also describes a clinical subtype of lupus erythematosus with characteristic immunological behavior and homogenous evolutionary and genetic basis.¹⁴

c) Acute cutaneous lupus erythematosus  

This is the classic malar rash or erythema in the shape of butterfly wings, consisting of confluent erythematous macules and papules, sometimes accompanied by edema, distributed bilaterally and symmetrically on the cheeks and the back of the nose. Sometimes this rash may be more extensive, affecting other areas of the face such as the chin and forehead, or even the trunk and extremities. In any case, lesions have acute onset and photo-induced evolution, and are fleeting, as they usually resolve within weeks without scarring (Figure 5). Often they develop over the course of already-diagnosed systemic lupus erythematosus, but sometimes they may be the first manifestation of the disease, preceding the systemic symptoms by months.¹¹

Figure 5 Acute cutaneous lupus erythematous

d) Other

Finally, there are other manifestations included in the group of specific manifestations, although less frequent. These include the following:

• Lupus erythematosus tumidus: This term was coined in the literature for the first time in 1930 by Gougerot and Burnier, when they described five patients who developed infiltrated, smooth, erythematous lesions without scales or any other surface changes. However, it was the late '70s when Gilliam et al. proposed an innovative classification of skin lesions of lupus erythematosus that basically distinguished the three types of specific lesions described above. In this classification, lupus erythematous tumidus was not considered separately, but rather was included as a variant of the chronic lupus erythematosus subgroup. It is likely, because of this, that tumidus lupus has been underestimated, and patients with these lesions diagnosed only as part of chronic cutaneous lupus erythematosus.⁸ In 2004, this variety was reclassified within a subgroup called intermittent cutaneous lupus erythematosus (ICLE) with the characteristics mentioned above.¹¹ The lesions from this entity consist of plaques with erythematous, edematous aspect, that, unlike chronic cutaneous lupus erythematosus, have no scaling, follicular plugging, or atrophy, and heal without leaving a scar. They appear in outbreaks, mostly in relation to sun exposure in spring and summer, in areas of skin exposed to sunlight such as the neck, shoulders, face, or arms¹⁵ (Figure 6). As with discoid lupus, it is exceptional that patients with lupus tumidus meet criteria for systemic lupus erythematosus. One of the most controversial aspects of lupus tumidus is the definition of its microscopic characteristics. For example, some studies have proposed the idea that in lupus tumidus the epidermis is intact,^16,17 while other authors find epidermal changes in most patients (atrophy, vacuolar degeneration, hyperkeratosis, follicular plugging) to a mild or moderate degree.¹⁸ This is an important fact, as the complete absence of damage to the epidermis could be enough to question the true relationship between lupus tumidus and lupus erythematosus, according to some authors. As for the findings in the dermis, lupus tumidus presents perivascular and periadnexal lymphocytic infiltration, like other forms of cutaneous lupus erythematosus, and abundant mucin deposits.




Figure 6 Lupus tumidus



• Lupus pernio or chilblain may be a manifestation of systemic lupus erythematosus or cutaneous lupus, and it shares many clinical and histological similarities with idiopathic chilblains. It develops almost exclusively in women during the winter months; it is characterized by pain, erythema, or purple plaques on the fingers, heels, soles of the feet, nose, and ears¹⁹ (Figure 7). Histopathological examination reveals perivascular lymphocytic infiltration, abundant edema of the dermis, and extravasation of red blood cells. Some biopsies show true lymphocytic vasculitis. The inflammatory infiltration often extends into the deep dermis and subcutaneous fat.²⁰





Figura 7 Lupus pernio

Relationship with the systemic disease

Cutaneous lupus erythematosus may be the only clinical manifestation of the disease. However, one must always keep in mind that systemic disease symptoms may appear at any time. The risk of that happening is very variable and depends on the type of skin lesion that the patient develops. In chronic cutaneous lupus erythematosus, systemic complications are rare; only between 5 and 10% of patients may, at any time, meet the American College of Rheumatology criteria for the diagnosis of systemic lupus erythematosus, and in general these are patients who develop extensive lesions (generalized discoid lupus). Moreover, in subacute cutaneous lupus erythematosus, about 50% of the patients meet these criteria, indicating a greater chance of finding accompanying systemic conditions or immune disorders. However, this activity is often severe and generally takes the form of muscle or joint complications; severe neurological or renal complications are only expected in 10% of cases.^21,14 In acute cutaneous lupus erythematosus, cutaneous lesions are generally one more clinical manifestation, with little impact within the constellation of symptoms presented by patients with systemic involvement; most cases are patients with systemic lupus erythematosus with activity.

Evaluation of activity and damage in cutaneous lupus erythematosus

Given the need for a validated instrument to facilitate future clinical trials, by converting subjective observations of cutaneous lupus erythematosus into objective and measurable data, the Cutaneous Lupus Disease Activity and Severity Index (CLASI) was developed.²² This instrument consists of two results: the first regarding disease activity, and the second describing the damage or consequences of it. This index is designed as a table, in which the horizontal rows indicate the anatomical areas, while the columns are scores of the major clinical symptoms. Activity is scored on the basis of the presence of erythema, scales, hypertrophy, mucosal involvement, and recent hair loss (last 30 days). Moreover, the damage is assessed based on parameters such as the presence of scars and scarring alopecia, pigmentation changes, and whether this is permanent.²³ It is noteworthy that the Cutaneous Lupus Disease Activity and Severity Index has been validated to be used by both dermatologists and rheumatologists and has a correlation coefficient higher than 0.85.²⁴ It has also proven to be sensitive to changes in disease activity and modification of sequelae with the intervention of drug therapy (Table II).

Quality of life

Cutaneous manifestations due to lupus have a big impact on the quality of life by interfering with personal appearance, and therefore with psychosocial development. Previous studies have described poorer quality of life as assessed by the DLQI questionnaire (Dermatology Quality of Life Index) or other questionnaires such as Skindex-29,²⁵ in the variety of chronic cutaneous lupus erythematosus and, of this, predominantly the discoid subtype. A lower "skin" quality of life has also been associated with facial lesions in women, a greater extent of the lesion, and cases of secondary alopecia. However, no association has been found with the time development of the disease or the subtype of skin lesion.²⁶ It is reported that some symptoms associated with CLE such as pain and itching also diminish the quality of life.²⁷

Treatment

The purpose of treatment of cutaneous lupus is primarily to improve the patient's appearance and prevent the development of scars, atrophy, or pigmentation disorders. General recommendations are, first, to rule out the possibility that the case of lupus is induced or aggravated by drugs. Secondly, it is important to recommend that smokers quit this habit, as smoking could aggravate skin lesions or interfere with the mechanism of action of drugs such as antimalarials.

The three pillars of treatment for cutaneous lupus erythematosus are photo-protection, topical corticosteroids, and antimalarials.^28,29 Photosensitivity is a frequent phenomenon in patients with cutaneous lupus, and photo-provocation studies have shown that the spectrum of ultraviolet radiation able to trigger lesions includes UVA, UVB, and sometimes visible light. Therefore, the use of photo-protection is essential in the treatment of these patients; so the ideal sunscreen should be broad-spectrum and waterproof. It is also important to recommend other measures such as avoiding sun exposure between 10 in the morning and three in the afternoon, and wearing clothing that is not too low-cut.

Topical application of corticosteroids is useful when lesions are sparse and limited to a small area of ​​skin, as often occurs in chronic cutaneous lupus and lupus tumidus. When lesions do not respond to topical treatment or, by extension, this is insufficient, the first-line systemic treatment is antimalarial. Three antimalarials can be used: hydroxychloroquine sulfate, chloroquine phosphate, and mepacrine (or quinacrine in the United States). Because hydroxychloroquine sulfate seems to have less risk of ocular toxicity compared to chloroquine phosphate, it is usually indicated as the first choice. If no favorable response is obtained within a period of 2-3 months, it may be replaced by chloroquine phosphate, quinacrine, or mepacrine. As for the dosage, in order to minimize the risk of retinopathy, it is recommended not to exceed the maintenance dose of 4 mg/kg/day of chloroquine and 6.5 mg/kg/day of hydroxychloroquine, calculating the dose relative to ideal weight, and provided that the renal and hepatic function of the patient are normal.³⁰

Oral glucocorticoids are ineffective in the treatment of chronic cutaneous lupus, and they have only certain utility in the treatment of acute and intense forms of subacute cutaneous lupus, acute cutaneous lupus, and vasculitis lesions. If prescribed, it should be done together with antimalarials, and at low and medium doses. In general, the chronic oral or intramuscular use of corticosteroids should be avoided unless it is necessary because of systemic disease.²⁹

The other drugs proposed for the treatment of cutaneous lupus have limited utility.31 Acitretin, an oral retinoid, may be effective in patients who develop the chronic hypertrophic variety, or when the lesions are on the palms and soles.³¹ Thalidomide, in several open studies, has been shown to be highly effective in treating cutaneous lupus, but it is a teratogenic drug, side effects are frequent, and relapse after stopping the drug is the norm. Lenalidomide, a derivative of thalidomide with fewer side effects, especially neurological, could be an alternative. Immunosuppressive agents have been described in the treatment of recalcitrant cutaneous lupus. Azathioprine is one of the most used, followed by methotrexate and mycophenolate mofetil.30 Regarding biological drugs, there is little experience in the treatment of cutaneous lupus, however, the use of belimumab has been suggested in cases of refractory cutaneous lupus.³²

Conclusions

Cutaneous lupus is a clinically heterogeneous entity, traditionally categorized into specific and nonspecific manifestations. Recently, the new classification criteria for generalized lupus erythematous include as specific manifestations: acute, subacute, chronic (discoid, hypertrophic, panniculitis, and LE pernio) and intermittent (tumidus) lupus.^11,33 In general, skin manifestations occur in up to 85% of patients with SLE, and their presence can affect the quality of life, so the establishment of proper and timely treatment should be a priority for the treating physician.

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