T h e Im m u n o p a t h o l o g y o f

Cutaneous Lupus
Erythematosus
Mark G. Kirchhof,

MD, PhD

, Jan P. Dutz,

MD

a,b,

KEYWORDS
 Cutaneous lupus erythematosus  Discoid lupus erythematosus  Chemokine
 Interferon-a  Cytokine
KEY POINTS
 Cutaneous manifestations of lupus erythematosus occur frequently in systemic lupus
erythematosus (SLE), may occur in the absence of systemic disease, and may precede
the diagnosis of SLE.
 Proposed pathophysiologic mechanisms are common to cutaneous lupus erythematosus
(CLE) and SLE, suggesting that response to skin disease may provide proof of principle for
therapy for this disease.
 Ultraviolet (UV) light is a prominent trigger factor, and increased interferon (IFN)-a production is a common initiator of CLE.
 Novel treatment strategies are aimed at maximizing inhibition of IFN-a production and
other potentially pathogenic cytokines.

INTRODUCTION

SLE is an autoimmune disease that is characterized by the development of autoantibodies and immunologic attack of different organ systems, including the skin. This
review aims to provide an overview of some of the pathogenic processes that may
be important in the development of SLE, specifically CLE, and then illustrates how
therapies might be tailored to modify these processes and treat disease.
Clinical Manifestations

The American College of Rheumatology (ACR) criteria for the diagnosis of SLE include
hematologic parameters such as elevated levels of antinuclear antibodies, end organ
Disclosure: JPD is funded by a Senior Scientist award at CFRI.
a
Department of Dermatology and Skin Science, University of British Columbia, 835 West 10th
Avenue, Vancouver, British Columbia V5Z 4E8, Canada; b Child and Family Research Institute,
University of British Columbia, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4,
Canada
* Corresponding author. Department of Dermatology and Skin Science, University of British
Columbia, 835 West 10th Avenue, Vancouver, British Columbia V5Z 4E8, Canada.
E-mail address: Jan.Dutz@vch.ca
Rheum Dis Clin N Am 40 (2014) 455474
http://dx.doi.org/10.1016/j.rdc.2014.04.006
rheumatic.theclinics.com
0889-857X/14/$ see front matter 2014 Elsevier Inc. All rights reserved.

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involvement such as lupus nephritis, and mucocutaneous manifestations.1 In order to

make a diagnosis of SLE, 4 of the 11 1982 ACR criteria need to be met.2 Given these
criteria, it is possible for someone to have a diagnosis of SLE despite the fact that the
person may only have mucocutaneous manifestation of disease. Newer criteria have
attempted to redress this imbalance and include new knowledge on the role of autoantibodies and low levels of complement.3 Cutaneous lesions may present years before
the development of systemic disease.4 Progression to systemic disease may occur
in as many as 18% by 3 years.5 As such any discussion of the cause of CLE must include
pathogenic processes inherent to SLE. Specific skin lesions of lupus (those in which histologic changes are diagnostic of lupus of the skin) can be divided into 3 broad categories based on the chronologic age of lesion. Acute cutaneous lupus classically
presents as nonscarring erythema over the malar region. Subacute cutaneous lupus
erythematosus (SCLE) can present clinically in a variety of ways, but the 2 most common are annular/polycyclic plaques and psoriasiform or papulosquamous plaques.
Finally, chronic cutaneous lupus erythematosus (CCLE) is perhaps the largest and
most diverse cutaneous form of lupus with lesions that vary from lupus panniculitis to
classic discoid lupus to chilblain lupus. The presence of CLE can give clues to systemic
manifestations in SLE. For example, CCLE in patients with SLE is associated with leukopenia, photosensitivity, and anti-Smith serology but decreased risk of serositis and
renal disease.6 Given a potential overlap in pathogenesis, and the ability to reliably measure skin disease activity, the skin has become a target organ of interest in the development of new pharmaceuticals for the treatment of SLE.7
PATHOGENESIS OVERVIEW

SLE, like many other autoimmune conditions, is the result of a complex interplay
between various pathogenic processes. Primary to the development of lupus is an
underlying genetic predisposition to the disease. In a genetically predisposed individual, it is thought that some sort of trigger initiates the disease processes. In the case
of lupus, these triggers may include infections, hormones, UV radiation, and exposure
to drugs and chemicals. These triggers initiate an inflammatory process that is
concomitant with exposure to autoantigens, likely through the antigens released by
apoptotic cells. Neutrophils and dendritic cells (DCs) may also play an important
role in the initiation of disease. Numerous cytokines and chemokines are involved in
propagating inflammatory responses, suppressing tolerogenic components of the immune system, recruiting immune cells, and promoting the activation of B and T cells.
Autoreactive B cells are intrinsic to the pathogenesis of lupus because they produce
the autoantibodies that are part of the diagnostic criteria of lupus and key in the clinical
manifestations of the disease. Intrinsic to pathogenesis of lupus are numerous feedback loops that amplify the immune response and ultimately lead to damage to end
organs such as the skin.
TRIGGERS
Genetics

Genetics plays an important role in the development of lupus, exemplified by the fact
that lupus has a 25% concordance rate among monozygotic twins compared with a
2% concordance for dizygotic twins.8 There have been numerous lupus-associated
genes identified that individually confer a modest risk of developing lupus.9
These genes mediate the function of immune cells such as B and T cells, antigenpresenting, cells and neutrophils and cellular signaling processes based on IFN
and other cytokines, as well as toll-like receptors (TLRs) and nuclear factor kB.10

The Immunopathology of CLE

Lupus-associated genetic changes are also linked to the clearance of nuclear debris,
apoptotic cells, and immune complexes. One of the most commonly reported
polymorphisms to predispose to the development of lupus is the major histocompatibility complex (MHC) genotype including HLA-DR3, HLA-DR2, and HLA-DRB1. Deficiencies of the complement pathway are also strong risk factors for the development
of lupus or lupus-like conditions. Overall, there have been well over 40 genes identified
as potentially contributing to the development of lupus.10 CLE has been associated
with polymorphisms near the locus of the skin-expressed IFN-k gene,11 and in polymorphisms of the TYK2, IRF5, and CTLA4 genes,12 all also associated with SLE suggesting a similarity in pathogenesis.
UV Light

UV light is a well-known trigger of CLE, and photosensitivity was one of the criteria
used to make the diagnosis of SLE in the 1982 ACR classification. The role of UV light
in the genesis of CLE lesions has recently been reviewed13: UV light has numerous
important effects in the pathogenesis of lupus including induction of a proinflammatory environment and apoptosis of keratinocytes.14,15 On UV exposure, the proinflammatory cytokines IFN-a, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a are
secreted.14,16,17 UV radiation also upregulates intracellular adhesion molecule expression and induces the secretion of chemokines that facilitate homing of immune cells to
the skin.18 UV radiation is absorbed by DNA of keratinocytes and results in alterations
such as the formation of strand breaks or cyclobutane pyrimidine dimers.19 The
combination of proinflammatory cytokines and DNA damage results in significant keratinocyte cell death. The apoptotic keratinocytes release potential autoantigens, such
as Ro52, that can serve as a stimulatory nidus for autoreactive B and T cells.20 UV
radiation also induces the expression of nuclear antigens on the surface of keratinocytes, and this may be related to the strong association of anti-Ro and anti-La to cutaneous forms of lupus.21 UV-oxidized DNA is resistant to degradation by cytosolic
nucleases such as TREX1, potentiating immune sensing by cytosolic receptors that
promote inflammatory IFN-a production.22 Overall, UV radiation promotes an autoimmune state that initiates a pathogenic process intrinsic to lupus.
Infections

Numerous infections have been linked to the development or the flare of lupus. Proposed mechanisms for this include molecular mimicry, superantigen stimulation of immune cells, epitope spreading, and alterations to the activation and survival of immune
cells. Among the commonly implicated viruses associated with lupus are cytomegalovirus (CMV), hepatitis C, and Epstein-Barr virus (EBV). High levels of EBV antibodies
have been correlated with skin and joint manifestations of lupus.23,24 The prevalence
of EBV antibodies is higher in patients with lupus than in the general population.
Molecular mimicry has been noted with EBV. Autoantibodies from patients with lupus
(notably anti-Ro, noted in photosensitive lupus) are able to bind EBV antigens, and
conversely, anti-EBV antibodies can cross-react with autoantigens commonly associated with lupus, such as double-stranded (ds) DNA.25 EBV-infected B cells may
become resistant to apoptosis and thereby overcome tolerogenic mechanisms.26
CMV has also been associated with lupus development, determined by correlating
the levels of anti-CMV immunoglobulin (IgM) or CMV DNA and the onset or flare of
lupus. CMV infection has been shown to induce expression of 60-kDa Ro on keratinocytes.27 Likewise, bacterial infections may stimulate the immune system as bacterial
PAMPs (pathogen associated molecular patterns) bind TLRs, which stimulate plasmacytoid DCs cells to produce IFN and facilitate the production of autoantibodies.

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Drugs and Chemicals

It has been well established that certain medications can induce both SLE and CLE. This
is exemplified by IFN-a-induced lupus, during the treatment of infections and neoplasms.28 Anti-TNF-a medications used in a variety of autoimmune diseases have
been shown to induce lupus-like cutaneous eruptions.29 This fact may relate to local induction of IFN-a in the skin, noted in psoriasiform eruptions induced by anti-TNF therapy.30 Induction of SCLE has been linked to terbinafine, calcium channel blockers, and
hydrochlorothiazide, all drugs that potentiate photosensitivity.31 Up to one-third of all
cases of SCLE may be attributed to such drug exposure.32 The relationship between
cigarette smoking and lupus is controversial. Cigarette smoking has been proposed
to increase the levels of proinflammatory cytokines such as TNF-a,33 thus possibly predisposing to the onset or worsening of lupus. In addition, several studies have shown a
decrease in the effectiveness of antimalarial therapy on CLE in patients who smoke.34
Hormones

The observation that SLE is far more frequent in premenopausal women suggests that
there is a significant hormonal component to the pathogenesis of lupus. Furthermore,
flares of SLE have been associated with changes in hormones such as those seen in
pregnancy or from exogenous administration of hormones either as replacement therapy or contraception. Estrogens and prolactin promote the survival and activation of
autoreactive B cells, thereby promoting the production of autoantibodies.35 Estrogens
are also able to modulate the polarization of T-helper cells to a TH2 phenotype with
increased production of IFN-a, IL-4, and IL-10 as well as stimulating the production
of TNF-a.36 In CLE, estrogen may facilitate the interaction between keratinocytes
expressing autoantigens and autoantibodies like anti-Ro and anti-La.37 The overall
sex ratio for CLE in one study over a 40-year period was female:male 5 1.8:1, which
thus includes a much higher proportion of males than is common for SLE.4
Apoptosis

Apoptosis of keratinocytes is a key process in the pathogenesis of CLE as has been

demonstrated by the detection of apoptotic keratinocytes in the basal layer of
CCLE lesions and in the suprabasal region of SCLE lesions.38 UV-radiation-induced
apoptosis is a significant stimulant for proinflammatory cytokines and autoantigen
availability.14,16 There is also evidence that apoptosis itself is able to generate novel
autoantigens that are then targeted by autoantibodies.21,39 Phosphorylation of proteins and caspase-mediated protein cleavage are 2 methods active during apoptosis
that generate novel autoantigens. These novel autoantigens may be able to break
tolerance. There also seems to be a decreased level of clearance of apoptotic cells
by macrophages, which may provide more time for the stimulation of autoreactive B
cells and the formation of autoantibodies.40
Cytokines
IFNs

The IFN cytokine family plays a key part in the pathogenesis of lupus; however, much
of the data have focused on IFN-a and IFN-g. IFN-a increases MHC expression, antibody production, and lymphocyte survival.41 In patients with SLE, IFN-a serum levels
correlate with disease activity and autoantibody levels.42 The main source of IFN-a in
patients with SLE is the plasmacytoid DC.43 Production of IFN-a by plasmacytoid DCs
is stimulated by immune complexes and, because IFN-a also stimulates autoantibody
production, this produces a feedback mechanism that can quickly generate rapid increases in IFN-a.44 IFN-a-induced proteins are upregulated and plasmacytoid DC

The Immunopathology of CLE

numbers are increased in lesions of skin lupus.45 Furthermore, the IFN-a-induced

gene signature is increased in the blood of patients with CLE and correlates with
the activity of the skin disease.46 Within the skin, IFN-a increases expression of chemokines and chemokine receptors, thereby facilitating homing of immune cells to the
active lesions of CLE.47 Furthermore, IFN-a stimulates the expression of deathinducing molecules such as TRAIL and the death receptor TRAIL-R1 on keratinocytes,
perhaps enhancing local keratinocyte cytotoxicity.48 Epithelial-expressed (type III)
IFNs such as IFN-l have also been suggested to have a primary immunestimulatory role in CLE.49 These stromal IFNs may be induced through stimulator of
interferon genes (STING) signaling after the recognition of damaged DNA by cytosolic
DNA receptors such as cyclic GMP-AMP synthase.50 Using elegant transgenic mice
crosses, it has been demonstrated that increased stromal IFN production, such as
the one that occurs if the deoxyribonuclease (DNAse) TREX1 is ablated, is sufficient
to ultimately drive B- and T-cell-mediated lupus-type autoimmunity.51
IFN-g is considered to be a typical TH1 cytokine and promotes cytotoxic immune
responses by upregulating antigen processing and presentation. IFN-g is produced
by natural killer cells and activated TH1 cells. IFN-g has been shown to be elevated
in the serum of patients with SLE and correlates with disease activity.52 A recent
transcriptomic analysis of CCLE skin lesions has shown a lesional enrichment of
INF-g-related genes and a paucity of IL-17-associated genes when compared with
psoriasis.53 The pathogenic effects IFN-g are presumed to be similar to that of
IFN-a involving increased autoantibody formation, increased MHC expression,
increased chemokine and chemokine receptor expression, and generally promoting
an inflammatory state.
TNF-a

TNF-a is produced by keratinocytes on exposure to UV radiation or bacterial endotoxin; however, the main source of TNF-a in the epidermis is believed to be mast
cells.54 When keratinocytes from patients with CLE are stimulated with IL-18 (another
proinflammatory cytokine implicated in lupus pathogenesis), TNF-a is produced in significant quantities compared with keratinocytes from normal controls.55 TNF-a is
expressed in the lesions of SCLE,56 and SCLE is associated with a TNF-a promoter
polymorphism.57 However, the primordial role of this cytokine in skin disease remains
conjectural because TNF inhibitors have not been singularly effective in treating the
condition and may trigger lupus-like eruptions29 as well as SLE.58
B-lymphocyte stimulator (BLyS) or BAFF

B-lymphocyte stimulator (BLyS/BAFF) is a cytokine and a member of the TNF ligand

family.59 BLyS is expressed by a wide variety of cells including monocytes, neutrophils, T cells, and DCs. BLyS promotes the survival, proliferation, and differentiation
of B cells and stimulates immunoglobulin secretion. In patients with lupus, BLyS levels
are elevated in serum and correlate with anti-dsDNA antibody levels. BLyS and BLyS
receptor are also overexpressed in lesional cutaneous lupus skin.60 BLyS expression
can be induced by PAMPs such as CpG, lipopolysaccharide, dsDNA, and peptidoglycans suggesting that infectious agents may be able to upregulate BLyS expression.61
These PAMPs can also induce expression of BLyS receptor on B cells through TLR-4and TLR-9-based signaling. This fact suggests that there might be a positive feedback
mechanism between the innate immune system and B cells.
IL-6

IL-6 is mainly produced by monocytes, fibroblasts, and endothelial cells.62 IL-6 promotes
the development and maturation of B cells into plasma cells, which ultimately leads to

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increased levels of autoantibodies.63 Monocytes, fibroblasts, endothelial cells, and keratinocytes have been shown to produce IL-6 when exposed to UV-B radiation.14,64 In
patients with lupus, IL-6 level is elevated in serum and correlates with disease activity
and autoantibody levels.64 In a murine model, keratinocyte-induced IL-6 production promoted SLE.65 IL-6 levels are elevated in the sun-exposed skin of patients with SLE.65
IL-10

IL-10 is generally regarded as an antiinflammatory cytokine, although it can have

proinflammatory effects in certain situations. IL-10 is produced by monocytes and
lymphocytes. IL-10 inhibits T-cell activation and TNF-a secretion, but supports
B-cell proliferation and differentiation as well as immunoglobulin production by B cells
from patients with lupus.66 Immune complexes in the sera of patients with SLE have
been shown to promote IL-10 production.67 A pilot trial of anti-IL-10 antibody therapy
demonstrated improvement in skin and joint disease in 6 patients with SLE.68
IL-17

The IL-17 cytokine is produced by TH17 T cells and has been implicated in numerous
autoimmune conditions including psoriasis and multiple sclerosis. IL-17 is able to
stimulate the production of other proinflammatory cytokines such as IL-6 and TNF-a
and chemokines that attract monocytes and neutrophils to areas of inflammation.69
The receptors for IL-17 are expressed on a variety of cell types and tissues including
T cells, B cells, vascular endothelial cells, and tissues from organs such as the lung,
heart, kidney, and gastrointestinal system. The fraction of TH17 cells in the peripheral
blood of patients with lupus is elevated, and increases in TH17 cells are correlated with
flares of disease particularly with accompanying vasculitis.70 IL-17 levels are elevated
in the serum of patients with lupus and correlate with disease activity and autoantibody production. Although elevated levels of IL-17A and IL-17F have been reported
in the serum and skin of patients with SLE and CLE (both CCLE and SCLE),71 a recent
transcriptome analysis of lesional CLE skin did not show an increase in IL-17-related
transcripts in CCLE lesional skin.53
Chemokines

Chemokines are important in recruiting immune cells to areas of inflammation. The

CXCL9, CXCL10, and CXCL11 chemokines are strongly expressed in the lesions of
cutaneous lupus.72 These CXCL chemokines are induced by IFN-a73 and are important in the recruitment of CXCR3-positive lymphocytes to the epidermis.74 This fact
is confirmed by the finding of high numbers of CXCR3-positive lymphocytes in lesional
skin with concomitant decreases in circulating CXCR3-positive lymphocytes.74
CXCL10 is most prominent at the interface between the epidermis and dermis where
CXCR3-positive lymphocytes invade the epidermis.75
ADAPTIVE IMMUNE SYSTEM
T Cells

One of the main themes of lupus pathogenesis is the downregulation of tolerogenic

mechanisms that normally control the survival and development of autoreactive
lymphocytes. In particular, the downregulation of T-regulatory cells seems to play
an important role in the development of lupus. Analysis of skin lesions from patients
with CLE shows that levels of Treg cells are reduced in number compared with
those in other inflammatory diseases.76 Transcriptome analysis of lesional skin from
11 patients with CCLE compared with that of psoriasis and normal skin has shown
a skew toward TH1-type T cells and IFN-g production.53

The Immunopathology of CLE

B Cells

The central role of B cells in the development of lupus involves breaking tolerance
resulting in autoreactive B cells and plasma cells that produce autoantibodies. Primary
to this process is the breaks in tolerance that occur both centrally and peripherally.
Deficiencies in early negative selection result in the persistence of mature naive B cells
that have the ability to recognize self-antigens.77 Regulatory B cells in patients with
lupus, although present at similar frequencies to normal control patients, lack the
functionality found in normal control patients.78 B cells are focally increased in lesions
of CCLE,79 but their role in local pathogenesis is unknown.
Autoantibodies

Numerous autoantibodies have been associated with lupus including antinuclear

antibody, anti-dsDNA, anti-SSA/Ro, anti-SSB/La, and anti-Smith.80 The role of these
autoantibodies in the pathogenesis of CLE is unclear. Clinical manifestations of disease seem to correlate with certain autoantibodies. Anti-SSA/Ro and antinucleosome
antibodies are associated with CLE.81 However, deposition of these autoantibodies
does not necessarily correlate with active disease and autoantibody deposits are
found within clinically normal skin as well as within active lesions.
Complement

The complement system involves both the innate and adaptive immune systems. One
of the most robust associations with the development of lupus is complement deficiency. C1q, C1r, and C1s deficiencies are associated with a high risk of developing
lupus, and specifically CLE.82 Deficiencies in these complement components and
others reduce the ability to clear immune complexes leading to increased availability
of autoantigens. Complement is also important in clearing apoptotic cellular material.
C1q-deficient mice show delayed clearance of apoptotic cells, which leads to secondary necrosis.83 C1q is also able to regulate the production of IFN by plasmacytoid
DCs.84 C1q inhibits IFN secretion when plasmacytoid DCs are stimulated by CpG
DNA or immune complexes; therefore, any deficiency in C1q results in increased
IFN secretion.
INNATE IMMUNE SYSTEM
DCs

DCs play numerous roles in the pathogenesis of lupus. DCs phagocytose apoptotic
cells and cellular debris, activate B cells, and secrete proinflammatory and stimulatory
cytokines. Phagocytosis by DCs is important in preventing exposure to self-antigens
and developing immune reactions to the autoantigens.85 DCs from patients with lupus
have been shown to have decreased abilities to phagocytose apoptotic cells.85 DCs
also participate in the stimulation of autoreactive B cells by presenting autoantigens
and releasing stimulatory cytokines such as IFN, IL-6, and BLyS. The importance
of DCs in the development of lupus was demonstrated in lupus-prone mice that developed less severe systemic disease when their DCs were depleted.86 Inflammatorytype DCs87 and activated conventional DCs88 are increased within the skin lesions
of lupus.
Neutrophils

Activated neutrophils die in a unique way termed NETosis that differs from necrosis
and apoptosis.89 During NETosis, the neutrophils release large amounts of DNA
that form net- or weblike structures termed neutrophil extracellular traps (NETs). In

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lupus, NETs are formed when neutrophils are activated by immune complexes containing nucleic acids. Patients with lupus also seem to have neutrophils that are more
likely to release NETs. The DNA within the NETs is protected from degradation. Sera
from patients with lupus have been shown to have an impaired ability to degrade
NETs, and this deficiency is associated with increased levels of anti-dsDNA antibodies.90 This deficient NET degradation may be related to DNase inhibitory antibodies because DNase function is lower in the sera of patients with lupus and NET
degradation can be rescued by exogenous DNase. The DNA associated with the
NETs may act as ligands for TLRs, thereby mediating plasmacytoid DC activation
and IFN production.91 Furthermore, IFN can potentiate NETosis leading to a selfperpetuating feedback loop. Mouse experiments have suggested the importance of
neutrophils in the development of lupus and CLE: when inflammatory lupus-like
skin disease is initiated by tape stripping, NETosis is noted with increased levels of
IFN production from activated plasmacytoid DCs.92 Increased NETs are detected
in lesional CLE skin.93
TLRs

TLRs, on DCs and B cells, play important roles in the interplay between the innate
immune system and the adaptive immune response. B-cell upregulation of BLyS in
the presence of microbial products depends on TLR-4 and TLR-9 signaling. Reports
have suggested that TLRs may bind and signal not only from engagement of exogenous
ligands but also from endogenous ligands such as UV-damaged DNA.94 TLR-9 or TLR7/8 may mediate responses to autoantigens in plasmacytoid DCs, resulting in IFN
production. Treatment of mice with dual TLR-7 and TLR-9 inhibitor causes a decrease
in autoantibody levels and clinical improvement of disease symptoms.95 Overall, TLRs
represent an interesting and growing area of study in the pathogenesis of lupus.
THERAPEUTIC IMPLICATIONS
Photoprotection

Because CLE can be triggered by sunlight exposure, the use of consistent UV light
protection is important. Studies of broad-spectrum sunscreen use before photoprovocation have demonstrated the prevention of UV-induced lesions.96
Topical Therapy

Topical therapy is practical for limited disease. Potent corticosteroids are the first-line
option and are most frequently used.97 Corticosteroids have multiple antiinflammatory
actions on both innate and adaptive immune cells. Recent work suggests that corticosteroids may also promote apoptotic cell clearance.98 Topical calcineurin inhibitors
are also effective in improving cutaneous lesions.99 However, once daily use of
clobetasol 0.05% ointment was found to be superior to twice daily use of tacrolimus
0.1%.100
Antimalarial Therapy

The antimalarials, hydroxychloroquine and chloroquine, are first-line therapies for widespread cutaneous disease.101 Hydroxychloroquine response requires adequate blood
levels,102 and thus blood level monitoring may improve outcomes. Response may be
slow, with improvement beyond 2 months, and may be enhanced by the addition of
quinacrine.103 Although it has been proposed that antimalarials improve CLE by inhibiting TLR-7/8 and TLR-9 signaling through an effect on endosomal pH,101 recent work has
suggested that these drugs actively bind nucleic acids and thereby prevent TLR-ligand
interaction104 leading to inhibition of downstream events such as decreased IFN-a

The Immunopathology of CLE

production and IL-6 release. Thus, antimalarial therapy in patients with SLE impairs the
ability of their plasmacytoid DCs to produce INF-a and TNF-a on stimulation with TLR 9
and TLR 7 agonists.105 This mechanism may also explain how chloroquine inhibits IL-1b,
IL-6, and TNF-a release in the skin after UV irradiation in patients with SLE.106
Immunosupressive and Immunomodulatory Therapy

For patients refractory to antimalarials, dapsone, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, retinoids, and thalidomide are therapeutic options.107
The clinical evidence for the use of these agents has been expertly reviewed.107
Roughly 10% of patients are refractory to treatment with these agents,108 and new
options for recalcitrant disease are required.
Methotrexate is an antimetabolite that has multiple modes of action. Analysis of
patients with psoriasis treated with methotrexate has indicated that this drug does
not change the TH1 or TH2 profile of T cells.109 Work from 2 groups has suggested
that one mode of action of this drug may be to alter lymphocyte trafficking, with a
decrease in the proportion of skin-homing cutaneous lymphocyte antigen-bearing
T cells.109,110 Newer agents that may alter skin-homing T-cell traffic, analogous to
agents limiting traffic of T cells to the gut, are eagerly awaited.
Thalidomide has been shown to improve CLE is a prospective study.111 This drug
has been described as one of the most effective for the treatment of resistant CLE,
limited in use by common neurotoxicity.107 Likewise, lenalidomide, a thalidomide
analog, may be of benefit in refractory cases.112 The mechanism of action of thalidomide and thalidomide analogs in CLE is still unclear. Apremilast, another thalidomide
analog and phosphodiesterase 4 inhibitor, improved cutaneous skin scores in patients
with chronic CLE.113 This drug inhibits T-cell production of IFN-g,114 among other
cytokines.
Retinoids have been shown to have an efficacy comparable to antimalarials in
the treatment of CLE, their use being limited by common cutaneous side effects
such as skin dryness. In a double-blind randomized trial comparing acitretin with
hydroxychloroquine, improvement occurred in 13 of 28 patients treated with acitretin
and in 15 of 30 patients treated with hydroxychloroquine.115 Isotretinoin (80 mg/d)
has been reported to induce rapid improvement in 8 patients (7 with CCLE and 1
with SCLE) treated, associated with normalization of histology.116 Alitretinoin has
recently been reported to improve single cases of CCLE, SCLE, and hypertrophic
CCLE.117 The mechanism of action of retinoids in CLE is unclear, although isotretinoin
has a prominent effect on T-cell production of IFN-g in acne vulgaris118 and acitretin
also inhibits IFN-g production in psoriasis.119 Because the mode of action differs from
those of antimalarials, combination therapy (retinoid and antimalarial/antimalarials)
may be beneficial in antimalarial-resistant skin disease.120
Few studies to date of T-cell inhibitors or cytokine inhibitors have shown convincing
activity for CLE. Perhaps, given the paucity of lesional IL-17-related transcripts in CLE,
only 3 case reports support an effect of ustekinumab on CLE.107,121,122 The presence
of IFN-g-related transcripts in lesional skin supports trial of inhibitors of this pathway.
Pathway network analysis of genes overexpressed in T cells in SLE suggests that
inhibitors of the JAK/STAT pathways may be therapeutically useful in SLE.123 JAK1
and JAK2 inhibitors block IFN-g production, and topical inhibitors are under development.124 JAK1 and JAK3 inhibitors such as tofacitinib, used in rheumatoid arthritis,
may have activity for CLE.125 However, a topical JAK/Syk inhibitor (R333) recently
did not achieve the primary end point in a phase 2 study (http://ir.rigel.com/phoenix.
zhtml?c5120936&p5irol-newsArticle&ID51867780&highlight). A specific monoclonal
antibody blocking IFN-g has been studied in a preliminary manner in CCLE (AMG 811,

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ClinicalTrials.gov # NCT01164917) and SLE. Although the studies were not powered
to assess efficacy, AMG 811 led to a dose-dependent modulation of the expression
of many of the genes associated with IFN-g signaling and a reduction in CXCL10.126
B-cell-directed therapies have so far demonstrated only a moderate effect on CLE.
B-cell depletion therapy with rituximab in 17 patients with cutaneous manifestations of
SLE resulted in temporary improvement in 53% of patients.127 Belimumab, an inhibitor
of BLyS, and the first drug approved specifically for the treatment of SLE, is noted to
improve rash, mucosal ulcers, and alopecia.128 More rigorous studies of these agents
in CLE with the use of standardized outcome measures such as the cutaneous lupus
activity score index (CLASI)129 are awaited.
Because elevated levels of IL-6 are noted in lupus, and in lesional CLE skin, inhibitors for this pathway are currently being assessed as therapeutic agents. One report
details the use of tocilizumab, an antibody to the IL-6 receptor, to treat refractory CLE
and urticarial vasculitis.130 Preliminary data from a phase 1 study of sirukumab (CNTO
136), an antibody to IL-6, demonstrated a decrease in levels of C-reactive protein in
treated individuals and a trend to lower CLASI inflammation scores.131 Further studies
on the effects of this agent on CLE are awaited.
Perhaps the most direct approach to therapy, given the prominence of IFN-a
transcripts within the skin, is direct inhibition of the type 1 IFN pathway. In this regard,
trials of sifalimumab, a monoclonal antibody to IFN-a, have shown inhibition of an IFNa-related transcriptome in the skin132 but only modest clinical change in systemic disease.133 Intravenous immunoglobulin (IVIG) infusions have been used as treatment of
multiple autoimmune diseases. IVIG has been used for severe hematologic and neurologic disease in SLE.134 IVIG use in a mouse model of SLE demonstrated improvement
in skin disease but not renal disease.135 In one study, 5 of 12 patients treated with IVIG
for CLE had excellent response.136 Responders predominantly had SCLE and had
failed multiple other therapies; no changes in immune parameters or systemic disease
were noted. A single case report details the use of IVIG for the successful treatment of
lupus panniculitis, after failure of standard therapy.137 The authors have had a similar
experience with an additional case. IgG has been reported to inhibit IFN-a production
by plasmacytoid DC through both intracellular pathways (promoting prostaglandin E
production) and by Fc receptor blockade.138 IVIG has also been shown to attenuate
TLR-9 response in B cells of patients with SLE who have been treated.139 A preliminary
study to assess the benefit of IVIG in CLE is underway (NCT01841619).
SUMMARY

Because SLE and CLE are clinically heterogeneous diseases, a simple pathophysiological understanding of these diseases remains elusive. There are multiple genetic
similarities between patients with skin-limited and systemic disease, arguing for a
common pathogenesis. The ability to photoprovoke skin lesions argues for an important initiator role for UV light. Multiple lines of evidence point to an important role for
abnormal responses to dead and dying cells with either a propensity for cell death
or deficiencies in the noninflammatory clearance of dead cells. Innate immune responses resulting in the local overproduction of INF-a lead to activation of the adaptive immune system at the interface of the dermis and epidermis, thus causing tissue
damage (Fig. 1A). This understanding of the pathways of damage in CLE has clarified
the understanding of the mode of action of commonly used treatments in CLE
such as antimalarial agents and corticosteroids (see Fig. 1B). The primacy of type 1
and possibly type 3 IFN pathways and IFN-g has suggested new therapeutic routes
such as inhibition of IFN-a and blockade of cytokine signaling (see Fig. 1C). It is hoped

Fig. 1. (A) Model of the pathogenesis of cutaneous lupus erythematosus: Keratinocytes (KC)
are damaged by ultraviolet light or other stimuli and are induced to undergo apoptosis. Either
increased cell death or defective clearance results in an immunostimulatory environment with
stimulation of TLR and cytosolic danger receptors. Neutrophils (Neut) and plasmacytoid dendritic cells (pDC) conspire to release INF-a summoning activated inflammatory dendritic cells.
This culminates in TH1 T-cell instruction and B-cell-mediated autoantibody production leading
to further stromal cell damage. (B) Based on the pathogenesis model in (A), currently available
therapies for cutaneous lupus erythematosus are indicated in red at the most likely sites of action. (C) Based on the pathogenesis model in (A), investigational therapies and novel therapeutic action points are indicated in magenta. STING, stimulator of interferon genes.

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Fig. 1. (continued)

that these new therapeutic avenues will lead to novel and effective therapies for this
difficult-to-treat disease and suggest strategies for the prevention of disease in the
genetically susceptible.
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