Lupus Erythematosus

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Lupus ErythematosusLUPUS AT A GLANCE

A group of heterogeneous illnesses that have

in common the development of immunity

to self-nucleic acids and their associated

proteins, with skin-only disease at one

end of the spectrum and severe visceral

involvement at the other.

Skin lesions may be specific to lupus or

nonspecific and are seen in other conditions

as well.

Acute cutaneous lupus erythematosus

(malar rash) is almost always associated

with underlying visceral involvement,

subacute cutaneous lupus patients meet

systemic lupus erythematosus criteria about

50% of the time (but typically express only

mild systemic clinical manifestations), and

chronic cutaneous lupus (discoid lupus

erythematosus, lupus panniculitis, chilblain

lupus, and tumid lupus erythematosus)

patients most often have skin-only or skinpredominant

disease.

Discoid lupus erythematosus causes scarring

and can be permanently disfiguring.

Subacute cutaneous lupus and acute

cutaneous lupus erythematosus are highly

photosensitive and are characteristically

nonscarring.

Lupus erythematosus-nonspecific skin

lesions include nonscarring alopecia,

mouth ulcers, photosensitivity, Raynauds

phenomenon, and vasculitis/vasculopathy,

among others. They often herald a systemic

lupus erythematosus flare.

Treatment consists of sunscreens,

local and systemic (short-term)

glucocorticoids, antimalarials, retinoids,

immunosuppressives, thalidomide, and

biologic therapies.

Lupus erythematosus occurs much more

commonly in women (9:1 female-male ratio).

Both systemic lupus erythematosus

and cutaneous lupus erythematosus are

associated with upregulation of class I

interferon signaling.LUPUS ERYTHEMATOSUS: A

CHALLENGE TO DEFINE, CLASSIFY,

AND TREAT

Lupus erythematosus (LE) is the root designation for

a diverse array of illnesses that are linked together by

the development of autoimmunity directed predominantly

at the molecular constituents of nucleosomes

and ribonucleoproteins. Some patients present with

life-threatening manifestations of systemic LE (SLE);

whereas others, who are affected with what likely

represents the same basic underlying disease process,

express little more than discoid LE (DLE) skin lesions

throughout their illness. It is convenient to conceptualize

LE as a clinical spectrum ranging from mildly

affected patients with only localized DLE skin lesions

to those at risk of dying from the systemic manifestations

of LE such as nephritis, central nervous system

disease, or vasculitis. The pattern of skin involvement

expressed by an individual patient with LE can provide

insight about the position on the spectrum where

the patients illness might best be placed.

The nomenclature and classification system originally

devised by James N. Gilliam divides the cutaneous

manifestations of LE into those lesions that show

characteristic histologic changes of LE (LE-specific

skin disease) and those that are not histopathologically

distinct for LE and/or may be seen as a feature of

another disease process (LE-nonspecific skin disease).

Within this context, the term LE-specific relates to

those lesions displaying an interface dermatitis. The

term cutaneous LE (CLE) is often used synonymously

with LE-specific skin disease as an umbrella designation

for the three major categories of LE-specific skin

disease: acute cutaneous LE (ACLE), subacute cutaneous

LE (SCLE), and chronic cutaneous LE (CCLE). This

will be the framework used in our discussion of the

extraordinarily diverse set of cutaneous lesions that

occur in patients with LE (Table 155-1).

The essence of LE is in its heterogeneity, and the

challenge for those who treat it is to recognize clinically

useful patterns within the mosaic of features that

constitute this protean illness. An overview of the systemic

manifestations of LE can be seen in the American

College of Rheumatologys (ACR) classification criteria

for SLE,1 which are presented in Table 155-2, and

from the outline of the systemic manifestations of SLE

presented in Table 155-3.

EPIDEMIOLOGY

The epidemiology and socioeconomic impact of LE in

general,2 and CLE specifically,3 have been reviewed. Skin disease is the second most frequent clinical manifestation

of LE after joint inflammation. As many as

45% of patients with CLE experience some degree

of vocational handicap. A recent quality of life study

suggested that the impact of skin manifestations in

patients with SLE was preceded only by pain and

fatigue related to their disease.4 The Dermatology Life

Quality Index and SF-36 have been used to measure

quality of life in patients with CLE. Both questionnaires

showed that patients with active skin lesions

had lower quality of life and that patients with associated

alopecia were particularly impacted.5

Malar, or butterfly rash (localized ACLE), has been

reported in 20%60% of large cohorts of patients with

LE. Limited data suggest that the maculopapular

or SLE rash of generalized ACLE is present in about

35%60% of patients with SLE. ACLE, like SLE in

general, is much more common in women than men

(8:1). All races are affected; however, the early clinical

manifestations of ACLE can be overlooked in a darkskinned

individual.

Patients presenting with SCLE lesions constitute

7%27% of LE patient populations. SCLE is primarily

a disease of white females, with the mean age of

onset in the fifth decade. Drug-induced SCLE patients

are somewhat older at disease onset, perhaps reflecting

greater exposure to drugs for age-related medical

problems (hypertension, cardiovascular disease).

The most common form of CCLE, a classic DLE

skin lesion, is present in 15%30% of SLE populations

selected in various ways. Approximately 5% of

patients presenting with isolated localized DLE subsequently

develop SLE. Rheumatologists have estimated

that SLE patients are sevenfold more common than isolated

cutaneous LE patients. However, dermatologists

have estimated that isolated cutaneous LE patients

may be 2-3 times more common that SLE patients.

Recently published population-based data have

argued strongly that the incidence and prevalence of

isolated forms of cutaneous LE are equivalent to those

of SLE.6 Although DLE can occur in infants and the

elderly, it is most common in individuals between 20

and 40 years of age. DLE has a female-male ratio of 3:2

to 3:1, which is much lower than that of SLE. All races

are affected, but investigations suggest that DLE might

be more prevalent in blacks.

ETIOLOGY AND PATHOGENESIS

The cause(s) of and pathogenetic mechanisms responsible

for LE-specific skin disease are not fully understood,

although recent work has provided many new

insights. The pathogenesis of LE-specific skin disease

is inextricably intertwined with SLE pathogenesis.

Simply put, SLE is a disorder in which the interplay

between host factors (susceptibility genes, hormonal

milieu, etc.) and environmental factors [ultraviolet

(UV) radiation, viruses, and drugs] leads to loss of

self-tolerance, and induction of autoimmunity. This is

followed by activation and expansion of the immune system,

and eventuates in immunologic injury to end organs

and clinical expression of disease7 (eFig. 155-0.1 in online

edition). Recent work has highlighted the important role

of interferon-signaling in the pathogenesis of both

SLE and LE-specific skin disease.

ENVIRONMENTAL FACTORS

Genetic predisposition for a lupus diathesis does not,

in itself, produce disease. Rather, it appears that induction

of autoimmunity in such patients is triggered by

some inciting event, likely an environmental exposure.

Drugs, viruses, UV light, and, possibly, tobacco, have

been shown to induce development of SLE.

Ultraviolet radiation (UVR) is probably the most

important environmental factor in the induction phase

of SLE and especially of LE-specific skin disease. UV

light likely leads to self-immunity and loss of tolerance

because it causes apoptosis of keratinocytes, which in

turn, makes previously cryptic peptides available for

immunosurveillance. UVB radiation has been shown

to displace autoantigens such as Ro/SS-A and related

autoantigens, La/SS-B, and calreticulin, from their

normal locations inside epidermal keratinocytes to the

cell surface.13 UVB irradiation induces the release of

CCL27 (cutaneous T cell-attracting chemokine), which

upregulates the expression of chemokines that activate

autoreactive T cells and interferon-(IFN-), producing

dendritic cells (DCs), which likely play a central

role in lupus pathogenesis.14,15

A recent, large, case-control study reported that

smokers are at a greater risk of