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Cutaneous Manifestations of “Lupus”: Systemic Lupus Erythematosus and Beyond

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Lupus, Latin for “wolf,” is a term used to describe many dermatologic conditions, some of which are related to underlying systemic lupus erythematosus, while others are distinct disease processes. Cutaneous lupus erythematosus includes a wide array of visible skin manifestations and can progress to systemic lupus erythematosus in some cases. Cutaneous lupus can be subdivided into three main categories: acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus erythematosus. Physical exam, laboratory studies, and histopathology enable differentiation of cutaneous lupus subtypes. This differentiation is paramount as the subtype of cutaneous lupus informs upon treatment, disease monitoring, and prognostication. This review outlines the different cutaneous manifestations of lupus erythematosus and provides an update on both topical and systemic treatment options for these patients. Other conditions that utilize the term “lupus” but are not cutaneous lupus erythematosus are also discussed.
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Review Article
Cutaneous Manifestations of Lupus: Systemic Lupus
Erythematosus and Beyond
Elizabeth E. Cooper ,
1
Catherine E. Pisano ,
1
and Samantha C. Shapiro
2
1
Department of Dermatology, Dell Medical School at the University of Texas, Austin 78701, USA
2
Department of Medicine, Division of Rheumatology, Dell Medical School at the University of Texas, Austin 78701, USA
Correspondence should be addressed to Elizabeth E. Cooper; elizabeth.cooper2@ascension.org
Received 1 January 2021; Accepted 11 May 2021; Published 19 May 2021
Academic Editor: Bruce M. Rothschild
Copyright © 2021 Elizabeth E. Cooper et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Lupus, Latin for wolf,is a term used to describe many dermatologic conditions, some of which are related to underlying systemic
lupus erythematosus, while others are distinct disease processes. Cutaneous lupus erythematosus includes a wide array of visible
skin manifestations and can progress to systemic lupus erythematosus in some cases. Cutaneous lupus can be subdivided into
three main categories: acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous
lupus erythematosus. Physical exam, laboratory studies, and histopathology enable dierentiation of cutaneous lupus subtypes.
This dierentiation is paramount as the subtype of cutaneous lupus informs upon treatment, disease monitoring, and
prognostication. This review outlines the dierent cutaneous manifestations of lupus erythematosus and provides an update on
both topical and systemic treatment options for these patients. Other conditions that utilize the term lupusbut are not
cutaneous lupus erythematosus are also discussed.
1. Introduction
Skin involvement is often a prominent feature of systemic
lupus erythematosus (SLE), a multiorgan, chronic autoim-
mune disorder that can lead to disability and death [1, 2].
The strongest risk factor for SLE is gender, with a female-
to-male incidence ratio of 7 to 15 : 1 in adults and 3 to 4 : 1
in children [3]. Though there is a less dramatic gender pre-
dominance in patients who have isolated cutaneous lesions,
the female-to-male ratio in these patients is still 3 : 1 [1]. It
should be noted that SLE is one of the top 20 leading causes
of death in females between 5 and 64 years of age [2]. SLE
is four times more prevalent in black women than in white
women, and patients of African descent tend to develop
disease earlier and have higher mortality [35].
While SLE commonly has cutaneous manifestations,
cutaneous lupus may occur in the absence of systemic lupus
erythematous. Acute cutaneous lupus erythematosus
(ACLE), subacute cutaneous lupus (SCLE), and discoid lupus
(DLE) are the three most common manifestations of cutane-
ous lupus erythematosus (CLE). There are also several less
common cutaneous manifestations of lupus, including
lupus tumidus, lupus panniculitis, bullous SLE, the toxic
epidermal necrolysis variant of lupus, chilblain lupus,
hypertrophic or verrucous discoid lupus, mucosal discoid
lupus, and lichenoid cutaneous lupus-lichen planus overlap
syndrome [6, 7]. Complicating the picture, several skin con-
ditions that are separate and distinct from lupus erythema-
tosus make use of the word lupusas well: lupus vulgaris,
lupus miliaris disseminatus faciei, and lupus pernio. These
skin conditions are related to tuberculosis, granulomatous
rosacea, and sarcoidosis, respectively. These are not true
forms of CLE.
After initial diagnosis of CLE, risk of progression to SLE
is between 5 and 18% within three to ve years [810].
Approximately one-third of CLE patients have an existing
diagnosis or will be diagnosed with SLE in the future [8].
Patients with ACLE, bullous lupus, and nonspecic cutane-
ous lesions of lupus (e.g., vasculopathic lesions, see
Figure 1) all have a higher risk of developing systemic lupus
Hindawi
International Journal of Rheumatology
Volume 2021, Article ID 6610509, 19 pages
https://doi.org/10.1155/2021/6610509
when compared to individuals diagnosed with SCLE, DLE,
lupus tumidus, lupus panniculitis, or chilblain lupus [1].
On a molecular level, most variants of CLE are charac-
terized by a lichenoid tissue reaction as a result of keratino-
cyte, endothelial cell, and dendritic cell activation [1].
Production of type I interferons with subsequent cluster of
dierentiation 4+ (CD4+) and CD8+ T cell recruitment
and activation leads to cytotoxic keratinocyte damage [1].
CLE results from a complex interplay of genetic and
environmental factors [1, 3]. Ultraviolet radiation, certain
medications, smoking, and viral infection can trigger an
inammatory cascade involving cells of the skin and
recruited inammatory cells [1, 3, 1113]. Genetic variation
based upon parentage and gene mutations contributes to the
wide variation in clinical presentation of cutaneous LE. The
three major types of CLE are not mutually exclusive, and
more than one type of cutaneous lesion may occur in a sin-
gle patient [6, 7]. The goal of this review is to critically
evaluate the most recent literature on lupus erythematosus-
specic cutaneous disease, as well as address cutaneous
ndings of unrelated conditions that make use of the term
lupusas a descriptor.
2. Cutaneous Manifestations of Lupus
2.1. Acute Cutaneous Lupus Erythematosus. Acute cutaneous
lupus erythematosus (ACLE) is frequently associated with
systemic lupus erythematosus, and it exists in both localized
and generalized forms. 95% of patients with ACLE have a
positive antinuclear antibody (ANA). In both subtypes of
ACLE, are-ups of rash frequently parallel systemic disease
activity, though exceptions may occur. ACLE lesions typi-
cally resolve without scarring, though postinammatory
dyschromia may occur, especially in darker skinned indi-
viduals [6, 7, 14].
The localized form of ACLE is commonly described as a
malar or butteryrash that covers the cheeks and nasal
bridge (Figure 2). The forehead and anterior neck may be
included, but the nasolabial folds are spared. Conuent,
reddish-purple discoloration with mild edema and/or pap-
ules is common. The rash classically lasts days to weeks and
can be triggered by sun exposure. It is present at diagnosis
in 40-52% of SLE patients [15]. The rash may commonly be
mistaken for rosacea, which presents with papules and pus-
tules, or seborrheic dermatitis, which involves the nasolabial
folds [7]. Telangiectasias, erosions, dyspigmentation, and
poikiloderma are all clues that support a diagnosis of ACLE.
A malar rash may also occur in dermatomyositis and can be
dicult to dierentiate from the classic malar rash of ACLE.
However, the malar rash of dermatomyositis classically does
not spare the nasolabial folds [16].
The generalized form of ACLE is commonly described as
a maculopapular rash, or photosensitive dermatitis. It is less
common than localized ACLE. The rash may occur both
above and below the neck, with a predilection for sun-
exposed areas. This form of ACLE may again resemble skin
ndings seen in dermatomyositis, though the rash involving
the hands in ACLE has been described as reverse Gottrons,
as it involves the skin located between the nger joints, and
not the skin overlying the joints [6].
Skin biopsy in ACLE reveals basal layer degeneration,
edema of the upper dermis, interface dermatitis with a mono-
nuclear cell inltrate at the dermal-epidermal junction,
mucin deposition, hyperkeratosis, and perivascular and peri-
adnexal inammation (lymphocytic inltrate) [1]. Direct
immunouorescence (DIF) can demonstrate the lupus
bandin a majority of cases, which refers to a granular depo-
sition of immunoglobulins and complement at the dermal-
epidermal junction [17]. While a positive lupus band test
supports a diagnosis of ACLE, a negative DIF does not rule
it out [6, 7]. Immunoglobulin M (IgM) and complement 3
(C3) are most commonly detected, and the presence of addi-
tional immunoreactants (i.e., IgG, IgA, C1q, and C4), an
uninterrupted linear band, and increased intensity of staining
all increase the specicity and predictive value of this nding.
DIF can be useful for distinguishing cutaneous lupus from
other inammatory skin conditions [18, 19]. Many studies
have shown that SLE patients will frequently have positive
DIF when sun-protected, nonlesional (i.e., no rash) skin is
biopsied [20]. Of note, a nonlesional lupus band test can be
positive in patients with other autoimmune diseases [18, 19,
21, 22]. It is important to note that histopathology with
Figure 1: Lupus vasculitis, with digital ischemia and mesenteric
ischemia, ultimately resulting in perforated bowel.
2 International Journal of Rheumatology
DIF cannot dierentiate between the rashes of lupus and der-
matomyositis, as both may have similar ndings [18, 21].
First-line treatment of ACLE includes general preventa-
tive measures such as sun protection and smoking cessation
(see Table 1) [6, 7]. Local treatments include topical steroids
or calcineurin inhibitors, especially in mild cases [6, 7, 23].
Antimalarial agents such as hydroxychloroquine and chloro-
quine are recommended as rst-line systemic agents. Dra-
matic clinical improvement after administration of these
drugs in ACLE has been repeatedly demonstrated in the liter-
ature, including one recent meta-analysis which established
signicant response in 91% of ACLE cases [23]. Short courses
of oral corticosteroids may be required in severe or refractory
cases, specically during a are-up when bridging to slower-
acting steroid-sparing medications. However, chronic sys-
temic steroid use is to be avoided due to multiple adverse
eects [6].
2.2. Toxic Epidermal Necrolysis (TEN) Variant of Lupus. The
TEN variant of lupus is a subtype of ACLE that presents as
large areas of erythema and denuded skin, similar to the
severe cutaneous adverse reactions of Stevens-Johnson syn-
drome (SJS) and toxic epidermal necrolysis (TEN). The
TEN variant of lupus can be seen in both CLE and SLE.
The rash may evolve subacutely from more typical lupus
rashes over time (e.g., subacute cutaneous LE, or from the
photosensitive maculopapular rash of ACLE), or it may
develop more rapidly de novo [1, 24, 25].
It can be dicult to distinguish SJS/TEN from the TEN
variant of lupus. Patients with lupus may have SJS/TEN in
isolation, drug-induced SJS/TEN with concomitant aggra-
vation of lupus erythematosus,or the TEN variant of lupus
[26]. When attempting to dierentiate etiologies, a careful
history with attention paid to oending drug agents is para-
mount. It is helpful to conrm a prior diagnosis of CLE or
SLE and assess for a preceding lupus are. Sparing of the
mucous membranes, or minimal/focal involvement of the
mucous membranes, and evident photodistribution of rash
may favor the diagnosis of lupus clinically.
Histopathology can also be helpful in identifying lupus
rashes. In typical SJS/TEN, multiple necrotic keratinocytes
are present within the entire epidermis; vacuolar changes
and lymphocytic inltrate are typically absent or sparse. In
contrast, solitary necrotic keratinocytes in the lower epider-
mis, junctional vacuolar changes, dense periadnexal and
perivascular lymphocytic inltrate, and mucin argue for the
TEN variant of cutaneous lupus [25].
The most commonly used treatment for the TEN variant
of ACLE is systemic corticosteroids, with either hydroxy-
chloroquine, intravenous immunoglobulin (IVIG), or myco-
phenolate mofetil added as adjuvant therapy if warranted
(Table 1) [27].
2.3. Subacute Cutaneous Lupus Erythematosus (SCLE). This
classication of CLE refers to a photosensitive eruption that
has a longer duration than ACLE. This rash is typically dis-
tributed on sun-exposed skin, with a predilection for the
upper torso, back, neck, and arms. The midface is usually
spared [1]. Oral lesions, though rare, have also been reported
[28]. Lesions may present as either erythematous or annular
polycyclic lesions (Figure 3), or they may have a nonindu-
rated, psoriasiform, papulosquamous appearance. The
supercial nature of the inammatory inltrate seen in SCLE
can often result in dyspigmentation (Figure 4), but scarring
or dermal atrophy is rare [1, 29]. Of note, the Rowell syn-
drome refers to the presence of erythema multiforme-like
Figure 2: Acute cutaneous lupus erythematosus. Classic malar butteryrash of the forehead, chin, and malar cheeks. Note the relative
sparing of the nasolabial folds.
3International Journal of Rheumatology
Table 1: A summary of treatment options for cutaneous lesions, in order of recommendation, distinct for each diagnostic category of
cutaneous lupus. Abbreviations: CLE, cutaneous lupus erythematosus; ACLE, acute cutaneous lupus erythematosus; TEN, toxic epidermal
necrolysis; IVIG, intravenous immunoglobulin; SCLE, subacute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; CHLE,
chilblain lupus erythematosus; LE/LP overlap, lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome.
Subset of CLE Lineage of treatment options Treatment of cutaneous manifestations
ACLE First line
Sun protection
Smoking cessation
Topical steroids
Topical calcineurin inhibitors
Antimalarials
Second line Oral corticosteroids
TEN variant of ACLE
First line Systemic corticosteroids
Second line
Antimalarials
IVIG
Mycophenolate mofetil
SCLE First line
Sun protection
Topical steroids
Topical calcineurin inhibitors
Antimalarials
Second line Oral corticosteroids
DLE
First line
Sun protection
Smoking cessation
Topical steroids (uocinonide >hydrocortisone)
Topical calcineurin inhibitors
Monthly intralesional triamcinolone
Antimalarials
Second line
Methotrexate
Systemic retinoids
Thalidomide
Lenalidomide
Dapsone
Mycophenolate mofetil (adjuvant)
Azathioprine
IVIG
Topical and systemic retinoids (hypertrophic DLE)
Tumid lupus First line Topical steroids
Hydroxychloroquine, chloroquine
Lupus panniculitis
First line
Topical or intralesional steroids for overlying DLE
Antimalarials
Systemic corticosteroids for initial phases only
Second line
Dapsone
Mycophenolate mofetil
Cyclophosphamide
Thalidomide
IVIG
Third line Rituximab
CHLE
First line Protection from the cold
Antibiotics for necrotic areas
Second line Topical steroids
Third line Systemic corticosteroids
Calcium channel blockers
Fourth line
Mycophenolate mofetil
Baricitinib
Ruxolitinib
4 International Journal of Rheumatology
lesions in lupus patients and can be categorized as a rare sub-
type of SCLE [30].
About 10-30% of cases of SCLE are drug-induced, with
antihypertensives (e.g., hydrochlorothiazide, angiotensin-
converting enzyme inhibitors, and calcium channel
blockers), antifungals (e.g., terbinane), tumor necrosis fac-
tor (TNF) inhibitors, antiepileptics, and proton pump inhib-
itors being the most common oending agents [1, 31, 32].
Patients with drug-induced SCLE often have an older age of
onset of disease than those with idiopathic SCLE, which is
likely secondary to increasing medication use with increasing
age. Duration of drug use prior to the onset of cutaneous
ndings is most commonly weeks to months but may be as
long as three years [31].
SCLE is highly associated with ANA and anti-SS-A/Ro
positivity [3335]. One recent retrospective review of 90
SCLE patients demonstrated 89% ANA positivity and 99%
anti-SS-A/Ro positivity [33], while another Italian study
demonstrated strong associations of SCLE with anti-SS-
A/Ro, anti-Smith, and anti-ribonucleoprotein (anti-RNP)
antibodies [36]. Caucasian race and smoking are also associ-
ated with increased risk of SCLE. As many as 20 to 50% of
patients with SCLE will go on to meet criteria for SLE, but
these patients tend to have a milder disease phenotype with
less internal organ manifestations of disease than the typical
SLE patient [37, 38]. SCLE may also be seen in patients with
primary Sjӧgrens syndrome [33].
Histopathology of SCLE is similar to the typical ndings
shared by many CLE lesions: interface dermatitis and hyper-
keratosis, basement membrane thickening, follicular plug-
ging, and supercial and deep lymphocytic cell inltrate
[29]. However, when compared to other forms of CLE, epi-
dermal changes and supercial lymphocytic inltrate are
much more common in SCLE. SCLE lesions also tend to have
less hyperkeratosis, less basement membrane thickening, less
periadnexal inltrate, and less follicular plugging when com-
pared to discoid lesions [39, 40]. Some studies have shown
that deposits of IgG and IgM are found more frequently
within the epidermis as opposed to the dermal-epidermal
junction [39]. It is postulated that this is due to anti-SS-
A/Ro autoantibody deposition within the epidermis [41].
When comparing the histopathology of drug-induced SCLE
versus idiopathic SCLE, leukocytoclastic vasculitis is more
prominent in drug-induced cases, and increased mucin
deposition is more typical of idiopathic cases [32].
Treatment of SCLE lesions includes the use of topical ste-
roids and/or calcineurin inhibitors. Oral antimalarial drugs
are rst-line systemic therapy for SCLE [6, 7].
Table 1: Continued.
Subset of CLE Lineage of treatment options Treatment of cutaneous manifestations
LE/LP overlap First line
Topical tacrolimus
Systemic retinoids
Cyclosporine
Bullous lupus
First line Dapsone
Second line Systemic corticosteroids
Antimalarials
Third line
Methotrexate
Azathioprine
Cyclophosphamide
Mycophenolate mofetil
Fourth line Rituximab
Neonatal lupus First line Sun protection
Laser therapy for residual telangiectasias
Figure 3: Subtle annular plaques on the left upper extremity of this
female patient diagnosed with subacute cutaneous lupus
erythematosus.
5International Journal of Rheumatology
2.4. Classic Discoid Lupus. Discoid lupus erythematosus
(DLE) is one of the most common cutaneous manifestations
of lupus and is categorized as a chronic cutaneous LE.
Lesions are classically distributed on the face, scalp, and ears
but may be more widespread in less than 20% of DLE cases
[42]. Patients have increased risk for progression to SLE if
widespread involvement is observed [4345]. It is uncom-
mon for a DLE patient to have lesions below the neck without
concurrent head and/or neck ndings. DLE lesions can also
aect the lips, nasal mucosa, conjunctivae, and genitals
[46]. Sun exposure seems to have a role in the development
of lesions, but discoid lesions can be found on sun-
protected skin [47]. Other triggers of DLE include trauma
(Koebner eect), cold exposure, infection, dermatitis, ultravi-
olet light (UV) exposure, and thermal burns [6].
DLE cutaneous ndings are characterized by variably
sized coin-shaped erythematous plaques with adherent follic-
ular hyperkeratosis and plugging (Figure 5). These lesions
have a high potential for disguration or scarring [42]. The
early indurated erythematous plaques of DLE can initially
be mistaken for psoriasis, lymphocytoma cutis, cutaneous T
cell lymphoma, granuloma faciale, polymorphous light erup-
tion, and sarcoidosis, among many other dermatologic diag-
noses [7]. Active lesions are inammatory with supercial
and deep dermal inltrate, causing the lesions to feel thick
and rm. Scalp plaques can result in scarring alopecia
depending on severity and duration (Figure 6) [42]. Long-
standing lesions often demonstrate various pigmentary
changes, classically with hypopigmentation centrally and
hyperpigmentation peripherally (Figure 7) [48]. Cases of
squamous cell carcinoma developing within longstanding
DLE lesions have been documented [4951].
A recent review article demonstrated that up to 28% of
DLE patients are at risk of developing SLE [43]. Reported fac-
tors that increased the likelihood of SLE progression include
widespread DLE lesions, joint involvement, nail changes,
anemia, leukopenia, high erythrocyte sedimentation rate,
and elevated ANA titer [43]. Another study indicated that
in addition to these factors, thrombocytopenia and the
false-positive Wassermann reaction could be strong indica-
tors of progression to disseminated DLE or SLE [45].
Histologic ndings in DLE have some overlap with other
CLE lesions, but overall, distinguishing features of active
lesions include hyperkeratosis, vacuolar degeneration of the
basal keratinocytes, signicant follicular plugging, lympho-
cytic adnexal and deep perivascular inltrates with subepi-
dermal band, papillary dermal edema, initial atrophy,
melanophages in the papillary dermis, and deposition of
mucin among collagen bers [7, 29, 40]. Pilosebaceous atro-
phy and more signicant basement membrane zone thicken-
ing are more likely in DLE rather than in SCLE lesions [1].
Dermal brosis, adnexal atrophy, vessel dilatation, and pres-
ence of melanophages corresponding to scarring aspects are
seen in more chronic, less active lesions [29]. In DLE
patients, the dermal-epidermal junction demonstrates partic-
ulate staining on DIF rather than the epidermal staining seen
in SCLE [40]. In fact, 90% of DLE lesions have a positive
lupus band test, with C3 and IgM being the most common
deposits [52]. DLE patients are less likely than other CLE
patients to have positive ANA, double-stranded deoxyribo-
nucleic acid (dsDNA), Smith, RNP, and anti-SS-A/Ro anti-
bodies [52, 53].
Topical steroids are considered rst-line therapy for
DLE, and the presence of discoid lesions is one of the few
instances in which it is recommended to use high-potency
topical steroids on the face (Table 1) [54]. One recent litera-
ture review found that uocinonide cream may be more
eective than hydrocortisone in clearing discoid lesions,
though patients were advised to limit treatment to two to
three consecutive weeks and to be aware of side eects (dis-
cussed below) [55]. Topical calcineurin inhibitors are useful
in thin-skinned areas where corticosteroids are inappropriate
[54]. In active, refractory discoid lesions, monthly intrale-
sional triamcinolone can be eective [56]. Systemic therapy
is often warranted in DLE cases unresponsive to topical and
intralesional therapy, or in patients with extensive disease.
In these cases, antimalarials are the mainstay of treatment.
Second-line systemics include methotrexate, systemic
retinoids, thalidomide, lenalidomide, dapsone, adjuvant
mycophenolate mofetil, azathioprine, and intravenous
immunoglobulin (IVIG) [54].
Preventative measures should also be taken in DLE
patients. Sun protection is an important component of ther-
apy for chronic discoid lesions or in hypopigmented skin,
where the risk of skin cancer development is higher [7].
Smokers may have more extensive cutaneous disease and
may be more dicult to treat as antimalarials appear to be
less eective in these patients, making smoking cessation a
vital component of treatment [7, 54, 57].
2.5. Hypertrophic, Verrucous Discoid Lupus. Hypertrophic
DLE is an unusual variant of DLE, representing only two per-
cent of the lesions seen in CLE [52]. It is often clinically
described as papulonodular or hyperkeratotic [58], and its
characteristic bright red appearance can mimic a cutaneous
neoplasm [29]. These lesions are frequently seen on the
extensor surfaces of the upper extremities, but involvement
of the face and upper trunk has been reported [59]. These
Figure 4: Dyspigmentation apparent during gradual resolution of
this rash in subacute cutaneous lupus erythematosus.
6 International Journal of Rheumatology
lesions can present concurrently with typical discoid lesions
on other sites of the body, which often aids in diagnosis [1, 52].
Histologically, these lesions typically demonstrate one of
two patterns. The rst demonstrates acanthosis, hyperkera-
tosis, and papillomatosis with a band-like mononuclear cell
inltrate in the upper dermis resembling hypertrophic lichen
planus. Within this rst subset of lesions, the granular layer is
thickened, and many eosinophilic dyskeratotic cells can be
found in the lower epidermis [59, 60]. The second pattern
demonstrates focal epidermal acanthosis with deep dermal
projections with only a sparse lichenoid cellular inltrate
and shares characteristics with a keratoacanthoma [5860].
Both patterns can present in conjunction with diagnostic fea-
tures of LE such as basement membrane thickening, hydro-
pic degeneration of the basal cell layer, and perivascular
and periadnexal lymphocytic inltrate.
In addition to treatment options described above for clas-
sic DLE, both topical and systemic retinoids can be eective
in treating hypertrophic DLE (Table 1) [52].
2.6. Mucosal Discoid Lupus. Oral involvement in CLE cases
ranges from 3 to 25%. Typical clinical presentation is a pla-
que or erosion with central white papules and white radiating
striae [61]. The characteristic histopathology seen in mucosal
lupus lesions include interface mucositis with lymphocytic
inltrate, necrotic keratinocytes, and hydropic degeneration
of the basal layer. DIF is frequently positive, often demon-
strating linear deposition of IgM, IgG, and C3 in the base-
ment membrane zone [62].
There is a risk of development of squamous cell carci-
noma (SCC) within mucosal lupus lesions, most frequently
in lip lesions [6365], but cases of SCC developing on the
palate, gingiva, and other mucosal surfaces also exist within
the literature [66]. Mucosal discoid lupus lesions should be
monitored closely for development of malignancy.
2.7. Lupus Erythematosus Tumidus (Tumid Lupus). Tumid
lupus is a form of chronic CLE that recurs and remits in
response to sun exposure and has a mild male predilection
when compared to other forms of CLE [7, 67, 68]. In this pre-
sentation of lupus, erythematous polycyclic plaques with
raised borders and smooth surfaces are typically the present-
ing feature. These plaques lack scale or follicular plugging
and can have central clearing, and the epidermis appears to
be uninvolved in pathology. The cutaneous ndings are
sometimes described as urticarial plaquesbut these xed
plaques should not be confused with urticarial vasculitis
[1]. The plaques typically occur on the face or trunk, or on
sun-exposed areas [29, 67, 68]. Clinically, lesions are similar
to lymphocytic inltrate of Jessner, a benign lymphocytic
inltrate of the skin presenting as asymptomatic erythema-
tous papules or annular plaques on the head and upper trunk
in middle-aged adults [1]. Some believe that tumid lupus and
Figure 5: Coin-shaped erythematous plaques seen on this female patients left cheek, biopsy results consistent with discoid lupus.
Figure 6: Scarring alopecia as a result of discoid lupus on the scalp
of this male patient.
7International Journal of Rheumatology
the lymphocytic inltrate of Jessner are the same disease or at
least very closely related [69].
There is a low prevalence of SLE in LE tumidus patients,
and the lack of immunoglobulin deposition within lesions
has caused many to debate whether LE tumidus is truly a
form of cutaneous LE or if this is an independent disease
process. LE tumidus lesions often resolve without residual
scarring or chronic skin changes [1, 67, 68], but reports of
tumid lupus patients later developing lesions characteristic
of other types of CLE have been reported [67, 68, 70, 71].
Histopathology of the lesions demonstrates intense der-
mal perivascular and periadnexal inammatory inltrates
[67, 68]. In LE tumidus, DIF is often negative or nonspecic
[1, 29], but in more chronic lesions, IgG and IgM may be
found along the basement membrane. Treatment options
include topical corticosteroids (rst line) and systemic anti-
malarial therapy (Table 1) [67, 68]. Some cases of spontane-
ous resolution of lesions have also been reported [67].
2.8. Lupus Panniculitis (Lupus Profundus). Lupus panniculi-
tis only makes up about 2-3% of cases of CLE [72], usually
occurring in adults with median onset between ages 30 and
40 [73], although an association with neonatal lupus has been
described [74]. There is a mild female predilection in this
condition.
Lupus panniculitis is a result of inammation of fat and
presents as tender, indurated plaques that can disgure
patients (Figure 8). These lesions are typically distributed
over the face, scalp, upper arms, upper trunk, buttocks, and
upper thighs, while the distal extremities are notably spared
[73]. Discoid lesions may present on the skin overlying the
panniculitis in as many as half to two-thirds of cases but
are sometimes too subtle to be recognized clinically and are
instead noted on histopathological examination. The overly-
ing skin can also feel bound down to the subcutaneous nod-
ule or plaque, creating depression in the skin and often
leading to ulceration and nally subcutaneous atrophy [1].
Histopathology of lupus panniculitis demonstrates nodu-
lar aggregates of lymphocytes, hyaline necrosis of fat lobules,
lymphocytic vasculitis, and mucin or calcium deposition.
Granulomas are sometimes present along the septa, but this
is typically not a prominent feature. DIF identies a positive
lupus band in most cases [74].
Lupus panniculitis tends to have a chronic course with
many relapses and remissions. Lesions can be debilitating
but typically do not aect long-term survival of patients.
Lupus panniculitis may either precede or follow other forms
of chronic cutaneous LE and is unlikely to progress to sys-
temic LE. If, however, progression to SLE does occur, patients
typically have mild systemic manifestations, such as arthral-
gias or the Raynaud phenomenon [72]. Patients can present
with lower-titer ANA as well as other extractable nuclear
antigens [72].
Antimalarials have been shown to have some ecacy in
lupus panniculitis, and given its typically chronic course,
treatment may be required for several years. Systemic corti-
costeroids are reserved only for treatment of the initial phases
of lupus panniculitis. Other systemic therapies include
dapsone, mycophenolate mofetil, cyclophosphamide, thalid-
omide, and IVIG [75]. Rituximab has emerged in several case
reports as a potential option for treatment as well [7678].
Overlying discoid lesions can be treated with topical or intra-
lesional steroids as discussed above.
2.9. Chilblain Lupus Erythematosus. Chilblain lupus (CHLE)
is a rare form of chronic CLE that clinically resembles frost-
bite. It is triggered by cold temperatures and presents with
painful violaceous or dusky papules, plaques, and nodules
in cold-exposed areas such as the ngers (Figure 9), toes,
heels, and more uncommonly the nose and ears [6, 7, 79].
These lesions can develop central erosions or ulcerations [7].
There is an autosomal dominant familial form of chil-
blain lupus with onset during childhood that is a result of
heterozygous mutations in TREX1 or SAMHD1 [1, 79, 80]
which upregulate type I interferon signaling [81]. These
patients may have positive ANA or arthralgia but do not usu-
ally progress to SLE. Sporadic CHLE typically presents in
middle-aged females rather than children and may be accom-
panied by discoid lupus [79, 82, 83], Raynauds phenomenon,
and livedo reticularis [79, 84]. In spontaneous CHLE, pro-
gression to SLE has been documented in as high as 18% of
cases [79]. Antibodies to SS-A/Ro can be found in a subset
of sporadic CHLE patients [84].
Histopathology is remarkable for epidermal atrophy,
interface vacuolization, and perivascular mononuclear inl-
trate [7]. Other features of cutaneous lupus including depo-
sition of IgM, IgA, and C3 with perivascular deposits of C3
and brinogen are also found on DIF of chilblain lupus
lesions [79].
Many patients respond well to protection from the cold
and treatment of infected necrotic areas with antibiotics.
Figure 7: Hypopigmented small plaques with border of
hyperpigmentation on the right preauricular region.
8 International Journal of Rheumatology
Topical steroids are next-line therapy, followed by systemic
steroids, and nally calcium channel blockers which counter-
act the possible pathogenic inuence of vasoconstriction in
CHLE [79]. Many cases of CHLE are unresponsive to anti-
malarials [23]. Successful treatment with mycophenolate
mofetil has been reported in refractory spontaneous cases
[83, 84]. Baricitinib alleviated symptoms in 3 patients with
familial CHLE [81, 85], and use of ruxolitinib has successfully
treated two cases of CHLE [86, 87].
2.10. Lichenoid Cutaneous Lupus Erythematosus-Lichen
Planus Overlap Syndrome. Cutaneous LE and lichen planus
(LP) are distinct dermatoses that can in some circumstances
occur as an overlap syndrome, or as a syndrome with mixed
clinical and histopathological features of both LE and LP
[88]. There is some controversy regarding the denition of
this rare syndrome. Some experts suggest that true LE/LP
overlap is dened as the presence of LE and LP within the
same lesion [88, 89]. However, many believe the coexistence
of LE and LP lesions in the same patient could be recognized
as an overlap syndrome. The diagnosis of the condition is
based on combined clinical, histological, and/or immuno-
pathological features of both diseases simultaneously.
This is a rare condition, but most cases occur between
ages 25 and 45 with a slight female predominance [90]. Of
the reported cases of LE/LP overlap syndrome, there seem
to be two dierent clinical presentations. The rst presenta-
tion includes painful, blue-red, scaly, centrally atrophic
Figure 8: Multiple tender, indurated hyperpigmented plaques aecting the left chest in this patient with lupus panniculitis.
Figure 9: Painful, subtly dusky papules and plaques on the ngers of a patient with chilblains lupus.
9International Journal of Rheumatology
plaques on the extremities, while the second presents as ver-
rucous, papulonodular lesions on the upper extremities and
hands [89, 91]. Lesions located in dierent sites have also
been reported in the literature, including mucous mem-
brane, scalp, and nail involvement, but these cases are not
as common. The course of disease is often chronic [91].
Isoniazid, procainamide, and acebutolol have each been
reported as inciting agents in isolated cases of LE/LP overlap
syndrome [9194].
Histopathology of the overlap syndrome may demon-
strate features of either LP or LE or features of both simulta-
neously [89]. Both LE and LP demonstrate histopathological
ndings of colloid bodies and basement membrane changes.
Colloid bodies are deeper and more abundant in LP, and
basement membrane cleft formation is also more commonly
seen in LP. On the other hand, thickened basement mem-
brane zones are more frequently seen in LE [90, 91].
Histopathology is sometimes insucient for diagnosis of
the overlap syndrome due to the signicant overlap between
LE and LP, so DIF can be helpful. DIF of lichen planus dem-
onstrates cytoid bodies staining for IgM (or sometimes IgG)
along with brin and brinogen in a band-like fashion along
the basement membrane zone [90, 91]. DIF of discoid lupus
lesions also demonstrates IgM staining of cytoid bodies but
usually displays immunoglobulin and complement deposi-
tion at the dermal-epidermal junction [90]. In the overlap
syndrome, DIF may demonstrate immunoglobulin deposits
in cytoid bodies or linear brinogen at the basement mem-
brane zone along with other distinct features of either LP or
LE [91].
Topical tacrolimus, systemic retinoids, and cyclosporine
have been shown to be ecacious in LE/LP overlap syn-
drome [88, 90, 91]. Follow-up for systemic disease in these
patients is necessary as there is a reported conversion to
SLE in about 5-10% of cases [95].
2.11. Bullous Lupus. Bullous lupus is found in less than ve
percent of patients with SLE. Bullae may be found on any
part of the body, but there is a predilection for sun-exposed
areas (face, chest, upper extremities, vermillion border, or
oral mucosa, as seen in Figure 10) [96]. Bullae or vesicles
can be found on both erythematous and nonerythematous
bases (Figure 11), typically heal without scarring, and are
not particularly pruritic. Most patients with bullous lupus
develop antibodies to type VII collagen, which is a shared
antigen in epidermolysis bullosa acquisita. Other clinical,
histologic, and immunologic features of bullous lupus help
distinguish between these two cutaneous disorders. The dif-
ferential diagnosis for bullous lupus also includes dermatitis
herpetiformis, bullous pemphigoid, and linear IgA bullous
dermatosis. Other noncutaneous clinical features of SLE
and DIF IgG subtyping allow for distinction among these
entities [96, 97].
Of note, it is important to dierentiate other cutaneous
manifestations of lupus that create epidermal detachment
(such as the TEN variant of LE described above) from bullous
lupus, primarily for treatment purposes, as bullous lupus
often has dramatic response to dapsone while other variants
do not. While antibodies to type VII collagen may develop in
bullous lupus, the TEN variant of lupus results from exces-
sive interface dermatitis within severe CLE lesions. Subse-
quent severe hydropic degeneration of the basal layer of the
epidermis can lead to bullae formation, and if this event is
exaggerated with massive apoptotic injury, the TEN-like
acute CLE is the rare result [96].
Skin biopsy in bullous lupus reveals a predominance of
neutrophils in the upper dermis with microabscesses within
the dermal papillae, subepidermal blistering, and a perivascu-
lar inammatory inltrate and mucin deposition in the der-
mis. Mucin, as with many variants of cutaneous lupus, is a
distinguishing feature of the histopathology. DIF is positive,
Figure 10: Involvement of the lips and palate in a case of bullous lupus.
10 International Journal of Rheumatology
with mainly IgG and/or IgM with C3 at the dermoepidermal
junction [96, 97].
Bullous lupus responds dramatically to low-dose dap-
sone. In cases of nonresponse, steroids, antimalarials, and
other immunosuppressants can be ecacious [96, 98]. Ritux-
imab may be eective for refractory cases [96, 98, 99].
2.12. Neonatal Lupus. Mothers who have anti-SS-A/Ro anti-
bodies have about a 2% risk of having a child with neonatal
lupus (NLE), with a recurrence rate of about 20% with each
subsequent child [100]. Some mothers of newborns with
NLE may have primary Sjӧgrens syndrome or SLE, but in
many cases, the mother is paucisymptomatic or asymptom-
atic [100]. Almost all babies with NLE have anti-SS-A/Ro
antibodies, and there are some reports of anti-RNP positivity
in these patients [101].
Earlier data showed an increased prevalence of NLE in
female infants, but more recent studies demonstrate roughly
equal incidence in boys and girls [100, 102]. Less than ve
percent of patients with neonatal lupus develop SLE later in
life [100].
NLE can be categorized as a neonatal form of subacute
LE, but unlike SCLE in adults, skin lesions of NLE often
occur on the face, especially periorbital and scalp regions.
This distribution exhibits the role of photosensitivity in rash
development, though it is possible for lesions to be present at
birth [1, 100]. The rash is typically macular annular or dem-
onstrates elliptic erythema, with papules or plaques occasion-
ally observed [100]. Lesions often resolve without scarring,
although residual dyspigmentation or telangiectasias can
persist [1].
NLE skin lesions occur in about 40% of cases, and other
clinical features include liver dysfunction, cytopenias (espe-
cially thrombocytopenia), and cardiac arrhythmias. Hepato-
biliary disease can vary from liver failure during gestation or
in the newborn, conjugated hyperbilirubinemia in the few
weeks following birth, or elevated aminotransferases at two
to three months of age [1]. Cardiac arrhythmias are seen in
only about 25% of cases [100], but the mortality rate of car-
diac NLE is about 20%, and the majority of aected newborns
require pacemakers. There are also some reports of hydro-
cephalus, microangiopathic hemolysis, and disseminated
intravascular coagulation in infants with internal organ man-
ifestations of NLE [1]. While extracutaneous involvement is
uncommon in NLE, evaluation for such is necessary in all
infants with NLE given the risks of 4untreated internal organ
manifestations of disease.
Management of infants without cardiac arrhythmias
(e.g., complete heart block) includes avoidance of sun expo-
sure and laser therapy for residual telangiectasias [1, 100].
Topical steroids or antimalarials are typically not advised,
as most manifestations of disease spontaneously resolve.
However, for atrioventricular heart block, counseling and
fetal and maternal screening are all necessary as there are
limited options for atrioventricular block in utero. Man-
agement in these cases is primarily expectant, and more
than 90% of these infants eventually require pacemaker
placement [100].
3. Treatment
3.1. Photoprotection. Patient education regarding heat, sun,
and certain drug exposures is important for all types of
CLE [7]. Sunscreen adherence is a very important compo-
nent of therapy, as both UVA and UVB radiation have been
shown to induce CLE lesions [103, 104]. At least 2 mg/cm
2
,
or about a quarter of a teaspoon per the average face, of a
sunscreen with sun protection factor (SPF) of at least 50
Figure 11: Small hemorrhagic vesicles on the hands of a bullous lupus patient.
11International Journal of Rheumatology
should be applied 20-30 minutes to skin before sun exposure
[104]. Physical sunscreens like zinc oxide or titanium dioxide
provide broad-spectrum protection against UVA and UVB
rays. Many other commercial sunscreens protect primarily
against UVB only, so choosing one that explicitly advertises
broad-spectrum coverage is important. Of note, UVA rays,
which penetrate glass, can reach patients through windows
while indoors or while driving, and patients should be coun-
seled accordingly [105].
Further steps include counseling patients on avoidance of
sunbathing or travel to places near the equator [2]. Indoor
uorescent lighting provides some increased risk of exacer-
bating CLE, and patients should also be encouraged to shield
bulbs [106, 107]. With avoidance of UV rays however, 25-
vitamin D levels should be monitored, and some experts
advise supplementation with at least 400 IU of vitamin D3
daily [108].
It should also be noted that while cutaneous lupus lesions
themselves can progress or worsen with sun exposure, certain
systemic agents used to treat CLE can cause photosensitivity,
potentially enhancing UV ray induction of CLE lesions.
These systemic agents mentioned include hydroxychloro-
quine, methotrexate, azathioprine, leunomide, and nonste-
roidal anti-inammatory drugs, among others. Patients
should be counseled on this enhanced risk of sun sensitivity
when started on these agents.
3.2. Smoking Cessation. Smoking cessation is paramount in
CLE management. Smoking is a risk factor for development
of many other autoimmune diseases, such as rheumatoid
arthritis, primary biliary cirrhosis, and Gravesdisease
[109]. Cigarette smokes toxic agents may cause genetic
mutations and negatively inuence the bodys immune
responses [110]. Many studies have demonstrated that smok-
ing is more prevalent among CLE patients, as well as associ-
ated with more severe disease in CLE patients. Furthermore,
the CLE skin lesions of patients who smoke are more likely to
be refractory to treatment with antimalarials [111113]. His-
torically, epidemiologic studies of smoking and SLE risk have
been somewhat conicting [109], with elevated SLE risk
among current smokers compared to nonsmokers, but not
among past smokers compared to nonsmokers [114, 115].
More recent studies have conrmed that both current and
past smokers do indeed have an elevated risk of SLE [109,
110]. Enough evidence exists in the literature to warrant
smoking cessation as a cornerstone of management in CLE.
3.3. Topical Therapy. Topical steroids may be helpful in treat-
ing CLE but are usually insucient as monotherapy.
Medium-potency triamcinolone 0.1% to high-potency clobe-
tasol propionate 0.05% may be used twice daily for two weeks
followed by a one- to two-week rest period if attempting to
limit side eects [6]. High-potency steroids for discoid
lesions on the face may be necessary, though the risk of skin
atrophy must be taken into account [1, 6]. Ointments,
creams, foams, lotions, solutions, and gels are all options,
and the choice of vehicle can be based on potency and patient
preference. Ointments in general provide more occlusion
and are therefore more easily absorbed compared to creams.
While ointments are helpful for aected dry, hyperkeratotic
areas like the hands and feet, ointments can cause cutaneous
side eects on the thin skin on the face or within skin folds
like the axillae or groin. Solutions, foams, and gels are typi-
cally better tolerated on hairy areas of skin than are oint-
ments or creams. Patients must be advised about the risks
and benets of topical steroids and counseled to monitor
for cutaneous side eects such as skin atrophy, striae, telangi-
ectasias, easy bruising, and hypertrichosis [1].
Monthly intralesional triamcinolone can be eective in
treating active discoid and LE tumidus lesions [1]. Triamcin-
olone is typically injected in concentrations of 5 to 10 mg/mL,
and the dose is dependent on the thickness and surface area
of the lesion being treated [6]. Topical tacrolimus ointment
and pimecrolimus cream have both shown some ecacy in
treating CLE and are useful for atrophy-prone areas such as
the face, eyelid, intertriginous, and groin regions, though
thicker lesions of DLE are less likely to respond [6]. Topical
retinoids like tretinoin and tazarotene can be useful for
hyperkeratotic lesions sometimes seen in DLE, though skin
irritation may occur with these agents [6].
3.4. Antimalarials. Oral aminoquinolone antimalarial agents
are ecacious and relatively safe for use in CLE, and they
have remained the gold standard for systemic therapy for at
least half a century. Hydroxychloroquine sulfate is most fre-
quently chosen, with chloroquine and quinacrine (mepa-
crine) as second options [1]. Routine ophthalmologic
monitoring is required while taking these agents, with cumu-
lative dose increasing chances of ocular toxicity over time
[116]. Concomitant use of hydroxychloroquine and chloro-
quine is not recommended due to increased cumulative risk
of retinal toxicity [7]. Quinacrine does not cause ophthalmo-
logic toxicity, but there is a risk of aplastic anemia with
higher doses of this medication [7]. Quinacrine is not com-
mercially available in the United States or Canada but may
be compounded by certied compounding pharmacies.
Antimalarials are contraindicated in patients with hypersen-
sitivity to 4-aminoquinolones, preexisting retinopathy, and
myasthenia gravis [117]. The most common side eects of
antimalarial agents are gastrointestinal upset, xerosis, and
skin hyperpigmentation, but ocular toxicity is the most
emphasized complication in the literature [118].
It should be noted that CLE response to antimalarials is
gradual, and patients need to be counseled in kind. Clinically,
it takes two to three months for visible change to be appreci-
ated, with even more time required to achieve maximal e-
cacy [1]. While antimalarials have good bioavailability after
ingestion, especially if taken with a fatty or protein-rich meal,
these agents accumulate in melanin-containing retina and
skin. This results in long drug half-lives (40-50 days) [117],
with slow pharmacokinetics delaying onset of action. When
initiating antimalarial therapy for cutaneous LE, topical or
intralesional agents can be administered concurrently to
provide more immediate results.
A recent meta-analysis found a pooled response rate to
antimalarials of 63% in CLE cases [103]. Chasset et al. found
that the cutaneous response rate to antimalarials was higher
for ACLE than for SCLE and lupus tumidus, with a low rate
12 International Journal of Rheumatology
of response in chilblain lupus [23]. However, results may
have been skewed by an increased use of concurrent systemic
steroids in ACLE patients.
3.5. Methotrexate. Methotrexate may be used as second-line
agent in patients with refractory CLE [6, 117, 119]. Studies
have demonstrated positive clinical response in patients
treated with low-dose methotrexate after hydroxychloro-
quine treatment failure, and in general, methotrexate has an
excellent safety prole [120, 121]. Methotrexate is terato-
genic, and the importance of contraception while taking this
drug cannot be stressed enough. Gastrointestinal upset,
fatigue, hair loss, and oral ulcers are commonly reported
adverse eects but may be mitigated by subcutaneous admin-
istration, or higher doses of prophylactic folic acid,
respectively. Lalani et al. recently demonstrated with a
meta-analysis relatively low prevalence of stomatitis and alo-
pecia (between 5.7 and 8.0% and between 1.0 and 4.9%,
respectively) in patients taking methotrexate [122]. Bone
marrow suppression and hepatotoxicity may occur, and rou-
tine lab monitoring is required while on therapy to ensure
patient safety [6].
3.6. Azathioprine. Azathioprine is another second-line agent
used in refractory CLE, though less ecacious than metho-
trexate [117]. However, azathioprine is safe for use during
pregnancy, making it an attractive option in certain cases
[119, 123]. Not many studies exist to demonstrate the ecacy
of azathioprine in cutaneous lupus, but several case series
support its use after other agents have failed [123, 124]. Rou-
tine lab monitoring is required while on therapy to monitor
for bone marrow suppression and hepatotoxicity. Though
rare, acute hepatitis and agranulocytosis may occur [124].
3.7. Mycophenolate Mofetil. Mycophenolate mofetil (MMF),
an inhibitor of T and B cell proliferation and autoantibody
production, has also been used in refractory CLE with some
success. A recent study on MMF in SLE patients, 57 of whom
held diagnoses of both CLE and SLE, demonstrated resolu-
tion of either rash, alopecia, or mucosal ulcers in 27 of the
aected patients within 12 months, though patients were also
receiving concomitant corticosteroids [125]. A Scandinavian
systematic review found a favorable response in a majority of
MMF-treated CLE patients (68.8%) [126]. Another encour-
aging retrospective study from the Journal of the American
Academy of Dermatology supported the use of adjuvant
MMF in refractory CLE [127]. However, a recent controlled
trial did not show statistically signicant improvement in
CLE with MMF, though the study had a small sample size
and was likely not adequately powered to demonstrate a
response [128]. Diering study results may be attributable
to the heterogeneity of cutaneous lupus manifestations,
simultaneous use of other therapies, and dierences in dose
and duration of MMF treatment.
3.8. Belimumab. Belimumab is a monoclonal antibody that
inhibits B-lymphocyte stimulator (BLyS), thereby inhibiting
B cell activation [129]. Belimumab is one of the few Food
and Drug Administration- (FDA-) approved drugs for lupus.
Recent studies revealing utility of belimumab as an adjuvant
treatment for skin manifestations of lupus have been highly
promising [129135]. A recent publication demonstrated
that patients with isolated CLE all had signicant improve-
ment in their cutaneous disease, but overall, SLE patients
with skin involvement as a group did not demonstrate statis-
tically signicant improvement [130]. Clinical response in
this study was better in patients with mild persistently active
lesions and for phototypes IV-VI [130]. One extensive litera-
ture review showed that certain patients may benet from
adjuvant belimumab more than others, including those with
low serum complement and positive dsDNA antibodies
[135]. This niche of patients has statistically signicant
improvement in mucocutaneous, musculoskeletal, immuno-
logic, and hematologic manifestations of disease [135].
3.9. Other Agents. CLE that is refractory to antimalarials and
agents listed above is particularly dicult to treat. Several
other agents have been reported in the literature, with evi-
dence typically limited to case reports. These include apremi-
last, ustekinumab, IVIG, rituximab, thalidomide, and
dapsone [6, 7, 50, 134]. Rituximab may be less ecacious in
chronic CLE [119]. Thalidomide can be eective in certain
cutaneous disease but, due to its many side eects, should
be reserved as a rescue therapy in refractory cases [119]. Dap-
sone has little success in CLE, except in cases of bullous lupus
[97, 119]. Anifrolumab, a human monoclonal antibody to
type I interferon receptor subunit 1, did reduce skin manifes-
tation severity in the TULIP-2 trial [136, 137]; further studies
are needed to determine how useful this drug will be for CLE.
4. Other LupusDermatologic Conditions
4.1. Lupus Vulgaris. Only one to two percent of all extrapul-
monary tuberculosis cases demonstrate cutaneous involve-
ment [138]. Lupus vulgaris, or tuberculosis luposa, is a rare
form of cutaneous tuberculosis that makes up only 10-15%
of cutaneous tuberculosis (TB) cases. Female predominance
in lupus vulgaris is 2 to 3 : 1 [1]. Lesions are often a result of
direct extension, or hematologic/lymphatic spread of TB, or
autoinoculation with the Bacillus Calmette-Guerin (BCG)
vaccine. The tuberculin skin test in these patients is usually
positive [1, 135, 136]. Lupus vulgaris typically presents as
patches and plaques, and these plaques are often psoriasi-
form in appearance [138]. Lupus vulgaris is most commonly
seen on the face, where it can be clinically dicult to dieren-
tiate from discoid lupus [138]. Disseminated lupus vulgaris is
very rare and presents as a granulomatous folliculitis [138].
Histology is remarkable for well-developed granulomas
with scarce caseation and nonspecicinammatory inltrate
[139]. Usually no acid-fast bacilli are visible on histopathol-
ogy [139]. Diagnosis is made by a combination of histology,
culture polymerase chain reaction (PCR), and interferon-
gamma release assays (IGRAs) [1]. Treatment of the underly-
ing TB infection is recommended [139].
4.2. Lupus Miliaris Disseminatus Faciei. Lupus miliaris disse-
minatus faciei (LMDF) is a rare, chronic, inammatory der-
matosis that mainly aects the faces of young adults of both
sexes [140]. Some experts consider LMDF to be a severe form
13International Journal of Rheumatology
of granulomatous rosacea (GR) given the perifollicular local-
ization of granulomas on histology. However, LMDF has
some distinct features from GR, such as involvement of
extrafacial sites and lack of erythema, telangiectasia, or ocular
symptoms [141]. LMDF also results in chronic scarring,
which is not true of GR. LMDF diers from GR on histopa-
thology, given that large granulomas with necrosis are
evident in LMDF lesions and the granulomas seen in GR
are small and devoid of necrosis [141]. Given the caseous
necrosis noted on histology, LMDF historically was thought
to be a variant of lupus vulgaris. However, staining and PCR
for M. tuberculosis is consistently negative in LMDF, and
antitubercular drugs are not ecacious in LMDF [141].
The exact etiology of LMDF remains unknown, and its cat-
egorization as a granulomatous condition aecting the face
is still debated [140].
LMDF presents with many yellow-brown to red papules
and nodules, typically aecting the periocular or central
facial regions, and demonstrates an apple-jellyappearance
on diascopy [140, 142, 143]. Facial scarring in this disease
process can often be permanent. Extrafacial involvement
does occur in LMDF, which can cause clinical diculty in
distinguishing LMDF from sarcoidosis, cutaneous tuberculo-
sis, or the necrobiotic form of granuloma annulare [1].
As mentioned previously, histopathology is remarkable
for dermal granulomas with frequent central caseating necro-
sis [142]. Staining for organisms is always negative. Treat-
ment strategies are broad, and reports of use of long-term
topical steroids, minocycline, dapsone, oral steroids, intrale-
sional steroids, isotretinoin, clofazimine, tranilast, cyclospor-
ine, and laser all exist in the literature [140, 143]. LMDF most
commonly has an indolent and self-limiting course with
spontaneous resolution over one to four years despite resid-
ual scarring [140]. No treatment seems to be consistently e-
cient in preventing scarring caused by LMDF [140].
4.3. Lupus Pernio. Lupus pernio is a rare, late cutaneous pre-
sentation of sarcoidosis. Sarcoidosis is a multisystem disorder
most commonly aecting young adults. Though involvement
of nearly all parts of the body has been reported, the lymph
nodes, lungs, eyes, skin, and liver are most commonly
aected. Lupus pernio demonstrates a female prevalence
and is more common in West Indian or African-American
sarcoid patients than white patients [144]. Lupus pernio is
associated with chronic sarcoidosis of the lungs in about
75% of patients and upper respiratory tract involvement in
about 50% of patients [145].
Lupus pernio presents as chronic violaceous papulono-
dules to large plaques with scale that typically appear on
the nose, cheeks, and ears [144]. These lesions can be compli-
cated by nasal ulceration and septal perforation, which can be
aggravated further by surgical intervention [144]. Lupus per-
nio rarely resolves spontaneously and can result in facial dis-
gurement as well as nasal obstruction or brotic pulmonary
complications if the nasal cavity and maxillary sinuses
become more extensively involved [146].
Histopathology of these lesions demonstrates changes
that can be found in all organs aected by sarcoidosis: nonca-
seating granulomas with a sparse lymphocytic component
referred to as naked granulomas[146]. These granulomas
are typically found in the dermis but can be subcutaneous.
Treatment of lupus pernio can be challenging given the
unpredictable course of disease. Therapeutic options include
local, intralesional, and, if needed, systemic corticosteroids,
as well as methotrexate, chloroquine, hydroxychloroquine,
azathioprine, cyclophosphamide, thalidomide, iniximab,
and even laser therapy [144, 146150]. Lenalidomide has
been reported to be successful in one refractory case of lupus
pernio [151].
5. Conclusions
Cutaneous lupus erythematosus is an umbrella term for a
diverse array of rashes with distinct clinical phenotypes, his-
topathology, and treatment options. The term lupusis also
utilized when describing a handful of other dermatological
conditions that are truly unrelated to lupus erythematosus,
often causing confusion for rheumatologists and dermatolo-
gists alike. Sun protection and smoking cessation are central
to the management of all types of CLE. Topical steroids are
often the starting point for cutaneous lupus, though antima-
larial agents are rst line when systemic therapies are
required. Should these modalities fail, a variety of other
immunosuppressive medications may permit steroid-
sparing while maintaining control of cutaneous lupus.
Data Availability
The data that support the ndings of this study are available
from the corresponding author, EEC, upon reasonable
request.
Conflicts of Interest
The authors declare that there is no conict of interest
regarding the publication of this paper.
Acknowledgments
The authors would like to thank Dr. Jason Reichenberg, Dr.
Ammar Ahmed, and Dr. Rhoopal Bhatt, for contributing
additional photographs of clinical ndings.
References
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19International Journal of Rheumatology
... An initial diagnosis of cutaneous LE (CLE) is associated with a 5-18% risk of developing SLE over the next 3-5 years, and these patients usually present with a mild course of the disease [4][5][6][7]. Concurrently, CLE may occur as a separate entity in the absence of systemic symptoms, and such a variant is characterized by a 2-3-fold higher incidence compared to SLE [8,9]. Genetic and environmental factors play a key role in the pathogenesis of CLE, as in SLE [10]. ...
... Extensive and tense vesiculo-bullous lesions develop, particularly affecting areas exposed to UV radiation, i.e., face, neck, upper trunk, upper limbs, red zone of the lips and mucous membrane of the oral cavity [18,25]. However, bullous lesions may also appear on the skin of other parts of the body [9]. Bullae are located on erythematous-background or normal-looking skin and resolve without scarring or milia formation. ...
... lips and mucous membrane of the oral cavity [18,25]. However, bullous lesions may also appear on the skin of other parts of the body [9]. Bullae are located on erythematousbackground or normal-looking skin and resolve without scarring or milia formation. ...
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Lupus erythematosus (LE) is an autoimmune inflammatory disease with complex etiology. LE may present as a systemic disorder affecting multiple organs or be limited solely to the skin. Cutaneous LE (CLE) manifests with a wide range of skin lesions divided into acute, subacute and chronic subtypes. Despite classic forms of CLE, such as malar rash or discoid LE, little-known variants may occur, for instance hypertrophic LE, chilblain LE and lupus panniculitis. There are also numerous non-specific manifestations including vascular abnormalities, alopecia, pigmentation and nail abnormalities or rheumatoid nodules. Particular cutaneous manifestations correlate with disease activity and thus have great diagnostic value. However, diversity of the clinical picture and resemblance to certain entities delay making an accurate diagnosis The aim of this review is to discuss the variety of cutaneous manifestations and indicate the clinical features of particular CLE types which facilitate differential diagnosis with other dermatoses. Although in diagnostically difficult cases histopathological examination plays a key role in the differential diagnosis of LE, quick and accurate diagnosis ensures adequate therapy implementation and high quality of life for patients. Cooperation between physicians of various specialties is therefore crucial in the management of patients with uncommon and photosensitive skin lesions.
... Cutaneous lupus erythematosus (CLE) is a form of lupus that affects the skin, causing lesions, rashes, and other changes, particularly in sun-exposed areas. This autoimmune disease occurs when the immune system mistakenly attacks healthy tissues, including the skin, resulting in inflammation and cellular damage [155]. Autoimmune skin diseases like CLE can be challenging to treat due to the need to suppress the immune response without compromising the patient's overall health [156]. ...
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Amphiphilic copolymers (ACs) are versatile systems with self-assembling and aggregating properties, enabling the formation of nanomaterials (NMs) such as micelles, vesicles, nanocapsules, and nanogels. These materials have been extensively explored for the delivery of various drugs and active compounds, enhancing the solubility and permeation of poorly water-soluble drugs into skin tissue. This improvement facilitates the treatment of skin diseases, including chronic conditions like cancer, as well as infections caused by bacteria, fungi, and viruses. This review summarizes recent applications of ACs in skin treatment, with a particular focus on their use in anti-cancer drug therapy. It covers the synthesis, classification, and characterization of ACs using various experimental techniques. Additionally, it discusses recent research on different drug delivery pathways using ACs, including encapsulation efficiency, release behavior, characteristics, applications, and responses to various chemical and physical stimuli (both in vivo and in vitro). Furthermore, this review provides a comprehensive analysis of the effects of ACs NMs on several skin diseases, highlighting their potential as alternative treatments.
... The clinical manifestations of SLE may range from mild localised skin disease to a life-threatening illness, such as lupus nephritis or neuropsychiatric SLE. 1,2 The complex interaction among genetic, environmental, and hormonal factors is key to clinical heterogeneity in SLE manifestations. The prevalence and incidence of SLE have been increasing in recent years. ...
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Background Cutaneous involvement is common in systemic lupus erythematosus (SLE) patients and may be essential to the disease activity. This study aimed to describe cutaneous manifestations spectrum and determine the association of cutaneous lesions with the disease activity and systemic involvement among SLE patients in Malang, Indonesia. Methods A cross-sectional study was conducted using 54 SLE patients from rheumatology outpatient clinic at Saiful Anwar General Hospital Malang, Indonesia. Cutaneous features were classified according to Gilliam and Sontheimer classification of cutaneous lupus. Disease activity and clinical manifestations were documented according to Mexican-SLE disease activity index (Mex-SLEDAI). Results Among 54 subjects, 50% of the patients had cutaneous manifestations. Subacute cutaneous lupus erythematosus (SCLE) was observed in 11.1% of patients, and malar rash in 20.4%. Subjects with cutaneous lesions had significantly higher Mex-SLEDAI scores, especially those who had SCLE (p<0.001), malar rash (p=0.002), alopecia (p=0.002), and photosensitivity (p=0.032). Six patients (11.1%) had skin infections with higher disease activity (9[8–11]vs.2[0–4];p<0.001). SCLE was significantly associated with malar rash (OR 11.7[1.8–76.5]), vasculitis (OR 43.0[4.1–445.6]), and fatigue (OR 15.0[2.1–108.8]). Malar rash was associated with photosensitivity (OR 8.4[1.6–44.0]), while oral or nasal ulcer was associated with fatigue (OR 8.6 [1.4–54.6]). Vasculitis (OR 5.9[1.0–35.1]) and nephritis (OR 11.7 [1.8–76.5]) were associated with the presence of skin infection. Conclusion SCLE and malar rash are the most common cutaneous lesions among subjects. Subjects with cutaneous lesions have relatively higher disease activity. Several skin lesions are also associated with SLE patients’ systemic manifestations.
... Used as a clinical tool, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) standardizes the way disease activity is characterized and offers guidance for spotting a clinical change. [12][13][14] This study aimed to evaluate the prevalence of cutaneous manifestations of SLE and to find out the association with organ involvement. Patients with SLE have both unique and general cutaneous characteristics. ...
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A BSTRACT Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease that affects both men and women differently and has a variety of multisystemic symptoms. One of the diseases most often affected target organs is the skin. Different ethnic and racial groupings may display variations in disease incidence, clinical heterogeneity, and severity depending on environmental, cultural, or genetic factors. This study is conducted to determine the prevalence of SLE’s cutaneous symptoms and their relationship to organ involvement. Materials and Methods Data were gathered for this study from the patient chart, the study design was the retrospective chart review after the consent of the patients and obtaining an ethical approval, The study was carried out in Aseer Central Hospital, Abha Saudi Arabia Results Out of a total of 100 patients 92% were females while 8% were males. The mean (SD) of the age of the respondent was 38.3 (8.5). 89.2 of the respondents had skin manifestations Conclusion A thorough understanding of SLE skin lesions will aid in the accurate identification of the condition and in the effective therapy of lupus patients. In order to more accurately diagnose cutaneous lesions in SLE patients, we need more dermatology and rheumatology clinics that combine expertise together.
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This systematic review critically evaluates preclinical and clinical data on the antibacterial and wound healing properties of cannabinoids in integument wounds. Comprehensive searches were conducted across multiple databases, including CINAHL, Cochrane library, Medline, Embase, PubMed, Web of Science, and LILACS, encompassing records up to May 22, 2024. Eighteen studies met the inclusion criteria. Eleven were animal studies, predominantly utilizing murine models (n = 10) and one equine model, involving 437 animals. The seven human studies ranged from case reports to randomized controlled trials, encompassing 92 participants aged six months to ninety years, with sample sizes varying from 1 to 69 patients. The studies examined the effects of various cannabinoid formulations, including combinations with other plant extracts, crude extracts, and purified and synthetic cannabis-based medications administered topically, intraperitoneally, orally, or sublingually. Four animal and three human studies reported complete wound closure. Hemp fruit oil extract, cannabidiol (CBD), and GP1a resulted in complete wound closure in twenty-three (range: 5–84) days with a healing rate of 66–86% within ten days in animal studies. One human study documented a wound healing rate of 3.3 cm2 over 30 days, while three studies on chronic, non-healing wounds reported an average healing time of 54 (21–150) days for 17 patients by oral oils with tetrahydrocannabinol (THC) and CBD and topical gels with THC, CBD, and terpenes. CBD and tetrahydrocannabidiol demonstrated significant potential in reducing bacterial loads in murine models. However, further high-quality research is imperative to fully elucidate the therapeutic potential of cannabinoids in the treatment of bacterial skin infections and wounds. Additionally, it is crucial to delineate the impact of medicinal cannabis on the various phases of wound healing. This study was registered in PROSPERO (CRD42021255413).
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A broad spectrum of dermatologic manifestations, known as cutaneous lupus erythematosus (CLE), may or may not be linked to the development of systemic disease. There are numerous subtypes of cutaneous lupus, such as acute cutaneous lupus (ACLE), subacute cutaneous lupus (SCLE), and chronic cutaneous lupus (CCLE). CCLE encompasses lupus tumidus, chilblain cutaneous lupus, LE profundus (LEP), and discoid lupus erythematosus (DLE). In order to diagnose these diseases, it is necessary to accurately classify the subtype. This is achieved through a combination of physical examination, laboratory studies, histology, antibody serology, and occasionally direct immunofluorescence, while also excluding systemic disease. The treatment of cutaneous lupus involves the provision of appropriate topical and systemic agents, as well as patient education regarding solar protection. In cases where the disease is pervasive, scarring, or treatment-refractory, systemic agents are recommended. In this chapter, we address the classification and diagnosis of the diverse subtypes of CLE and offer a comprehensive update on therapeutic management.
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Introdução: As afecções de pele e subcutâneo secundárias ao Lúpus Eritematoso são condições dermatológicas complexas que resultam da interação entre fatores genéticos e ambientais, desencadeando respostas imunes que levam a lesões cutâneas características. A compreensão dessas manifestações cutâneas é essencial para um diagnóstico preciso e um tratamento eficaz. Objetivo: Revisar e classificar as lesões cutâneas associadas ao Lúpus Eritematoso, fornecendo uma abordagem clínica detalhada para auxiliar na identificação, diagnóstico e tratamento dessas afecções dermatológicas. Metodologia: Realizou-se uma revisão bibliográfica narrativa, utilizando os descritores MeSH pertinentes e selecionando artigos de revisão sistemática publicados nos últimos 5 anos. Foram incluídos estudos em inglês, português e espanhol, totalizando 31 artigos analisados. Além disso, foram consultados protocolos e diretrizes da Sociedade de Dermatologia para embasar a discussão. Resultados: Os resultados da revisão destacaram a classificação das lesões cutâneas do Lúpus Eritematoso em três subtipos: agudo, subagudo e crônico. Cada subtipo apresenta características clínicas, histopatológicas e laboratoriais distintas, permitindo uma melhor propedêutica e abordagem terapêutica personalizada. A identificação precoce da doença sistêmica é crucial para orientar o tratamento e monitorar os efeitos adversos das terapias empregadas. Conclusão: A abordagem multidisciplinar no diagnóstico das afecções de pele e subcutâneo secundárias ao Lúpus Eritematoso é fundamental para uma avaliação abrangente e individualizada de cada paciente. A identificação dos subtipos de lesões cutâneas permite uma intervenção terapêutica mais direcionada e eficaz, contribuindo para a melhoria da qualidade de vida dos pacientes. No entanto, são necessárias mais pesquisas para aprofundar o conhecimento sobre os mecanismos patogênicos envolvidos e desenvolver terapias inovadoras e personalizadas para essas condições dermatológicas complexas.
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For the first time and in a large study we have shown that patients with active SLE, HRQoL were negatively affected by the presence of moderate/severe skin lesions compared to patients with active SLE with no/mild skin lesions.
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: Rheumatological disorders are considered rare in children, with a global incidence of 2% - 5%. However, this number may be higher in developing countries due to underreporting. Approximately 10% - 20% of all rheumatological disorders in adults present initially during pediatric age. Rheumatological diseases exhibit a wide array of clinical presentations involving the skin, musculoskeletal system, vasculature, and various organ systems. Skin manifestations may serve as crucial clinical features in rheumatological diseases during the initial presentation. Rheumatic diseases with diverse dermatological manifestations are well-documented. Thorough and meticulous skin examination by pediatric rheumatologists is essential for accurate diagnosis and early treatment of these diseases. Our review proposes a collaborative approach between pediatric rheumatology and dermatology for managing such cases in the future.
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Purpose of review: Cutaneous lupus erythematosus (CLE) is a highly heterogeneous autoimmune disease. No specific Federal Drug Administration (FDA)-approved therapies for CLE-alone are available, and resistance to conventional treatments is common. This review will summarize current treatment approaches and pending treatment strategies. Recent findings: Research into the pathogenesis of CLE is accelerating. A skewed type I interferon production and response contribute to CLE lesions. The pathophysiology of lesions may be similar among the lesional subtypes, and patients with a more TLR9-driven disease mechanism may have more benefit from hydroxychloroquine. Case reports continue to support the use of dapsone for CLE, especially bullous lupus erythematosus. Rituximab and Belimumab have efficacy in patients with systemic lupus erythematosus and severe active CLE. The significant role for type I interferons in CLE and encouraging clinical data suggest anifrolumab as a very promising agent for CLE. Dapirolizumab, BIIB059, Ustekinumab and Janus kinase inhibitors also have supportive early data as promising new strategies for CLE treatment. Summary: Continued research to understand the mechanisms driving CLE will facilitate the development and approval of new targets. The pipeline for new treatments is rich.
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Lupus miliaris disseminates faciei (LMDF) is a rare inflammatory dermatosis characterized by an asymptomatic papular eruption in the central face, of which the etiology and pathogenesis are not clear. There is a lack of standard treatment recommendations, especially for severe cases. Here we report a new case of successful treatment of severe LMDF by the combination therapy of oral isotretinoin and methylprednisolone. This article is protected by copyright. All rights reserved.
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Objective Methotrexate (MTX) increases the risk of alopecia and stomatitis, but the prevalence of these adverse events among rheumatic patients taking MTX is poorly defined. We conducted a systematic literature review and meta‐analysis to estimate the prevalence of alopecia and stomatitis with MTX in rheumatic diseases. Methods We searched PubMed, The Cochrane Library, and CINAHL databases for double‐blind randomized controlled trials (RCTs) with an MTX monotherapy arm. Alopecia, stomatitis, and oral/mouth ulcers data were extracted. The quality of trials was assessed by 2 authors. We included trials published since 1990 that used at least 10 mg of MTX weekly, coadministered with folic or folinic acid. We estimated the prevalence using random‐effects models because heterogeneity was anticipated. Two estimates of prevalence were included; the lower bound estimate included all trials (assuming no alopecia and stomatitis if not mentioned), and the upper bound estimate included only those that specifically described prevalence estimates of alopecia or stomatitis. Results Of 3,954 studies identified, 20 RCTs were included, with a total of 24 MTX monotherapy arms, of which 10 reported the prevalence of alopecia (n = 1,113), and 21 reported stomatitis or mouth/oral ulcers (n = 2,056). The prevalence of alopecia was between 1.0% and 4.9%. The prevalence of stomatitis was between 5.7% and 8.0%. Conclusion This meta‐analysis gives more precise estimates of mucocutaneous adverse events that occur in rheumatic disease patients taking MTX. These estimates will help inform patient decision‐making regarding MTX.
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Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-β and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab.
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Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007–12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
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Background: Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. Methods: We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. Results: A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. Conclusions: Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.).
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Background: Mucosal involvement is frequently seen in cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). There is no consensus regarding the prevalence, and a wide range of lesions has been reported. Its prognostic significance is currently unknown and a matter of controversy. Objective: To classify oral lesions in lupus, evaluate their prevalence and assess their possible association with disease activity. Methods: We conducted a descriptive study between 2016 and 2017. A total of 150 lupus patients were matched by sex, age and smoking status with 151 healthy individuals. All subjects underwent a careful evaluation of oral mucosa. On the same day of the clinical assessment, each patient underwent a peripheral venous blood and urine analysis. All patients underwent a full medical history, physical examination and a careful examination of the oral cavity. For each one, we obtained photographs of ten areas of the oral cavity. Two dermatologists of our group blindly recorded the presence and morphology of oral lesions. The disease activity of CLE patients was scored using the Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index, and in SLE patients, activity was measured using the Systemic Lupus Erythematosus Disease Activity Index. Results: In CLE patients, there was a statistically significant correlation between higher cutaneous disease activity and the following oral findings: discoid plaques, cobblestone and red/brown-pigmented macules. In patients with CLE, red macules on jugal mucosa were statistically associated with anaemia and positive antinuclear antibodies titres; additionally, the presence of gingivitis was related to systemic inflammation. In SLE patients, gingival telangiectases were statistically significantly associated with leucopenia, hypocomplementemia and systemic inflammation. Limitations: Biopsies on mucosal lesions were not performed. Conclusion: Some specific oral lesions correlate with disease activity in CLE and SLE.
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Bullous systemic lupus erythematosus (BSLE) is a rare complication of systemic lupus erythematosus (SLE) characterized by cutaneous vesicles and bullae with a primarily neutrophilic infiltrate on histopathology. Bullous SLE is a heterogeneous disease without pathognomonic clinical features, making the diagnosis and differentiation from other blistering diseases challenging. We present the case of a single patient with SLE in whom 3 different clinical appearances of BSLE manifested over 5 years. The cutaneous eruption dramatically improved with rituximab at the initial presentation and continued to respond to rituximab during subsequent flares over the subsequent 5 years.