Chapter 155

Lupus Erythematosus
Melissa I. Costner & Richard D. Sontheimer

ETIOLOGY AND PATHOGENESIS

Genetic Factors
The genetic association between LE-specific skin
disease and serologically determined major histocompatibility complex (MHC) class II DR specificities is well known. For example, patients with SCLE
and overlapping features of Sjgrens syndrome
are more likely to have the HLA-DR3, DQA1*0501,
DQB1*0502 haplotype. Other susceptibility genes
outside the MHC region have also been implicated.
These include interleukin 1 (IL-1) receptor antagonist and tumor necrosis factor- (TNF-). Werth
and colleagues8 found a substantial increase in
the prevalence of a promoter polymorphism of
TNF- (-308A) in patients with SCLE. TNF- may
be a marker allele for the extended HLA-A01,B08,
DRB1*0301 haplotype that is associated with a
number of autoimmune conditions, including
SCLE.9 Genetic deficiency of the early complement
components C1q, C4, and to a lesser extent, C2,
predispose patients to the development of lupus.10
In fact, complete congenital deficiency of C1q is the
strongest single genetic risk factor yet identified for
the development of photosensitive SLE.11
One of the most striking clinical observations
in SLE is the diseases female predilection. Indeed,
there is a lifetime female-male ratio of 9:1. This
sexually dimorphic prevalence is likely due to the
effect of sex hormones on the immune system.
High levels of estrogen have been shown to cause
patients with SLE to have an increase in (1) the
number of self-reactive lymphocytes that bypass
developmental deletion, (2) an increase in CD4/CD8
ratio (favoring humoral responsiveness), and (3) the
number of B cells leaving the bone marrow that
express high-affinity recognition of self-DNA.12

THE IMPORTANT ROLE OF

INNATE IMMUNITY IN THE
PATHOGENESIS OF LUPUS
Interferon - and Dendric Cells
DCs have a key role in antigen recognition and
stimulation of the immune system. Immature DCs
perform a watch-dog like role in all peripheral
tissues. They are essential to the maintenance of peripheral tolerance to self-antigens. They constantly
sample their environment, capture self-antigens
released in normal tissue turnover (apoptosis), and
in the absence of inflammation, primarily act as
housekeepers, keeping self-antigens in check. In
the company of inflammation or microbes, they
mature and move to draining lymph nodes, where
they present antigen to T cells via MHCs. With appropriate costimulatory molecules, T- and B-cell
activation ensues, with subsequent launching of an
adaptive immune response.22
DCs develop from precursor monocytes and have
two different lineages, myeloid DCs, which then
differentiate into immature and mature DCs and
plasmacytoid DCs. Plasmacytoid DCs are found in
lymphoid organs, such as bone marrow, spleen,
tonsils, and lymph nodes, and are noteworthy for
producing large amounts of IFN- in response
to many viruses and certain bacteria. They have
recently been found to infiltrate LE-specific skin
lesions as well. IFN- causes monocytes to differentiate into myeloid DCs, which are able to capture
circulating apoptotic cells. These can then present
self-antigens to autoreactive CD4 T cells and also
support B-cell proliferation and differentiation,
leading to the clinical expression of LE.23
More recently, several important studies using
microarray data, have revealed a genomic signature of upregulated IFN--inducible genes from
peripheral blood mononuclear cells of SLE patients,
as well as from lesions of LE-specific skin disease.15
Additionally, it has been shown that IFN- increases
as patients disease flares. Recent studies have
shown that local production of type I IFNs in CLE
induces Th1-biased inflammation via induction
of IFN-inducible proteins (MxA) and chemokines
(CXCL-9, CXCL-10, and CXCL-11), with recruitment of
pathogenic T lymphocytes into the skin.24

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236 Chapter 155: Lupus Erythematosus

In short, there has been convergence of data from

several studies, leading to the suggestion that IFN-
plays a central role in the pathogenesis of lupus.
NEUTROPHILS.
Another trigger for IFN-alpha release by DCs appears to be related to a newly described form of
neutrophil cell death called NETosis. The recent
discovery of the chromatin based neutrophil extracellular trap (NET) reveals that NETs are part of the
innate immune pathway that immobilize microbes.
Antimicrobial peptide LL37 antibody is expressed
at high levels in SLE. Along with anti-HNP (heteronucleoprotein) antibodies, anti-LL37 activates
neutrophils to release NETs. The production of NETs
by these autoantibodies appears to stimulate the
production of IFN-alpha by PDCs.24a
TOLL-LIKE RECEPTORS.
It appears that circulating DNA/anti-DNA complexes trigger TLR 7, 8, and 9 signaling, which acts
as an amplification loop by inducing proliferation of
autoreactive B cells, and IFN- secretion from DCs.
Antimalarials have recently been shown to inhibit
TLR signaling, and it may be through this mechanism of action that antimalarials display efficacy in
lupus.25

Cell Mediated Immunity in the

Pathogenesis of Lupus
TUMOR NECROSIS FACTOR-.
TNF is likely involved in the pathogenesis of cutaneous lupus. TNF induces apoptosis through the
FAS-associated death domain. TNF has been shown
to be elucidated by keratinocytes exposed to UVR.
TNF is produced in large amounts by epidermal
keratinocytes in patients with SCLE.26 However,
there have also been numerous reports of the
development or worsening of cutaneous lupus
while on anti-TNF therapy; and the development
of dsDNA antibodies and lupus-like syndromes is
well described with drugs such as etanercept and
infliximab. This is likely due to the upregulation of
IFN by TNF inhibition, disrupting the homeostasis of
these two proinflammatory cytokines.27
T CELLS.
T cells play a key role in both the induction and
expansion phases in the development of SLE. T cells
are involved in the development of both central
and peripheral tolerance. Self-antigens are pre-

sented by DCs to autoreactive T cells. Binding of the

surface signaling molecules, such as the T-cell receptor, to their ligands leads to T-cell activation. In
SLE, and in CLE, T cells display markers of increased
activation, increased numbers of DR+ antigens.28 T
cells also provide cognate help to autoreactive B
cells, leading to production of autoantibodies.
B CELLS.
B cells are involved in the expansion phase of LE
pathogenesis, in that they can present antigen to
autoreactive T cells and further amplify T-cell activation. The production by B cells of autoantibodies
against nuclear antigens is the hallmark of SLE.29
Several of these autoantibodies are thought to
be directly pathogenic, including dsDNA and Ro/
SS-A antibodies. Such autoantibodies likely play a
direct role in the injury phase of LE. They form immune complexes, which may cause tissue damage
by means that include direct cell death, cellular
activation, opsonization, and the blocking of target
molecule function. B cells may not be as important
in CLE as they are in other manifestations of the
disease, as supported by the suggestion that antiB-cell therapies such as rituximab are less effective
for CLE.
Clearly, there are several key constituents involved
in the pathogenesis of LE. The sheer number of
potential players in disease development is one the
main reasons for the highly variable expression of
the disease. Recent data uncovering convergence
points (i.e., IFN-) in the pathogenetic expression
of disease have already led to early development
of new drugs for LE. Additionally, the complexity
of the pathogenesis of LE suggests that multiple
pharmacotherapeutics (a layering of drugs with different pathomechanisms) may be required to treat
patients with recalcitrant disease.

CLINICAL FINDINGS
Clinical Findings
VESICULOBULLOUS SKIN CHANGE IN LUPUS
ERYTHEMATOSUS.
The existing nomenclature surrounding vesiculobullous skin change in LE is also a source of potential confusion. Bullae may develop in ACLE and
SCLE as a manifestation of particularly aggressive
liquefactive degeneration of the epidermal basal
layer, resulting in basal cell dissolution and simulating the clinical and histopathologic appearance of
TEN. Vesiculo-bullous changes can develop at the

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Chapter 155:

active edge of annular SCLE lesions, and subepidermal bullous changes occasionally develop in DLE
lesions.
The cutaneous entity described as bullous SLE appears to be a distinct entity, with formation of tense
blisters of varying size in the setting of a patient
with systemic disease, particularly nephritis. Histopathologically, marked neutrophilic infiltration with
dermal papillary microabscess formation is present
similar to that of dermatitis herpetiformis (DH) and
the inflammatory variant of epidermolysis bullosa
acquisita. However, the direct immunofluorescence
findings are more typical of those of LE. Type VII collagen autoantibodies are present in some patients.
DRUG-INDUCED CUTANEOUS LUPUS
ERYTHEMATOSUS.
Drug-induced lupus shares symptoms and laboratory characteristics with idiopathic SLE, and numerous drugs have been implicated in inducing various
features of SLE, e.g., procainamide, hydralazine,
isoniazid, chlorpromazine, phenytoin, minocycline,
and most recently, anti-TNF medications. Classic
drug-induced SLE is associated with antihistone antibodies and manifests similarly to SLE but without
cutaneous involvement.
Drugs can also induce or exacerbate lupus-specific
skin lesions, especially SCLE (see Table 155-4). Many
medications have been implicated, including ACE
inhibitors, calcium channel blockers, thiazide diuretics, sulfonylureas, antiepilepticcs, antimalarials,
tetracyclines, antifungals, and NSAIDS. These medications likely unmask SCLE in an immunogenetically susceptible individual, perhaps via photosensitizing mechanisms. SCLE has recently been reported
with the use of leflunomide for rheumatoid arthritis,
and Sjogrens syndrome. Anti-TNF medications and
interferon- have been reported to induce both
SCLE and DLE skin lesions, likely by interfering with
homeostasis between these molecules.48,49

Lupus Erythematosus-Nonspecific
Skin Lesions
A large number of cutaneous lesions that are
found in LE patients are not specific for LE, that
is, they also occur in patients that do not have or
never develop LE (Table 155-1) and do not share
the histologic features of LE-specific skin disease.
Such skin lesions are usually found in the patients
with underlying SLE or a significant risk thereof.
Nonspecific skin findings in LE include vasculitis,

Lupus Erythematosus 237

photosensitivity reactions, alopecia, Raynauds phenomenon, livedo reticularis, soft-tissue calcification,

bullous lesions, urticaria, cutaneous mucinosis, skin
necrosis, ulcerations, and nail changes.
LUPUS ERYTHEMATOSUS-NONSPECIFIC
LESIONS AS DIAGNOSTIC CRITERIA FOR
SYSTEMIC LUPUS ERYTHEMATOSUS.
As with some forms of LE-specific skin disease (e.g.,
ACLE), the presence of nonspecific skin lesions may
be an indicator of underlying SLE activity. In studies
looking at skin lesions in patients with SLE, higher
activity scores were seen in association with photosensitivity, Raynauds phenomenon, oral ulcers,
nonscarring alopecia (all lupus nonspecific lesions),
in addition to malar rash and cicatricial alopecia.5053
The high prevalence rates of these conditions in
SLE has led to their past and/or present inclusion in
the ACR criteria for diagnosis of SLE. Photosensitivity, defined clinically as an abnormal response to
UVR, appears to be a relatively sensitive indicator of
SLE. Several different studies have documented between 50% and 93% incidence rates of photosensitivity in patients with SLE. Because of the frequency
of photosensitivity in SLE, all patients should be
taught the importance of protecting skin from
UVR. Oral ulcers are present in roughly 25%45%
of SLE patients54,55 and up to 25% of DLE patients.56
Although these lesions can show LE-specific histopathologic changes on biopsy, particularly in DLE
patients, they often are nonspecific. LE-nonspecific
alopecia, diffuse nonscarring alopecia that is different than the scarring alopecia associated with DLE,
has been referred to as lupus hair and presents as
coarse, dry hair that has increased fragility. It often
results in broken hairs and may be more prominent
over the frontal hairline. This likely has considerable
overlap with a diffuse nonscarring alopecia caused
by telogen effluvium.
CUTANEOUS VASCULAR REACTIONS.
Reactions that are focused on the cutaneous
vasculature are important to recognize in patients
with SLE, as they can frequently indicate underlying systemic vascular pathology. Raynauds phenomenon is the most common vascular reaction in
lupus patients: one study documented Raynauds
phenomenon in 39.6% of patients with SLE.57
Additionally, it has been shown that Raynauds phenomenon seems to herald a worse prognosis and
is associated with higher disease activity scores.50,52
The presence of Raynauds phenomenon in patients
with SLE may correlate with an increase risk in DLE

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238 Chapter 155: Lupus Erythematosus

lesions on the hands. Skin changes that can be seen

in association with chronic severe Raynauds phenomenon include focal ulcerations on the fingertips
and periungual areas that result in pitted scarring
on resolution, prominent nail fold capillary ectasia
and drop out, punctate cuticular hemorrhage due
to incompetent nail fold capillaries, fingertip tuft
atrophy, digital calcinosis, and pterygium inversus
unguium (see Chapter 170).
Patients with SLE often develop vessel pathology
in the form of vasculitis. In SLE, all sizes of vessels
may be affected.58 When leukocytoclastic vasculitis
(LCV) presents in patients with SLE, other causes
of LCV, such as medications and infections, should
be excluded before a diagnosis of primary lupusassociated LCV is assigned. Cutaneous vasculitis in
a patient with SLE may predict the development of
lupus nephritis.53 Urticarial vasculitis is not uncommon in SLE patients and presents as tender urticarial papules and plaques, often over bony prominences, which last longer than 24 hours. It often
involves nondependent areas of skin.59 Involvement
of medium and/or large vessels in the skin, may
present as purpuric plaques with stellate or retiform
borders with or without cutaneous necrosis and
ulceration, or subcutaneous nodules, and can be a
marker for associated mononeuritis multiplex and/
or visceral vasculitis.60 LE-nonspecific vasculitis must
be distinguished from vasculopathy due to thromboembolism because it may present with similar
clinical findings. LE-nonspecific vasculopathy is
most commonly the result of antiphospholipid
antibodies. Digital skin lesions in SLE patients are
frequently falsely attributed to vasculitis61
Livedo reticularis should be considered as a separate LE-nonspecific cutaneous vascular reaction,
although it has clear overlap with vasculopathy. It
manifests as net-like, blanchable, complete or incomplete, red-purple rings on the extremities and is
the result of impeded flow of blood through vessels.
Macular erythema over the thenar- and hypothenar
eminences of the palms has been reported in lupus
patients. Reticulated palmar erythema can also be a
sign of vasculopathy associated with antiphospholipid antibodies. Dilated capillaries of the nail folds
have been found in LE patients but less frequently
than in patients with dermatomyositis (including
clinically amyopathic dermatomyositis) or systemic
sclerosis. Erythromelalgia (erythermalgia) is characterized by intense burning pain in the feet and
hands, accompanied by local macular erythema
and warmth. It differs from Raynauds phenomenon
in that it worsens with exposure to heat instead of

cold. It may be seen as an isolated clinical entity

or in association with several different underlying
illnesses, including SLE. Telangiectasia and erythema of the proximal nail fold were found in 76%
of patients who had both DLE and SLE, but none in
patients with DLE in the absence of SLE, suggesting
that it, too, is a rather sensitive indicator for systemic disease activity.57
OTHER LUPUS ERYTHEMATOSUSNONSPECIFIC SKIN LESIONS.
Urticaria is sometimes associated with LE and is
thought to be a manifestation of the immune
dysregulation of the disease process. One study
found chronic urticaria in 44% of 73 SLE patients,
sometimes occurring as the presenting disease
manifestation.54 SLE patients may present with
LE-nonspecific cutaneous mucinosis. Such patients
may develop indurated erythematous papules,
nodules, or plaques, typically on the trunk and/or
arms. Histopathologic examination of these lesions
reveals diffuse dermal mucin deposits. A number of
nail changes have been noted in LE patients, including leukonychia, nail pitting or ridging, onycholysis,
onychomadesis, and red lunula.6264
Other conditions seen more commonly in the setting of LE that are on the list of LE-nonspecific skin
lesions include lichen planus, acanthosis nigricans,
cutis laxa, anetoderma, multiple dermatofibroma,
acquired ichthyosis, and interstitial granulomatous
dermatitis.6570

HISTOPATHOLOGY
Less Common Sub-types of Lupus
Erythematosus-Specific Skin
Disease
The histopathology of hypertrophic DLE lesions
is similar to that of classic DLE lesions except for a
much greater degree of epidermal acanthosis and
hyperkeratosis. At times, prominent acanthosis may
simulate keratinocytic neoplastic processes such as
squamous cell carcinoma.
In LE panniculitis the absence of the characteristic epidermal and dermal changes of LE can make
the histologic diagnosis difficult. In LE panniculitis,
subcutaneous tissue displays a lobular lymphocytic
panniculitis with perivascular infiltration with lymphocytes, plasma cells, and histiocytes in the deep
dermis and subcutaneous fat (including lymphoid
nodule formation); vessel wall thickening and invasion by mononuclear cells (lymphocytic vasculitis);

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Chapter 155:

absence of polymorphonuclear leukocytes; hyaline

fat necrosis; prominent fibrinoid degeneration of
collagen; and mucinous degeneration and calcification in old, established lesions. It is occasionally
confused histologically with cutaneous lymphoma
and has even demonstrated clonality in a minority
of cases.75
Except for the differences related to the absence
of hair follicles and stratum corneum in mucous
membranes, the microscopic changes of mucosal
DLE are highly reminiscent of those in cutaneous
DLE lesions.
Chilblain LE shows an interface dermatitis, with superficial and deep perivascular lymphocytic infiltration much like classic DLE. However, a lymphocytic
vasculitis and fibrin within the lumina of dermal
blood vessels are present in addition.72,73 In tumid
LE, the dermal changes of DLE are present, namely,
a variable perivascular mononuclear infiltrate with
prominent mucin between collagen bundles; but
the classic epidermal changes that occur in other
forms of LE-specific skin disease are not present.39
Histopathologic changes in vesiculo-bullous lesions
of LE are noted above under Section Vesiculobullous Skin Change in Lupus Erythematosus.

TREATMENT
Systomatic Therapy
OTHER IMMUNOSUPPRESSIVES.
Azathioprine (Imuran) (1.52.0 mg/kg/day orally)
can play a glucocorticoid-sparing role in the
severely affected patient with CLE. Mycophenolate
mofetil (MMF) (2.53.0 g/day orally) is a purine analogue similar to azathioprine, but with more specific
inhibition of the de novo pathway in lymphocytes.
This characteristic may allow for more efficacy and
less toxicity in treating severe, recalcitrant CLE, and
such results have been reported in several studies.9093 Although one study describes the lack of
efficacy of MMF in CLE,94 one of the authors (Melissa
I. Costner) has noted complete or partial response
in most patients treated with an average daily dose
of 3 g of MMF. Strict observance of dietary restrictions seems to enhance efficacy. Methotrexate
(7.525.0 mg orally 1 day per week) is effective for
severe refractory CLE. A double-blind, randomized, placebo-controlled trial in patients with SLE
showed that moderate doses of methotrexate
(1520 mg weekly) effectively controlled cutaneous
and articular activity and permitted a reduction
in prednisone dose.95 Leflunomide is an inhibitor

Lupus Erythematosus 239

of de novo pyrimidine synthesis that is approved

for the treatment of rheumatoid arthritis. Several
small series have reported beneficial results in SLE
patients. However, there have also been reports of
leflunomide-induced cutaneous lupus, thus this
drug should be used carefully in patients with LE.89
Efficacy with cyclosporine and even pulse cytoxan
for refractory disease has been reported.96
BIOLOGIC THERAPIES.
(See Chapter 234).
There have been a few reports documenting
efficacy of anti-TNF medications (etanercept,
adalimumab, and infliximab) in the treatment of
recalcitrant CLE.9799 However, these agents have
much more often been reported to induce both
SLE and CLE100,101 and should be used with caution.
These observations highlight the importance of TNF
homeostasis in patients predisposed to LE.27,102
Rituximab, a genetically engineered chimeric
monoclonal antibody directed against the CD20
antigen found on the surface of developing B
cells, has been studied systematically in SLE.103
Case reports have suggested efficacy in refractory CLE as well.104,105 B-lymphocyte stimulator
(BLyS) is a recently discovered member of the TNF
cytokine family. BLyS is made by monocytes and
macrophages with subsequent release when these
cells are activated. BLyS binds to a receptor found
only on B cells, which stimulates maturation into
antibody-secreting plasma cells. A fully human
monoclonal antibody directed against BLyS, belimumab, inhibits the biologic activity of BLyS. A recent
phase III trial showed improvement in patients with
SLE.106 This drug has been recently approved by the
FDA for the treatment of SLE.
Efalizumab, a recombinant humanized monoclonal IgG1 antibody directed against CD11a/LFA-1,
has been reported to be very effective in the treatment of refaractory CLE.107,108 However, efalizumab
was withdrawn from the US market in 2009 due to
three cases of progressive multifocal leukoencephalopathy.
Because abnormal regulation of IFN- appears
to play a central role in the pathogenesis of both
cutaneous and systemic manifestations of LE, early
clinical trials are currently underway to examine the
clinical efficacy of a monoclonal antibody to IFN-
(MEDI-545-MedImmune) in LE skin lesions of various subtypes occurring in the context of SLE.109

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240 Chapter 155: Lupus Erythematosus

Surgical and Cosmetic Therapy

DLE lesions can produce permanent scarring
alopecia, cosmetically disturbing dermal atrophy,
and pigmentary changes. Patients so affected often
ask about the possibility of cosmetic correction of
these changes. Surgical interventions such as hair
transplantation and dermabrasion carry finite risks
because CLE is characterized by a tendency for
nonspecific mechanical trauma, including surgical
incision or laser ablation, to exacerbate disease activity (i.e., Koebner phenomenon/isomorphic effect).
Some patients tolerate scar revision techniques,
including dermabrasion, if they are on maintenance
systemic therapy (e.g., antimalarials). Anecdotal
reports of the successful management of active
CLE with argon and pulsed dye laser therapy have
appeared. Resurfacing of atrophic scars with the
erbium:yttrium-aluminum-garnet laser or carbon
dioxide resurfacing laser has been reported to
be beneficial.110,111 Pulsed dye laser treatment has
also been shown to be effective and safe therapy
in patients with refractory DLE.112 The injection
of atrophic lesions with collagen or other similar
materials should be avoided, however one of the
authors (Melissa I. Costner) has been involved in the
care of patients with atrophy caused by facial lupus
profundus, who have been successfully treated
with injections of poly-l-lactic acid.

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