Lupus erythematosus: systemic and cutaneous manifestations

Lupus erythematosus: systemic andcutaneous manifestations

Naomi Rothfield, MDa,*, Richard D. Sontheimer, MDb,d, Megan Bernstein, MDc

aDivision of Rheumatology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USAbDepartment of Dermatology and Residency Training Program, University of Oklahoma Health Sciences Center,

Oklahoma City, OK 73104, USAcUniversity of Connecticut Health Center, Farmington, CT 06030, USA

Abstract Skin and joint involvements are the most commonly occurring manifestations of systemic

lupus erythematosus. There are 3 forms of cutaneous lupus: chronic cutaneous (discoid) lupus, subacute

cutaneous lupus, and acute cutaneous lupus. Joint manifestations are usually not associated with warmth

of the joints and may be only associated with pain and swelling. Painful or swollen joints respond

rapidly to small or moderate doses of corticosteroids, whereas cutaneous manifestations usually respond

to antimalarial drugs. Anti-Ro is associated closely with a photosensitive rash and with subacute lupus.

D 2006 Elsevier Inc. All rights reserved.

Introduction

Systemic lupus erythematosus (SLE) is a multisystem

disease of unknown cause that is characterized by the

presence of multiple autoantibodies. Typically, it affects

the skin, joints, kidneys, lungs, nervous system, serous

membranes, and other systems. The autoantibodies are

typically antinuclear antibodies. The clinical course is

extremely variable and ranges from life-threatening to mild

diseases that never require hospitalization. The disease is

predominantly present in women, especially those who are

in their 20s and 30s, but it may occur in children and in

elderly individuals.

0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.clindermatol.2006.07.014

* Corresponding author. Tel.: +1 860 679 3604, +1 860 679 2160;

fax: +1 860 679 1287.

E-mail addresses: [email protected] (N. Rothfield)8

[email protected] (R.D. Sontheimer)8 [email protected]

(M. Bernstein).d Tel.: + 1 405 271 4662; fax: +1 405 271 7216.

Cutaneous manifestations of SLE are present in 85% of

patients during the course of the disease, and musculoskel-

etal abnormalities are present in approximately 95%.1 Joint

and skin manifestations thus occur in nearly all patients with

SLE. The disease tends to mimic the manifestations present

at onset during subsequent exacerbations.

Musculoskeletal manifestations

Musculoskeletal manifestations are the most common

feature of SLE.1 Arthritis with objective evidence of pain on

motion, tenderness, effusion, or periarticular soft-tissue

swelling is present at the time of diagnosis in 88% of

patients. Some patients develop arthritis after the diagnosis

had been made, such that 89% of patients have arthritis

during the disease. Other patients have arthralgia without

objective evidence of arthritis, such that 95% of patients

have either arthritis or arthralgia.

In some patients, arthralgia or arthritis may precede the

onset of multisystem disease by many years. The most

common joints involved are the proximal interphalangeal

Clinics in Dermatology (2006) 24, 348–362

Manifestations of lupus erythematosus 349

joints (present in 82% of patients). The distribution is nearly

always symmetrical. The knees are involved in 76% of

patients, followed by the wrists and metacarpophalangeal

joints. The ankles, elbows, and shoulders are involved less

frequently. Knee effusions can be moderately severe.

Aspiration reveals a clear fluid with less than 3000 white

blood cells per microliter. Most cells are small lymphocytes,

and there is a low protein level. Antinuclear antibodies and

lupus erythematosus (LE) cells may be found in the fluid.

Serum complement proteins are usually low, reflecting

similarly low levels in the serum. Synovial histopathology is

nonspecific with diffuse proliferation of lining cells and

some perivascular mononuclear cells, enlarged endothelial

cells, and thrombi. The arthritis disappears completely

within a few days after treatment with corticosteroids for

systemic diseases.

If a patient presents with a single swollen or painful

joint, one should suspect an alternate diagnosis, such as

infectious or crystalline arthritis, for which appropriate

diagnostic (eg, joint aspiration) and therapeutic measures

should be instituted.

During the course of the disease, patients may develop

deformities, but these are not related to joint destruction.

Typical swan-neck deformities with ulnar deviation of the

fingers develop after 3 to 4 years of disease in approxi-

mately 10% of patients who continue to have mild inter-

mittent joint pains. Radiographs of the hands reveal no bony

erosion or loss of joint space. Joint subluxation is a result of

involvement of the tendons and spasm of the small muscles

of the fingers.

Morning stiffness is present in 50% of patients, and

typical subcutaneous nodules occur in 10%. Tenosynovitis

occurs in approximately 10% of patients, with some

patients experiencing rupture of the infrapatellar, deltoid,

or Achilles tendons.

Avascular necrosis occurs in approximately 15% of

patients after prolonged treatment with high doses of

corticosteroids. Avascular necrosis is most common in the

femoral heads and presents as anterior groin pain, trochan-

teric bursal pain, or anterior thigh pain. Radiographs may be

negative early after the onset of pain, but magnetic

resonance imaging may allow early diagnosis.

Muscle pain is present in approximately 30% of patients,

with enzyme abnormalities occurring in approximately 20%

of patients before treatment.

Fibromyalgia is common in patients with SLE and must

be distinguished from the joint and muscle pain associated

with the disease.

Cutaneous manifestations

Pathophysiology

The pathophysiologic mechanisms of LE-specific skin

disease continue to be elucidated.2 It is thought that

development of skin disease is related to the same

autoimmune abnormalities responsible for the systemic

components of LE. Current theories discuss the relationship

between genetic susceptibility, autoimmune induction and

subsequent expansion, and injury to the immune system.3

Genetic susceptibility is probably related to genes that

decrease the threshold for self-reactivity and allow a

sustained immune response after the first response or to

the type and extent of end-organ damage.4 Case-control

studies have demonstrated that the major histocompatibility

complex class II alleles DRB and DQA are associated with

SLE in human beings.5 The autoimmune induction phase

refers to the development of self-reactive T cells that

demonstrate loss of self-tolerance.2 Mechanisms of induc-

tion may include molecular mimicry induced by infectious

antigens, abnormal expression of human leukocyte antigen

DR, malfunction of thymic or peripheral tolerance, and

presentation of cryptic peptides during apoptosis. The

expansion phase involves the progressive development of

abnormal autoimmune clonal expansions of B and T cells

that have self-recognition capabilities. The final injury phase

results in clinical disease and is likely related to autoanti-

bodies and immune complexes causing tissue damage.

Mechanisms likely include direct cell death, activation of

the complement system, opsonization, and the inhibiting

function of target molecules.2

Clinical characteristics

The cutaneous manifestations of lupus are categorized

according to the Gilliam classification of LE skin disease.6

This system divides lupus skin diseases into LE-specific

skin diseases, which show distinctive histologic changes of

LE, and LE-nonspecific skin diseases, which include man-

ifestations that can be seen in lupus and in other diseases.

Characteristic histopathologic skin changes of LE-specific

skin disease include hyperkeratosis; atrophy of the epider-

mis; liquefactive degeneration of the basal epidermis; and an

infiltrate of mononuclear cells in the perivascular, perifol-

licular, and dermal-epidermal junction, perivascular areas,

and perifollicular areas.7 Other characteristic changes

include epidermal basement membrane thickening and

melanin pigment incontinence.2 Varying mosaics of these

features are seen in the 3 major categories of LE-specific

disease: acute cutaneous LE (ACLE), subacute cutaneous

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

Acute cutaneous LE

Acute cutaneous LE is categorized as localized ACLE or

generalized ACLE. Localized ACLE is characterized by

erythema over the malar eminences of the face and bridge

of the nose (butterfly blush). The nasolabial folds are

typically spared. This distribution resembles the shape of a

butterfly. Acute cutaneous LE is often associated with

active SLE (Fig. 1). The rash may have a fine surface scale

and be associated with edema. When especially severe,

Fig. 1 Acute cutaneous LE. In addition to the butterfly areas

(malar eminences and nose bridge), the forehand and chin areas

can also be affected in severe cases such as this. Note sparing of the

nasolabial folds and areas of sun-protected skin (eg, upper eyelids).

N. Rothfield et al.350

ACLE produces vesiculobullous skin changes. The butter-

fly rash has been noted in 52% of patients with SLE at the

time of diagnosis.1 The clinical activity of ACLE typically

cycles in parallel with the activity of the underlying SLE.

Acute cutaneous LE is frequently associated with exposure

to sunlight or artificial sources of UV light. The lesions

typically heal well without scarring. In darkly pigmented

individuals, however, postinflammatory hyperpigmentation

and/or hypopigmentation can remain long after the red-

dened inflammatory component of ACLE had resolved.

Acute cutaneous LE may be confused with seborrheic

Fig. 2 Subacute cutaneous LE. Left panel, Annular morphological s

panel, Papulosquamous/psoriasiform subtype. Note the retiform array pr

with either subtype.

dermatitis or acne rosacea; the former condition involves

the nasolabial folds, whereas the latter condition is

characterized by the presence of papules and pustules that

are not found in the facial rash of SLE unless secondary

infection is present.

Generalized ACLE is described as a diffuse or papular

erythema of the face, upper trunk, or extremities that

resembles a viral exanthem or drug eruption. One study

reported generalized ACLE in 35% of patients with SLE.8

Lesions develop quickly and last for hours to days. The

development of this rash is most often associated with

systemic disease activity and is usually related to sun

exposure. Facial involvement can be extensive. The rash

spares the distal interphalangeal, proximal interphalangeal,

and metacarpophalangeal joints, an important differentiating

feature from dermatomyositis, which can otherwise resemble

ACLE. Complications of ACLE include postinflammatory

hyperpigmentation, especially in darker-skinned individuals.

HistopathologyThe histopathology of ACLE is less striking than that of

SCLE and of discoid LE (DLE). Acute cutaneous LE demons-

trates a sparse dermal cellular infiltrate, focal liquefactive

degeneration of the basal epidermis, and upper dermal edema.

Epidermal necrosis can be noted in the most severe forms of

ACLE and may resemble toxic epidermal necrolysis.2

Subacute cutaneous LE

Subacute cutaneous LE is subdivided into 2 morpholog-

ical variants—annular SCLE and papulosquamous SCLE.

Annular SCLE has also been referred to as lupus margin-

ubtype. Note the polycyclic array formed as lesions merge. Right

oduced as lesions merge. There was no dermal scarring associated

Table 1 Drugs implicated in triggering the clinical expression

of SCLE (listed alphabetically within groups)

Diuretics

Hydrochlorothiazidea

Spironolactonea

Calcium-channel blockers

Diltiazema

Nifedipinea

Nitrendipine

Angiotensin-converting enzyme inhibitors

Captoprila

Cilazapril

Acid blockers

Lansoprazole

Omeprazoleb

Ranitidinea,b

Nonsteroidal antiinflammatory agents

Naproxena

Piroxicama

b-blockersAcebutolol

Oxprenolol

Lipid-lowering agents

Pravastatina

Simvastatina

Antimicrobials

Griseofulvina

Terbinafinea

Antihistamines

Cinnarizine/triethylperazine

Anticonvulsants

Phenytoina

Antimalarials

Hydroxychloroquinea

Sulfonylureas

Glyburidea

Chemotherapy

Taxotere (docetaxel)a

Tamoxifen

Others

Bupropiona

Etanercept/infliximaba

Interferon alfaa

Insecticides

d-Penicillamineb

Procainamide

Leflunomidea

Tetracycline derivatives (COL-3)a

Tiotropium (inhaled)

Reproduced with publisher’s permission from Reference 67.a Reported to be capable of producing photosensitive skin reactions

in individuals without SCLE.b Unpublished personal observation by the authors of SCLE

induction with drug in question.


atus, symmetrical erythema centrifugum, autoimmune an-

nular erythema, and LE gyratum repens.

Subacute cutaneous LE presents with erythematous mac-

ules and papules that subsequently develop into papulosqu-

amous or annular plaques. Most patients tend to develop

predominantly one type of lesion, although some will display

the elements of both simultaneously. Subacute cutaneous LE

is highly photosensitive, with lesions being seen most

commonly on the V area of the neck and upper chest, upper

back, shoulders, extensor surfaces of the arms and forearms,

and dorsum of the hands (the knuckles are typically spared)

(Fig. 2). Interestingly, the face and scalp are much less

commonly involved. Subacute cutaneous LE occurs infre-

quently below the waist. Less-common presentations of SCLE

include appearance simulating erythema annulare centrifu-

gum,2 erythema multiforme,9 and Rowell’s syndrome (lesions

resembling erythema multiforme with La/SS-B antibodies).2

Progression of annular SCLE lesions may include develop-

ment of vesicles and crusting.2,9-11 Subacute cutaneous LE has

been reported to occasionally produce a clinical picture

resembling toxic epidermal necrolysis.12 Other rare variants

of SCLE include exanthematous,9 pityriasiform,9,13 follicular

erythematous,2 acral annular presentation,14 and exfoliative

erythroderma.15 Lesions resolve without scarring; however,

there can be vitiligolike leukoderma that may last for a

significant amount of time and can be permanent.2

A growing number of drugs have been noted to induce

SCLE (Table 1). These medications include phenytoin,

diltiazem, thiazides, tumor necrosis factor inhibitors,

terbinafine, and antihistamines, among others. Interestingly,

systemic medications used to treat SLE, including hydrox-

ychloroquine and quinacrine, have also been implicated in

the development or worsening of cutaneous LE lesions.16

Drug-induced LE classically cannot be differentiated from

idiopathic cutaneous LE lesions based on histopathology

alone. Possible clues to drug-induced lupus include blood

or tissue eosinophilia and histologic findings of lymphocyte

migration into the acrosyringium as well as palisading

granulomatous inflammation in the interstitium.16,17 Dis-

continuation of the causative drug can but does not always

result in resolution of lesions.18

Patients with SCLE often have mild systemic disease

activity associated with the cutaneous outbreak. This

systemic activity is most commonly musculoskeletal with

associated serologic evidence of disease activity, most

commonly including 70% that are anti-Ro (SS-A).19 Anti-

Ro/SS-A has been associated with photosensitivity in 90%

of patients with SCLE.20 Severe central nervous system,

progressive renal, and severe systemic vasculitis are

uncommon in association with SCLE, occurring in no more

than 10% of SCLE cases.

HistopathologyThe histopathology of SCLE is of LE-specific skin disease

but cannot always be differentiated from the lupus-specific

skin diseases ACLE and DLE. The classic findings of

LE-specific skin disease, such as hyperkeratosis, degenera-

tion of the basal cell layer, and a mononuclear cell infiltrate in

the dermal-epidermal junction and dermis, are seen in

varying degrees in SCLE, ACLE, and DLE.


Focal liquefactive degeneration, sparse mononuclear

infiltrates in the upper one third of the dermis (usually in

the perivascular and adnexal areas), dermal edema, and

infrequent necrosis of the epidermis are seen in SCLE.21

The epidermis may be mildly atrophic, and there may be

vesicular changes at the active border.10,11,22 Typically,

SCLE lesions have less follicular plugging, hyperkeratosis,

adnexal mononuclear cell infiltrates, and dermal melanoph-

ages as compared with DLE lesions.2

Chronic cutaneous LE

Chronic cutaneous LE is subdivided into classic DLE,

hypertrophic/verrucous DLE, LE profundus/LE pannicu-

litis, mucosal DLE, lupus tumidus, chilblains lupus, lichen

DLE, and other rare variants.

Classic DLE is the most common form of CCLE and

occurs in 20% of patients with SLE.1 Most patients

having classic DLE lesions never develop features of

SLE, however. The disease presents as a well-demarcated

red-purple macule or a papule with a superficial scale.

This lesion increases in size into a coin-shaped, or

discoid, plaque with peripheral hyperpigmentation sec-

ondary to inflammation. There are increased adherent

scales with extension into dilated hair follicles. The center

of the lesion becomes depressed with scarring, depigmen-

tation, and telangiectasia. In some cases, the plaques

extend into adjacent plaques, forming large disfiguring

lesions (Fig. 3).

Fig. 3 Chronic cutaneous LE. Left panel, An early lesion showing ker

standing lesion showing dermal scarring and disfiguring pigmentary cha

The hair follicle becomes plugged by thick scales.

Peeling the back of the scale of a DLE lesion can reveal

keratotic spikes protruding from the undersurface. These are

referred to as a carpet tack sign. Progression of follicular

involvement can result in scarring alopecia.

These DLE lesions are most commonly on the scalp,

face, ears, V region of the neck, and extensor surfaces of the

arms. As does ACLE, DLE spares the nasolabial folds.

Discoid LE lesions can occasionally occur anywhere on the

body, including areas that are not exposed to the sun.2 The

scalp as well as the external canal and conchal bowl of

the ears are common locations of DLE lesions that are not

related to sunlight exposure.

Scalp involvement occurs in approximately 60% of

patients with DLE, and the scalp can be the only involved

region in approximately 10%.23 Permanent scarring alopecia

occurs secondary to follicular destruction and has been

noted in 34% of patients in one study.24 In contrast, DLE

lesions occurring solely below the neck are much less

common; they are typically seen on the extensor surfaces of

the hands, forearms, and arms.2 Patients exhibiting classic

DLE lesions above and below the neck (generalized DLE)

have a somewhat higher risk of developing clinically

significant SLE as compared with those having lesions only

above the neck (localized DLE).

Nail involvement in DLE is also common.25,26 Nail plate

dystrophy is a manifestation of the DLE lesion in the nail

plate itself. Other nail involvements secondary to other

types of cutaneous lupus can also occur and may include

atotic follicular plugging and dermal atrophy. Right panel, A long-

nges.


pitting, leukonychia striata, onycholysis, clubbing, nail bed

erythema, and telangiectasia.2,25

Variants of DLE include palmoplantar and follicular

DLE. Painful palmoplantar DLE is an erosive variant

that can be difficult to manage.2,27,28 Follicular DLE is

characterized by approximately 1-cm follicular papules that

are most commonly located in the elbow region.

The Koebner phenomenon (isomorphic response) is

defined as the tendency for skin lesions of a disease to

develop in areas of nonlesional skin that have undergone

trauma. It is seen in patients with cutaneous LE.2,29 Trauma;

exposure to UV, cold, and X ray; infection; diathermy;

chemical burns; various types of dermatitis; and scars have

been noted as triggers to outbreak of DLE lesions.2,29,30

Ueki29 noted a latent period of 4 weeks after the trauma

toward development of cutaneous LE lesions. Sunlight

exposure is a trigger for DLE lesions, although not as

significantly as for ACLE and SCLE lesions. It has been

noted that UV-B is a trigger for DLE lesion outbreak,

although there are evidence that long-wave UV-A is a

trigger as well.2,31-34 Recent evidence postulate that there is

a UV-induced cycle that leads to an amplified production of

chemokines, apoptosis, and necrosis, subsequently causing

autoimmune T-cell activation, as well as plasmacytoid

dendritic cells, which produce interferon alfa. It is thought

that this increases subsequent chemokine production

and invasion of leukocytes, which may lead to cutaneous

LE manifestations.35

Hypertrophic, or verrucous, DLE is a variant in which

the hyperkeratotic element of DLE is the predominant

feature. The lesions are most commonly noted on the

face, upper back, extensor surfaces of the arms,3 as well

as the palms and soles. Lupus planus has been the term

used to describe the lesion with overlapping features of

hypertrophic LE and lichen planus. In addition, a rare

variant of hypertrophic DLE, referred to as LE hyper-

trophicus et profundus, produces a facial lesion with

violet-red, thick, and rolled edges as well as significant

central atrophy.3

Lupus erythematosus profundus, also referred to as LE

panniculitis when there is solely subcutaneous involve-

ment,3 is a rare form of CCLE that has been reported in

1% to 3% of patients with cutaneous LE.36-38 There is

involvement of the deep dermis and subcutaneous fat.

Lesions are firm mobile 1 to 3-cm nodules with adherent

overlying skin creating superficial depression in the skin.3,39

The most common locations include the head, trunk,

breasts, proximal extremities, and buttocks.3 Approximately

50% of patients with lupus panniculitis will also have

overlying skin changes of classic DLE or classic DLE

lesions elsewhere on their bodies.

Diagnosis of LE profundus can be challenging because it

can often mimic other lesions. A recent study by Massone

et al36 demonstrated that histopathologic differentiation can

be used to distinguish it from subcutaneous panniculitis–like

T-cell lymphoma. The histopathologic criteria of LE

profundus recommended for use in differentiation include

presence of epidermal involvement, lymphoid follicles with

reactive germinal centers, mixed cell infiltrates with

significant plasma cells, and groupings of B lymphocytes.

In addition, polyclonal T-cell receptor–c gene rearrange-

ment is another feature of LE profundus that could

distinguish it from malignant lesions.36 Significant facial

involvement can mimic lipatrophy.3 Lupus erythematosus

panniculitis lesions within breast tissue can resemble breast

carcinoma clinically and radiographically. This has been

referred to as lupus mastitis.3,39

Mucosal DLE presents as an erythematous papule in the

oral, nasal, conjunctival, or genital mucosa that progresses

into a chronic plaque. The oral mucosa is the most common

site, with the buccal mucosa being the most frequent oral

site. Chronic plaques are sharply demarcated with irregular

white borders with peripheral telangiectasia and radiating

white striae. Lesions can mimic lichen planus.3 Superficial

palatal lesions can have a honeycomb appearance. Compli-

cations include painful ulceration and malignant transfor-

mation to squamous cell carcinoma.3

Lupus tumidus (urticarial plaque cutaneous LE variant)

demonstrates erythematous beefy and indurated plaques

with minimal superficial change. Histopathologically, there

are increased deposition of mucin and inflammation of the

superficial periadnexal and perivascular areas.3 Evidence

supporting lupus tumidus as a subset of CCLE have been

noted in case and cohort studies.3,40,41

Chilblains lupus (periodic LE) is a variant of CCLE in

which red-purple papules and plaques develop in response to

cold temperatures and humidity. The lesions can evolve

over time into atrophic plaques with scarring and telangiec-

tasia that are indistinguishable from chronic DLE lesions.

Lesions typically occur on the fingers, toes, and face.

These lesions are similar clinically and histologically to

idiopathic chilblains.

HistopathologyClassic DLE demonstrates hyperkeratosis and follicular

plugging. There is characteristic loss of organized basal

epidermis, whereas the spinous layer of the epidermis may

be atrophic. Other changes in the basal layer of the epidermis

include edema, liquefactive degeneration, epidermal base-

ment membrane thickening, increased formation of melanin

pigment, and pigment incontinence. There is a mononuclear

cell infiltrate of macrophage and T lymphocytes in the

dermis, with plasma cells in chronic lesions at times leading

to significant mucin deposition. The inflammatory infiltrate

can extend deeper as compared with ACLE and SCLE

lesions, with invasion into the reticular dermis.2

Lupus erythematosus–nonspecific skin disease

Lupus erythematosus–nonspecific skin disease includes

many skin changes that are frequently associated with LE

but are not specific to the disease itself. The lesions most

commonly occur in association with SLE.


Nonscarring alopecia occurs in various forms in associ-

ation with LE. Lupus hair is the term for thin hair and

nonscarring alopecia that is typically in the peripheral scalp

during disease flares.2,3 Telogen effluvium can occur in the

context of SLE as a transient phenomenon, also occurring

during increased LE activity.2 Alopecia areata occurs more

rarely in association with LE. Nonscarring alopecia can also

result from drugs that are used to treat systemic LE activity

(eg, methotrexate, cyclophosphamide).

Vasculitis lesions typically present in the skin of patients

with LE as small-vessel leukocytoclastic vasculitis. Clini-

cally, dependent palpable purpura or urticarial vasculitis

lesions result. Less commonly, larger vessels in the deep

dermis and subcutaneous tissue are affected, producing

periarteritis nodosa–like lesions resulting in nodules and/or

ulceration. Cutaneous vasculitis has been reported in 20%

to 70% of patients with SLE.3 Other vascular lesions such

as Degos’ disease–like lesions, livedo reticularis, and

secondary atrophie blanche may occur in association with

the antiphospholipid antibody syndrome.42 Periungual

telangiectasia occurs in 10% to 15% of patients with

SLE43 but is seen more often and more prominently in

those with dermatomyositis and systemic sclerosis. Ray-

naud’s phenomenon has been reported in 18% to 46% of

patients with SLE.3

Other lesions that have been noted in association with

LE include rheumatoid nodules, sclerodactyly, bullous

lesions, calcinosis cutis, thrombophlebitis, urticaria, eryth-

romelalgia, papulonodular mucinosis, cutis laxis/aneto-

derma, acanthosis nigricans, erythema multiforme, leg

ulcers, and lichen planus.

Cutaneous manifestations have been associated with the

antiphospholipid antibody syndrome. The antiphospholipid

syndrome denotes the clinical association between the

presence of antiphospholipid antibodies and a syndrome

of hypercoagulability. The syndrome may occur in certain

infectious diseases or in the absence of any disease; it may

occur in patients with SLE. The hypercoagulability results

in arterial and venous thromboses. It is also associated

with a high proportion of pregnancy losses after 10 weeks

of gestation. Livedo reticularis is seen in patients with

SLE with and in those without the antiphospholipid

antibody syndrome. It is seen in 11% to 22% of

patients with the antiphospholipid syndrome.44,45 Splinter

hemorrhages, leg ulcers, blue toe syndrome, and skin

infarcts may also be seen. The pathology involves the

presence of thrombotic microangiopathy, and true vascu-

litis is not seen.

Immunopathology/Lupus band test

The lupus band test is commonly discussed in reference to

the systemic and cutaneous manifestations of SLE. Immu-

noglobulins and complement proteins were first identified on

the dermal-epidermal junction of LE lesional skin biopsy

specimens, and this phenomenon has been referred to as the

lupus band.46 Although initially thought to be specific for LE,

the lupus band has been found in other skin diseases.47

Immunoreactant deposits in the nonlesional skin of

patients with LE were first noted by Burnham and Fine.48

Similar deposits in normal skin have been reported in

patients with rheumatoid arthritis, Sjfgren’s syndrome,

scleroderma, Raynaud’s syndrome, polydermatomyositis,47

and lepromatous leprosy.49

Because there has been controversy about the terminol-

ogy of this test, it has been proposed that using the terms

lesional lupus band test and nonlesional lupus band

test would minimize confusion between the types of test

being studied.2

The strongest association of a positive nonlesional lupus

band test finding has been with SLE. It is therefore also

logical that patients with DLE without extracutaneous

disease have negative lupus band test findings.23 One

study reported that 25% of patients with SLE who have

DLE lesions had positive nonlesional lupus band test

findings.23 There is controversy about the diagnostic

specificity of the nonlesional lupus band test. It has been

shown that there is a very high diagnostic specificity with

the presence of 3 or more immunoreactants.2,47,50 It is

important to note that sun-damaged skin can have a false-

positive nonlesional lupus band test result; therefore, the

greatest specificity is in nonlesional skin from sun-

protected regions with 3 or more immunoreactants pres-

ent.2,47 Serial studies on nonlesional skin showed an

association between the presence of immunoglobulins as

well as complement proteins and the clinical as well as

serologic disease activity of the systemic disease.51

There are few published studies on direct immunofluo-

rescence in ACLE. One study noted 5 of 5 ACLE lesional

skin biopsy specimens to have positive lesional lupus band

test results.2

In SCLE, DLE, and ACLE, more than 60% of patients

have proteins in their lesional skin.22 In biopsy specimens of

lesional skin, therefore, the presence of bandlike granular

deposits on direct immunofluorescence does help confirm

the diagnosis of SLE, but a negative test finding does not

rule out the diagnosis of lupus.

The diagnosis of SLE should never depend on the

presence of immune deposits in the dermal-epidermal

junction of either involved or normal skin.

Other clinical manifestations

General features

Fatigue is present in nearly all patients with SLE during

periods of disease activity and can precede the appearance

of rashes or joint swelling. Fever is present in approximately

80% of patients at the time of diagnosis and may be of low

grade or spiking. Fever in a treated patient with SLE should

be considered to be a result of infection until proven


otherwise. Weight loss is present in approximately 85% of

patients at the time of diagnosis unless the nephrotic

syndrome is present.

Cardiovascular manifestations

Clinically evident pericarditis is present in approximately

25% of patients. Pericardial tamponade is unusual. Myocar-

dial disease may cause myocardial infarction as a result of

arteritis early in the course of the disease in younger patients.

Myocardial infarction in corticosteroid-treated patients is an

important cause of death late in the course of the disease.

Raynaud’s phenomenon is present in approximately 20% of

patients and may precede the development of multisystem

disease. Cryoglobulinemia is commonly present in patients

with an onset of Raynaud’s phenomenon at the time of

diagnosis. Such patients also may have nephritis. Raynaud’s

phenomenon may disappear with treatment of the systemic

disease. Thrombotic episodes occur in patients with the

lupus anticoagulant (see discussion on the antiphospholipid

antibody syndrome).

Pulmonary manifestationsPleural involvement occurs in 40% of patients, and the

effusions are usually small or moderate. The fluid is a

transudate that contains the same immunoglobulins and com-

plement proteins as does the peripheral blood. An unusual

manifestation is lupus pneumonitis characterized by dyspnea,

rales, and areas of platelike atelectasis. This diagnosis should

be made only after a rigorous search for an infectious agent.

Pathologic abnormalities are common in autopsied lungs and

are usually nonspecific. Pulmonary hemorrhage caused by

pulmonary vasculitis is a rare but life-threatening manifesta-

tion. Pulmonary hypertension occurs rarely.

Renal diseaseClinical evidence of renal disease occurs in 50% of

patients, but pathologic abnormalities are present in

additional patients. Immunofluorescent studies on biopsy

specimens of autopsy material from nearly all patients

reveal deposits of immunoglobulins or complement pro-

teins. Mesangial immune deposits are present in nearly all

patients with and those without clinical evidence of lupus

nephritis. The type and severity of the renal disease bear no

relation to the presence of other manifestations of the

disease, which may be either severe or mild. The pathologic

diagnosis is made by performing renal biopsy, which may

reveal mesangial nephritis, diffuse proliferative nephritis, or

membranous nephritis. Sclerosing nephritis is seen in end-

stage renal disease. Interstitial nephritis may be found

frequently. The prognosis is good in patients who have focal

nephritis and in those with a serum creatinine level lower

than 1.3. Male patients have a poorer prognosis.

Nervous system disease

Peripheral neuropathy occurs in 14% of patients and is

usually sensory, but a mixed sensory-motor disturbance is

seen in approximately 5% of patients with typical asymmet-

ric involvement of mononeuritis multiplex. The episodes

occur during periods of disease activity in other systems.

Less commonly, a picture suggestive of the presence of the

Guillain-Barre syndrome is present. Cranial nerve signs

occur in approximately 16% of patients. Optic neuritis may

be one of the presenting manifestations, as well as transverse

myelitis. I am currently caring for 2 patients with SLE who

have developed classic multiple sclerosis. Central nervous

system involvement occurs most often as organic brain

syndrome and seizures. Seizures occur in approximately

15% of patients, usually at the onset of the disease rather than

late in its course. Grand mal seizures are most common, but

chorea, jacksonian fits, petit mal, and temporal lobe seizures

also occur. Organic brain disease characterized by impair-

ment of orientation, perception, and ability to calculate may

occur usually during the first year after diagnosis and usually

occurs in the setting of disease activity in other systems.

Severe headaches may occur along with other manifestations

of the disease. Cerebrovascular accidents occur in the

antiphospholipid antibody syndrome (see below).

Psychologic problems

Depression and anxiety are common in patients with SLE

and should be neither considered to be a part of the disease

nor treated with increasing corticosteroid doses. Patients

need reassurance and may require treatment with antide-

pressants and antianxiety medications.

Gastrointestinal manifestations

Abdominal pain is the most common symptom and may

be a result of mesenteric arteritis. Perforation of the small or

large intestines may occur. This manifestation occurs in

patients with disease activity in other systems. Pancreatitis

occurs rarely. Hepatomegaly is present in approximately

30% of patients and is more common in children. Liver

enzyme elevations may occur.

Spleen and lymph nodesSplenomegaly is present in 20% of patients and is more

common in children. Lymphadenopathy is present in

approximately 50% of patients with active disease.

Ocular manifestationsFifteen percent of patients have conjunctivitis or epis-

cleritis. Both manifestations are more common in patients

with extensive cutaneous manifestations. Retinal arteritis

may occur.

Parotid gland enlargement and Sjogren’s syndrome

Enlarged parotid glands may occur in approximately 8%

of patients, most of whom do not have xerostomia.

Associated Sjfgren’s syndrome may be present with a

positive Schirmer’s test finding in 20% of patients, a

positive parotid scan finding in 58%, and a positive lip

biopsy finding in 50%.52


Menstrual abnormalities and pregnancy

Cessation of menses during the initial 3 to 6 months of

treatment occurs frequently. Stillbirths and spontaneous

abortions are common in untreated patients with active

disease and are associated with the antiphospholipid

antibody syndrome (see below). Children may be born with

congenital heart block by mothers with SLE who have anti-

Ro antibodies.

Laboratory findings

One or more hematologic abnormalities are present in

nearly all patients with SLE who have active disease. Most

commonly, mild to moderate normocytic and normochro-

mic anemia is present. Coombs’ test–positive hemolytic

anemia occurs in approximately 10% of patients. Mild to

moderate leukopenia is present in 17% of patients, and

lymphopenia is also usually present during disease activity.

Mild thrombocytopenia is present in approximately one

third of patients, but less than 100,000 platelets/mm3 is

present in only 5%. Qualitative thrombocyte defects are

also common.53 The erythrocyte sedimentation rate is

elevated in nearly all patients with SLE and usually falls

to normal levels when the disease becomes inactive. Serum

C-reactive protein levels are elevated during disease

activity and in infected patients. Cryoglobulins of the

mixed IgG-IgM type are found in 10% of patients. Elevated

serum gamma globulin is present in 80% of patients with

active disease. Rheumatoid factor is present in 14% of

patients. Serum complement levels are depressed in active

disease in most patients.

Autoantibodies

Patients with SLE always have a positive antinuclear

antibody test finding; this test is an excellent screening test.

A titer of 1:160 is significant, but that of 1:40 may be found

in approximately 30% of healthy individuals. In addition,

the antinuclear antibody test finding is positive in many

other rheumatic diseases and is not diagnostic of SLE. A

negative antinuclear antibody test finding essentially rules

out the disease. Anti–double-stranded DNA is present in

approximately 70% of patients with SLE and is highly

specific for SLE. Anti-Sm antibodies are also highly

specific for SLE but are found in only 25% of patients.

Anti-DNA antibodies correlate with disease activity and

may disappear when the disease goes into remission,

whereas anti-Sm antibodies are present throughout the

course of the disease. Other autoantibodies such as anti-La

and anti-Ro are found in patients with SLE, those with

Sjfgren’s syndrome, and those with subacute cutaneous

lupus. Anti-Ro antibodies occur in patients with SLE who

have babies with congenital heart block or congenital SLE;

thus, it is important to determine whether anti-Ro is present

in all patients with SLE so that anti-Ro–positive patients can

be followed closely during a pregnancy. Antiribonucleo-

protein is found in SLE and systemic sclerosis. Antiphos-

pholipid antibodies, lupus anticoagulant, and a VDRL

(Venereal Disease Research Laboratories) test should be

ordered, and, if the results are positive, the patients should

be treated with a daily aspirin.

Complement proteins

C3 and C4 are frequently low during periods of active

disease and return to normal levels during disease remissions.

Precipitating factors

Sun exposure may induce the onset of SLE and cause

exacerbations of the disease. Infections, especially bacterial

infections, may occur before the onset of the disease or

cause an exacerbation. Infections especially occur before

clotting episodes in patients with antiphospholipid anti-

bodies. Surgery or any trauma that induces necrosis of tissue

and the release of nuclear antigens may cause an exacerba-

tion of SLE. Pregnancy is associated with the onset of lupus

during the last trimester or the postpartum period. Thera-

peutic abortions may also be followed by exacerbation of

the disease, especially in patients with active disease at the

time of the therapeutic abortion.

Treatment: systemic manifestations

Conventional agents

Systemic glucocorticoids are the standard form of

treatment for patients with SLE. Some patients require very

low doses of prednisone (V10 mg) to alleviate manifestations

of the disease. Patients with nephritis, central nervous system

lupus, or pulmonary hemorrhage may require very high

doses, and intravenous therapy is frequently recommended

to them. Cyclophosphamide and mycophenolate may be

used in conjunction with high doses of glucocorticoids.

Author, Naomi Rothfield, treats patients with rising anti-

DNA levels associated with falling complement levels with

an increased dose of prednisone because of experience with

onset of lupus nephritis in patients who were not treated so.

The newer agents in the treatment of severe SLE have

recently been reviewed.54 In patients with seizures, organic

brain disease, or transverse myelitis, intravenous bolus

glucocorticoids are used along with cyclophosphamide.

Significantly in patients whose renal biopsy specimens show

more than focal lupus nephritis, cyclophosphamide or

mycophenolate is given with corticosteroids. In systemic

vasculitis and pulmonary hemorrhage, intravenous bolus

glucocorticoids and cyclophosphamide are also used.

Antimalarials are effective in the treatment of cutaneous

manifestations of the disease and help in the treatment of

arthralgias, arthritis, and fatigue. They may also prevent

major damage to the kidneys and central nervous system.55


We have shown that patients taking antimalarials have a

significantly higher bone density as compared with those

not taking antimalarials when all other factors are taken into

consideration.56

Nonsteroidal antiinflammatory drugsNonsteroidal antiinflammatory drugs may be effective in

the treatment of musculoskeletal manifestations of the

disease, but the risk of renal insufficiency is high and

I avoid the use of these agents.

Experimental agents

Stem cell transplantation preceded by high-dose chemo-

therapy has been studied in patients with severe SLE who

did not respond to corticosteroids plus intravenous cyclo-

phosphamide57 Fifteen patients were followed for 3 years

and had improvement. The European registry of autologous

stem cell transplantation cases reported remissions in 33 of

50 patients, in addition to 10 relapses and 12 deaths.58 A

report on immunoablation alone without stem cell support

described 14 patients with moderate to severe SLE

unresponsive to corticosteroids and immunosuppressive

therapy.59 The patients received 50 mg/kg of cyclophos-

phamide; all had improved at 10 to 47 months of follow-up,

and no death had occurred. Complete responses were

reported in 5 of the 14 patients.

Anti–B-cell antibodies have been used in SLE, and good

results have been reported in uncontrolled observational

studies.60-66 The largest study was on 90 patients who have

refractory SLE with a 3- to 40-month follow-up.61 A

decrease in disease activity was noted in 80% of the

patients, and the infusions were well tolerated, with adverse

events caused by hypersensitivity to the chimeric antibody

occurring in 10%. At present, there are a number of

multicenter double-blind clinical trials of anti–B-cell anti-

bodies in SLE being carried out. Dehydroepiandrosterone

has been studied in a multicenter double-blind clinical trial

that used pharmaceutical-grade dehydroepiandrosterone.

There was no sufficient evidence of efficacy to warrant

US Food and Drug Administration approval.65,66 Over-the-

counter dehydroepiandrosterone products vary extensively

in potency and purity and are not recommended.

Treatment: cutaneous manifestations

Comments here will be directed at the treatment of LE-

specific skin diseases such as SCLE and CCLE. The second

author (RDS) has recently addressed this subject more

comprehensively elsewhere.67,68 Acute cutaneous LE (eg,

facial butterfly-shaped erythema reactions) and LE-nonspe-

cific skin lesions (eg, cutaneous vasculitis) are typically

seen in the context of active SLE. The systemic immuno-

modulatory/immunosuppressive treatments required to con-

trol the SLE activity will typically in a parallel fashion be of

benefit to the ACLE- and LE-nonspecific skin lesions.

Before beginning active treatment of LE skin disease,

one should consider the possibility of drug-induced cutane-

ous LE, especially drug-induced SCLE.69 Over the past

15 years, it has become increasingly clear that SCLE skin

lesions accompanied by circulating Ro/SS-A autoantibodies

can be found to be triggered by medications from a number

of drug classes.70-73 As such, recognition of this association

and withdrawal of the offending triggering drug can within

several months result in complete resolution of SCLE skin

disease activity without other active treatments. Table 1

shows an outline of the drugs that have been reported or

observed to be triggers for drug-induced SCLE.67,68

The initial management of all LE-specific skin diseases

should include education regarding protection from sunlight

and artificial sources of UV light and the avoidance if

possible of potentially provocative photosensitizing drugs

such as those indicated in Table 1. With regard to specific

medical therapy, local/topical measures should be maxi-

mized first and systemic agents should then be used if

significant disease activity continues.

Protection from UV light

Issues relating to photoprotection in patients with LE

have been discussed elsewhere in depth by one of the

authors.74

Physical protectionPatients should be advised to avoid direct sun exposure,

particularly during the midday hours and during the summer

months when the UV component of sunlight is least

attenuated by the atmosphere. Tightly woven clothing and

hats should be worn in conjunction with broad-spectrum

sunscreens to achieve maximal shielding from sunlight. The

use of broad-brimmed hats should be encouraged. Several

clothing lines offering maximized protection from UV light

are currently being marketed. Ultraviolet-light blocking

films can be applied to home and automobile windows.

Plastic/acrylic shields can be placed over fluorescent light

tubes to block the small amount of UV-B and UV-A

radiation that can leak from such sources.

Chemical sunscreensThe use of chemical sunscreens has been shown in

phototesting studies to be able to block the induction of

cutaneous LE lesions.75 Patients should select broad-

spectrum sunscreens that contain agents that block UV-B

with a sun protection factor (SPF) of 30 or greater. Under

everyday use conditions, the actual SPF of the product is

much lower than the advertised SPF. This is mainly because

patients tend to use much less of the product on their skin

than that used during the initial laboratory determination of

the SPF value for the product. In the United States,

preparations containing avobenzone (Parsol 1789), zinc

oxide, and titanium dioxide provide the broadest degree

of UV-A protection. Sunscreen products that contain the

highly effective chemical UV-A blocker, mexoryl SX


(eg, Anthelios L, La Roche-Posay Laboratoire), are cur-

rently available outside the United States. Mexoryl SX is

more resistant to photodegradation than the formulations of

avobenzone/Parsol 1789 that have previously been available

in the United States. Sunscreen products containing a

photostabilized form of avobenzone provided by the Helio-

plex technology have recently been introduced in the United

States (eg, Neutrogena Ultra Sheer Dry-Touch Sunblock

SPF 55), however.

Sunscreen products that are most resistant to being

washed off by sweating or bathing should also be selected.

Sunscreens should be applied at least 30 minutes be-

fore sun exposure and reapplied after bathing or apprecia-

ble perspiration.

Opaque corrective camouflage cosmetic products (eg,

Dermablend, Covermark) are designed to optimally conceal

pigmentary changes and scarring. These products offer the

dual benefit of being highly effective physical sunscreens

and aesthetically pleasing cosmetic masking agents for

patients suffering psychologically from chronic disfiguring

skin disease as a result of cutaneous LE.76 The proper use of

such products can improve the quality of life of patients.77

Local corticosteroids

TopicalInitial treatment usually includes daily application of a

formulation containing a medium-strength topical cortico-

steroid (eg, triamcinolone acetonide 0.1%). If this does not

provide adequate relief, more potent topical corticosteroids

such as clobetasol propionate 0.05%, betamethasone dipro-

pionate 0.05%, diflorasone diacetate 0.05%, and amcino-

nide 0.1% can be tried. Daily application of these products

to lesional skin for 2 weeks followed by a 2-week rest

period off treatment can lower the risk of local complica-

tions such as steroid atrophy and telangiectasia and that of

systemic absorption. Cutaneous LE represents one of the

very few clinical situations in which such potent topical

fluorinated corticosteroids can be recommended for use on

atrophy-prone areas such as the face because the alternatives

are disfiguring skin disease and risk of side effects from

systemic therapy. Unfortunately, topical corticosteroids

alone do not provide adequate improvement for most

patients with cutaneous LE.

IntralesionalIntralesional corticosteroid therapy (triamcinolone hex-

acetonide using a 30-G needle) is practical in some settings

such as localized DLE. Side effects are dose dependent and

include subcutaneous atrophy and leukoderma at the

injection sites. Patients with SCLE typically have too many

lesions for this approach to be tolerated, however.

OralIt is a good policy to avoid oral corticosteroid therapy as

much as possible in patients having isolated forms of

cutaneous LE because of the risks of side effects (eg,

avascular bone necrosis). Burst and taper oral pred-

nisone therapy can be of benefit, however, while waiting

for slower-acting agents such as antimalarials to become

fully effective.

Local calcineurin inhibitors

Several topical formulations of the calcineurin inhibitors

tacrolimus and pimecrolimus have been examined in

cutaneous LE, including SCLE.78-80 It has been one of the

authors’ personal experience (RDS) that LE lesions on facial

skin can respond to these preparations better than LE skin

lesions on other parts of the body can. It is hoped that

higher-strength formulations of tacrolimus/pimecrolimus

that are currently being developed will have greater clinical

efficacy in cutaneous LE, as has been observed anecdotally

with compounded formulations.79

Antimalarials

Although a number of systemic medications have been

reported anecdotally to be of benefit to patients with

cutaneous LE, by far, those having the highest safety-

benefit ratios are the aminoquinoline antimalarial agents. In

addition, hydroxychloroquine is one of the few drugs that

have been proven by controlled clinical trials to be of

benefit in cutaneous LE.81,82 There is general agreement

within the academic dermatology community that approx-

imately 75% of patients with SCLE will respond to single-

agent or combination antimalarial therapy. The 3 agents

most frequently prescribed in the United States for patients

with SCLE are hydroxychloroquine sulfate (Plaquenil,

Sanofi-Synthelabo), chloroquine phosphate (Aralen,

Sanofi-Synthelabo), and quinacrine (currently available in

the United States only as a compounded formulation of

the dihydrochloride salt that must be encapsulated). In

general, hydroxychloroquine is best tolerated with the least

side effects.

Therapy with hydroxychloroquine alone should be tried,

initially starting at 6.5 mg/kg per day in 2 divided doses

(~400 mg/d for the average-sized person). Hydroxychlor-

oquine reaches steady-state levels in 6 to 8 weeks, and its

full clinical efficacy cannot be judge before then. Its full

clinical effects can take even longer. If there is no significant

improvement by 2 to 3 months, 100 mg/d of quinacrine can

be added to the hydroxychloroquine.83-86 If the response is

inadequate after 4 to 6 weeks of combined hydroxychlor-

oquine and quinacrine therapy, 250 mg/d of chloroquine can

be substituted for the hydroxychloroquine in this combina-

tion because an occasional patient with cutaneous LE will

respond better to chloroquine than to hydroxychloroquine.

Hydroxychloroquine and chloroquine should not be used

concurrently because of the enhanced risk of developing

retinopathy. Once disease activity is controlled, the hydrox-

ychloroquine can be decreased to 200 mg/d for mainte-

nance. Authorities recommend a treatment period of 1 to

2 years to fully suppress cutaneous LE activity. As noted


previously, there is evidence that cigarette smoking through

unknown mechanisms can interfere with the efficacy of

antimalarials in cutaneous LE and/or directly exacerbate

cutaneous LE activity.

It should also be realized that the aminoquinoline

antimalarials, especially hydroxychloroquine, are being

increasingly recognized to have a salutary effect on the

extracutaneous manifestations of SLE (Canadian Hydroxy-

chloroquine Study Group, 1991; Molad, 2002). The

malaise, fatigue, and arthralgia that patients with cutaneous

LE can experience can thus respond to antimalarials

that have been given to control cutaneous LE disease

activity. As with the cutaneous LE disease activity, the

musculoskeletal manifestations of patients with cutaneous

LE will take several months to be fully impacted after

starting antimalarials.

When using either hydroxychloroquine or chloroquine,

ophthalmologic monitoring is required to minimize the risk

of retinal toxicity (quinacrine is not retinopathic). A baseline

ophthalmologic evaluation should be obtained before

starting antimalarial therapy to document any preexisting

change that might otherwise be attributed to the medication.

The frequency with which patients are subsequently

monitored has been debated. The most recent set of

guidelines published by the American Academy of Oph-

thalmology in April 200287 suggests that this should be

repeated at yearly intervals in complicated patients (ie, those

taking antimalarials for N5 years; those taking larger-than-

recommended daily doses; those having high body fat

levels; those having concomitant kidney or liver disease;

and those who are N60 years old). These guidelines have

indicated that uncomplicated patients should have repeat

ophthalmologic examinations every 5 years.

This ophthalmologic evaluation should at minimum

include a funduscopic examination, visual field testing

(including central fields with a red object), and visual

acuity testing. Use of the self-administered Amsler grid at

home to detect the earliest evidence of visual field defects

has become popular. Retinal changes can become irrevers-

ible if not detected early. It has been suggested that the risk

of retinal toxicity is minimized when the total daily dose of

hydroxychloroquine does not exceed 6.5 mg/kg per day

(3.5 mg/kg per day for chloroquine). There does not appear

to be an upper limit on the safe total lifetime dose of these

drugs if these daily maximum dosing recommendations are

not exceeded.

Periodic assessments of hematologic and hepatic func-

tion are carried out by most dermatologists during

the hydroxychloroquine and chloroquine therapy to identify

the occasional patient who will suffer an idiosyncratic

reaction. It should be noted however that when using

hydroxychloroquine for rheumatoid arthritis, the American

College of Rheumatology guidelines indicate that no such

routine hematologic monitoring is necessary.88 It should be

noted that full-dose hydroxychloroquine or chloroquine

therapy in an individual having subclinical porphyria

cutanea tarda can produce an acute hepatotoxic reaction

that can in turn produce symptoms simulating an acute

surgical abdomen. Quinacrine hydrochloride is more likely

to induce hemolysis in glucose-6-phosphate dehydroge-

nase–deficient patients than is hydroxychloroquine or

chloroquine, and routine hematologic monitoring should

be carried out with this agent. Neurotoxicity and muscular

toxicity (including cardiotoxicity) can occur with the

aminoquinoline antimalarials but were much more of a

problem in the past when much higher daily doses of these

drugs were used.

Antimalarial agents can induce a number of dermato-

logic changes. All can cause a blue-black pigmentation of

the skin (particularly in sun-exposed areas), palatal mucosa,

nails, and pretibial surfaces. They can also rarely cause

bleaching of lightly pigmented hair, although this is rare

with currently recommended daily doses. Quinacrine

frequently causes diffuse yellowing of the skin, sclera,

and bodily secretions that are fully reversible on discon-

tinuation of the drug. On occasion, quinacrine produces a

lichenoid drug reaction that can be the harbinger of severe

bone marrow toxicity if the drug is not discontinued.89 The

lichenoid drug eruptions that can be produced by all of the

aminoquinoline antimalarials can simulate the appearance

of cutaneous LE lesions, including SCLE, resulting in a

highly confusing clinical setting.16

Other systemic antiinflammatory agents

Other systemic antiinflammatory drugs that might be

considered in an antimalarial-refractory patient with cuta-

neous LE include dapsone 90-92; isotretinoin (Accutane) and

acitretin (Soriatane) 82,93; thalidomide 94,95; gold (auranofin;

Ridaura, aurothiomalate; aurothioglucose) 96; and clofazi-

mine.97 With rare exception, however, it should be noted

that these agents had been used only anecdotally in

cutaneous LE. Among these agents, thalidomide is probably

the most uniformly beneficial and rapidly acting agent. This

drug carries a number of risks other than its well-known

teratogenicity (eg, sensory neuropathy, hyperacoagulable

state induction in the setting of antiphospholipid antibody

production, secondary amenorrhea), however.

Experimental therapy

Ultraviolet-A1 phototherapyPreliminary animal work has suggested that UV-A (320-

400 nm) irradiation might dampen the autoimmune abnor-

malities in experimental murine models of SLE.98 In

addition, small controlled trials from 2 groups of inves-

tigators have suggested that patients with SCLE might

actually benefit from very low doses of whole-body UV-A1

irradiation (340-400 nm).99-101 The true value of this

somewhat controversial form of treatment remains to be

confirmed by controlled studies in larger groups of patients,

however. Caution should be taken in interpreting these data


in view of the evidence that UV-A, including long-wave

UV-A1, can play an exacerbating role in the cutaneous

manifestations of SLE.102

Recombinant biologic response modifiersVariant tumor necrosis factor–a gene expression has been

implicated as a predisposing genetic factor for SCLE. This

and the remarkable efficacy of thalidomide, a known

inhibitor of tumor necrosis factor–a expression, in SCLE

and other forms of cutaneous LE have suggested the

possibility that the recombinant tumor necrosis factor–ainhibitors (eg, etanercept, infliximab, and adalimumab)

might potentially be of benefit to patients with SCLE. A

drug-induced form of cutaneous LE, including SCLE, has

now been recognized as a potential complication of

treatment with this class of biologics. Despite this, there

exists an anecdotal report describing rapid improvement of

SCLE in a patient with rheumatoid arthritis who was treated

with etanercept.103

In addition, other recombinant biologics that interfere

with antigen-presenting cell/T-cell interaction that have

proven to be of benefit in psoriasis (alefacept, Amevive;

efalizumab, Raptiva) theoretically could be of benefit in

other T-cell–dependent autoimmune skin diseases such as

cutaneous LE. There is one recently published case of a

therapeutically refractory patient with SCLE who appeared

to have responded quickly and remarkably well to efalizu-

mab (Raptiva).104

B-cell–depleting recombinant biologics acting through

CD20, such as rituximab (Rituxan), have been recently

reported in preliminary studies to be of possible benefit in

humoral autoimmune diseases such as SLE and pemphi-

gus.105-109 It would be interesting to know what their impact

might be on cutaneous LE.

Acknowledgment

Dr Sontheimer’s contribution to the preparation of this

work was supported by the Richard and Adeline Fleischaker

Chair in Dermatology Research of the University of

Oklahoma Health Sciences Center.

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Lupus erythematosus: systemic and cutaneous manifestations

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