RHEUMATOLOGIC DERMATOLOGY SECTION 7
Lupus Erythematosus 41
Synonyms/variants: � Discoid lupus erythematosus: a subset o
chronic cutaneous lupus erythematosus � Lupus pro undus: a variant
o lupus panniculitis � Lupus erythematosus tumidus: tumid lupus
Key features
 There are several variants o cutaneous lupus, de ned in part by
the location and depth o the infammatory in ltrate
 Acute cutaneous lupus involves primarily the epidermis and upper
dermis and is usually associated with systemic disease
 Subacute cutaneous lupus involves primarily the epidermis and
upper dermis and is associated with anti-Ro/SSA autoantibodies
and photosensitivity; the majority o patients do not have
signi cant systemic disease
 Discoid lesions o lupus involve the epidermis, upper and lower
dermis, and adnexal structures, and they can scar; the majority o
patients do not have signi cant systemic disease
 Lupus erythematosus tumidus involves the dermis but there is no
prominent epidermal or adnexal involvement
 Lupus panniculitis involves the subcutaneous tissue and may
result in dis guring depressed scars
INTRODUCTION
Lupus erythematosus is a multisystem disorder that prominently
a ects the skin. Cutaneous lesions are a source o disability and, on
many occasions, an indicator o internal disease.
HISTORY
The term “lupus erythemateaux” was frst used by Cazenave in the
mid-1800s1. Cazenave and others helped to articulate the di erence
between lupus erythematosus (LE) and lupus vulgaris, a clinical variant
o cutaneous tuberculosis. Due in part to observations o Hutchinson,
Osler and Jadassohn, it was recognized that cutaneous lesions o LE
may be associated with signifcant internal abnormalities, including
arthritis, nephritis, serositis, cytopenias and neurologic disease. In
1964 and during the ollowing years, Dubois developed the concept o
lupus as a spectrum o disease, ranging rom isolated cutaneous lesions
to li e-threatening, multiorgan disease. Gilliam also developed the
concept o a spectrum o disease, and, in 1979, he, Sontheimer and
Thomas described a subset o cutaneous disease, which they termed
“subacute” cutaneous lupus 2. The description was virtually identical to
that o “ANA-negative” lupus (see Ch. 40), reported by Maddison,
Provost and Reichlin in 19813.
Important diagnostic advances included discovery o the LE cell phe-
nomenon by Hargraves, Richmond and Morton in 19484; the ANA by
Friou in 19575; the lupus band by Burnham, Neblett and Fine in 19636;
and the association o specifc clinical mani estations o lupus with
specifc autoantibodies by a variety o investigators7–9. With regard to
skin disease, the associations o anti-Ro (also known as anti-SSA)
autoantibodies with neonatal lupus by Weston et al. in 198110 and with
subacute cutaneous lupus (SCLE) by Sontheimer et al. in 198211 are
noteworthy milestones.
Antimalarial therapy in the orm o quinine was used or cutaneous
lupus by Payne in 189412. By the late 1950s, synthetic antimalarials
Lela A Lee and Victoria P Werth
had become a mainstay o therapy. Systemic corticosteroids and other
immunosuppressive agents also came into use during the mid twenti-
eth century.
EPIDEMIOLOGY
Systemic lupus erythematosus (SLE) is a common disease with signif-
cant morbidity and mortality. The strongest actor a ecting risk or
lupus is gender: women with systemic lupus outnumber men by at least
6 to 113. Since lupus occurs most commonly in women during their
childbearing years, it is likely that hormonal actors in uence suscep-
tibility to lupus. Consistent with the importance o sex steroids in the
expression o disease, lupus is rare in prepubertal children. With regard
to patients who have only cutaneous lesions, there appears to be a
somewhat lower emale-to-male ratio (perhaps 3 : 1) but there is still a
emale predominance.
Ethnicity is also a major risk actor, and its e ect in some populations
is almost as strong as that o gender. For example, the prevalence o
SLE is our old higher in A rican-American women as compared to
Caucasian American women (4 in 1000 vs 1 in 1000)13. In addition,
A rican-Americans tend to develop disease at an earlier age and have a
higher mortality rate. A long-term study o a multi-ethnic cohort o
587 SLE patients rom Texas, Alabama and Puerto Rico ound that
A rican-Americans and Hispanics rom Texas had more severe disease
than Caucasian Americans or Hispanics rom Puerto Rico, suggesting
that both genetic and non-genetic actors play a role14.
It is di fcult to compare data rom di erent countries, and this is
sometimes even a problem with data rom within the same country,
due in part to di erences in case identifcation and validation (reviewed
in re . 15). It is likely that Caucasian populations in Europe have a
similar prevalence o lupus as do Caucasians living in the US. It also
appears that the prevalence o lupus among both Asians and Latin
Americans is similar to that o Caucasian Americans. A retrospective
study rom a single county in Minnesota indicated that the incidence
o cutaneous LE, excluding patients who also had SLE, was similar to
the incidence o SLE15.
PATHOGENESIS
The pathogenesis o cutaneous LE is complex, and it involves an inter-
action between genetic and environmental actors. The latter include
ultraviolet radiation (UVR), medications, and possibly viruses. This
interplay triggers a complex in ammatory cascade o cytokine, chemo-
kine and in ammatory cell responses that include cells residing within
as well as recruited to the skin. Overall, the lichenoid tissue reaction,
defned as epidermal basal cell damage and a band-like lymphocytic
infltrate in the upper dermis, characterizes most subsets o cutaneous
LE. It involves activation o keratinocytes, endothelial cells and skin
dendritic cells plus the production o type I inter erons (IFNs), ollowed
by the recruitment and activation o CD4+ and CD8+ cytotoxic T cells.
The end result is cytotoxic keratinocyte damage.
Genes that can a ect overall immunoreactivity include those whose
protein products are involved in B- and T-cell unction, innate immu-
nity, immune complex clearance, apoptosis, ubiquitination, DNA
methylation or cellular adhesion16. Examples rom all these gene
classes, in addition to genes with unknown unction, have been impli-
cated in some way in human or animal models o SLE (Table 41.1; see
Ch. 4).
Both genetic background based upon ancestry and mutations in spe- 615
cifc genes contribute to the clinical heterogeneity in cutaneous LE. For
SECTION
example, the incidences o photosensitivity and discoid LE (DLE) di er proin ammatory. Alternatively, or in addition, these autoantibodies
7 in those o northern versus southern European ancestry17, and SCLE is could lead to disease via activation o proteins and cells o the immune
RHEUMATOLOGIC DERMATOLOGY

associated with the HLA-B8-DR3 extended haplotype (including TNF2),
as well as C2 and C4 defciencies18. Genes previously associated with
SLE, e.g. TYK2, IRF5 and CTLA4, also con er an increased risk or
developing DLE and SCLE19, while mutations in TREX1, which encodes
a DNA exonuclease, are associated with amilial chilblain lupus20. In
the latter patients, dys unction o the exonuclease leads to an accumu-
lation o IFN-stimulatory nucleic acids.
Autoantibodies clearly play a role in SCLE and neonatal lupus, where
anti-Ro (more specifcally, anti-Ro60 and anti-Ro52) and anti-La
autoantibodies are requently observed (see Ch. 40); in the case o
neonatal lupus, these antibodies are transmitted transplacentally.
Blocking the unction o either Ro60 or Ro52 presumably predisposes
one to these diseases. O note, Ro60 plays an important role in cell
survival ollowing UVR, possibly via binding to mis olded non-coding
RNAs and targeting them or degradation, and mice which lack Ro60
develop a lupus-like syndrome21. Ro52 has a known regulatory role in
in ammation, targeting both inter eron regulatory actor 3 (IRF3)
and IRF8 or degradation22; thus, antibodies to Ro52 may be
system, ollowing immune complex ormation.
Both ultraviolet B (UVB) and ultraviolet A radiation have been impli-
cated in exacerbation o cutaneous LE, although UVB is a more e fcient
cause o photo-induced changes in the skin23. UVR induces apoptosis,
which leads to translocation o cellular and nuclear antigens 24, and
there may also be a reduction in the clearance o apoptotic cells 25. In
addition, UVR increases keratinocyte production o Ro5226.
A number o proin ammatory cytokines, including tumor necrosis
actor (TNF)-α, interleukin (IL)-1, HMGB1 (high-mobility group box
1), and IL-1827–29, are induced by UVR. Following UV irradiation o
keratinocytes, a complex array o chemokines, including chemokine
(C-C moti ) ligand 5 (CCL5), CCL20, CCL22, and chemokine (C-X-C
moti ) ligand 8 (CXCL8), is produced. O note, there is an increase in
these chemokines within lesions o cutaneous LE, likely leading to
leukocyte recruitment to the skin30. These e ects require adhesion
molecules, with activation o endothelial cells (increased expression o
ICAM-1, VCAM-1 and E-selectin) and induction o ICAM-1 on basal
keratinocytes (Fig. 41.1A)31,32.

Table 41.1 Genes associated with systemic lupus

GENES ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS erythematosus. For detailed in ormation on the
unction o these protein products, see
B- and T-cell unction HLA-DR – major histocompatibility complex, class II www.genecards.org. The most strongly associated
BLK – B lymphoid tyrosine kinase genes are in bold. Adapted from ref. 16.
BANK1 – B-cell sca old protein (with ankyrin repeats) 1
CTLA4 – cytotoxic T lymphocyte antigen 4
FCGR2B – Fc ragment o IgG, low a nity IIb, receptor (CD32)
LYN v-yes-1 – Yamaguchi sarcoma viral related oncogene homolog
PTPN22 – protein tyrosine phosphatase, non-receptor type 22 (lymphoid)
STAT4 – signal transducer and activator o transcription 4
PDCD1 – programmed cell death 1
IRAK1 – interleukin-1 receptor-associated kinase 1
TNFSF4 – tumor necrosis actor (ligand) super amily, member 4
IL21 – interleukin 21
Innate immunity IRF5 – inter eron regulatory actor 5
TNFAIP3 – tumor necrosis actor, alpha-induced protein 3
SPP1 – secreted phosphoprotein 1 (osteopontin)
TREX1 – three prime repair exonuclease 1 (see text)
TYK2 – tyrosine kinase 2
IRAK1 – see above
STAT4 – see above
Immune complex FCGR3A – Fc ragment o IgG, low a nity IIIa, receptor (CD16a)
clearance
FCGR3B – Fc ragment o IgG, low a nity IIIb, receptor (CD16b)
CRP – C-reactive protein, pentraxin-related
ITGAM – integrin, alpha M (complement component 3 receptor 3 subunit; CD11b)
C4A – complement component 4A
C4B – complement component 4B
C2 – complement component 2
C1Q – complement component 1, q subcomponent
Apoptosis ATG5 – autophagy related 5 homolog
STAT4 – see above
Ubiquitination UBE2L3 – ubiquitin-conjugating enzyme E2L 3
TNFAIP3 – tumor necrosis actor, alpha-induced protein 3
DNA methylation MECP2 – methyl CpG binding protein 2 (Rett syndrome)
Cellular adhesion ITGAM – see above
Other/unknown PXK – PX domain containing serine/threonine kinase
ICA1 – islet cell autoantigen 1
SCUBE1 – signal peptide, CUB domain, EGF-like 1
NMNAT2 – nicotinamide nucleotide adenylyltrans erase 2
XKR6 – XK, Kell blood group complex subunit-related amily, member 6
616 KIAA1542
 CH AP T E R

PATHOGENESIS OF LUPUS ERYTHEMATOSUS DIFFERENT FORMS OF CUTANEOUS LUPUS AND THEIR ASSOCIATION WITH 41
SYSTEMIC LUPUS ERYTHEMATOSUS SLE

Lupus Erythematosus
A Type of cutaneous lupus Association with SLE
Sun
• Acute cutaneous lupus ++++
UVA UVB erythematosus (ACLE)
• Subacute cutaneous lupus ++
Stratum erythematosus (SCLE)
corneum
• Chronic cutaneous lupus
TGF-α Chemokine induction erythematosus (CCLE)
IL-1 CXCL8, CCL5, CCL20
Epidermis
– Discoid lupus erythematosus (DLE)
IL-12 
Localized (head and neck) +
IL-18 Initiation of 
Widespread/disseminated ++
Keratinocyte HMGB1 immune response 
Hypertrophic +
– Lupus erythematosus tumidus +/–
ICAM-1 (LET)
– Lupus panniculitis +
– Chilblain lupus ++
BMZ = Adhesion • Other variants
molecule – Bullous eruption o SLE ++++
E-selectin – Rowell’s syndrome ++ to ++++
ICAM-1
VCAM-1 Table 41.2 Di erent forms of cutaneous lupus and their association with
Dermis TNF-α systemic lupus erythematosus (SLE).
IL-12
Prostaglandins Endothelial
cell
LE30,34 (Fig. 41.1B). IFN-α urther drives the di erentiation o mono-
cytes to plasmacytoid dendritic cells, which are potent producers o
B
Sun IFN-α/β, thus orming an amplifcation loop35. Increased numbers o
UV
plasmacytoid dendritic cells have been ound within cutaneous LE
injury lesions34. Epidermal and dermal dendritic cells can acquire keratinocyte-
derived antigens and prime CD8+ T cells to these antigens within the
Lichenoid skin-draining lymph nodes36. Corroborating evidence or the role o
Epidermis tissue
reaction
IFN-α is provided by the induction o cutaneous LE in patients receiving
IFN-α or other medical conditions. The increased IFN signature seen
in SLE has also been detected in peripheral blood mononuclear cells
CXCL11 rom patients with DLE and SCLE, but not those with LE tumidus37.
The IFN-upregulated chemokines can recruit CXCR3-positive CD4+
CXCL10 CXCL9 and CD8+ T cells to the skin, as well as immature plasmacytoid den-
dritic cells, contributing to the characteristic inter ace infltrate o cuta-
neous LE30,38. In addition, via the production o IFN-α, plasmacytoid
dendritic cells drive the activation and expansion o T cells. There is
also evidence or the presence o granzyme B and TIA1 (poly(A)-binding
Immune protein), two cytotoxic granule-associated proteins involved in apopto-
IFN-γ
complexes IFN-α sis, in the skin o all subsets o cutaneous LE, although somewhat less
so in SCLE, suggesting that there are ewer CD8+ T cells in SCLE38. In
TH1 cell patients with disseminated, scarring DLE, high numbers o circulating
pDC CXCR3
= Chemokine CCR4+ cytotoxic T cells were detected39. One study ound decreased
numbers o Foxp3+CD4+CD25 + T regulatory cells in the skin, but not
the blood, o cutaneous LE patients, and Treg cells are known to down-
Virus
IFN-α regulate the immune response40.
A scenario that integrates current theories regarding the pathogenesis
o several subsets o cutaneous LE is shown in Figure 41.1. In the
Fig. 41.1 Pathogenesis of lupus erythematosus. A In photosensitive
cutaneous LE, ultraviolet radiation (UVA and UVB) triggers cytokine and proposed model, a response to UVR triggers cytokine and chemokine
chemokine production, initiating an immune response. B A lichenoid tissue production by keratinocytes as well as endothelial cell activation,
reaction is the endpoint o a complex cascade that includes activation o thereby initiating the immune response (see Fig. 41.1A). In the context
dendritic cells, release o inter eron (IFN), production o chemokines, and o genetic risk and environmental actors, a complex cascade ensues
activation o T cells. BMZ, basement membrane zone; CCL, chemokine (C-C that includes activation o dendritic cells, release o IFN, activation o
moti ) ligand; CXCL, chemokine (C-X-C moti ) ligand; CXCR, chemokine (C-X-C T cells, and production o chemokines; a positive eedback loop ulti-
moti ) receptor; HMGB1, high-mobility group box 1; IL, interleukin; ICAM, mately results in a lichenoid tissue reaction (see Fig. 41.1B).
intercellular adhesion molecule; pDC, plasmacytoid dendritic cell; TNF, tumor
necrosis actor; VCAM, vascular cell adhesion molecule. Adapted from Dutz JP et al.,
In: Wallace DJ, Hahn BH (eds). Dubois’ Lupus Erythematosus, 7th edn. Philadelphia: Lippincott, Williams &
Wilkins, 2006, and Meller S, Gilliet M, Homey B. Chemokines in the pathogenesis of lichenoid tissue
CLINICAL FEATURES
reactions. J Invest Dermatol. 2009;129:315–19.

Cutaneous Lupus – Three Major Forms

IFN is another cytokine that plays a role in the pathogenesis o cuta-
neous LE. Increased secretion o IFN can result rom binding o apo-
ptotic cells to Fcγ receptors on macrophages; binding o viral pathogens,
DNA, RNA or immune complexes to Toll-like receptors on plasmacy-
toid dendritic cells; and single nucleotide polymorphisms (SNPs) in
genes that encode proteins in the IFN pathway33. Notably, an increase
in proteins upregulated by IFN, including the chemokines CXCL9 and
CXCL10, has been observed in the skin o patients with cutaneous
Classifcation
The most commonly used classifcation o cutaneous lesions in LE is
that o the late Pro essor James Gilliam41. He segregated skin lesions
into those that are specifc and those that are not specifc. Within the
category o specifc cutaneous lesions, he subdivided these into acute,
subacute and chronic (Table 41.2). This choice o terms was based upon
the observation that three distinct types o cutaneous LE are commonly 617
seen: the o ten transient acute cutaneous LE (ACLE) typifed by malar
SECTION
erythema; the requently long-lived, intensely in ammatory discoid Discoid lupus erythematosus
7 lesions which can lead to permanent disfguring scars (DLE); and a
Discoid lesions represent one o the most common skin mani estations
RHEUMATOLOGIC DERMATOLOGY

photosensitive eruption characteristically more long-lasting than ACLE

o lupus, and they are certainly the most common type o cutaneous
but without the potential or scarring, or which the term subacute
LE that a dermatologist is requested to evaluate. Discoid lesions are
cutaneous LE (SCLE) was coined. Typically grouped within the chronic ound most o ten on the ace, scalp and ears (Fig. 41.3), but may
cutaneous LE category are not only DLE, but also the less common LE
be present in a widespread distribution (Fig. 41.4). It is unusual or
tumidus, lupus panniculitis and chilblain lupus.
discoid lesions to be present below the neck without lesions also being
Formal studies have not been done comparing duration o disease
present above the neck43. On occasion, discoid lesions occur on mucosal
activity or the various types o cutaneous LE, and there is a consider-
sur aces, including the lips, nasal mucosa, conjunctivae and genital
able range in the duration o activity within each subtype. On occasion,
mucosa.
ACLE and SCLE lesions may be chronic, and DLE and LE tumidus
Some patients with discoid lesions exhibit a photodistribution, and
lesions may be relatively short-lived. In act, some authorities have
sun exposure appears to have a role in lesional development. However,
proposed that LE tumidus should be removed rom the chronic category
many patients have discoid lesions in sun-protected skin, and there is
and be given its own category, intermittent cutaneous LE42. These
no clear association between sun exposure and their development.
caveats aside, Gilliam’s classifcation schema has proven utility in the
Discoid lesions have the potential or scarring, and, with time, a
organization o the various types o cutaneous LE and it is the basis or
substantial proportion o patients develop disfguring scarring. Active
the classifcation herein, accompanied by a ocus on the morphology
lesions are intensely in ammatory, with a pronounced in ammatory
and histopathology o lesions (Fig. 41.2). The three major orms o
infltrate in both the superfcial and deep dermis. As a result, active
cutaneous LE will be discussed frst, ollowed by the remaining entities
lesions tend to eel indurated on palpation. The adnexa are prominently
outlined in Table 41.2.

PREDOMINANT LOCATIONS OF INFLAMMATORY INFILTRATES IN SUBSETS OF CUTANEOUS LUPUS ERYTHEMATOSUS

ACLE SCLE DLE LET LEP

Fig. 41.2 Predominant locations of in ammatory in ltrates in subsets of cutaneous lupus erythematosus. The types o cutaneous lupus erythematosus are:
acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), discoid lupus erythematosus (DLE), lupus erythematosus tumidus
(LET) and lupus panniculitis (LEP); the latter three are orms o chronic cutaneous lupus erythematosus (see Table 41.2). The primary locations o the in ltrates are
as ollows: super cial dermis, ACLE and SCLE; super cial plus deep dermis and periadnexal, DLE; super cial and deep dermis, LET; and subcutaneous at, LEP. The
nal diagnosis requires clinicopathologic correlation.

CHARACTERISTIC SITES OF INVOLVEMENT FOR THE THREE MAJOR SUBTYPES OF CUTANEOUS LUPUS ERYTHEMATOSUS

Acute cutaneous LE Subacute cutaneous LE Chronic cutaneous LE

Alopecia
within lesions
"Butterfly"
rash

LE tumidus

Lupus panniculitis

Discoid LE

Chilblain lupus

618
Fig. 41.3 Characteristic sites of involvement for the three major forms of cutaneous lupus erythematosus (LE).
 CH AP T E R

41

Lupus Erythematosus
A B C

D E F

Fig. 41.4 Various presentations of discoid lesions of lupus erythematosus. Lesions, which avor the head and neck
region, may show erythema, scaling, atrophy and dyspigmentation in addition to scarring (and alopecia) (A–D). The
scarring process may be destructive (E). Less common sites include the palms (F) and soles (G), where lesions can be
keratotic or ulcerative as in lichen planus. The patients with plantar involvement had systemic lupus erythematosus and
responded well to isotretinoin. H Occasionally, hypertrophic lesions develop with signi cant hyperkeratosis. C, Courtesy,
Kalman Watsky, MD; H, Courtesy, Julie V Scha er, MD.
G

involved, with ollicular plugging and scarring alopecia commonly
observed. Dyspigmentation is to be expected in longstanding lesions,
typically with hypopigmentation in the central area and hyperpigmen-
tation at the periphery (Fig. 41.5), but sometimes with vitiligo-like
depigmentation. Rarely, squamous cell carcinoma develops in a long-
standing discoid lesion.
O the various orms o chronic cutaneous LE, discoid lesions (o ten
re erred to as DLE) are the most common (see Table 41.2). Patients
with only discoid lesions may have associated arthralgias, but, over
time, only 5–15% o these patients eventually develop clear-cut
SLE44–46a. The risk may be higher in patients with widespread (dissemi- 619
nated) discoid lesions43,45,46. However, it is important to remember that
SECTION
discoid lesions represent one o the 11 ARA criteria or SLE (see below)
7 and can be a common presenting mani estation o SLE.
RHEUMATOLOGIC DERMATOLOGY
An unusual variant o DLE is hypertrophic DLE, characterized by
thick scaling overlying the discoid lesion or occurring at the periphery
o the discoid lesion. The intensely hyperkeratotic lesions are o ten
prominent on the extensor arms (see Fig. 41.4H), but the ace and upper
trunk may also be involved. Frequently, there are typical discoid lesions
present in other locations.
Subacute cutaneous lupus erythematosus
SCLE is typically photosensitive, with lesions confned to sun-exposed
skin. It is notable that the mid acial skin is usually spared, while the
sides o the ace, upper trunk and extensor aspects o the upper extremi-
ties are commonly involved (Fig. 41.6; see Fig. 41.3)47. In some patients,
the disease may be mild, with only a ew small scaly patches appearing
a ter sun exposure.
Lesions o SCLE may have an annular confguration, with raised red
borders and central clearing (Fig. 41.7), or a papulosquamous presenta-
tion with an eczematous or psoriasi orm appearance. SCLE lesions
characteristically have a relatively sparse, superfcial in ammatory
infltrate, and, consequently, there is usually no induration. Lesions
o ten result in dyspigmentation, particularly hypopigmentation or even
depigmentation, but do not scar.
Fig. 41.5 Discoid lupus lesions with
dyspigmentation and scarring
alopecia. Hypopigmentation o ten
develops centrally with
hyperpigmentation at the periphery.
Courtesy, Joyce Rico, MD.
620 A B
In some instances, lesions o SCLE have appeared in patients receiv-
ing certain medications, in particular hydrochlorothiazide and terbin-
afne, but also calcium channel blockers, nonsteroidal anti-in ammatory
drugs (e.g. naproxen), griseo ulvin and antihistamines. The lesions may
or may not clear once the medication is discontinued.
The long-term prognosis o patients who have SCLE is not com-
pletely known, largely because this subset o cutaneous LE only recently
has been widely recognized. It is clear that a certain percentage o
patients, perhaps 10–15%, will over time develop signifcant internal
disease, including nephritis 44. Since anti-Ro autoantibodies are associ-
ated with Sjögren’s syndrome as well as SCLE, it is not surprising that
some patients have eatures o both conditions, and some may have
serious internal mani estations o Sjögren’s syndrome such as pulmo-
nary or neurologic disease.
An important eature o SCLE, rom the standpoint o understanding
the pathogenesis o lupus, is its regular association with the anti-Ro
autoantibody (see Ch. 40). Although investigators di er in their opin-
ions as to the prevalence o anti-Ro in SCLE, it is likely that a
substantial majority o patients with this condition (approximately
70% in a large series, reported range o 60–100%) have anti-Ro
antibody47,48.
Acute cutaneous lupus
The lesions o ACLE are exemplifed by the development o bilateral
malar erythema (“butter y rash”; Fig. 41.8). These lesions tend to be
transient, ollow sun exposure, and resolve without scarring (but some-
times with dyspigmentation). An association with anti-dsDNA
Fig. 41.6 Subacute
cutaneous lupus
erythematosus (SCLE).
Numerous erythematous
annular plaques on the
back, some o which
have associated white
scale. Note the
photodistribution.
Courtesy, Kathryn
Schwarzenberger, MD.
Fig. 41.7 Subacute cutaneous lupus erythematosus
(SCLE). Lesions are most commonly seen on the
sun-exposed aspects o the upper extremities. The
margins o the annular lesions may have scale-crust
(A) or be composed o multiple papules (B). A, Courtesy,
Jean L Bolognia, MD.

antibodies and lupus nephritis has been proposed and is plausible44,
although some patients with a malar rash have neither anti-dsDNA
antibodies nor lupus nephritis. Patients presenting with this type o
eruption must be evaluated care ully or evidence o internal disease.
The morphology o the lesions ranges rom mild erythema to intense
edema. The presence o telangiectasias, erosions, dyspigmentation and
epidermal atrophy (i.e. poikiloderma) may help to distinguish the malar
erythema o ACLE rom that o common acial eruptions such as sebor-
rheic dermatitis and the vascular type o rosacea. Occasionally, there is
a papular component, and occasionally lesions develop scaling (see Fig.
41.8C). The duration may range rom a ew hours to several weeks.
The ace, particularly the malar area, is most commonly a ected, but
sometimes lesions may be more widespread in distribution (Fig. 41.9;
see Fig. 41.3). When lesions occur on the hands, the knuckles are typi-
cally spared. It is not unusual or the acute cutaneous eruption to be
accompanied by oral ulcerations.
Rarely, patients with lupus develop an acute eruption clinically
similar to toxic epidermal necrolysis or erythema multi orme major
(Fig. 41.10). The presence o erythema multi orme-like lesions in lupus
patients has been termed Rowell’s syndrome49. These lesions may
represent a severe variant o ACLE or, in some cases, SCLE.
The three major types o cutaneous LE are not mutually exclusive.
In a given patient, more than one type o cutaneous lesion may occur.
Cutaneous Lupus – Additional Variants
(see Table 41.2)
Lupus erythematosus tumidus
Some patients with cutaneous LE have lesions characterized by indura-
tion and erythema but no scale or ollicular plugging. The epidermis
appears to be uninvolved in the disease process, although there is an
intense dermal in ammatory infltrate. LE tumidus lesions may be the
A B
Fig. 41.8 Acute cutaneous lupus erythematosus (ACLE). The acial erythema, o ten re erred to as a “butterfy rash” may be variable (A), edematous (B) or have
associated scale (C). The presence o small erosions can aid in the clinical di erential diagnosis. A, Courtesy, Kalman Watsky, MD.
Fig. 41.9 Acute
cutaneous lupus
erythematosus (ACLE).
This patient had ACLE
lesions on the arms as
well as the ace.
CH AP T E R
same as the “urticarial plaques” described in lupus patients. However,
these fxed plaques should not be con used with urticarial vasculitis 41
Lupus Erythematosus
(see Ch. 24). Some authors state that the lesions are most common on
the ace, although they can be quite common on the trunk (Fig. 41.11).
Morphologically, the lesions are similar to those o Jessner’s lym-
phocytic infltrate and may have central clearing (see Ch. 121); some
believe that Jessner’s lymphocytic infltrate and LE tumidus are either
very closely related or one and the same50.
Both the very low prevalence o SLE and the relatively low prevalence
o immunoglobulin deposition within the cutaneous lesions in patients
reported to have LE tumidus have made it di fcult to determine whether
LE tumidus is actually a variant o LE or an independent entity.
However, the presence o LE tumidus lesions in patients with other
specifc types o cutaneous LE is evidence in avor o its being classifed
as a orm o cutaneous LE. LE tumidus has been reported to be repro-
ducible by phototesting in the majority o patients51. The lesions tend
to resolve without scarring or atrophy.
Lupus panniculitis
Intense in ammation in the at leads to indurated plaques that can
evolve into disfguring, depressed areas. Lesions o lupus panniculitis
have a distinctive distribution, occurring predominantly on the ace,
upper arms (Fig. 41.12), upper trunk, breasts, buttocks and thighs (see
Fig. 41.3). Some patients have discoid lesions overlying the panniculi-
tis, and, in those cases, the condition is sometimes re erred to as
lupus pro undus. For urther discussion o lupus panniculitis, see
Chapter 100.
Chilblain lupus
Chilblain lupus (SLE pernio; Fig. 41.13) consists o red or dusky purple
papules and plaques on the toes, fngers, and sometimes the nose,
elbows, knees and lower legs. The lesions are brought on or exacerbated
C
Fig. 41.10 Toxic epidermal necrolysis-like eruption of acute lupus
erythematosus. This presentation has also been re erred to as a orm o acute
syndrome o apoptotic pan-epidermolysis (ASAP). 621
SECTION
7
RHEUMATOLOGIC DERMATOLOGY
Fig. 41.12 Lupus panniculitis. Erythematous plaque on the upper arm. The
lesions may resolve with lipoatrophy.
by cold, particularly moist cold climates. These lesions may represent
the concurrence o ordinary chilblains with LE (see Ch. 88), although,
with time, the lesions may develop a gross and microscopic appearance
consistent with a discoid lesion.
Neonatal lupus erythematosus
A neonatal orm o SCLE may occur in in ants whose mothers have
anti-Ro autoantibodies. In babies who have neonatal lupus erythema-
tosus (NLE), the SCLE-like lesions are histologically identical to those
o SCLE in adults, and there is a strong association with anti-Ro anti-
bodies. Indeed, almost 100% o babies with NLE have anti-Ro antibod-
ies52. Unlike SCLE in adults, lesions have a predilection or the ace,
especially the periorbital region and scalp (Fig. 41.14). Photosensitivity
is very common in NLE, but sun exposure is not required or lesions
to orm, as it is possible or lesions to be present at birth. Neonatal
lupus skin lesions typically resolve without scarring, although dyspig-
mentation may persist or many months, and some children have
residual telangiectasias.
Children who have the cutaneous lesions o NLE may also exhibit
internal mani estations. The major extracutaneous fndings are con-
genital heart block (with or without cardiomyopathy), hepatobiliary
disease and thrombocytopenia. The heart block is almost always
present by birth, but on rare occasions has developed a ter birth. Clini-
cally signifcant cardiomyopathy occurs concurrently in a small per-
centage o babies who have heart block. Usually, the cardiomyopathy
622 is apparent in the neonatal period, but it is possible or it to become
apparent only a ter several months have elapsed. Cardiac NLE has a
Fig. 41.11 Lupus erythematosus tumidus. Annular pink plaques on the chest
(A) and pink–violet plaques on the ace (B). None o the lesions have epidermal
change. B, Courtesy, Julie V Scha er, MD.
Fig. 41.13 Chilblain lupus. Violaceous plaques, some with scale, on toes. I
there is a amily history o this disorder, the possibility o mutations in TREX1,
which encodes a DNA exonuclease, can be considered.
mortality rate o approximately 20%, and about two-thirds o children
require pacemakers53.
Hepatobiliary disease and cytopenias, especially thrombocytopenia,
may be present at birth, or they may develop within the frst ew
months o li e54. Hepatobiliary disease has been reported to present as
liver ailure during gestation or in the neonatal period, as conjugated
hyperbilirubinemia during the frst ew weeks o li e, or with mild eleva-
tions o aminotrans erases at 2–3 months o li e.
It is common or babies with NLE to exhibit only one o the above
clinical mani estations, and thus many children with cutaneous NLE
have no other signifcant clinical fndings. However, children who have
skin signs o NLE should be evaluated or internal mani estations with
a physical examination in addition to an electrocardiogram, complete
blood count, and liver unction tests, when indicated.
Other Variants
In the clinical setting o lupus, bullous lesions may appear or several
reasons. On occasion, bullous or crusted lesions occur simply as a result
o the intensity o the basal cell damage in lesions o ACLE or SCLE
(see Fig. 41.7A) or, possibly, DLE. Rarely, a dramatic, acute eruption
similar to erythema multi orme major or toxic epidermal necrolysis
(TEN) may occur in patients with preexisting ACLE or SCLE, or it may
appear de novo. Blisters occurring within ACLE and SCLE lesions and
erythema multi orme-like and TEN-like cutaneous lupus ft within the
category o lupus-specifc skin lesions.
The term bullous eruption o SLE, or bullous SLE, has been used to
describe a blistering eruption that consists o vesicles and bullae whose

histopathology o ten resembles dermatitis herpeti ormis, with a primar-
ily neutrophilic infltrate and microabscesses within the dermal papillae
(Fig. 41.15)55. In some patients, the clinical and histologic eatures may
resemble bullous pemphigoid or epidermolysis bullosa acquisita.
Immunoreactants are o ten ound at the basement membrane zone and
antibodies to type VII collagen have been detected in several patients56.
This eruption may represent the concurrence o lupus with an autoim-
mune blistering disease due to autoantibodies to a component o the
basement membrane zone. There are also a number o case reports o
other autoimmune bullous diseases appearing in patients with lupus
(reviewed in re . 57).
A lupus/lichen planus overlap syndrome has been described, in which
lesions have eatures o both conditions (see Ch. 11).
Systemic Lupus Erythematosus
Lupus erythematosus is potentially a multiorgan disease, although in
individual patients it is o ten only one or a ew organs that are signif-
cantly a ected. The organ systems most commonly a ected are joints,
skin, hematologic, pulmonary, renal and the CNS. Many o the internal
organ mani estations classically associated with lupus are part o the
criteria or the classifcation o SLE (see Table 41.7), and re erence to
these criteria may serve as a use ul reminder o the possible character
o internal organ involvement (e.g. non-erosive arthritis, pleuritis,
Fig. 41.14 Neonatal lupus erythematosus. Annular erythematous plaques on
the orehead and scalp. Note the resemblance to the annular orm o subacute
cutaneous lupus erythematosus. Courtesy, Julie V Scha er, MD.
Fig. 41.15 Bullous eruption of systemic lupus erythematosus. Vesicles and
bullae due to autoantibodies against type VII collagen can develop in patients
with systemic disease.
CH AP T E R
pericarditis, proteinuria, cellular casts in the urine, seizures, psychosis,
hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia). 41
Lupus Erythematosus
However, it should be remembered that these systemic eatures have
been selected as criteria due to their use ulness in distinguishing SLE
rom other rheumatic diseases. They are not necessarily the most
common systemic eatures o SLE, and certainly do not represent a
comprehensive listing o possible organ involvement. Signs and symp-
toms such as ever, weight loss, atigue, myalgias and lymphadenopathy
are exceedingly common, i nonspecifc, and may be use ul indicators
o increased risk or SLE in patients who present with cutaneous lesions.
Although ACLE is the cutaneous phenotype with the strongest associa-
tion with systemic disease, patients with any type o cutaneous LE may
develop internal involvement.
Nonspeci c Cutaneous Lesions
Vascular lesions are common in patients with LE, particularly in those
who have systemic disease (Table 41.3). These lesions include Ray-
naud’s phenomenon (see Ch. 43), livedo reticularis, palmar erythema
and periungual telangiectasia. Purpura, urticarial papules or ulcera-
tions due to vasculitis may occur, as well as cutaneous in arction
resembling Degos’ disease or atrophie blanche. Patients with cutane-
ous LE who have any o these fndings should be evaluated or sys-
temic disease. Livedo reticularis, thromboses, ulcerations, and lesions
resembling Degos’ disease have each been associated with antiphos-
pholipid antibodies58 (see Ch. 23). The association o livedo reticularis
with ischemic CNS disease has been called Sneddon syndrome, and
the phenotype o the antiphospholipid syndrome has been called
Hughes syndrome59.
Alopecia o ten occurs as a result o scarring discoid lesions. However,
non-scarring di use alopecia can appear in patients with systemic
disease. It has been reported that patients with lupus have an
increased likelihood o alopecia areata compared with the general
population60.
Sclerodactyly, calcinosis and rheumatoid nodules, fndings more con-
sistent with scleroderma or rheumatoid arthritis, have been observed
in some patients with lupus, although many o the patients with these
fndings may have overlap syndromes rather than classic lupus. Other
skin fndings reported to occur in patients who have lupus include
erythromelalgia, papulonodular mucinosis (o Gold; see Ch. 46) and
anetoderma (see Ch. 99).
Patients with SLE have more subtle nail old capillary abnormalities
than do patients with scleroderma or dermatomyositis. Prominent
large, tortuous capillaries and areas o marked avascularity are not
characteristic o SLE.
CUTANEOUS FINDINGS NONSPECIFIC THAT SUGGEST THE DIAGNOSIS OF
SYSTEMIC LUPUS ERYTHEMATOSUS
Di use non-scarring alopecia
Raynaud’s phenomenon
Nail old telangiectasias and erythema
Vasculitis
• Urticarial vasculitis
• Small vessel vasculitis (e.g. palpable purpura)
• Polyarteritis nodosa-like lesions
• Ulcerations
Cutaneous signs o antiphospholipid syndrome
• Livedo reticularis
• Ulcerations
• Acrocyanosis
• Atrophie blanche-like lesions
• Degos’-like lesions
Livedoid vasculopathy
Palmar erythema
Papular and nodular mucinosis
Table 41.3 Cutaneous ndings (nonspeci c) that suggest the diagnosis of
systemic lupus erythematosus. These are in addition to skin signs o other
autoimmune connective tissue diseases, which raise the possibility o an 623
overlap syndrome.
SECTION
PATHOLOGY and discoid lesions. Some o the more distinctive histologic eatures o
7 cutaneous LE are basal cell damage (also re erred to as vacuolar degen-
RHEUMATOLOGIC DERMATOLOGY

eration or hydropic change), lymphohistiocytic in ammatory infltrates

Routine Histopathology
Histologic fndings in cutaneous LE depend in large part on the subtype
(Fig. 41.16; see Fig. 41.2). Characteristic fndings in ACLE, SCLE,
discoid lesions, LE tumidus, and lupus panniculitis are outlined in
Table 41.4. However, in practice, an overlap in histologic fndings
occurs among the various clinical phenotypes, particularly ACLE, SCLE
and, primarily in discoid lesions, periadnexal in ammation, ollicular
plugging, and scarring. In lesions o ACLE, dermal changes can be rela-
tively subtle although basal cell damage may be pronounced. In SCLE,
epidermal changes and a superfcial lymphocytic infltrate are common.
In contrast to discoid lesions, SCLE lesions tend to have little or no
hyperkeratosis, basement membrane thickening, periadnexal infltrate,

A B

Fig. 41.16 Histologic features of cutaneous lupus erythematosus (LE). A Acute cutaneous LE showing inter ace dermatitis with vacuolization o basal
keratinocytes and sparse super cial lymphoid in ltrates. B Chronic discoid LE showing ocal inter ace dermatitis and dense perivascular and periadnexal lymphoid
in ltrates throughout the entire dermis. A thickened basement membrane is a characteristic nding and can be highlighted by PAS staining (insert). Courtesy, Lorenzo
Cerroni, MD.

CHARACTERISTIC HISTOLOGIC FINDINGS IN CUTANEOUS LUPUS ERYTHEMATOSUS LE

Histologic nding Acute cutaneous LE Subacute cutaneous LE Discoid lesions of LE LE tumidus Lupus panniculitis
Vacuolar alteration o ++ ++ + − +/−
basilar layer
Apoptotic keratinocytes + ++ + − +/−
Hyperkeratosis − − + − −
Epidermal atrophy + ++ + − +/−
Pilosebaceous atrophy − − ++ − +/−
Follicular plugging − + ++ − +/−
Basement membrane + + ++ − −
zone thickening
Lymphocytic in ltrate in + + ++ + +/−
the upper dermis
Lymphocytic in ltrate in − − ++ + +
the lower dermis
Lymphocytic in ltrate in − − + − ++
the subcutis
Lymphocytic in ltrate, − +/− ++ +/− +/−
periadnexal
Dermal edema ++ − + + −
Dermal mucin + +/- + ++ +/−
Dermal brosis − − + − −
Focal hemorrhage + − − − −
Fibrin deposition + − + − −
Table 41.4 Characteristic histologic ndings in cutaneous lupus erythematosus (LE). The table is intended as a broad overview only. Not every eature will be
624 present in every lesion, some eatures may be present that are not indicated as characteristic, and overlap exists amongst subtypes. [−], not a de ning eature;
[+/−], a eature that may be present in some lesions; [+], a eature that is typically present; [++], a de ning eature that may be prominent.

ollicular plugging, deep dermal infltrate, or scarring 61. LE tumidus has
prominent dermal mucin deposition and lymphocytic infltrates with
a lack o epidermal change. While changes o lupus panniculitis are
most prominent in the subcutis, an overlying discoid lesion can be
ound in many cases62.
Immunopathology of Lesional Skin
Examination o the skin or deposits o immunoreactants is called
direct immuno uorescence (DIF). DIF o lesional skin does not replace
routine histologic staining as the method o choice or establishing a
diagnosis o cutaneous LE. DIF is not even necessary as an adjunctive
diagnostic test i the histopathology and clinical presentation are defni-
tive. In those cases where the routine histopathology is equivocal, DIF
can be a valuable asset in establishing a diagnosis.
The most characteristic DIF fnding in cutaneous LE is antibody
deposition at the dermal–epidermal junction and around hair ollicles6.
These deposits are typically granular, and they are composed primarily
o IgG and/or IgM (Fig. 41.17), although IgA can also occasionally be
seen. In addition, deposits o complement proteins are to be expected.
Some investigators have reported that in SCLE, granular deposits o
IgG and IgM are observed primarily within the epidermis rather than
at the dermal–epidermal junction63. There is evidence that the epider-
mal deposits are due to anti-Ro autoantibodies depositing directly
within the skin64.
In ACLE, SCLE and DLE, DIF o lesional skin is positive in the
majority o cases. In general, a positive DIF supports the diagnosis o
cutaneous LE, but a negative DIF does not exclude the diagnosis. It has
been noted that DIF is most likely to be positive in well-established,
active lesions. There is relatively little in ormation about the expected
requency o positive DIF in LE tumidus. Many reports have noted
nonspecifc fndings. In lupus panniculitis, DIF may show immuno-
reactants around dermal vessels, but granular deposits at the dermal–
epidermal junction are not uni ormly present.
Immunopathology of Normal-Appearing Skin
In normal-appearing skin, the presence o antibody deposits at the
dermal–epidermal junction correlates reasonably well with systemic
disease. The antibody deposits are sometimes re erred to as a “lupus
band”, and examination or them as the “lupus band test”. The termi-
nology is con using, because some authors use the term “lupus band”
to apply to the antibody deposits at the dermal–epidermal junction,
whether the skin tested is normal-appearing or lesional, and other
Fig. 41.17 Direct immuno uorescence of cutaneous lupus. Granular deposits
o IgM are present at the dermal–epidermal junction within lesional skin.
Antibody deposits at the dermal–epidermal junction are the most
characteristic immunohistologic nding in lesions o cutaneous lupus and
normal skin o patients with systemic lupus erythematosus. Courtesy, Janet Fairley,
MD.
CH AP T E R
authors reserve the term “lupus band” to describe antibody deposits in
normal-appearing skin. It has been proposed that, i this terminology 41
Lupus Erythematosus
is used, the investigator should modi y the term “lupus band” by a
preceding adjective o “lesional” or “non-lesional”, so that the subject
o discussion is clearly identifed37. The antibody and complement
deposits at the dermal–epidermal junction are usually described as
granular, although some experienced observers have identifed subtypes
o deposits, variously classifed as fbrillar, thready, stippled, shaggy,
linear, lumpy-bumpy or homogeneous 65.
Weak, discontinuous deposits may be seen in persons who do not
have LE, including healthy adults, particularly when chronically sun-
exposed skin is examined. For this reason, many investigators do not
consider a non-lesional lupus band test to be positive unless the depo-
sition o immunoreactants is strong and continuous. A true positive
non-lesional lupus band test occurs in three-quarters or more o
patients with SLE i sun-exposed skin is examined, and in about one-
hal o patients with SLE i sun-protected skin is examined66. A posi-
tive non-lesional lupus band test is unlikely to occur in patients who
do not have SLE, but there are instances where the non-lesional lupus
band test has been positive in patients with other autoimmune
diseases.
In most cases, clinical evaluation and serologic testing or specifc
autoantibodies provides the required in ormation, and the non-lesional
lupus band test is super uous. In cases where the clinical presentation
or laboratory fndings are atypical, the non-lesional lupus band test may
have diagnostic value.
DIFFERENTIAL DIAGNOSIS
The di erential diagnosis varies considerably with the subtype o cuta-
neous LE under consideration. Some o the major entities in each o
the di erential diagnoses are outlined in Table 41.5.
In evaluating a patient with cutaneous lesions, lesional biopsy or
H&E is, in general, the most valuable diagnostic test. An approach to
the diagnosis o cutaneous LE is shown in Figure 41.18. In an occa-
sional situation, such as that o a patient with known SLE who has
transient acial lesions that appear to be ACLE, the clinician may orego
a biopsy because o the high likelihood o obtaining nonspecifc fndings
and the cosmetic sequela o a scar on the ace. Thus, the diagnostic
tree presented is not intended to be ollowed strictly or each situation,
but rather is meant as a general overview o the diagnostic approach,
to be individualized or each patient.
In evaluating a patient with cutaneous lesions or the presence o
systemic disease, the dermatologist can take a directed history, per orm
a cutaneous examination looking or signs o possible systemic disease
(such as vasculitic lesions), and per orm blood and urine testing or
evidence o hematologic or renal disease, ANA, and SLE-specifc
autoantibodies (Table 41.6). Many clinicians also obtain an ESR and
complement levels. Autoantibodies to dsDNA, Sm and possibly also
ribosomal P are relatively specifc or SLE, and are, there ore, help ul
indicators o a high likelihood o systemic disease (see Ch. 40). Autoan-
tibodies to Ro, La, U1RNP, histones and ssDNA are common in patients
with SLE, but they are not disease-specifc. An ANA is help ul i nega-
tive, as it is quite unusual or patients with SLE to have a negative
ANA. It is common or the ANA to be positive in patients with cutane-
ous lesions, and a positive ANA is neither an indicator o systemic
disease nor o LE. Positive ANAs may be ound in patients with many
other diseases (see Ch. 40) and even in apparently normal individuals.
Approximately a third o apparently normal individuals have a positive
ANA at a dilution o 1 : 40, 13% at a dilution o 1 : 80, and 5% at a
dilution o 1 : 16067.
In many cases, the decision to make a diagnosis o SLE is done on
the basis o whether or not the patient’s fndings ulfll our or more
criteria or the classifcation o SLE (Table 41.7)68. It should be
noted that the classifcation was developed by rheumatologists to help
distinguish patients with SLE rom patients with other rheumatic dis-
eases. In particular, most o the control subjects evaluated in the study
that defned the SLE criteria were patients with rheumatoid arthritis.
There ore, the criteria are especially use ul in distinguishing SLE rom
other conditions that a ect joints, and they are quite use ul as a means
o standardizing patient groups or experimental protocols. However, 625
the criteria should not be used in lieu o clinical judgment, i.e. patients
SECTION

7 DIFFERENTIAL DIAGNOSES OF CUTANEOUS LUPUS SUBTYPES DIAGNOSTIC ALGORITHM FOR CUTANEOUS LUPUS
RHEUMATOLOGIC DERMATOLOGY

ACUTE CUTANEOUS LUPUS/MALAR RASH

• Rosacea (including corticosteroid-induced) Clinical examination consistent with cutaneous lupus
• Seborrheic dermatitis (especially photosensitive orm)
• Sunburn
• Drug-induced photosensitivity (phototoxic and photoallergic)
Lesional biopsy for histology
• Dermatomyositis
• Erysipelas
• Pemphigus erythematosus
• Dermatitis, atopic, contact and photocontact
• Acne vulgaris (rarely) Histologic findings Histology inconsistent
Histology consistent
strongly support with lupus
SUBACUTE CUTANEOUS LUPUS with lupus but
diagnosis of
not definitive
• Psoriasis cutaneous lupus
• Dermatophytosis, including tinea incognito
• Photolichenoid drug eruption
• Granuloma annulare Accept diagnosis
• Figurate erythemas (e.g. erythema annulare centri ugum) of cutaneous lupus; Lesional biopsy
• Dermatitis, atopic, contact and photocontact evaluate for for DIF
• Pemphigus oliaceus systemic disease

DISCOID LESIONS
• Facial discoid dermatosis
• Tinea aciei, tinea capitis, tinea corporis
DIF characteristic DIF non-specific
• Lichen planus and lichen planopilaris of lupus or negative
• Jessner’s lymphocytic in ltrate
• Polymorphous light eruption
• Sarcoidosis
Accept diagnosis or Individualize
• Lymphocytoma cutis
provisional diagnosis approach
• Lymphoma cutis of cutaneous lupus;
• Granuloma aciale evaluate for
• Dimorphic ungal in ections, lupus vulgaris systemic disease
• When single lesion, non-melanoma skin cancer
TUMID LUPUS LESIONS
• Jessner’s lymphocytic in ltrate* Fig. 41.18 Diagnostic algorithm for cutaneous lupus. This algorithm is
• Polymorphous light eruption
intended as a guide to diagnosis and should be individualized or each
situation. For example, lesional biopsy or direct immunofuorescence (DIF)
• Reticular erythematous mucinosis
may be per ormed at the same time as a lesional biopsy or routine histology.
LUPUS PANNICULITIS Less de nitive histologic ndings might sometimes be acceptable i the patient
• Other panniculitides (see Ch. 100) is already known to have SLE. Whether a diagnosis is clear-cut or provisional
*Some authorities believe that Jessner’s lymphocytic infltrate and LE tumidus are the may be, on occasion, a subjective determination.
same condition.

Table 41.5 Di erential diagnoses of cutaneous lupus subtypes. Mothers

o boys with chronic granulomatous disease and patients with Sjögren’s EVALUATION FOR SYSTEMIC LUPUS ERYTHEMATOSUS
syndrome have an annular erythema similar to annular SCLE; patients with
GVHD can develop SCLE-like lesions. HISTORY
PHYSICAL EXAMINATION
• Speci c cutaneous lesions (see Table 41.2)
• Nonspeci c cutaneous lesions (see Table 41.3)
who do not have our or more criteria may still have SLE, and, con- • Lymphadenopathy, arthritis
versely, it is possible to meet our criteria and yet not have SLE.
The SLE classifcation criteria do emphasize the need to exclude LABORATORY TESTS
drug-induced systemic lupus. The latter presents as a lupus-like sys- • ANA with pro le (anti-dsDNA, -Sm)
temic illness with arthralgias, myalgias, pleuritis and ever, but lacking • Urinalysis
nephritis and CNS disease. It is observed in patients who are receiving • CBC with di erential, platelet count
specifc medications, in particular procainamide and hydralazine, and • Chemistries (BUN, creatinine)
who develop antihistone autoantibodies (although these autoantibodies • Erythrocyte sedimentation rate
are nonspecifc and are also common in patients with SLE). In contrast • Complement levels (C3, C4)
to drug-induced SCLE with anti-Ro autoantibodies (see above), patients Table 41.6 Evaluation for systemic lupus erythematosus. ANA, antinuclear
with drug-induced SLE rarely have specifc lesions o cutaneous LE, but antibodies; BUN, blood urea nitrogen; CBC, complete blood count; ds,
they may have nonspecifc lesions. O note, patients receiving TNF double-stranded; Sm, Smith.
inhibitors may develop autoantibodies, particularly ANA and anti-
dsDNA, and on occasion develop cutaneous lesions that can resemble
ACLE, SCLE or DLE.
relatively rapid response. The systemic side e ects o corticosteroids
are largely avoided, although the cutaneous side e ects are not. It is
TREATMENT requently the case that topical corticosteroids need to be o high
potency in order or a response to occur, and discoid lesions are one
o the ew instances where it may be appropriate to use high-potency
Topical Therapy corticosteroids on the ace. Patients should be instructed about the
626 Topical or intralesional corticosteroids are a mainstay o therapy (Table risks and benefts o therapy, the need to limit the application to
41.8). They o er a high degree o sa ety as well as the potential or a a ected areas, and the need or monitoring or cutaneous side e ects.
 CH AP T E R
Table 41.7 The American College of
THE AMERICAN COLLEGE OF RHEUMATOLOGY 1982 REVISED CRITERIA FOR CLASSIFICATION OF Rheumatology 1982 revised criteria for 41
SYSTEMIC LUPUS ERYTHEMATOSUS* classi cation of systemic lupus erythematosus69.

Lupus Erythematosus
ECG, electrocardiogram; Sm, Smith; WBC, white
Criterion De nition blood cell.
1. Malar rash Fixed erythema, fat or raised, over the malar eminences, tending to spare
the nasolabial olds
2. Discoid rash Erythematous raised patches with adherent keratotic scaling and ollicular
plugging; atrophic scarring may occur in older lesions
3. Photosensitivity Skin rash as a result o unusual reaction to sunlight, by patient history or
physician observation
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician
5. Arthritis Non-erosive arthritis involving two or more peripheral joints, characterized
by tenderness, swelling or e usion
6. Serositis a) Pleuritis – convincing history o pleuritic pain, rubbing heard by a
physician, or evidence o pleural e usion
OR
b) Pericarditis – documented by ECG, rub or evidence o pericardial e usion
7. Renal disorder a) Persistent proteinuria greater than 0.5 g/day or greater than 3+ i
quantitation not per ormed
OR
b) Cellular casts – may be red cell, hemoglobin, granular, tubular or mixed
8. Neurologic a) Seizures – in the absence o o ending drugs or known metabolic
disorder derangements, e.g. uremia, ketoacidosis or electrolyte imbalance
OR
b) Psychosis – in the absence o o ending drugs or known metabolic
derangements, e.g. uremia, ketoacidosis or electrolyte imbalance
9. Hematologic a) Hemolytic anemia with reticulocytosis
disorder
OR
b) Leukopenia – less than 4000/mm3 total WBC on two or more occasions
OR
c) Lymphopenia – less than 1500/mm3 on two or more occasions
OR
d) Thrombocytopenia – less than 100 000/mm3 in the absence o o ending
drugs
10. Immunologic a) Anti-DNA antibody to native DNA in abnormal titer
disorder
OR
b) Anti-Sm: presence o antibody to Sm nuclear antigen
OR
c) Positive nding o antiphospholipid antibodies based on: (1) an
abnormal serum level o IgG or IgM anticardiolipin antibodies; (2) a positive
test result or lupus anticoagulant using standard methods; or (3) a
alse-positive serologic test or syphilis known to be positive or at least 6
months and con rmed by Treponema pallidum immobilization or fuorescent
treponemal antibody absorption test (FTA-ABS)
11. Antinuclear An abnormal titer o antinuclear antibody by immunofuorescence (or an
antibody equivalent assay) at any point in time and in the absence o drugs known to
be associated with “drug-induced lupus” syndrome
*The proposed classifcation is based on 11 criteria. For the purpose o identi ying patients in clinical studies, a person shall
be said to have systemic lupus erythematosus i any our or more o the 11 criteria are present, serially or simultaneously,
during any interval o observation.

Particularly in active discoid lesions and LE tumidus lesions, intrale-
sional triamcinolone, o ten given in a concentration o 4–5 mg/ml, can
be very e ective. The injections may be repeated monthly while the
lesions are active. There are anecdotal reports o the use o new topical
immunomodulators (e.g. tacrolimus) or cutaneous lesions.
Systemic Therapy
Antimalarial therapy has been used or more than a hal -century or
cutaneous LE, and it remains the gold standard or systemic therapy.
Hydroxychloroquine sul ate is the most commonly chosen antimalarial,
as it is usually well tolerated. Chloroquine and quinacrine (mepacrine)
are alternatives. In patients who are not responsive to hydroxychloro-
quine sul ate, quinacrine may be added to the regimen69a. Quinacrine
can turn the skin yellow, although it does not invariably do so. The
dose o hydroxychloroquine sul ate chosen is usually 200 mg once or
twice per day. It has been reported that i the dose does not exceed
6.5 mg/kg ideal body weight/day, eye toxicity is quite unlikely70. For
chloroquine, the usual dose is 125–250 mg/day, with the eye toxicity- 627
minimizing dose being no more than 3.5–4 mg/kg ideal body weight/
SECTION
immunosuppressive agents such as mycophenolate mo etil or azathio-
7 THERAPY OF CUTANEOUS LUPUS prine, clo azimine, sul asalazine and systemic corticosteroids 71.
RHEUMATOLOGIC DERMATOLOGY

LOCAL THERAPY
Sun protection (2)
Topical and intralesional corticosteroids (2)
Topical calcineurin inhibitors (2)
Topical retinoids (3)
SYSTEMIC ANTIMALARIAL THERAPY
Hydroxychloroquine (200 mg po qd–bid in adults; up to 6.5 mg/kg ideal body
weight/day) (2)
Chloroquine (125–250 po qd in adults; up to 3.5–4 mg/kg ideal body weight/day)
(2)
Quinacrine (100 mg po qd) (2)
Combination o hydroxychloroquine or chloroquine and quinacrine (2)
SYSTEMIC THERAPY FOR ANTIMALARIAL RESISTANT CUTANEOUS DISEASE
Retinoids (e.g. acitretin, isotretinoin) (2)
Thalidomide (50–100 mg po qd or clearing and, i necessary, 25–50 mg po
qd–twice weekly or maintenance) (2)
Dapsone (primarily or bullous eruption o SLE) (2)
Immunosuppressive agents (e.g. mycophenolate mo etil, azathioprine) (2)
Sul asalazine (2)
Clo azimine (3)
Systemic corticosteroids (3)
Immune response modi ers (e.g., rituximab, abatacept,* belimumab, anti-IL-6 Ab,
anti-IL-10 Ab) (3)
*Not more e ective than placebo in non li e-threatening SLE.
Table 41.8 Therapy of cutaneous lupus. Key to evidence-based support:
(1) prospective controlled trial; (2) retrospective study or large case series;
(3) small case series or individual case reports. bid, twice daily; qd, daily.
day70. Quinacrine is thought by most not to cause eye toxicity. For
patients on hydroxychloroquine sul ate or chloroquine, eye examina-
tions should be done by a physician knowledgeable in antimalarial eye
toxicity.
The response to antimalarials is relatively slow. It may take 2 or 3
months or e fcacy to be appreciated, and sometimes several more
months to achieve maximal e fcacy. Consequently, or patients who
are beginning therapy or cutaneous LE, topical or intralesional therapy
should usually be given along with antimalarial therapy. It has been
observed that there is a larger than expected percentage o cigarette
smokers among patients who present with cutaneous lupus, and that
smokers may have more extensive cutaneous disease. It has also been
observed that smokers do not respond as well to antimalarial therapy
as do non-smokers. Thus, smoking cessation may be a use ul adjunc-
tive therapy in some individuals.
Some patients do not respond either to single antimalarial therapy
or to the combination o quinacrine with either hydroxychloroquine
sul ate or chloroquine. Disease that is re ractory to antimalarials
is o ten re ractory to other therapies as well. Nonetheless, it is reason-
able to seek a therapy that will work well, i the risks o therapy are
deemed to be worth the potential benefts. In antimalarial-resistant
patients, therapeutic options include oral retinoids, thalidomide,
Dapsone has been used, but usually with little success except in the
rare subset o bullous eruption o SLE. Both retinoids and thalidomide
are potent teratogens, making them di fcult choices in women o
childbearing potential. Thalidomide also requently causes a peripheral
neuropathy. For that reason, some clinicians have advocated giving
thalidomide in low or intermittent dosing in an attempt to minimize
toxicity. In the uture, immune response modifers (such as rituximab,
and anti-B-lymphocyte stimulator [BlyS], -IL-6 and -IL-10 antibodies)
may play an important role in the treatment o cutaneous LE.
In patients with systemic LE but no major organ involvement (i.e.
potentially li e-threatening involvement o visceral organs), treatment
or mild disease includes NSAIDs, while corticosteroids and immuno-
suppressives (e.g. azathioprine, le unomide, mycophenolate mo etil)
are usually prescribed or moderate to severe disease. When there is a
mild degree o major organ involvement, corticosteroids are the primary
treatment, but or moderate to severe involvement, pulse cyclophos-
phamide +/− pulse corticosteroids are o ten recommended. Immune
response modifers (biologic therapies) are reserved or re ractory disease
(see Table 41.8)72. For a recent more comprehensive review, the reader
is re erred to re erence 73.
Adjunctive Therapy
Sun protection is a vital part o therapy or many patients because the
sun exacerbates or initiates their skin lesions. For others, sun protec-
tion is important or cancer prevention, particularly in hypopigmented
skin or in chronic discoid lesions, where the risk o skin cancer develop-
ment may be higher. Cancer prevention is also essential or patients
who are on immunosuppressive therapy. Lastly, it has been reported
that sun exposure can exacerbate systemic disease in patients who have
SLE. There ore, there are a variety o reasons why sun protection should
be emphasized, even in persons whose skin lesions are not induced or
exacerbated by sun exposure.
Sunscreens should be applied to exposed skin daily, and more o ten
i sun sensitivity is great or sun exposure is intense or prolonged. Broad-
spectrum, high-SPF sunscreens are pre erred (see Ch. 132). In some
cases, the addition o a physical sunblock such as titanium dioxide or
zinc oxide is use ul. Protective clothing is important to emphasize, as
the proper protective clothing is o ten signifcantly more e ective than
sunscreens. Sun avoidance is even more e ective than protective chem-
icals and clothing. Midday sun is particularly high in UVB, a spectrum
o UV radiation to which many patients are susceptible. It is more di -
fcult to minimize UVA exposure, as UVA is present in substantial
quantities throughout the day and can penetrate some types o window
glass. Education on the optimal use o sunscreens and protective cloth-
ing and e ective approaches to sun avoidance is important or most
patients with lupus. Care ul attention should be given to vitamin D
and calcium intake.
For some patients, cosmetic cover-up is the most help ul therapeutic
intervention (see Ch. 153). Particularly in situations where the disease
activity has subsided but dyspigmentation remains, cosmetic camou-
age o the hyperpigmentation or hypopigmentation may be the best
approach.

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 RHEUMATOLOGIC DERMATOLOGY SECTION 7

Dermatomyositis 42 
Joseph L Jorizzo and Ruth Ann Vleugels

dermatomyositis exist without objective evidence o muscle infamma-

Synonyms: � Dermatomyositis/polymyositis � Idiopathic  tion, re erred to as amyopathic dermatomyositis, and ormally known
in ammatory myopathies � Idiopathic in ammatory  as dermatomyositis sine myositis. For dermatologists, establishing the
dermatomyopathies diagnosis o dermatomyositis is important because it is a serious, treat-
able, multisystem disease that has a di erent prognosis and treatment
approach rom LE. The malignancy association in adults provides the
dermatologist with an opportunity to assist medical colleagues in
detecting the tumor at an early stage because the skin disease o ten
precedes the onset o symptoms related to the malignancy. The diag-
Key features nosis is commonly missed, which gives the dermatologist an opportu-
  Autoimmune connective tissue disease of uncertain etiology  nity to make a very meaning ul contribution.
demonstrating a bimodal age distribution with both juvenile and  The treatment o dermatomyositis with muscle and/or systemic
adult forms involvement requires systemic corticosteroids (e.g. prednisone 1 mg/kg/
  Clinical and laboratory signs of proximal extensor in ammatory  day) with a taper that is slower than in the treatment o systemic LE.
myopathy I this approach is used, as many as three-quarters o patients may enter
a clinically disease- ree period without medication, usually within 2–3
  Distinctive, photodistributed, pink–violet poikiloderma favoring  years 2.
the scalp, periocular region, and extensor surfaces, in addition to 
nail fold telangiectasias
  Histopathologic evidence of interface dermatitis with mucin in  HISTORY
skin biopsy specimens and lymphocytic myositis in biopsy 
specimens from a ected muscle Polymyositis and dermatomyositis have been recognized as clinical
  Therapy includes systemic corticosteroids and possibly  entities or more than 100 years. Although the rst adult patients with
immunosuppressive drugs with the prognosis being very good,  dermatomyositis and malignancy were described early in the twentieth
except for adults with associated advanced malignancy, refractory  century, a causal association was not suggested until the 1940s. A
myositis or systemic involvement major step orward in the understanding o these disorders occurred in
1975, when Bohan and Peter proposed generally accepted clinical cri-
teria or their diagnosis 3,4. Over the past 15 years, it has become more
widely accepted that a subset o patients has skin-limited disease (i.e.
amyopathic dermatomyositis). For this reason, Sontheimer5 has pro-
posed a revised classi cation o the idiopathic infammatory myopa-
INTRODUCTION thies that includes amyopathic orms o dermatomyositis, with muscle
Along with polymyositis and inclusion body myositis, dermatomyositis involvement no longer required or a de nitive diagnosis (Table 42.1).
is classi ed as one o the idiopathic infammatory myopathies. Der-
matomyositis is a disease o presumed autoimmune pathogenesis that
presents with a symmetric, proximal extensor infammatory myopathy EPIDEMIOLOGY
and a characteristic cutaneous eruption. Previously, polymyositis was
Dermatomyositis and polymyositis are relatively rare diseases that
thought to represent the same disease process, but just limited to the
occur throughout the world. In adults, both dermatomyositis and poly-
muscle. However, there is now increasing evidence that the pathoge-
myositis a ect women two to three times more o ten than men. The
netic mechanisms o polymyositis and dermatomyositis di er signi -
incidence o dermatomyositis ranges rom 2 to 9 per million amongst
cantly. In polymyositis, clonally expanded, autoreactive CD8+ T cells
various populations7–9 and seems to be increasing, although this may
invade myocytes expressing MHC class I antigens and cause necrosis
simply be a result o increased detection, as well as better diagnosis and
via the per orin pathway. In contrast, there are data to support the
reporting. Table 42.2 summarizes the ndings in our recent
theory that autoantigens activate a humoral immune process in der-
studies9–12.
matomyositis, in which complement is deposited in capillaries causing
capillary necrosis and ischemia1. Because an appreciation o these
pathogenetic di erences occurred rather recently, previous studies o ten
pooled cases o dermatomyositis and polymyositis, making interpreta- PATHOGENESIS
tion o their data challenging.
Dermatomyositis is believed to result rom an immune-mediated
Both dermatomyositis and polymyositis can occur in association with
process triggered by outside actors (e.g. malignancy, drugs, in ectious
other autoimmune connective tissue diseases, including overlap syn-
agents) in genetically predisposed individuals. Table 42.3 illustrates
dromes with additional eatures o lupus erythematosus (LE), sclero-
some o the evidence that supports this theory13–33. Serum antinuclear
derma, Sjögren’s syndrome, rheumatoid arthritis, and mixed connective
autoantibodies are o ten present, as are other myositis-speci c autoan-
tissue disease. Dermatomyositis is characterized by a bimodal age dis-
tibodies, as summarized in Table 42.434,35. The antisynthetase antibod-
tribution, with up to one-quarter o patients in the adult group having
ies are directed against cytoplasmic antigens; there ore the antinuclear
an associated occult malignancy. Patients with juvenile dermatomyosi-
antibody test may even be negative. Patients with antisynthetase anti-
tis do not have an increased risk o malignancy but do have an increased
bodies o ten have overlap syndromes. The term antisynthetase syn-
incidence o calcinosis cutis and associated small vessel vasculitis. 631
drome has been coined to re er to patients with these autoantibodies,
There is a subset o patients in whom the cutaneous mani estations o
SECTION
ever, erosive polyarthritis, “mechanic’s hands”, Raynaud’s phenome- characteristic, as are nail old telangiectasias (Fig. 42.1). I the photo-
7 non, and interstitial lung disease36. distribution and nail old changes are missed, the eruption may be
RHEUMATOLOGIC DERMATOLOGY

misdiagnosed as other conditions characterized by poikiloderma, such

as cutaneous T-cell lymphoma. O ten, the dermatologist correctly
CLINICAL FEATURES notices the photodistribution but thinks rst o a photodrug eruption

Cutaneous Disease
The most important diagnostic eature o the cutaneous eruption
o dermatomyositis is poikiloderma. This eature occurs both in
patients with dermatomyositis, where it is characterized by a pink–
violet color, and in patients with lupus erythematosus, where the
poikiloderma is red. Poikiloderma includes eatures o hyperpigmenta-
tion, hypopigmentation, telangiectasias and epidermal atrophy, and
these eatures are common to both diseases. I the clinician misses the
poikiloderma, the eruption o dermatomyositis may occasionally be
misdiagnosed as psoriasis because some lesions can present as well-
marginated plaques on the elbows and knees and be covered with ne
silvery scale.
Additional clinical clues to the diagnosis o dermatomyositis are a
photodistribution and nail old changes. Photodistributed poikiloderma
involving the “V” o the chest and the upper back is o ten re erred to
as the “shawl sign”. Cuticular dystrophy (i.e. “ragged” cuticles) is quite
REVISED CLASSIFICATION SYSTEM FOR THE IDIOPATHIC INFLAMMATORY
DERMATOMYOPATHIES
Dermatomyositis
Adult-onset
Classic DM
Classic DM with malignancy
Classic DM as part of an overlapping connective tissue disorder
Clinically amyopathic DM*
Amyopathic DM
Hypomyopathic DM
Juvenile-onset
Classic DM
Clinically amyopathic DM
Amyopathic DM
Hypomyopathic DM
Polymyositis
Isolated polymyositis
Polymyositis as part of an overlapping connective tissue disorder
Polymyositis associated with internal malignancy (?) †
Inclusion body myositis
*Both adult-onset and juvenile-onset amyopathic DM and hypomyopathic DM can be
further subcategorized as “provisional” and “con rmed” when patients have biopsy-
con rmed hallmark cutaneous manifestations of DM without muscle weakness and with
normal muscle enzymes for ≥6 months (provisional) or 24 months (con rmed).
† omeprazole, ipecac (repeated exposures), interferon-α-2b, tegafur, etoposide,
Although more recent population-based studies have clearly con rmed that adult-onset
classic DM is associated with a signi cant risk for internal malignancy, these same studies
have questioned whether such a relationship exists for polymyositis.
Table 42.1  Revised classi cation system for the idiopathic in ammatory
dermatomyopathies. This classi cation scheme recognizes, with equal  BPH, benign prostatic hyperplasia; ICAM, intercellular adhesion molecule; TNF,
weighting, the cutaneous and muscle manifestations of this group of disorders.  tumor necrosis factor.
Adapted from ref. 6
PATHOGENESIS OF DERMATOMYOSITIS
GENETICS13–15
•  Monozygotic twins a ected
•  Associated human leukocyte antigens (HLA)
– HLA-DR3 and -B8 (juvenile dermatomyositis)
– HLA-DR52 (patients with anti-Jo-1 antibodies)
– HLA-DR7 and -DRw53 (patients with anti-Mi-2 antibodies)
– HLA-B14 and -B40 (adults with dermatomyositis overlap)
– HLA-DRB1*15021 (Japanese with juvenile dermatomyositis)
•  TNF-α 308A allele polymorphism
CELLULAR IMMUNITY/APOPTOSIS16–22
•  Histopathologic  ndings in skin and muscle (CD8+ lymphocytes)
•  Lymphocyte-mediated experimental myositis in mice
•  Increased Ki-67 and p53 expression in keratinocytes after UVB irradiation
•  Increased CD40 expression on muscle cells
•  Decreased circulating CD54 (ICAM-1)-positive lymphocytes
•  Fas ligand on T cells and Fas receptor on muscle cells
•  MHC class I overexpressed in a ected muscle tissues
•  Elevated expression of COX-1, COX-2 and 5-LOX mRNA in a ected muscle 
tissues
HUMORAL IMMUNITY23
•  Association with autoimmune diseases (Hashimoto’s thyroiditis, Graves’ disease, 
myasthenia gravis, type I diabetes mellitus, primary biliary cirrhosis, dermatitis 
herpetiformis, vitiligo, and other autoimmune connective tissue diseases)
•  Myositis-speci c antibodies versus antibodies against aminoacyl-tRNA 
synthetases, non-synthetases, cytoplasmic antigens, and nuclear antigens. 
Examples include: antisynthetase, anti-Jo-1 (lung disease) and anti-Mi-2 (most 
speci c for dermatomyositis)
INFECTIOUS PRECIPITANTS24,25
•  Seasonal variation
•  Picornavirus substrate for aminoacyl-tRNA synthetases
•  Escherichia coli, muscle protein and a capsid protein of a picornavirus that 
induces mouse myositis all have some homology in amino acid sequences with 
Jo-1
•  Echovirus infection in patients with hypogammaglobulinemia
•  Coxsackievirus-9 myositis
•  AIDS myositis
DRUG AND VACCINE PRECIPITANTS26–31
•  Hydroxyurea, D-penicillamine, TNF-α inhibitors, nonsteroidal anti-in ammatory 
drugs, lipid-lowering drugs (statins > gem brozil), cyclophosphamide, BCG 
vaccine; single case reports of phenytoin, alfuzosin (α-agonist for BPH), 
 
articaine, sulfacetamide sodium ophthalmic drops
MALIGNANCY ASSOCIATION (ADULTS) 32,33
Table 42.3  Pathogenesis of dermatomyositis. BCG, Bacillus Calmette-Guérin; 
 

CLINICAL SUBTYPES OF DERMATOMYOSITIS – DEMOGRAPHICS AND ASSOCIATED FINDINGS

Clinical subtype
Adult-onset classic Adult-onset clinically amyopathic Juvenile-onset classic Juvenile-onset clinically
dermatomyositis9 dermatomyositis10 dermatomyositis11 amyopathic dermatomyositis12
No. of patients 20 291 120 38
Mean age (years) 51.9 50 7.7 10.5
Malignancy detected 6/20 (30%) 41/291 (14%) 0/120 (0%) 0/38 (0%)
Sex ratio (F : M) 3 : 1 3 : 1 2.2 : 1 3 : 2

632 Table 42.2  Clinical subtypes of dermatomyositis demographics and associated ndings.
 CH AP T E R

SERUM AUTOANTIBODIES IN ADULT AND JUVENILE DERMATOMYOSITIS 42 

Dermatomyositis
Autoantibodies Target antigen function Clinical phenotype Autoantibody frequency, %
Adult DM Juvenile DM

Anti-aminoacyl-tRNA  Intracytoplasmic protein  Antisynthetase syndrome  up to 20% 1–3

synthetases (e.g. anti-Jo-1  synthesis (myositis, mechanic’s hands, 
[histidyl], anti-PL-7 [threonyl];  Gottron’s papules, arthritis, 
see Ch. 40) fever, Raynaud’s phenomenon, 
high frequency of interstitial 
lung disease)
Anti-SRP Protein translocation Acute-onset necrotizing  5 <1
myopathy (severe weakness, 
high CK); may be refractory to 
treatment
Anti-Mi-2 Helicase – transcription Adult DM and juvenile DM  15 <10
(hallmark is cutaneous disease, 
milder muscle disease with 
good response to treatment)
Anti-p155/140 See Ch. 40 Cancer-associated myositis in  80 (amyo); 20–30 (classic) ~25
adult DM; severe cutaneous 
disease in adult DM and 
juvenile DM
Anti-p140 Likely NXP-2 – nuclear  Juvenile DM with calcinosis NA ~25
transcription, RNA metabolism
Anti-SAE Post-translational modi cation Adult DM; may present with  NA NA
clinically amyopathic DM
Anti-CADM-140 (MDA5) Innate immunity Clinically amyopathic DM;  10–15 NA
rapidly progressive interstitial 
lung disease
Table 42.4  Serum autoantibodies in adult and juvenile dermatomyositis DM . The autoantigen CADM-140 was subsequently found to be identical to two 
previously identi ed gene products, interferon induced with helicase C domain protein 1 (IFIH1) and melanoma di erentiation-associated gene 5 (MDA5). CADM, 
cancer-associated dermatomyositis; CK, creatine kinase; NA, not applicable; NXP-2, nuclear matrix protein NXP2; SAE, small ubiquitin-like modi er activating 
enzyme; SRP, signal recognition particle.  Adapted rom re . 35.

Fig. 42.1  Dermatomyositis cuticular dystrophy and nail fold
telangiectasias. The cuticles are “ragged” and within the proximal nail fold,  sclerosis, especially limited disease with CREST eatures (calcinosis,
dilated capillary loops alternate with vessel dropout (insert). Atrophy,  Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, tel-
telangiectasias and hypopigmentation are present on the  ngers.  Courtesy, Julie V
Schafer, MD.
or lupus erythematosus and does not include dermatomyositis in the
di erential diagnosis.
The eatures that are most characteristic, and that distinguish der-
matomyositis rom lupus erythematosus, are the violaceous hue o
the poikiloderma and the tendency o lesions to be distributed around
the eyes (the heliotrope sign) and on extensor sur aces. However, the
heliotrope sign can be quite subtle, with only mild erythema o the
eyelids, and it may wax and wane over time. Associated periorbital
edema can range rom mild to marked (Fig. 42.2). In addition, a more
di use acial erythema, or even malar erythema, is o ten present (see
Fig. 42.12).
The cutaneous lesions o dermatomyositis are accentuated on exten-
sor sur aces, including the knuckles. When lesions on the knuckles
develop a secondary lichenoid quality, they are termed Gottron’s papules
(Fig. 42.3); violaceous discoloration o the knuckles, elbows and/or
knees is known as Gottron’s sign (Fig. 42.4). Calcinosis cutis is more
prevalent in juvenile dermatomyositis, a ecting between 25% and 70%
o patients7,37. The cutaneous lesions o dermatomyositis are o ten
pruritic (Fig. 42.5), and this can signi cantly a ect the patients’ quality
o li e38–40. O note, pruritus is a eature that can occasionally help
distinguish dermatomyositis rom LE.
Additional mani estations range rom poikiloderma o the scalp to
centripetal fagellate erythema (Fig. 42.6A) to erosions and ulcerations
(Fig. 42.6B; Table 42.5)41–43. It is also important to look or dermatologic
signs o other connective tissue diseases in patients with dermatomy-
ositis, because o the requency o overlap syndromes. The most
common cutaneous ndings would be signs o overlap with systemic
angiectasias), annular lesions suggestive o subacute cutaneous lupus
erythematosus, or nodules suggestive o rheumatoid arthritis. Cutane-
ous small vessel vasculitis can occur as an associated nding, especially
in patients with juvenile dermatomyositis.
It is important to understand that patients may present with classic
cutaneous mani estations o dermatomyositis but no muscle disease.
Care ul patient evaluation and longitudinal assessment will demon-
strate that some o these patients have skin disease alone (amyopathic
dermatomyositis) while others eventually evolve into ull-blown der-
matomyositis (with muscle disease) or they develop hypomyopathic
dermatomyositis, i.e. no muscle weakness clinically, but myositis by 633
SECTION

7
RHEUMATOLOGIC DERMATOLOGY

Fig. 42.2  Dermatomyositis eyelid edema and heliotrope sign. 

A In ammation of the upper eyelid can be more subtle in darkly pigmented 
skin; note involvement of the lateral nasal root and the cheeks. B The 
characteristic pink–violet color is seen with involvement of the hairline, lower 
forehead, upper eyelids and cheeks; the edema is striking and involves the 
nasal root as well as the eyelids.  B, Courtesy, Jean L Bolognia, MD.
B

radiographic or laboratory testing44. The clinical characteristics o

patients with classic dermatomyositis and with amyopathic dermato-
myositis have recently been reviewed10, in particular with respect to
di erences in malignancy risk. Although it has generally been thought
that the malignancy risk is greater in the setting o classic dermatomy-
ositis, there have been several case series that have observed associated
malignancies in patients with amyopathic dermatomyositis, even in
those who remain muscle disease- ree or years and there ore can be
considered con rmed cases o amyopathic disease. Fulminant lung
disease has also been reported in patients with amyopathic dermato-
myositis. There ore, both malignancy screening and evaluation or
systemic involvement are recommended, irrespective o muscle
involvement.

Systemic Disease
Patients with dermatomyositis usually present with complaints o
malaise and loss o energy. The dermatologic mani estations precede
the onset o objective muscle disease in most patients; however, when
the muscle disease begins, it is indistinguishable clinically rom that
seen in patients with polymyositis. The myopathy a ects proximal
muscle groups, especially the extensor groups (triceps and quadriceps),
in a symmetric ashion. In advanced disease, all muscle groups can be
a ected. Patients may be unable to complete simple tasks such as
combing their hair or rising to their eet rom a sitting position. The
634 a ected muscle groups are o ten tender to palpation in more advanced
disease. Muscle strength should be graded on sequential visits by
C
Fig. 42.3  Dermatomyositis Gottron’s papules. A The  at-topped (lichenoid) 
papules overlying the proximal interphalangeal (IP) and metacarpophalangeal 
(MCP) joints are subtle and were misdiagnosed as verrucae vulgaris in this 
child. B Obvious accentuation of skin lesions over the MCP joints, with 
coalescence of pink–violet lichenoid papules. C Papulosquamous plaques with 
a somewhat linear con guration proximally; clues against psoriasis are the 
Gottron’s papules of the distal IP joints, cuticular dystrophy and nail fold 
telangiectasias.  A, B, Courtesy, Julie V Schafer, MD.

Fig. 42.4 
Dermatomyositis
Gottron’s sign. Thin 
pink papules and 
plaques of the elbow  
(A) and knee (B). Some 
of the papules on the 
elbow are  at-topped 
(lichenoid).  Courtesy, Julie V
Schafer, MD.
B disease, and prompt treatment o the muscle disease may mask the
muscle groups (e.g. right and le t triceps 3/5, right and le t quadriceps
4/5, etc.), although other more ormal methods o quanti cation, such
as the use o a hand-held pull gauge, have been described45. Symptoms
o true dysphagia should prompt investigation or overlap with sclero-
derma, although patients with advanced muscle disease can have
cricopharyngeal muscle dys unction and consequently di culty initiat-
ing swallowing. Distal esophageal involvement can present as gastro-
esophageal refux disease.
Calcinosis is more common in patients with juvenile dermatomy-
ositis than in adults and is most o ten associated with a delay in the
institution o systemic corticosteroids or with advanced, therapy-
resistant disease. In addition to calcinosis cutis, deposits may occur
in the deep ascia and in intramuscular connective tissue. Lesions
occur as hard, irregular nodules, which on occasion drain a chalky
material via stulae to the sur ace. Calcinosis cutis avors sites
o trauma, such as the elbows, knees and ngers, but can occur any-
where. The lesions may be pain ul and can complicate return to
normal unction.
Pulmonary disease occurs in approximately 15–30% o patients with
dermatomyositis, and generally presents as a di use interstitial brosis
that is similar to that seen in patients with rheumatoid arthritis or
scleroderma 46. A recent study suggested that lung disease may be
present in as many as 65% o patients47; however, this conclusion was
CH AP T E R
42 
Dermatomyositis
Fig. 42.5  Dermatomyositis involvement of the upper back. The pink–violet 
plaques, some with associated scale, were very pruritic, as evidenced by 
multiple excoriations. Linear streaks of erythema are also seen.  Courtesy, Jean L
Bolognia, MD.
based on a small series o patients (n = 17) and methodologic issues
were raised48. Pulmonary involvement is a particular eature o the
antisynthetase syndrome36. Patients may also develop acute respiratory
distress syndrome (ARDS). Because this disease is resistant to cortico-
steroid therapy, it ollows a course independent rom that o the muscle
disease and can adversely a ect prognosis in much the same way as in
patients with mixed connective tissue disease.
Cardiac disease is not commonly symptomatic. When it is, it usually
presents as arrhythmias or as conduction de ects49. Patients with der-
matomyositis are o ten not thoroughly evaluated or possible cardiac
true requency o cardiac disease. In one retrospective review, cardiac
involvement was shown to be the major prognostic actor or death in
patients with dermatomyositis (not associated with an underlying
malignancy)50. Additional reported indicators o poor prognosis (other
than malignancy) include older age, progressive disease, initiation o
therapy a ter 24 months o muscle weakness, longer duration o symp-
toms be ore diagnosis, pulmonary disease, dysphagia, and extensive
cutaneous involvement o the trunk51.
For the patient with dermatomyositis, a thorough review o systems
should include a discussion o arthritis, renal disease, gastrointestinal
disease, pulmonary disease, cardiac disease, and other mani estations
such as neuropathy and Raynaud’s phenomenon. Their presence may
suggest systemic involvement and/or overlap with other connective
tissue diseases – in particular, systemic LE, rheumatoid arthritis and
scleroderma. One dermatology-based case series observed a 19% overlap
rate in adult patients with dermatomyositis2.
Malignancy
The reported requency o an internal malignancy in adults with der-
matomyositis varies rom less than 10% to over 50%. The malignancy
association occurs with adult dermatomyositis, but not with the
juvenile orm or with polymyositis. Patients with amyopathic dermato-
myositis also appear to be at increased risk or an associated malig-
nancy. A disproportionate number o the associated malignancies are
carcinomas. Genitourinary malignancies, especially ovarian cancer, and 635
colon cancer may be overrepresented52,53; in some Southeast Asian
SECTION
populations, nasopharyngeal carcinoma is overrepresented54. Other
7 commonly seen malignancies include breast, lung, gastric, pancreatic,
RHEUMATOLOGIC DERMATOLOGY

lymphomas (including non-Hodgkin), and other emale genital

cancers53,55. The risk o malignancy may return to normal a ter 2–5
years33,53,56. Callen has suggested that the best approach to patient
management in this setting is ongoing vigilance with requent and
thorough medical histories, repeated review o systems, complete physi-
cal examinations, and screening laboratory tests.57 More recently, he
has advocated additional investigations, including CT o the chest,
abdomen and pelvis, in the malignancy assessment (Table 42.6)56. With
regard to long-term survival, as expected, patients with cancer-associated
infammatory myopathy (including dermatomyositis) have an in erior
survival curve when compared to patients with juvenile or non-cancer-
associated adult myopathies 50.

A EVALUATION OF THE PATIENT WITH DERMATOMYOSITIS

•  History, including potential triggers (see Table 42.3) and previous malignancies, 
and a review of systems
•  Physical examination – skin, muscle and complete general examination 
(including, in adults, breast and pelvic* [women], testicular and prostate [men], 
and rectal [both sexes]); in Southeast-Asian patients, consider full ENT 
examination
•  Laboratory evaluation
•  Cutaneous – Skin biopsy(ies)
•  Muscle – •  Serum creatine kinase, serum 
aldolase, occasionally urine creatine†
•  Electromyography (EMG); muscle 
biopsy; MRI or U/S (if EMG or muscle 
biopsy are negative or declined; 
increasingly, MRI is being done in 
lieu of EMG and muscle biopsy, if 
classic cutaneous  ndings and 
consistent histology)
•  Pulmonary – •  Pulmonary function tests (PFTs) with 
CO di usion
•  Chest X-ray and/or high-resolution 
chest CT
•  Cardiac – •  Electrocardiogram (EKG)
•  If symptomatic, echocardiogram 
B and/or Holter monitor
•  Esophageal – •  If symptoms, barium swallow
Fig. 42.6  Dermatomyositis less common presentations. A Flagellate  •  General – Complete blood count, comprehensive 
erythema of the posterior trunk. B Secondary changes with the lesions include  metabolic panel with fasting levels of 
scale, erosions and serous as well as hemorrhagic crusts.  glucose and lipids‡, autoantibody 
panel
•  Malignancy screen (adults) §,¶  •  Urinalysis, stool occult blood testing
•  Serum prostate-speci c antigen 
(PSA) [men]
•  Serum CA125 [women]
•  Mammogram and transvaginal pelvic 
U/S [women]
•  CT of chest, abdomen and pelvis
CUTANEOUS MANIFESTATIONS OF DERMATOMYOSITIS
•  Colonoscopy, if age-appropriate, iron 
de ciency anemia, occult blood in 
Common Uncommon
stool, or symptoms
Heliotrope sign (Fig. 42.2) Cutaneous erosions or ulcerations   •  Upper endoscopy – if colonoscopy 
Eyelid edema (Fig. 42.2) (Fig. 42.6B) negative in the setting of iron 
Gottron’s papules (Fig. 42.3) Holster sign (poikiloderma of the  de ciency anemia, occult blood in 
Gottron’s sign (Fig. 42.4) lateral thighs) stool, or symptoms
Photodistributed poikiloderma  Flagellate erythema (Fig. 42.6A) •  If planning chronic systemic  DEXA bone density scan (see Ch. 125)
corticosteroids
(includes facial erythema, shawl  Vesicobullous lesions
sign) (Fig. 42.12) Exfoliative erythroderma *Includes Papanicolaou smear.
†
Scalp poikiloderma (see Fig. 13.3) Panniculitis Aspartate transaminase (AST), alanine transaminase (ALT), and lactic dehydrogenase (LDH)
Non-scarring alopecia Gingival telangiectasias may also be elevated due to myositis.
‡
Nail fold changes (includes ragged  Pustular eruption of the elbows and  Fasting levels of glucose and lipids are important in children.
§
Malignancy screening should be performed at the time of diagnosis and annually for a
cuticles, nail fold telangiectasias*)   knees
minimum of 3 years thereafter; history and physical examination can be performed more
(Fig. 42.1) Lipoatrophy (especially in juvenile  frequently.
Calcinosis cutis (especially in juvenile  dermatomyositis) ¶
Can also consider serum protein and immuno xation electrophoreses.
dermatomyositis) Small vessel vasculitis (especially in 
juvenile dermatomyositis) Table 42.6  Evaluation of the patient with dermatomyositis. CO, carbon 
*Dilated capillary loops alternating with vessel dropout. monoxide; CT, computerized tomography; DEXA, dual energy x-ray 
636 absorptiometry; ENT, ear, nose and throat; MRI, magnetic resonance imaging; 
Table 42.5  Cutaneous manifestations of dermatomyositis. U/S, ultrasound.
 CH AP T E R
PATHOLOGY Patients with normal muscle enzyme levels should be ollowed at
regular intervals because these patients can have occult muscle disease, 42 

The characteristic changes seen in skin biopsy specimens rom patients
with dermatomyositis can be very subtle (Fig. 42.7) and include epider-
mal atrophy, basement membrane degeneration, vacuolar alteration o
basal keratinocytes, and dermal changes consisting o interstitial mucin
deposition and a sparse lymphocytic in ltrate. In some cases, a col-
loidal iron stain may help to highlight the presence o mucin. The
histopathologic changes may be indistinguishable rom those seen in
specimens rom patients with poikilodermatous lesions o LE. Gottron’s
papules show a lichenoid in ltrate but have acanthosis rather than
epidermal atrophy58.
Muscle biopsy specimens also show characteristic changes. The com-
bination o type II muscle ber atrophy, necrosis, regeneration, and
hypertrophy with centralized sarcolemmal nuclei, plus lymphocytes in
both a peri ascicular and a perivascular distribution, is classic 59. It is
best or the clinician to request that the surgeon sample triceps muscle
rather than the usually biopsied deltoid muscle because the latter is
o ten spared until late in the disease. Another option, especially or
patients with mild involvement, is to choose the biopsy site based upon
MRI ndings (see below).
Dermatomyositis
evolve into classic dermatomyositis, or remain as amyopathic dermato-
myositis44. Additional baseline investigations or pulmonary disease
(o ten predicted by anti-Jo-1 antibodies; see Table 42.6), or cardiac
disease, or symptomatic esophageal disease (barium swallow or man-
ometry) and or eatures o overlap connective tissue disease should be
per ormed at this stage, prior to the institution o systemic therapy
unless immediate therapy is warranted to halt rapidly progressive
disease. Adult patients should have screening or occult malignancy
annually or at least 2–3 years, or more requently based upon symp-
toms. A detailed history, review o symptoms, and complete physical
examination should be per ormed at regular intervals o 4–6 months.
Adult patients with amyopathic dermatomyositis should have similar
evaluations or malignancy and associated systemic disease.
The classic muscle enzymes that should be assessed at baseline and
at regular intervals throughout the treatment period are creatine kinase
(CK) and aldolase. Aspartate and alanine transaminases and lactate
dehydrogenase are o ten elevated as well, since they also are released
rom damaged muscle tissue. It has been estimated that 95% o patients
with dermatomyositis have an elevated CK at some point during their

DIFFERENTIAL DIAGNOSIS AND EVALUATION

Although a detailed di erential diagnosis o the patient who presents APPROACH TO ADULT DERMATOMYOSITIS
with proximal muscle weakness in the absence o skin lesions (i.e. the
di erential diagnosis o polymyositis) is beyond the scope o this der-
matologic review, it is the subject o a recent textbook60. Two validated Characteristic cutaneous eruption
instruments, the Dermatomyositis Skin Severity Index (DSSI) and the
updated Cutaneous Dermatomyositis Disease Area and Severity Index
(CDASI), can be used to classi y the severity o the cutaneous disease Confirmatory histology
o dermatomyositis. These indices should be help ul in assessing thera-
peutic responses in uture clinical trials61,62.
The patient with a characteristic cutaneous eruption should have a Evaluation for myositis:
skin biopsy per ormed to con rm the clinical impression o dermato-
• Examination for proximal extensor muscle weakness
myositis (Fig. 42.8). Once the presumed diagnosis is con rmed his- • Serum muscle enzyme levels
topathologically, then a search or muscle and/or associated systemic • Electromyography
disease must begin, because it is their presence or absence that dictates • Muscle biopsy
therapeutic decisions (see Table 42.6). The evaluation or myositis can • Ultrasound and/or MRI of proximal muscles*
include: strength testing o proximal extensor muscles and other
muscles, serum levels o muscle enzymes, an electromyogram, and/or
triceps muscle biopsy. However, increasingly, an MRI (Figs 42.9 & + ** −
42.10) or ultrasound (Fig. 42.11) o proximal muscles is obtained prior • Evaluation for overlapping
to, or in lieu o , a muscle biopsy; the latter applies especially to patients Dermatomyositis autoimmune connective Presumed
tissue diseases amyopathic
with classic cutaneous lesions (both clinically and histologically).
• Chest radiograph or high dermatomyositis
resolution CT scan + PFTs (dermatomyositis
• Electrocardiogram*** sine myositis)
• Evaluation for malignancy,
baseline and at regular
Start systemic intervals for at least 2-3 years Start therapy for
therapy (see text, Table 42.6) skin lesions

Examination for muscle

+ weakness and
Dermatomyositis measurement of enzyme
levels at 2-3 month
intervals for 2 years

−
Amyopathic
dermatomyositis

*Some clinicians perform MRI prior to or in place of electromyography

and muscle biopsy
**The subset of patients with subclinical myositis (referred to as "hypomyopathic"
dermatomyositis by some authors) may or may not subsequently develop
clinically significant myositis
***Particularly in patients with evidence of myositis

Fig. 42.8  Approach to adult dermatomyositis. The approach for children is 

Fig. 42.7  Dermatomyositis histopathologic features. The vacuolar changes  similar but without the malignancy evaluation. Some authors classify patients 
within the basal layer can be subtle. In the dermis, dilated blood vessels and a  with no evidence of myositis ≥6 months after the onset of skin disease as 
sparse lymphocytic in ltrate are seen (poikilodermatous changes).  Courtesy, having amyopathic dermatomyositis, but such individuals may go on to  637
Lorenzo Cerroni, MD. develop muscle disease. PFTs, pulmonary function tests. 
SECTION
7
RHEUMATOLOGIC DERMATOLOGY
B
Fig. 42.9  T2-weighted MR images of the pelvic region. A In a normal control 
patient. B In a patient with dermatomyositis. This shows increased signal 
intensity (white color; arrow) di usely in multiple muscle groups. The increased 
signal correlates with in ammation.  MRI (see Figs 42.9 & 42.10) and ultrasound (see Fig. 42.11) o
Fig. 42.10  T2-weighted MR images of the proximal thigh in a patient with
dermatomyositis. Note the increased signal density, primarily in the extensor 
muscles (white color, arrows). The increased signal correlates with 
in ammation.  o patients (75–85%) can become muscle disease- ree, o treatment,
illness8. Urine creatine is elevated in some patients who have a normal
serum CK, but this test is not routinely per ormed. Myoglobin, another
protein released by damaged muscle, can be detected in the serum even
in patients with mild muscle disease. Its detection in urine is a cause
or concern, and, rarely, severe myoglobinuria can result in acute renal
ailure.
Electromyography (EMG) is a sensitive but nonspeci c test in patients
with dermatomyositis. Over 90% o patients have abnormal EMG
results. The combination o an abnormal electromyogram with classic
cutaneous lesions (clinically and histologically) makes the diagnosis o
dermatomyositis very likely. EMG ndings are less help ul in patients
with polymyositis because there is overlap with other myopathies in
the di erential diagnosis63.
In the absence o classic cutaneous lesions, the muscle biopsy is a
very important test or con rming the diagnosis and excluding other
infammatory myopathies. Surgeons will usually biopsy the deltoid
muscle or convenience, but this muscle is relatively spared until late
638 in the disease; there ore, the surgeon should be directed to per orm a
triceps muscle biopsy.
A B
Fig. 42.11  Ultrasound images of the triceps muscle. A Cross-sectional 
ultrasound image from normal (control) triceps muscle. B Ultrasound image 
from a ected triceps muscle in a patient with dermatomyositis. An increase in 
interstitial echoes is seen (arrows). 
muscles are sensitive tests that can add greatly to patient evaluation.
Both can be used to determine the appropriate site or a muscle biopsy44.
Ultrasound is less expensive and easier to per orm sequentially. MRI
may be the most sensitive test or muscle disease, but it is more expen-
sive44,64. Recent studies suggest that MRI might be use ul in evaluating
children or so t tissue changes that might precede calcinosis cutis64.
The di erential diagnosis o the dermatologic ndings in dermato-
myositis is summarized in Table 42.7.
TREATMENT
A therapeutic ladder or the treatment o patients with dermatomy-
ositis is summarized in Table 42.8. As with many rare dermatologic
diseases, double-blind, placebo-controlled trials are lacking. However,
a dermatology-based case series supported the belie that a number
a ter a period o 24–48 months, utilizing a slow corticosteroid taper2.
Long-term ollow-up o pediatric patients also con rmed this conclu-
sion65,66. There is a clear discordance between response o the muscle
disease to therapy and response o the skin disease2. Available therapy
or the skin disease is clearly inadequate, with many patients exprienc-
ing persistent cutaneous disease and pruritus, especially o the scalp,
which can become a major complaint once the muscle disease is
under control. Aggressive topical therapy and systemic therapy (e.g.
antimalarials or weekly methotrexate) added speci cally or the skin
disease o ten do not provide adequate relie . It is clear however, that,
except in adult patients with an advanced malignancy, the prognosis
or corticosteroid-treated dermatomyositis in children and in adults
is excellent, especially when compared with a mortality o up to 50%
in the pre-corticosteroid era66.
The treatment o dermatomyositis must take into account the dis-
cordance between the response o the muscle disease and that o the
dermatologic disease to systemic therapy. The search or muscle
involvement must be thorough, even in the patient with normal serum
muscle enzymes. Two positive objective tests documenting muscle
disease (e.g. EMG and muscle biopsy, or one o these plus MRI or
muscle ultrasound) should trigger the initiation o systemic cortico-
steroid therapy in doses aimed at control o the muscle disease
(i.e. generally prednisone 1 mg/kg/day). Patients with dermatologic
 CH AP T E R

DIFFERENTIAL DIAGNOSIS OF DERMATOMYOSITIS THERAPEUTIC LADDER FOR DERMATOMYOSITIS 42 

Dermatomyositis
SYSTEMIC LUPUS ERYTHEMATOSUS SYSTEMIC THERAPY
Physician might notice the nail fold telangiectasias and photodistributed  Oral prednisone: 1 mg/kg/day tapered to 50% over 6 
poikiloderma but miss the muscle weakness, heliotrope, extensor distribution,  months and to zero over 2–3 years (1) 
pruritus, and the violaceous hue (true lupus erythematosus might be present in  Option to use pulse, split-dose, or 
the setting of an overlap syndrome) (Fig. 42.12) alternate-day (2)
PSORIASIS Methotrexate: 5–20 mg weekly (2)
Involvement of elbows and knees with papulosquamous lesions can lead to  Azathioprine: 2–3 mg/kg/day (1)
misdiagnosis Others: High-dose IVIg (2 g/kg/month) (1)
AIRBORNE OR ALLERGIC CONTACT DERMATITIS Pulse cyclophosphamide (0.5–1.0 g/m2 
Eyelid edema can be marked in dermatomyositis; look for additional sites of  monthly) (2)
dermatitis Chlorambucil (4 mg/day) (2)
PHOTODRUG ERUPTION Cyclosporine (3–5 mg/kg/day) (2)
Photodistribution Tacrolimus (0.12 mg/kg/day) (3)
CUTANEOUS T CELL LYMPHOMA Mycophenolate mofetil (1 g twice 
The poikiloderma often begins in intertriginous zones rather than on the scalp,  daily) (2)
face and extensor surfaces Sirolimus (5 mg/day × 2 weeks, 2 mg/
ATOPIC DERMATITIS day × 2 weeks, then 1 mg/day) (3)
Usually in children, where the physician focuses on the pruritus and secondary  In iximab (5–10 mg/kg every 2 weeks 
licheni cation initially) (3)
SCLERODERMA Etanercept (3)†
The nail fold telangiectasias are similar in appearance, but the dyspigmentation  Rituximab (375 mg/m2/infusion for 4 
is quite di erent; edema of the hands is an early sign (true scleroderma may be  weekly infusions) (2)
present in the setting of an overlap syndrome) Fludarabine (3)
TRICHINOSIS Hematopoietic stem cell 
Patients have painful muscles and periorbital edema, but not other features transplantation (3)
PHOTODISTRIBUTED FORM OF MULTICENTRIC RETICULOHISTIOCYTOSIS Plasmapheresis (3) †
Firm papules have distinct histologic features CUTANEOUS LESIONS

Table 42.7  Di erential diagnosis of dermatomyositis. Sunscreens (high sun protection factor including protection against UVA) (3)

Topical corticosteroids (3)
Topical tacrolimus (3)
Hydroxychloroquine (200 mg twice daily; increased frequency of drug eruptions 
in patients with dermatomyositis) (2)
Hydroxychloroquine (200 mg twice daily) plus quinacrine (100 mg/day) (3)
Low-dose weekly methotrexate (5–15 mg weekly) (2)
Mycophenolate mofetil (3)
High-dose IVIg (2 g/kg/month) (1)
Retinoids (3)
Dapsone (3)
Thalidomide (3)
Le unomide (3)
Antiestrogens (e.g. tamoxifen, anastrazole) (3)
TNF-α inhibitors (e.g. in iximab, etanercept) (3)*
Rituximab (3)
Tacrolimus (3)
*Reported cause of drug-induced dermatomyositis.
†
Double-blind trial showed no bene t.

Table 42.8  Therapeutic ladder for dermatomyositis. Key to evidence-based 

support: (1) prospective controlled trial; (2) retrospective study or large case 
series; (3) small case series or individual case reports. 

Fig. 42.12  Dermatomyositis. Misdiagnoses include psoriasis, contact  pulse prednisone, split-dose prednisone in doses above 1 mg/kg/day,
dermatitis, and if there is signi cant facial involvement as in this patient, acute  and/or initiation o a steroid-sparing agent such as low-dose weekly
cutaneous lupus erythematosus.  methotrexate at the onset. Again, an attempt is made to taper the
prednisone to 0.5 mg/kg/day in a single morning dose by 6–8 months.
Attention to general health maintenance principles and osteoporosis
mani estations alone can be treated as described below, with repeated prevention is a key element o patient management (see Ch. 125). This
clinical muscle examination and enzyme screening (i.e. generally CK can be accomplished by joint longitudinal care with an internist or
and aldolase) at 2–3-month intervals. I muscle disease is con rmed, pediatrician. Adults also need requent (e.g. every 4–6 months or at
then systemic corticosteroid therapy is initiated. least 2–3 years) complete physical examinations or malignancy.
I CK and aldolase serum levels are minimally elevated and cortico- Children with juvenile dermatomyositis should be ollowed by a pedi-
steroid therapy is initiated early, the disease generally comes under atrician com ortable with monitoring their developmental milestones
control rapidly over 2–4 weeks and corticosteroids can be used as while on immunosuppressive therapy (e.g. at least every 6 months). In
monotherapy with doses tapered to hal the starting dose by 6 months. addition, lipodystrophy and metabolic abnormalities, including hyper-
I the disease is advanced and enzyme levels are high (e.g. CK > triglyceridemia and insulin resistance, have become increasingly recog- 639
1000 U/1), the disease can be much more di cult to control, requiring nized as potential complications o juvenile dermatomyositis 67,68.
SECTION
There is support or steroid-sparing therapies (especially in the setting treatment o amyopathic dermatomyositis o ten di ers signi cantly
7 o severe or recalcitrant disease), including IVIg69, methotrexate70, chlo- rom the treatment o classic dermatomyositis in that systemic corti-
rambucil71, pulse cyclophosphamide72,73, cyclosporine (also or lung
RHEUMATOLOGIC DERMATOLOGY

costeroids are not traditionally utilized.

disease)74,75, fudarabine76, mycophenolate mo etil77,78, azathioprine79,
tacrolimus80, siroliumus81, infiximab82, etanercept 83, rituximab84 and
hematopoietic stem cell transplantation85. A placebo-controlled study
showed no bene t rom plasmapheresis or leukapheresis in dermato-
myositis86. In children with severe or re ractory disease, IVIg is o ten
administered86a. Adjunctive physical therapy is also very important in
improving muscle strength and endurance87. Bene ts o exercise and
rehabilitation have been demonstrated, even in the course o active
disease and without inducing fares o the myositis88.
Dermatologic disease can be particularly challenging therapeutically,
and not all patients clear their cutaneous mani estations when their
muscle disease remits on systemic corticosteroids. Patients with der-
matologic disease without active muscle disease are generally not
treated with systemic corticosteroids as a mainstay o their therapy,
and they o ten present a unique therapeutic challenge. As a result, the
For cutaneous disease, anecdotal reports and small case series support
the use o topical corticosteroids (which are especially use ul when there
is licheni cation due to chronic pruritus as a component o the illness),
topical tacrolimus89, antimalarial therapy 90,91 (either as monotherapy or
in combination, which is less dramatic in its e ect than when used or
LE lesions), low-dose weekly methotrexate, mycophenolate mo etil92,
IVIg93, dapsone94 and thalidomide95, as well as additional agents listed
in Table 42.8. Calcinosis cutis may respond to diltiazem and/or surgical
excision; other therapies include low-dose war arin, bisphosphonates,
probenecid, aluminum hydroxide, and electric shock wave lithotripsy
(ESWL). Early and aggressive therapy o juvenile dermatomyositis does
seem to reduce the risk o calcinosis cutis, which can be extremely
challenging to treat. The rare panniculitis associated with dermatomyo-
sitis may respond to antimalarial therapy96.

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 CH AP T E R
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51.  Iorizzo LJ, Jorizzo JL. The treatment and prognosis of  dermatomyositis and a gradient of severity. Medicine  polymyositis with anti-tumor-necrosis-factor-alpha: 

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Dermatol. 2008;59:99–112. 69.  Dalakas MC. Controlled studies with high-dose  83.  Norman R, Greenberg RG, Jackson JM. Case reports of 
52.  Marie I, Hatron PY, Levesque H, et al. In uence of age on  intravenous immunoglobulin in the treatment of  etanercept in in ammatory dermatoses. J Am Acad 
characteristics of polymyositis and dermatomyositis in  dermatomyositis, inclusion body myositis, and  Dermatol. 2006;54:S139–42.
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53.  Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of  S37–45. dermatomyositis: an open-label pilot study. Arthritis 
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2001;357:96–100. intravenous methylprednisolone and methotrexate.   transplantation for autoimmune disorders. Curr Opin 
54.  Huang YL, Chrn YJ, Lin MW, et al. Malignancies  Clin Rheumatol. 2000;19:138–41. Hematol. 2008;15:594–600.
associated with dermatomyositis and polymyositis in  71.  Sinoway PA, Callen JP. Chlorambucil. An e ective  86.  Miller FW, Leitman SF, Cronin ME, et al. Controlled trial 
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Dermatol. 2009;161:854–60. recalcitrant dermatomyositis. Arthritis Rheum.  and dermatomyositis. N Engl J Med. 1992;326: 
55.  Barnes BE, Mawr B. Dermatomyositis and malignancy. A  1993;36:319–24. 1380–4.
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J Cutan Pathol. 1985;12:389–94. polymyositis/dermatomyositis. J Rheumatol.  home exercise programme in patients with polymyositis 
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Systemic Sclerosis (Scleroderma) and  
Related Disorders
Chapter Contents
Systemic sclerosis  643
Eosinophilic  asciitis 651
Nephrogenic systemic fbrosis 652
Sti  skin syndrome 654
Sclerodermoid syndromes induced by exogenous substances 654
SYSTEMIC SCLEROSIS
Synonyms: Systemic sclerosis: � Scleroderma � Progressive systemic 
sclerosis
Subtypes of clinical involvement: � Di use � Limited (includes CREST 
syndrome)
Key features
  An autoimmune connective tissue disease o  unknown etiology
  Characterized by symmetric hardening o  the skin o  the fngers,  Vascular dysfunction in the form of impaired angiogenesis is an early
hands and  ace that may generalize
  Raynaud’s phenomenon is common and digital ulcers develop
  Internal organ involvement is  requent and a ects the lungs, 
gastrointestinal tract, heart and kidneys; lung involvement is the 
leading cause o  death
  Treatment  ocuses on internal organ involvement; e ective  strictive (e.g. cold, endothelin) and vasodilatory (e.g. nitric oxide)
therapy  or cutaneous fbrosis remains inadequate
Introduction
Systemic sclerosis (SSc, scleroderma) is an autoimmune connective
tissue disease (AI-CTD) of unknown etiology that affects the skin,
blood vessels and internal organs. The name systemic sclerosis is
meant to convey the systemic nature of the disease, which has two
major clinical subtypes: limited and diffuse. Limited SSc is character-
ized by brotic skin changes that are limited to the ngers, hands and
face and includes the CREST syndrome. In diffuse SSc, generalized
brotic skin changes are seen and they usually start in the ngers and
hands but spread to involve the forearms, arms, trunk, face and lower
extremities. Because SSc is not invariably progressive, the word “pro-
gressive” has been dropped from the terminology for this condition.
The diagnosis of SSc is based on clinical ndings and laboratory
abnormalities 1. The differential diagnosis of symmetric and widespread
cutaneous induration includes SSc as well as generalized morphea,
eosinophilic fasciitis, scleromyxedema, nephrogenic systemic brosis,
and scleredema (favors neck and upper trunk) (Table 43.1).
History
The rst reported case of SSc (in 1754) was a young Italian woman
who developed progressive induration of her skin. From the clinical
description, it is impossible to determine whether she had true SSc or
another sclerodermoid disorder.
RHEUMATOLOGIC DERMATOLOGY SECTION 7
M Kari Connolly
43 
Epidemiology
SSc has a worldwide distribution and affects all races. The annual
incidence and prevalence rates in the US are approximately 20 and 250
cases per million population, respectively1. Women are affected three
to four times as often as men are. Although SSc can occur in children
and the elderly, the onset is typically between the ages of 30 and 50
years. Black patients have an earlier mean age of onset and a higher
likelihood of diffuse disease2. Approximately 1.5% of SSc patients have
one or more affected rst-degree relatives, representing a 10- to 15-fold
higher risk of SSc in family members than in the general population3.
SSc is associated with a signi cant mortality rate, with an overall
10-year survival of less than 70%1. Parameters that predict a worse
prognosis include male sex, black race, older age at diagnosis, internal
organ involvement at diagnosis, skin brosis affecting the trunk, and
elevated erythrocyte sedimentation rate (ESR) 1.
Pathogenesis
The pathogenesis of SSc is unknown. Key pathogenic abnormalities in
the skin and internal organs are vascular dysfunction, immune activa-
tion with autoantibody production, and tissue brosis characterized
by deposition of collagen and other extracellular matrix proteins
(Fig. 43.1)4–6.
Vascular dysregulation
event in the pathogenesis of SSc6. The blood vessels affected range from
the smallest capillaries within the proximal nail fold to the large pul-
monary arteries. Endothelial cell injury occurs early (before brosis is
evident), based on changes seen by electron microscopy, such as perivas-
cular leak and edema7. Surrounding smooth muscle cells are also
affected and have altered production of and responsiveness to vasocon-
factors. Structural abnormalities such as intimal proliferation leading
to luminal occlusion develop and lead to hypoxia which induces syn-
thesis of pro brotic cytokines, broblast activation and collagen pro-
duction8. Raynaud’s phenomenon and digital ulcers are caused by
reversible vasospasm as well as irreversible arterial damage with intimal
proliferation and luminal obstruction. Scleroderma renal crisis and
pulmonary artery hypertension are manifestations of large vessel
dysregulation.
Immune dysregulation
Patients with SSc produce speci c, and therefore diagnostic, autoanti-
bodies (e.g. anticentromere, anti-topoisomerase I [Scl-70]; see Ch. 40),
and these autoantibodies also have prognostic implications 9,10. Com-
plexes containing topoisomerase I autoantibody, when bound to the
surface of broblasts, have been found to stimulate monocyte adhesion
and activation. In addition, anti-endothelial cell antibodies from SSc
patient sera can trigger endothelial cell apoptosis. One group described
stimulatory autoantibodies against the platelet-derived growth factor
(PDGF) receptor in SSc sera which induced reactive oxygen species and
expression of type I collagen by normal human broblasts11. However,
two subsequent studies were unable to con rm these ndings12.
Lymphocytic in ltrates have been observed in both the skin and lungs
of SSc patients before the development of brosis. Oligoclonal T-cell
expansion has been identi ed in lesional skin, indicating an antigen-
driven response, and T cells demonstrate a Th2-predominant pro le
with increased production of pro brotic cytokines such as interleukin
(IL)-4 and IL-13. More recently, Th17 cells and IL-17 have been impli- 643
cated as playing a role in SSc, as have the innate immune system and
SECTION

7 MAJOR CLINICAL AND LABORATORY MANIFESTATIONS OF SYSTEMIC SCLEROSIS AND OTHER SELECTED CONDITIONS
CHARACTERIZED BY CUTANEOUS INDURATION
RHEUMATOLOGIC DERMATOLOGY

Systemic sclerosis Morphea Eosinophilic fasciitis Scleredema Scleromyxedema NSF

Major clinical variants •  Limited •  Plaque-type  •  Post-in ectious 

•  Di use morphea (type I)
•  Linear morphea •  Monoclonal 
•  Generalized  gammopathy-
morphea associated (type II)
•  Diabetes mellitus-
associated (type III)
Raynaud’s  ++ − − − − −
phenomenon
Symmetric induration ++* − ++* ++ ++ +
Sclerodactyly ++ − − − − −
Facial involvement + − plaque-type and  − ± types I and II + −
generalized − type III
+ linear (en coup de 
sabre)
Systemic  ++ − + − ++ +
involvement
Antinuclear  ++ ± generalized and  − − − −
antibodies linear
− plaque-type
Anticentromere  + limited − − − − −
antibodies
Anti-topoisomerase I  + di use − − − − −
(Scl-70) antibodies
Monoclonal  − − + type II ++ −
gammopathy
Spontaneous  − ++ plaque-type ++ ++ type I − ±†
remission + generalized ± types II and III
± linear
*May be preceded by edematous phase.
†
With improved renal function.

Table 43.1  Major clinical and laboratory manifestations of systemic sclerosis and other selected conditions characterized by cutaneous induration. NSF, 
nephrogenic systemic fbrosis; ++, almost always; +, common; ±, sometimes; –, rare or unusual   Courtesy, Vincent Falanga, MD.

INTERACTIONS BETWEEN ENDOTHELIAL CELLS, LEUKOCYTES AND FIBROBLASTS IN SCLERODERMA PATHOGENESIS

EC damage Endothelial lesion

from free Matrix or cytokine ligand–receptor
Autocrine or paracrine activation via
radical species interactions and cell shape changes
fibroblast-delivered cytokines
and recurrent Cellular activation, modulate gene expression and
hypoperfusion adhesion and mRNA transcript stability
migration
into ECM
Fibroblast

Immune Intracellular mRNA Collagens

Transcription Procollagen
mediated Cell surface signals translation (I, III, IV, V, VI)
vascular receptors
damage Lymphocyte
Intracrine regulatory
Monocyte/ Activated mechanisms
macrophage cells/products
(TGF-β, CTGF, IL-1,
Mast cell -4, -6, -8, PDGF, Proteoglycans
IGF-I, IFNs types I, II) Fibronectin
Platelets β1 integrins Fibrillins

Fig. 43.1  Interactions between endothelial cells, leukocytes and broblasts in scleroderma pathogenesis. CTGF, connective tissue growth  actor; EC, endothelial 
cell; ECM, extracellular matrix; IFN, inter eron; IGF, insulin-like growth  actor; PDGF, platelet-derived growth  actor; TGF, trans orming growth  actor  Genetic 
susceptibility loci that may increase the risk o  developing scleroderma include a region on chromosome 15q (which contains the fbrillin-1 gene) as well as 
polymorphisms in STAT4 and the promotor  or CTGF   Adapted from Hochberg MC, Silman AJ, Smolen JS, et al (eds). Rheumatology, 3rd edn. Edinburgh: Mosby, 2003.

644
 CH AP T E R
types I (α,β) and II (γ) interferons. SSc patients also have expansion of Clinical Features
naive B cells and chronic activation, but a decreased number, of memory
Diagnostic criteria and classi cation
43 

Systemic Sclerosis (Scleroderma) and Related Disorders

B cells.
Fibrosis
Fibrosis represents the nal common pathway in SSc. There is exces-
sive deposition of collagens, proteoglycans, bronectin, brillins and
adhesion molecules (e.g. β1-integrins), which sequester cytokines and
growth factors (see Fig. 43.1). Attention has focused on transforming
growth factor-β (TGF-β) and connective tissue growth factor (CTGF).
The latter is induced by TGF-β and may be responsible for maintenance
of collagen synthesis.
Given the complex extracellular matrix changes seen in SSc13, both
the broblast and the myo broblast have been a focus of attention.
Some evidence suggests that there is an inherent defect, an autocrine
loop, or a hypersensitivity to growth factors in SSc broblasts. However,
the possibility exists that SSc broblasts actually have a normal phe-
notype, but are exposed to an abnormal microenvironment with
enhanced activity of growth factors or ischemic mediators. The accu-
mulation of collagen in SSc seems to be primarily the result of increased
synthesis, rather than decreased degradation.
For the purposes of clinical trials, the classi cation scheme of the
American College of Rheumatology has been helpful, with either
the one major criterion – symmetric cutaneous sclerosis proximal to
the metacarpophalangeal (MCP) or metatarsophalangeal (MTP) joints
– or two or more minor criteria – sclerodactyly (Fig. 43.2); digital pitted
scars or loss of substance from nger pads (Fig. 43.3); bibasilar pulmo-
nary brosis – considered diagnostic of SSc1,2.
Based upon the degree of skin involvement, there are two major
clinical subtypes: limited and diffuse1. When the skin disease involves
the distal and proximal portions of the extremities plus the trunk and
face, it is considered diffuse disease, but when the induration is limited
to the distal extremities and face, it is considered limited disease1.
While both subtypes represent systemic diseases, there are variable
degrees of internal organ involvement (Table 43.2). Typically, diffuse
SSc is associated with early internal organ involvement (within 5 years
of disease onset) and a worse prognosis1, whereas patients with limited
SSc tend to develop internal involvement later in the disease course,
occasionally after decades.
The acronym CREST syndrome describes the clinical features in a
subset of patients with limited SSc: calcinosis, Raynaud’s phenom-
enon, esophageal involvement, sclerodactyly and telangiectasia. Rarely,
patients present with characteristic internal organ involvement, Ray-
naud’s phenomenon and positive serologies but no cutaneous involve-
ment, which is referred to as systemic sclerosis sine scleroderma.

Cutaneous features
Many patients with SSc experience an early edematous phase, which
often features pitting edema of the digits (Fig. 43.4). The skin

COMPARISON OF CLINICAL AND LABORATORY FEATURES OF DIFFUSE AND

LIMITED SYSTEMIC SCLEROSIS

Di use SSc (%) Limited SSc (%)

Raynaud’s phenomenon 90 99
Finger swelling 95 90
Tendon  riction rubs 70 5
Arthralgia 98 90
Fig. 43.2  Late stage of systemic sclerosis with di use cutaneous
scleroderma. Note the fxed  exion contractures, sclerodactyly, and the digital  Proximal weakness 80 60
ulceration overlying the third proximal interphalangeal joint   Calcinosis 20 40
Mat telangiectasias* 60 90
Esophageal dysmotility 80 90
Small bowel  40 60
involvement
Interstitial lung disease 70 35
Pulmonary hypertension 15–20 20–25
Cardiomyopathy 15 10
Renal crisis 20† 1
Sicca syndrome 15 35
Antinuclear antibodies 90 90
Anticentromere  5–30 50–90
antibody
Anti-topoisomerase I  20–60 10–15
(Scl-70) antibody
Cumulative survival   70 90
(5 years)
(10 years) 50 70
*In addition, nail fold capillary abnormalities are observed in >90% of SSc patients.
†
Has decreased with the use of angiotensin-converting enzyme (ACE) inhibitors.

Table 43.2  Comparison of clinical and laboratory features of di use and

Fig. 43.3  Pitted scars of the digital pulp in a patient with systemic sclerosis.  limited systemic sclerosis (SSc).  Adapted from Hochberg MC, Silman AJ, Smolen JS, et al. (eds). 645
Courtesy, Kalman Watsky, MD. Rheumatology, 3rd edn. Edinburgh: Mosby, 2003. © Elsevier 2003.
SECTION
Fig. 43.4  Early, Fig. 43.6  Mat/matted
7 edematous phase of (squared-o )
systemic sclerosis. Note  telangiectasias in two
RHEUMATOLOGIC DERMATOLOGY

the demonstration o   patients with systemic

pitting edema on two o   sclerosis. The frst 
the digits   Courtesy, Jean L patient (A) had CREST 
Bolognia, MD. syndrome (limited-
disease subtype) while 
the second patient  
(B) presented 
with di use 
hyperpigmentation and 
had interstitial lung 
A disease   B, Courtesy, Jean L
Bolognia, MD. 

Fig. 43.5  The “salt and pepper” sign. Leukoderma with retention o  

peri ollicular pigmentation in a patient with systemic sclerosis  

subsequently hardens and develops a taut, shiny appearance (indurated

phase). Eventually, there may be gradual thinning of the skin (late
atrophic phase). The ngers can develop exion contractures and ulcers
(see Fig. 43.2) while involvement of the face can lead to a beaked nose,
microstomia and a somewhat youthful appearance.
There are a number of cutaneous changes other than brosis in
patients with SSc. Dyspigmentation in areas of sclerosis is commonly
observed. Some patients develop diffuse hyperpigmentation, with
accentuation in sun-exposed areas and sites of pressure. The “leuko-
derma of scleroderma” is characterized by localized areas of depigmen-
tation with sparing of the perifollicular skin; this helpful diagnostic Fig. 43.7  Calcinosis cutis of the nger in a patient with systemic sclerosis. 
nding is sometimes referred to as the “salt and pepper” sign (Fig.
43.5). Pigment may also be retained in the skin overlying super cial
veins. This leukoderma favors the upper trunk and central face and
may overlie uninvolved or sclerotic skin.
Telangiectasias are more common in patients with limited SSc but Dystrophic calcinosis cutis most commonly develops on the extremi-
also occur in patients with diffuse disease (see Table 43.2). The tel- ties, usually near joints and in distal locations (Fig. 43.7). In addition,
angiectasias most often involve the face, lips and palms. These tel- the skin is often dry due to decreased sweating, and pruritus can be
angiectatic macules are matted or squared-off (Fig. 43.6). Capillary quite marked. Fibrotic skin in SSc may show diminished hair growth,
abnormalities in the proximal nail fold are present in more than 90% but this is variable; hypertrichosis can also occur, particularly during
of SSc patients and can be useful in supporting the diagnosis14. Use of the recovery phase. Overall, the cutaneous changes are extremely trou-
an ophthalmoscope or dermatoscope may enhance appreciation of the blesome to patients with SSc. For example, in a questionnaire-based
646 changes. A distinct pattern of capillary loss (“drop out”) alternating study involving 300 patients with SSc, facial involvement and micros-
with dilated loops is characteristic of SSc. tomia were the patients’ greatest concerns 15.
 CH AP T E R

CLINICAL AND LABORATORY FEATURES OF PRIMARY AND SECONDARY 43 

RAYNAUD’S PHENOMENON

Systemic Sclerosis (Scleroderma) and Related Disorders

Feature Primary Raynaud’s Secondary Raynaud’s
Sex F : M 20 : 1 F : M 4 : 1
Age at onset Puberty >25 years
Frequency o  attacks Usually <5 per day 5–10+ per day
Precipitants Cold, emotional stress Cold
Ischemic injury Absent Present
Abnormal capillaroscopy Absent >95%
Other vasomotor  Yes Yes
phenomena
Antinuclear antibodies Absent/low titer 90–95%
Anticentromere  Absent 50–60%
antibody
Anti-topoisomerase I  Absent 20–30%
(Scl-70) antibody
In vivo platelet activation Absent >75%
Table 43.3  Clinical and laboratory features of primary and secondary Fig. 43.8  Raynaud’s phenomenon in a patient with severe sclerodermoid
Raynaud’s phenomenon.  Adapted from Hochberg MC, Silman AJ, Smolen JS, et al. (eds). chronic graft-versus-host disease. The fngers have a violaceous hue as well as 
Rheumatology, 3rd edn. Edinburgh: Mosby, 2003. © Elsevier 2003. areas o  blanching (white) and digital ulceration  Oral sildenafl led to a 
signifcant improvement  

Raynaud’s phenomenon is characterized by episodic vasospasm of

the digital arteries resulting in white, blue and red discoloration of the DIFFERENTIAL DIAGNOSIS OF RAYNAUD’S PHENOMENON
ngers secondary to cold stimuli. Raynaud’s phenomenon occurs in
STRUCTURAL VASCULOPATHIES
two settings (Table 43.3). Primary Raynaud’s phenomenon (Raynaud’s
disease) typically develops in adolescent girls and young women and is Large and medium-sized arteries
not associated with any underlying medical problems 16. Primary Ray- Thoracic outlet syndrome
naud’s phenomenon is common and estimated to affect 3% to 5% of Brachiocephalic trunk disease (atherosclerosis, Takayasu’s arteritis)
the population. In contrast, secondary Raynaud’s phenomenon is Buerger’s disease (thromboangiitis obliterans)*
uncommon and is associated with an underlying medical problem (Fig. Crutch pressure
43.8; Table 43.4). Notably, SSc represents one of the leading causes of Small arteries and arterioles
secondary Raynaud’s phenomenon. An approach to differentiating
Systemic sclerosis
primary from secondary Raynaud’s phenomenon is presented in Figure Systemic lupus erythematosus
43.9. Dermatomyositis
Cutaneous ulcers are common in patients with SSc (Fig. 43.10). Overlap syndromes
Whereas ulcers on the tips of the digits are probably due to ischemia, Cold injury
those on the interphalangeal joints are more likely to persist because Vibration disease (hand-arm vibration syndrome, hypothenar hammer 
of continued trauma (see Fig. 43.2). Ulcers can lead to osteomyelitis syndrome)
and even amputation (autoamputation or surgical intervention). Chemotherapy (bleomycin, vinca alkaloids, cisplatin, carboplatin)
Vinyl chloride disease
Arsenic poisoning
Extracutaneous features NORMAL BLOOD VESSELS – ABNORMAL BLOOD ELEMENTS
The majority of patients with SSc have internal organ involvement Cryoglobulinemia (monoclonal or mixed)
(Table 43.5), which is the cause of signi cant morbidity and mortality Cryofbrinogenemia
in this disease1,2. Occasionally, a patient with SSc will present with Cold agglutinin disease
internal organ involvement before skin involvement is evident. The Myeloproli erative disorders (e g  essential thrombocythemia)
most commonly affected organs are the gastrointestinal tract, lungs, NORMAL BLOOD VESSELS – ABNORMAL VASOMOTION
heart and kidneys. However, renal crisis is no longer the leading cause Primary (idiopathic) Raynaud’s phenomenon
of death in SSc, having been replaced by pulmonary disease. There are Drug-induced (ergot alkaloids, bromocriptine, inter eron, estrogen, cyclosporine, 
two major forms of pulmonary involvement in SSc 1,2. The rst is inter- sympathomimetic agents, clonidine, cocaine, nicotine)
stitial lung disease (alveolitis) that eventuates into pulmonary brosis. Carpal tunnel syndrome
The second form of involvement is pulmonary arterial hypertension. Pheochromocytoma
Screening tests for both disorders are outlined in Table 43.5. Carcinoid syndrome
Re ex sympathetic dystrophy
Other vasospastic disorders (migraine, Prinzmetal)
Autoantibodies *Can also a ect small arteries.
Autoantibody testing is useful in con rming the diagnosis of SSc
Table 43.4  Di erential diagnosis of Raynaud’s phenomenon  Paraneoplastic 
(see Ch. 40). Most patients have elevated titers of antinuclear antibod- acral vascular syndrome, which can present with Raynaud’s phenomenon as 
ies (ANA)1,9, with the nucleolar and discrete speckled patterns being well as acrocyanosis and gangrene, has been observed in patients with various 
relatively speci c for SSc. Patients with antibodies to topoisomerase solid tumors (e g  lung or ovarian carcinoma)   Adapted from Hochberg MC, Silman AJ,
I (Scl-70) are more likely to have diffuse disease with an increased Smolen JS, et al. (eds). Rheumatology, 3rd edn. Edinburgh: Mosby, 2003. © Elsevier 2003.
risk of interstitial lung disease. In contrast, patients with anti-
centromere antibodies are more likely to have limited disease. Autoan- 647
tibodies to RNA polymerase are usually associated with diffuse disease.
SECTION
Fig. 43.9  Evaluation of the patient with Raynaud’s
7 EVALUATION OF THE PATIENT WITH RAYNAUD’S PHENOMENON phenomenon. RNP, ribonucleoprotein; Sm, Smith; ds, 
double-stranded  
RHEUMATOLOGIC DERMATOLOGY

Patient with Raynaud's phenomenon*

Asymmetric/single-digit attacks, absent Uncomplicated

pulses, asymmetric blood pressure or symmetric attacks
evidence of tissue necrosis**

Exclude structural disease of large or Exclude:

medium-sized arteries
(e.g. thoracic outlet syndrome; see
Table 43.4) by performing vascular
studies (e.g. Doppler ultrasonography,
digital plethysmography or angiography)
Environmental exposures (e.g. vibration, cold injury)
Chemical exposures (e.g. vinyl chloride)
Medications (e.g. bleomycin)
Neuropathy (e.g. carpal tunnel syndrome)
(See Table 43.4)

Hand exam:
Sclerodactyly
Digital pits
Digital ulcers
1° Raynaud’s Nailfold capillary exam:
− Giant loops or tortuosity
phenomenon
Vascular drop out
Evaluate for other signs and symptoms of AI-CTD
Test for antinuclear antibodies (ANA)§

Does not meet criteria + anti-topoisomerase l Ab, + anti-RNP, SS-A/SS-B,

for diagnosis of an Al-CTD + anti-centromere Ab, or Sm, or dsDNA Ab
nucleolar ANA pattern and/or
and/or Clinical features of another
Clinical features of systemic AI-CTD
sclerosis

Depending on clinical suspicion,

evaluate/monitor for signs and
symptoms of AI-CTD or 2° Raynaud’s phenomenon 2° Raynaud’s phenomenon
other systemic diseases associated with systemic associated with another
(see Table 43.4) sclerosis AI-CTD

* Defined as a history of sensitivity to the cold and episodic pallor, cyanosis or both after cold exposure.
** Also consider evaluating for microvascular occlusion syndromes (e.g. cryoglobulinemia).
§ Positive predictive value for an associated autoimmune connective tissue disease (AI-CTD) is approximately 30%.

Fig. 43.10  Ulceration of the elbow in a patient with systemic sclerosis.  Courtesy,
Joyce Rico, MD.

648
 CH AP T E R

EVALUATION AND TREATMENT OF INTERNAL ORGAN INVOLVEMENT IN PATIENTS WITH SYSTEMIC SCLEROSIS 43 

Systemic Sclerosis (Scleroderma) and Related Disorders

Symptoms/signs* Studies Treatment

Pulmonary: Shortness o  breath, dyspnea on  •  Interstitial lung disease: •  Interstitial lung disease: 

•  Interstitial lung disease exertion, dry cough  Pulmonary  unction tests, including  immunosuppression, primarily 
•  Pulmonary artery hypertension Tachypnea, bibasilar rales, signs o  right- DLCO † cyclophosphamide or mycophenolate 
sided CHF (e g  peripheral edema,  High-resolution CT † mo etil
hepatomegaly, dilated neck veins) •  Pulmonary artery hypertension: •  Pulmonary artery hypertension: 
Echocardiogram vasodilators including endothelin 
Right heart catheterization receptor antagonists (bosentan, 
sitaxsentan, ambrisentan), 
prostacyclin analogues (iloprost 
[inhaled], epoprostenol [IV], trepostinil 
[sc]), and PDE5 inhibitors (sildenafl, 
tadalafl)
Cardiac Shortness o  breath, dyspnea on  Electrocardiogram Diuretics, ACE inhibitors, β-blockers 
exertion, palpitations  Right heart catheterization (unless contraindicated), angiotensin II 
Signs o  right- or le t-sided CHF (e g   receptor blockers, aldosterone 
tachypnea, rales, peripheral edema [see  antagonists
above]) May need to consider withdrawal o  
calcium channel blockers
Renal, including scleroderma renal  Headache, blurry vision  Blood pressure Blood pressure control, in particular the 
crisis‡ Hypertension BUN, creatinine, urinalysis use o  ACE inhibitors
Gastrointestinal Dyspepsia, dysphagia, postprandial  Upper gastrointestinal series (barium  Proton-pump inhibitors  or 
bloating, constipation, diarrhea  swallow) with small bowel  ollow- gastroesophageal re ux
Signs o  malnutrition through Domperidone or metoclopramide to 
Manometry improve motility and bloating
Endoscopy
Malabsorption evaluation
*Patients may be asymptomatic.
†
At baseline and every 6–12 months for rst ve years after initial diagnosis, then yearly.
‡
Suspected if, compared to baseline, the systolic pressure is elevated >20 mmHg or the diastolic pressure is elevated >10 mmHg.

Table 43.5  Evaluation and treatment of internal organ involvement in patients with systemic sclerosis. ACE, angiotensin-converting enzyme; BUN, blood urea 
nitrogen; CHF, congestive heart  ailure; CT, computerized tomography; DLCO, di usion capacity o  carbon monoxide; IV, intravenous; PDE5, phosphodiesterase type 
5; sc, subcutaneous

Anti brillarin antibodies (present in <10% of SSc patients) are associ- Fig. 43.11  Systemic
ated with diffuse SSc but can also occur in other AI-CTDs such as sclerosis histologic
systemic lupus erythematosus (SLE)10. features. There is a 
dense sclerosis o  the 
dermis with decreased 
Pathology adnexal structures and 
Histologically, areas of cutaneous induration are characterized by “trapping” o  remaining 
compact or hyalinized collagen, excessive deposition of collagen, adnexal structures that 
atrophic eccrine and pilosebaceous glands, loss of subcutaneous fat, and are encased by collagen  
a sparse lymphocytic in ltrate in the dermis and subcutis (Fig. 43.11). Sparse perivascular 
infltrates o  lymphocytes 
Adnexal structures, especially eccrine glands, may be “trapped” by the
are present   Courtesy, Ronald
excessive deposition of collagen. However, the different subsets of SSc P Rapini, MD.
cannot be distinguished histologically17.
Direct immuno uorescence studies are usually negative in patients
with SSc. While endothelial damage can occur in cutaneous blood
vessels, this nding is only seen at the ultrastructural level7; reduplica-
tion of the basement membrane is also observed. It should be noted
that, in its end stage, areas of sclerosis may be indistinguishable his-
tologically from other diseases characterized by collagen deposition,
such as morphea (which tends to have a more robust in ammatory
in ltrate than SSc in its earlier stages).

Di erential Diagnosis
The differential diagnosis of dermal sclerosis is extensive18. Table 43.1
compares the features of SSc to those of morphea, eosinophilic fasciitis,
scleredema, scleromyxedema and nephrogenic systemic brosis. SSc
can be distinguished by the characteristic symmetric induration of the
skin of the distal extremities (especially the upper extremity), nail fold
capillary ndings, association with Raynaud’s phenomenon, autoanti- SSc. The cutaneous sclerosis of chronic GVHD typically begins as
body pro le, and internal organ involvement. Some patients with SSc circumscribed morpheaform plaques that favor the trunk (which may
also have features of another AI-CTD (e.g. overlap syndromes). Addi- eventually coalesce and become more reminiscent of scleroderma) as
tional entities in the sclerodermoid differential diagnosis are presented well as lesions that resemble lichen sclerosus or eosinophilic fasciitis
in Table 43.6. Localized forms of scleroderma (e.g. morphea) are dis- (see Ch. 52). Patients with chronic GVHD can also have pulmonary 649
cussed in Chapter 44. Chronic GVHD can mimic certain features of (e.g. bronchiolitis obliterans) and gastrointestinal involvement.
SECTION

7 DIFFERENTIAL DIAGNOSIS OF SCLERODERMOID CONDITIONS

RHEUMATOLOGIC DERMATOLOGY

Clinical features

MUCINOSES
• Scleredema Induration o  the upper back, neck and  ace; occasional internal involvement (see Ch  46)
• Scleromyxedema Waxy papules (o ten in a linear array); di use induration  avoring the  ace, upper trunk, arms and thighs; monoclonal 
gammopathy; neurologic, gastrointestinal and pulmonary involvement (see Ch  46)
IMMUNOLOGIC
• Chronic GVHD* Morphea orm plaques  avoring the trunk, which may become generalized; eosinophilic  asciitis (see Ch  52)
• Eosinophilic  asciitis Symmetric induration with a “pseudo-cellulite” appearance on the extremities (sparing hands and  eet) (see text)
• Generalized morphea* Expansion and coalescence o  morphea plaques to involve a large portion o  the trunk and extremities (see Ch  44)
• Fibroblastic rheumatism Sclerodactyly; fbrotic nodules on the hands
PARANEOPLASTIC
• POEMS syndrome Sclerotic skin on the extremities (see Ch  114)
• Amyloidosis (primary systemic)† Di use induration  avoring the  ace, distal extremities and trunk (see Ch  47)
• Carcinoid syndrome Sclerotic skin on the legs (see Table 53 3)
NEOPLASTIC
• Carcinoma en cuirasse* Sclerodermoid encasement o  the chest by metastatic carcinoma (usually breast cancer)
METABOLIC
• Diabetic cheiroarthropathy Thickened skin and limited mobility o  the hands (see Table 53 4)
• Porphyria cutanea tarda*,‡ Morphea orm plaques in sun-exposed areas (see Chs 44 & 49)
NEUROLOGIC
• Re ex sympathetic dystrophy* Pain ul, cold, swollen extremity eventually develops cutaneous sclerosis (see Ch  6)
• Spinal cord injury Sclerotic skin in a ected areas
TOXIN MEDIATED
• Nephrogenic systemic fbrosis* Associated with exposure to gadolinium-based contrast agents (US, 1997–present; now worldwide) (see text)
• Eosinophilia–myalgia syndrome Associated with L-tryptophan ingestion (US, 1989) (see text)
• Toxic oil syndrome* Associated with toxic oil ingestion (Spain, 1981) (see text)
DRUG OR CHEMICAL INDUCED SEE TEXT
• Bleomycin* Acrosclerosis, Raynaud’s phenomenon; pulmonary fbrosis (more common, usually no concurrent skin lesions)
• Taxanes* Edema  ollowed by sclerosis o  the lower extremities; acrosclerosis
• Vinyl chloride, chlorinated  Acrosclerosis, acral fbrotic papulonodules, Raynaud’s phenomenon, acro-osteolysis; pulmonary fbrosis
hydrocarbons*
VENOUS INSUFFICIENCY
• Lipodermatosclerosis* Woody induration and hemosiderin pigmentation on the lower legs; may also involve the pannus (see Ch  100)
GENETIC DISORDERS
• Restrictive dermopathy§ Tight, thin skin over the entire body; joint contractures; LMNA or ZMPSTE24 mutations
• Hutchinson–Gil ord progeria Sclerotic skin on the lower trunk, buttocks and thighs; LMNA mutations (see Ch  63)
• Werner syndrome Tight, sclerotic skin on the distal extremities; RECQL2 mutations (see Ch  63)
• Sti  skin syndrome* Fibrosis o  the skin/ ascia o  the buttocks and thighs with hip contractures (see text)
• Phenylketonuria Sclerotic skin on the thighs and buttocks with hip contractures (see Ch  63)
• Winchester syndrome* Di use, symmetric, leathery skin thickening; fbrotic plaques or bands; MMP2 mutations (see Table 70 2)
• Ataxia–telangiectasia Tight, sclerotic  acial skin (see Ch  60)
• Huriez syndrome Sclerodactyly; atrophic skin on dorsal sur aces o  hands and  eet; palmoplantar keratoderma (see Ch  58)
• H syndrome Hypertrichosis in association with areas o  hyperpigmentation and induration (primarily lower trunk and lower extremities), 
sensorineural hearing loss, short height, heart anomalies, hepatosplenomegaly, scrotal masses, hypergonadotropic 
hypogonadism, antibody-negative insulin-dependent diabetes mellitus,  acial telangiectasias; mutations in SLC29A3 which 
encodes nucleoside transporter hENT3
*Can overlap with morpheaform disorders, which are listed in Table 44.1.
†
Primary cutaneous amyloidosis can also occur in patients with systemic sclerosis and generalized morphea.
‡
May also be observed in patients with congenital erythropoietic porphyria and hepatoerythropoietic porphyria.
§
Sclerodermoid changes are typically present at birth.

Table 43.6  Di erential diagnosis of sclerodermoid conditions  Disorders with a clinical presentation similar to systemic sclerosis are re erred to as sclerodermoid, 

while those reminiscent o  morphea are re erred to as morpheaform (see Ch  44)

650

Treatment
SSc is a challenging disease to treat. Therapeutic interventions focus
primarily on internal organ involvement, but unfortunately most of
these treatments have had no signi cant impact on cutaneous
manifestations19.
Raynaud’s phenomenon
First-line therapy for Raynaud’s phenomenon is behavioral and involves
educating patients to keep warm and avoid smoking to minimize the
frequency and severity of attacks.
Second-line therapy is pharmacologic, starting with vasodilators16.
Calcium channel blockers (e.g. nifedipine) have been the most widely
used medications. Angiotensin II receptor blockers (e.g. losartan) may
also be effective, and combinations of these medications can be used.
More recently, phosphodiesterase type 5 inhibitors (e.g. sildena l,
tadala l) that target the nitric oxide-mediated vasodilation pathway
have been employed, and results have been mixed20–22. Care must be
taken so that the vasodilators do not excessively lower systemic blood
pressure. In addition, calcium channel blockers may exacerbate gastro-
esophageal re ux disease.
Oral antiplatelet agents (e.g. low-dose aspirin) and/or pentoxifylline
may theoretically provide additional blood ow to compromised distal
sites and may be used empirically. While biofeedback can also be
helpful, topical preparations in general have been ineffective.
Cutaneous ulcers
Digital ulcers on the ngers are dif cult to treat and a source of great
morbidity. The approach to digital ulcers includes the treatments for
Raynaud’s phenomenon outlined above. Detailed occupational and rec-
reational histories are important to identify risk factors and sources of
injury. Based upon two randomized controlled trials, bosentan, an oral
endothelin receptor antagonist, has been approved in Europe, but not
the US, for the prevention of new digital ulcers in SSc patients23. While
disappointing results were observed in a double-blind randomized trial
of oral iloprost (a prostacyclin analogue) 24, when administered intrave-
nously, it resulted in a reduction in digital ulcers and improved healing25.
More limited studies of the subcutaneous prostacyclin analogue trepro-
stinil suggest that it may also be effective. In refractory cases, nerve
blocks and sympathectomies may be considered.
In patients with SSc, autolytic debridement of ulcers via occlusive
dressings is thought to be safer than mechanical debridement. In
general, moist hydrocolloid dressings provide a better wound healing
environment than dry or wet-to-dry dressings. Enzymatic debriding
agents (e.g. collagenase) and topically applied growth factors (e.g. PDGF)
have been utilized in a few SSc patients. Skin equivalents or grafts can
also be used to stimulate the wound bed and decrease wound pain.
Cutaneous sclerosis
In the early stage of SSc, cutaneous and subcutaneous edema develops
rapidly, but during the indurated and atrophic stages, the cutaneous
involvement progresses more slowly and tends to gradually improve,
independent of treatment. Unfortunately, objective, quantitative
measurements of cutaneous brosis that are sensitive to change over
short periods of time are currently lacking for SSc. The traditional
instrument for measuring skin involvement in SSc is the modi ed
Rodnan skin score1. Although this is a validated outcome measure, it
is not ideal and is relatively insensitive to small changes over short
periods of time. An adapted engineering tool, the durometer, may be
more suitable for assessing cutaneous induration and hardness in
patients with SSc26.
In a trial of D-penicillamine in 134 patients with diffuse disease,
there was no difference between the low-dose and the high-dose treat-
ment groups27. Although minocycline looked promising in a pilot study,
a larger follow-up study failed to show a bene t28. Methotrexate can
be helpful in SSc patients with overlap polymyositis. However, in a
randomized, placebo-controlled trial (involving 71 patients with early
SSc) where methotrexate was administered for 1 year, there was a trend
in favor of methotrexate but it did not reach statistical signi cance29.
A long list exists of additional agents that have been tried in SSc, but
ultimately most have been shown to be ineffective. For example, inter-
ferons were abandoned due to lack of bene t. Relaxin, a hormone that
relaxes ligatures, did decrease skin scores, but it had no bene t
CH AP T E R
systemically and is no longer used. Photopheresis has been shown to
have a marginal effect on skin scores. PUVA and UVA1 may also have 43 
a role in SSc therapy29a,29b.
Systemic Sclerosis (Scleroderma) and Related Disorders
Other cutaneous complications
Calcinosis cutis represents a serious problem for which no effective
medical therapy exists. Low-dose warfarin (i.e. a dose that does not alter
the prothrombin time) can decrease the in ammatory reaction associ-
ated with calcium deposits. Although there were case reports of the
effectiveness of calcium channel blockers for calcinosis, this was not
observed in larger patient series. In certain situations, surgical removal
of the calcium deposits may be necessary. Treatment with extracorpor-
eal shock wave lithotripsy has also been reported. Telangiectasias can
be treated cosmetically with pulsed dye laser therapy.
Internal organ involvement
Treatment of speci c internal organ involvement is outlined in Table
43.5. Detailed discussions of these therapeutic approaches are available
in other texts1,2. Of note, the use of ACE inhibitors to treat scleroderma
renal crisis has been a major therapeutic advance1.
In several retrospective studies, immunosuppression with cyclophos-
phamide was reported to be bene cial in the treatment of interstitial
lung disease. A prospective, randomized, controlled trial showed
a modest bene t with oral cyclophosphamide (1 to 2 mg/kg/day for
1 year) compared to placebo 30. There are signi cant potential side
effects, such as cytopenias, hemorrhagic cystitis and an increased
risk of bladder carcinoma. Other immunosuppressive agents such as
mycophenolate mofetil, azathioprine, chlorambucil, 5- uorouracil,
cyclosporine and systemic corticosteroids may also be bene cial for
certain patients, but their use has not been well studied.
Advances in the treatment of pulmonary artery hypertension have
also occurred, in particular the use of oral vasoactive compounds, some
of which are also used for Raynaud’s phenomenon and digital ulcers.
These include endothelin receptor antagonists (bosentan31, sitaxsentan,
ambrisentan) and phosphodiesterase type 5 inhibitors (sildena l,
tadala l). Prostacyclin analogues (iloprost [inhaled], epoprostenol
[intravenous], treprostinil [subcutaneous]) are approved for pulmonary
arterial hypertension in SSc patients32, but are no longer sole or rst-
line therapy.
Autologous hematopoietic stem cell transplantation is currently
being studied in both Europe and the US. The “SCOT” trial, “sclero-
derma cyclophosphamide or transplant”, is underway in the US and
should help clarify how effective high-dose immunosuppression is in
treating SSc patients. Lastly, treatment with the tyrosine kinase inhibi-
tor imatinib has shown some promise in small studies 33 and warrants
further investigation for SSc as well as for other brosing disorders such
as chronic GVHD and nephrogenic systemic brosis.
EOSINOPHILIC FASCIITIS
Synonyms: � Shulman’s syndrome � Di use  asciitis with eosinophilia
History
Eosinophilic fasciitis was rst reported in 1975 by Shulman, who
described a brosing disorder characterized by the rapid onset of
woody induration of the extremities in association with peripheral
eosinophilia34.
Clinical Features
A history of strenuous physical activity precedes the clinical ndings
in about 30% of patients with eosinophilic fasciitis. Initial manifesta-
tions include edema and pain of the involved extremities, which quickly
progresses to brosis and a dimpled or “pseudo-cellulite” appearance 651
(Fig. 43.12). The distribution is symmetric, but usually spares the
SECTION

7
RHEUMATOLOGIC DERMATOLOGY

Fig. 43.12  Eosinophilic fasciitis clinical features. Induration o  the skin with  Fig. 43.13  Eosinophilic fasciitis histologic features. Thickening o  the deep 
a dimpled or “pseudo-cellulite” appearance, also re erred to as rippling or  ascia and septae o  the subcutis with an in ammatory infltrate comprised o  
puckering   Courtesy, Joyce Rico, MD. lymphocytes, histiocytes and eosinophils   Courtesy, Philip E LeBoit, MD.

hands, feet and face. The “groove sign” refers to linear depressions
where veins appear to be sunken within the indurated skin. PROPOSED DIAGNOSTIC CRITERIA FOR NEPHROGENIC SYSTEMIC FIBROSIS –
Laboratory ndings include an elevated ESR, hypergammaglobulin- CLINICAL AND HISTOPATHOLOGIC
emia and a striking peripheral eosinophilia35. Antinuclear antibodies
Clinical Histologic
are not elevated (compared to controls) and complement levels are
normal. Pancytopenia, anemia, thrombocytopenia and myeloprolifera- MAJOR CRITERIA •  Increased dermal cellularity (score 
tive disorders have been reported in association with this disease. Some •  Patterned plaques +1)
authors have advocated that patients with eosinophilic fasciitis and •  Joint contractures •  CD34+ cells (score +1)
•  “Cobblestoning” •  Thick and thin collagen bundles 
unexplained anemia undergo bone marrow biopsy to evaluate for a (score +1)
hematologic malignancy. Patients with chronic GVHD can develop •  Marked induration/peau d’orange 
appearance •  Preserved elastic fbers (score −1 i  
eosinophilic fasciitis (see Ch. 52). absent)
•  Septal involvement (score +1)
Pathology •  Osseous metaplasia (score +3)
Histologically, there is a thickening of the deep fascia, which may be MINOR CRITERIA
10 to 50 times the normal width (Fig. 43.13). Within the fascia and •  Puckering/linear banding
subfascial muscle, a patchy in ltrate composed of lymphocytes and •  Superfcial plaque/patch
plasma cells is seen. Eosinophils and mast cells may be present, •  Dermal papules
and dermal brosis is a feature36. •  Scleral plaques (age < 45 years)
Interpretation Clinical Histologic score
Treatment Highly consistent with  2 or more major criteria 4
Once the diagnosis of eosinophilic fasciitis is established via fascial NSF
biopsy and/or MRI (see Fig. 52.7), prompt treatment is essential to Consistent with NSF 1 major criterion 3
preserve mobility and function. Therapy is usually initiated with oral
corticosteroids. Response is typically noted within the rst few weeks, Suggestive o  NSF 2 or more minor criteria 2
and clinical improvement may be seen over several months. The dose Inconsistent with NSF 1 or no minor criteria 1
of prednisone is tapered over 6–24 months as tolerated. If an inadequate NSF excluded Diagnostic o  another  0
response is observed, hydroxychloroquine, cyclosporine, dapsone, entity
methotrexate, PUVA or in iximab may be used alone or in combina-
tion with prednisone. UVA1, alone or in combination with a retinoid, Table 43.7  Proposed diagnostic criteria for nephrogenic systemic
brosis clinical and histopathologic.  Adapted from Girardi M, Kay, J, Elston DM, et al.
can also be considered. Nephrogenic systemic brosis: clinicopathological de nition and work-up recommendations J Am Acad
Dermatol. www.ncbi.nlm.nih.gov/pubmed/21724294

NEPHROGENIC SYSTEMIC FIBROSIS

Synonym: � Nephrogenic fbrosing dermopathy
History
Nephrogenic systemic brosis (NSF) is a relatively new entity in the
differential diagnosis of scleroderma-like disorders that affects both the
skin and internal organs (see Table 43.1)37. Acute kidney injury or
chronic severe renal insuf ciency, together with exposure to gadolinium-
based contrast agents used in medical imaging, are now known to be
the underlying causative factors in this disorder38. In addition to
a strengthening of black box warnings, the FDA in 2010 stated that
652 three contrast agents – gadopentetate dimeglumine (Magnevist™),
gadodiamide (Omniscan™) and gadoversetamide (OptiMARK™)
– were contradicted in patients with acute kidney injury or chronic
severe kidney disease.
Epidemiology and Pathogenesis
NSF is most often observed in middle-aged adults but has been described
in children and elderly patients. It has no sex or race predilection. Since
the recognition of the causal link between renal dysfunction and expo-
sure to gadolinium-based contrast medium, the number of new cases
per year has markedly decreased. Exposure to a greater amount of con-
trast material as is used in magnetic resonance angiography is thought
to increase the risk of developing NSF.
Although the evidence that gadolinium is present in affected tissue
in NSF patients is irrefutable, the mechanisms by which the brosis
develops is unknown. One hypothesis involves aberrant tissue targeting
 CH AP T E R

43 

Systemic Sclerosis (Scleroderma) and Related Disorders

A B

Fig. 43.14  Nephrogenic systemic brosis (NSF) clinical features. Thickening 

and induration o  the skin can be obvious (A), or lesions may present as purple–
brown plaques (B)  Scleral plaques (C) in a patient less than 45 years o  age is a 
minor criterion  or NSF   A, Courtesy, Jean L Bolognia, MD. B, Courtesy, Kalman Watsky, MD.

of the “circulating brocyte”, a bone marrow-derived leukocyte that is

normally recruited to injured tissues, where it participates in matrix
deposition and remodeling.

Clinical Features
NSF presents with patterned, thick, indurated plaques distributed sym-
metrically on the extremities (Fig. 43.14A,B) and trunk. The plaques
are erythematous to hyperpigmented and can have an irregular advanc-
ing edge with an “amoeboid” appearance. Con uent involvement on
the extremities often results in joint contractures. The condition is
frequently associated with considerable pain and loss of mobility. Extra-
cutaneous manifestations include yellow scleral plaques (Fig. 43.14C)
and systemic brosis affecting the heart, lungs and skeletal muscle.
Proposed diagnostic clinical criteria are outlined in Table 43.7.

Pathology
Because the disease process typically extends along brous septa into
the subcutis, a deep biopsy specimen is required for diagnosis (Fig.
43.15). Histologic features include a haphazard arrangement of thick-
Fig. 43.15  Nephrogenic systemic brosis histologic features. There is an  ened collagen bundles and increased dermal broblast-like cells that
increase in the cellularity and amount o  collagen in the dermis and within the  stain positively for CD34 and procollagen I (an immunohistochemical
septae o  the panniculus  The spindle cells (insert) stain positively  or CD34 and  pro le identical to that of the circulating brocyte). Vascular prolifera-
procollagen I   Courtesy, Lorenzo Cerroni, MD. tion, mucin deposition and an increased number of dendritic cells can
also be observed in NSF, but there is no signi cant lymphoplasmacytic
in ltrate. By energy dispersive spectroscopy, particles of gadolinium can 653
be detected within involved tissues39.
SECTION
Treatment
7 The lesions of NSF are refractory to treatment with corticosteroids and
RHEUMATOLOGIC DERMATOLOGY
other immunosuppressive drugs. There have been anecdotal reports
of improvement with imatinib, rapamycin, UVA1 phototherapy, extra-
corporeal photochemotherapy, photodynamic therapy, plasmapheresis,
high-dose IVIg, and discontinuation of erythropoietin.
STIFF SKIN SYNDROME
Synonym: � Congenital  ascial dystrophy
History
Stiff skin syndrome was rst described by Esterly and McKusick in
197140.
Epidemiology
This condition may be congenital or develop during early childhood.
Familial occurrences have been described, but the mode of inheritance
has not been established.
Pathogenesis
The underlying genetic defect is not de nite but mutations in the
brillin-1 gene have been implicated. The presence of giant “amianthoid-
like” collagen brils in affected fascia has been postulated to re ect a
disturbance in the organization of collagen and glycosaminoglycans in
the extracellular matrix.
Clinical Features
Stiff skin syndrome is characterized by “rock hard” induration and
thickening of the skin and subcutaneous tissues, which is most pro-
nounced on the buttocks and thighs, with characteristic sparing of the
inguinal folds41. The hands and feet are not involved. Mild hypertricho-
sis is often observed in affected areas. Restricted joint mobility leads to
a characteristic posture of hip and knee exion and prominent lumbar
lordosis while standing, and patients may have short stature. The con-
dition is stable or slowly progressive, and abnormalities of internal
organs are not typically observed. Patients with unilateral involvement
have been reported, some with features that overlapped with sclere-
dema, deep morphea and linear melorheostotic scleroderma.
Pathology
Histologic examination demonstrates markedly thickened, hyalinized
fascia without an associated in ammatory in ltrate. Thickened colla-
gen bundles and mucin deposition may or may not be present in the
overlying dermis.
Treatment
Stiff skin syndrome has a chronic course, and no effective treatments
have been reported. Physical therapy can help to prevent progressive
joint contractures.
SCLERODERMOID SYNDROMES INDUCED BY
EXOGENOUS SUBSTANCES
Exposure to drugs, chemicals and other exogenous substances can lead
to cutaneous and extracutaneous sclerosis (see Table 43.6)42. The clini-
cal presentation may be similar to that of SSc, including acrosclerosis,
Raynaud’s phenomenon and pulmonary brosis. Other exposures to
exogenous agents can result in the development of circumscribed scle-
rotic plaques resembling morphea. Exogenous substances that induce
sclerodermoid conditions are discussed below, and those responsible for
morpheaform lesions are discussed in Chapter 44.
Toxic Oil Syndrome
654 In 1981, the toxic oil syndrome affected more than 25 000 people
in Spain; 600 died and approximately 300 remained permanently
disabled. It resulted from the ingestion of aniline-degraded and reproc-
essed rapeseed oil, which led to a speci c immune response in geneti-
cally susceptible individuals. New cases are no longer seen, as exposure
to these contaminated cooking oils was halted. Many of the manifesta-
tions of toxic oil syndrome have been reproduced in experimental
animal models, and clinical symptoms and severity in mice were shown
to be dependent on the genetic background. In humans, toxic oil syn-
drome started with a morbilliform eruption and u-like symptoms such
as fever and headache; peripheral eosinophilia was observed in half of
affected individuals. The in ammatory process subsequently affected
the CNS, lungs and salivary glands. Skin involvement either resolved,
evolved into a lichen planus-like eruption, or progressed to a morphea-
form or sclerodermoid picture.
Eosinophilia Myalgia Syndrome
In 1989, a contaminated preparation of L-tryptophan led to an outbreak
of “eosinophilia–myalgia syndrome”, which affected more than 1500
people in the US and led to at least 30 fatalities. The acute phase of
the condition was characterized by severe myalgias, fever, dyspnea,
edema, a macular exanthem and peripheral eosinophilia. Despite the
discontinuation of L-tryptophan intake, approximately half of patients
went on to a chronic phase that featured diffuse, deep sclerodermoid
induration of the extremities (with acral sparing), progressive peripheral
neuropathy and myopathy.
Sclerodermoid Syndromes Induced by Drugs
Several drugs, particularly bleomycin and the taxanes (see Table 43.6),
can induce cutaneous sclerosis and pulmonary brosis mimicking SSc.
Additional medications that have been associated with sclerodermoid
changes include other chemotherapeutic agents such as peplomycin (a
bleomycin analogue), cisplatin, carboplatin, gemcitabine, uracil-tegafur
and topotecan, as well as ergot alkaloids, L-5-hydroxytryptophan ±
carbidopa, penicillamine, appetite suppressants and cocaine. Speci c
autoantibodies are usually absent, and the sclerosis often (but not
always) regresses upon withdrawal of the drug.
Sclerodermoid Syndromes Induced by Chemicals
Exposure to certain organic chemicals can lead to a clinical picture that
resembles SSc (see Table 43.6). In contrast to the acute onset of the
toxic oil and eosinophilia–myalgia syndromes, exposure to vinyl
chloride (typically by individuals who clean the autoclaves used to
polymerize the monomer), organic solvents (e.g. trichloroethylene,
trichloroethane, perchloroethylene), pesticides or epoxy resins induces
a slowly progressive process of sclerosis. It typically begins with insidi-
ous acrosclerosis and Raynaud’s phenomenon (especially with vinyl
chloride exposure), but morpheaform plaques and brotic nodules can
also develop. Acral osteolysis, hepatic toxicity and pulmonary involve-
ment are often observed. In addition, patients experience fatigue, weight
loss, arthralgias and myalgias. Autoantibodies are absent, and cessation
or reversal of the disease process follows removal of the exposure.
Silicosis
The incidence of SSc is approximately 20-fold higher in individuals
with occupational exposure to silica, such as miners and foundry
workers, than in the general population. In an epidemiologic study
from Germany, three-quarters of men with typical SSc had been
exposed to silica dust in the workplace. The mean duration of expo-
sure was 14 years, with a mean delay in onset of the disease of 24
years from the rst exposure. Quartz is absorbed via inhalation and
percutaneously, and silicosis is caused by particles with a diameter
less than 5 microns. Once absorbed, silica cannot be removed from
the body. Although silica has nonspeci c proin ammatory and pro -
brotic effects, HLA and TNF-α subtype associations suggest the need
for a speci c pre-existing immunophenotype for disease progression to
occur. SSc associated with pulmonary silicosis is clinically, serologi-
cally and immunologically indistinguishable from the idiopathic form
of the disease. Silica exposure has also been associated with the devel-
opment of other AI-CTD, including Sjögren’s syndrome, SLE and
rheumatoid arthritis.
 CH AP T E R
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Morphea and Lichen Sclerosus
Morphea and lichen sclerosus are in ammatory skin diseases that
ultimately evolve into two distinct modes o scar ormation. Morphea
a ects primarily the dermis and may extend to subcutaneous struc-
tures. Lichen sclerosus is most o ten a disease o the genital mucosa
(but may also involve extragenital sites) and it a ects both the epider-
mis and the superfcial dermis. Neither one leads to involvement o
internal organs other than occasionally the underlying muscle or bone.
While an individual patient may have both disorders simultaneously,
they are addressed separately because o their multiple dissimilarities.
Therapy o these two diseases will be discussed together.
MORPHEA
Subtypes/synonyms: � Plaque-type morphea – localized 
scleroderma, circumscribed scleroderma � Linear morphea – linear  EPIDEMIOLOGY
scleroderma � Morphea en coup de sabre – scleroderma en coup de
sabre � Deep morphea – morphea profundus
Key features
  Asymmetric sclerotic plaques, usually 2–15 cm in diameter
  Active lesions can have a lilac border with central hypo- or  to be increasing slightly2.
dyspigmentation, while inactive lesions often become  The prevalence o morphea increases with age. It is approximately
hyperpigmented
  The sclerosis may extend deeply into the fat or underlying  disease is more prevalent in women than in men (2.6 to 1), with the
structures (e.g. fascia, muscle, bone), causing disability
  There is no associated systemic disease
  Often progresses for several years, then regresses; the linear  and diagnosis.
subtype is usually persistent
INTRODUCTION
Morphea is a clinically distinct in ammatory disease, primarily o the
dermis and subcutaneous at, which ultimately leads to a scar-like
sclerosis. The small vessel changes, the in ammatory infltrate and the
ultimate structural modifcations are identical in morphea and sys-
temic sclerosis, but the two diseases are distinct entities that can easily
be distinguished clinically. Morphea has an asymmetric patchy or linear
distribution, whereas systemic sclerosis usually begins as symmetric
tightening o the hands and fngers that extends progressively toward
the proximal upper extremities. Although generalized morphea may
resemble early di use scleroderma, the presence in the latter condition
o Raynaud’s phenomenon, digital sclerosis, and involvement o the
gastrointestinal tract and the lung generally allows separation o sys-
temic sclerosis rom morphea. Distinguishing between deep morphea
and eosinophilic asciitis can prove more di fcult.
Morphea has associated morbidity and impacts quality o li e as a
result o symptoms such as pain, skin tightness or decreased range o
motion o joints1. In ~10% o patients, scar ormation may lead not
just to the usual disfgurement but also to signifcant contractures or
growth retardation, handicapping the a ected individual or li e 2. Thus,
prompt treatment (e.g. UVA1, PUVA) is indicated when morphea
a ects more than the superfcial dermis.
RHEUMATOLOGIC DERMATOLOGY SECTION 7
44 
Martin Röcken and Kamran Ghoreschi
HISTORY
A condition o thickened skin was frst mentioned by Hippocrates
around 400 BC. The term “scleroderma” is derived rom the Greek
words skleros (hard or indurated) and derma (skin). The frst descrip-
tion o a generalized “hardness” o the skin in a young woman was by
an Italian physician, Carlo Curzio, in 1753, and the French physician
Gintrac coined the term “sclérodermie” in 1847. Thomas Addison has
been credited with the frst detailed description (in 1854) o morphea,
which he re erred to as Alibert’s keloid syndrome3. In 1924, Matsui
described the typical histopathologic changes o scleroderma, including
the increase in collagen and thickening o vessel walls in involved skin.
O’Leary and Nomland4 elaborated the distinctive eatures o systemic
sclerosis versus morphea in 1930.
Even though morphea has been long recognized as a well-defned entity,
ew population-based studies have been published. One o the best
analyses is a survey rom Olmsted County, Minnesota, that attempted
to register all patients with the disorder rom 1960 to 19935. During
this period, the annual incidence rate was 27 per million inhabitants.
According to this study, 56% o patients had plaque-type, 20% linear,
13% generalized, and 11% deep morphea. Overall, the incidence appears
500 and 2200 per million at ages 18 and 80 years, respectively2. The
exception o linear morphea, which has no gender pre erence. Data
published on the incidence and prevalence o morphea probably re ect
an underestimation, as they critically depend on clinical recognition
Morphea is very rarely li e-threatening. In the Olmsted County study,
the survival rate o patients with morphea was not signifcantly di er-
ent rom that o the general population5. However, in 11% o the
patients, substantial disability occurred. This is o particular concern
since disability occurs primarily with linear morphea, and the latter
o ten has its onset be ore age 18 years (approximately two-thirds o
patients)5.
PATHOGENESIS
Autoantibodies are usually as prevalent in morphea as in the general
population, with two exceptions: (1) an increased prevalence o anti-
single strand DNA (ssDNA), -topoisomerase IIα, -phospholipid,
-fbrillin-1 and -histone antibodies in patients with morphea (see Ch.
40); and (2) high titers o antinuclear antibodies (ANA) in juvenile
patients with linear morphea and individuals with generalized morphea.
Autoantibodies that activate receptors on fbroblasts, in particular the
platelet-derived growth actor receptor (PDGFR), and presumably trigger
a cascade that leads to increased collagen synthesis have not been
described in patients with morphea (see Ch. 43).
Neither histology nor immunohistology o a single lesion will distin-
guish between morphea and systemic sclerosis. In most clinicopatho-
logic reviews, it is assumed that the two diseases are triggered by
distinct events. However, the development o sclerosis ollowing the 657
initiating event seems to ollow a common pathway. It is there ore
SECTION
assumed that pathogenic steps leading to systemic sclerosis also con- STAT4 polymorphisms (e.g. rs7574865) and an increased susceptibility
7 tribute to the development o morphea, so they will be included in this to systemic sclerosis, especially the limited subtype, was recently
reported9,10.
RHEUMATOLOGIC DERMATOLOGY

discussion.
Currently, sclerosis o the skin is thought to involve three major,
closely connected components: vascular damage, activated T cells, and
altered connective tissue production by fbroblasts (Fig. 44.1)6.
Vascular Changes
A prominent eature o advanced sclerosis is a reduction in the number
o capillaries. Studies per ormed in systemic sclerosis suggest that
microvascular injury is a very early – and perhaps even the primary –
While IL-4 is the most potent orce in driving Th2-cell di erentiation
(see Fig. 4.10 )11, it is also produced by Th2 lymphocytes. Because IL-4
enhances pathologic collagen production by fbroblasts and induces
recruitment o eosinophils, it is believed that immune responses domi-
nated by IL-4- as well as IL-13- and TGF-β-producing cells are critically
involved in the development o skin sclerosis. This concept is supported
by clinical and experimental data:
l In situ analysis o progressing in ammatory margins o skin

event. Endothelial cell markers such as soluble adhesion molecules and
vascular endothelial growth actor (VEGF) are elevated in the sera o
patients with systemic sclerosis, indicating endothelial activation. The
morphologic changes principally a ect capillaries and small arterioles
50–500 microns in diameter. The initial changes include expression o
adhesion molecules and endothelial swelling, ollowed by thickening o
sclerosis has revealed predominantly IL-4 expression 12.
l Th2-associated cytokines IL-13 and IL-33 have been shown to
promote skin fbrosis experimentally in mice and early treatment
o scleroderma-developing mice with anti-IL-4 antibodies
prevented scleroderma13,14.
l Systemic retinoids (which interact with TGF-β signaling) appear to

the basement membrane and intimal hyperplasia. An extrapolation is reduce pathologic collagen synthesis by fbroblasts and case series
that similar changes may be occurring in patients with morphea. suggest that retinoids can improve sclerosis in patients with
sclerodermoid GVHD 15,16.
Control of Fibroblast Function by
T-Cell-Derived Cytokines
Pioneering work by Leroy7 showed that fbroblasts isolated rom scle- PATHOGENESIS OF SCLEROSIS
rotic tissue produce increased amounts o collagen (types I, II and III)
and other extracellular matrix proteins when they are cultured in vitro. T Lymphocytes IL-4 Fibroblasts Collagen
These fbroblasts can maintain this phenotype or weeks over several
passages. This raised the question as to whether scleroderma results
rom an inborn or an acquired error in collagen metabolism within
fbroblasts. Today, most data avor the concept that abnormal collagen
production is due to instructions rom surrounding cells. T cells in
particular have the capacity to modi y collagen synthesis by fbroblasts
and they are regularly present, at least in a perivascular location and
especially at the leading edge o developing sclerosis (see Fig. 44.1). TGF-b Fibrosis
Pathologically enhanced production o collagen and other extracel-
lular matrix proteins is induced by T-cell-derived cytokines, especially
interleukin (IL)-4, IL-13 and trans orming growth actor-β (TGF-β).
IL-4 is produced by CD4+ T helper type 2 (Th2) lymphocytes (see Ch.
4) and can directly enhance TGF-β production8. In contrast, pathologic Endothelial cells
production o collagen (types I, II, III) and other extracellular matrix
Activation
proteins can be signifcantly suppressed by inter eron-α (IFN-α) or IFN-
γ. IFN-γ is produced by CD4+ Th1 lymphocytes and IFN-α is capable Fig. 44.1  Pathogenesis of sclerosis. Three components are involved during 
o promoting Th1 responses8. Th1 di erentiation also implicates IL-12 the formation of sclerosis: vascular damage, lymphocyte activation, and altered 
signaling via the transcription actor STAT4. An association between connective tissue production. IL, interleukin; TGF, transforming growth factor. 

Fig. 44.2  Animal model for scleroderma. Transfer of 

ANIMAL MODEL FOR SCLERODERMA scleroderma phenotype from diseased animals (TSK 
mice) to healthy syngeneic mice (C57BL/6) by bone 
marrow cells. Lack of tight skin and autoantibody 
C57BL/6 TSK TSK production by back-crossing TSK mice with mice that 
but no response to IL-4 cannot respond to IL-4 or mice that produce minimal 
amounts of TGF-β. IL, interleukin; TGF, transforming 
growth factor; TSK, tight skin strain of mice. 
*

Bone marrow cells TSK

with strongly reduced
TGF-β production

Skin ˜ sclerosis Skin

Serum ˜ autoantibodies Thickening
Sclerosis
Hydroxyproline
Collagen
Reduced diameter
Serum autoantibodies
Topoisomerase I Skin ˜ normalization
Fibrillin-I Serum autoantibodies ˜ normal
658 * back-cross

Fig. 44.3  Early in ammatory plaque-type morphea of the trunk. Early-stage 
lesion presenting as an erythematous edematous plaque. 
One therapeutic approach or morphea would be to shi t rom Th2
responses to Th1 responses. However, a series o placebo-controlled
clinical trials that tested the e fcacy o IFN-γ or IFN-α in morphea had
negative results17. Perhaps establishment o more e ective cytokine-
based therapies or skin sclerosis requires a more detailed understand-
ing o cytokine actions in vivo.
Lastly, when scleroderma fbroblasts are compared to control fbro-
blasts, there are di erences in intracellular signaling proteins. Examples
include activation o p38 mitogen-activated protein kinase and higher
levels o both Ha-Ras protein and reactive oxygen species (ROS)18,19.
These fndings and data rom animal studies demonstrating the devel-
opment o skin fbrosis a ter injections o pro-oxidative agents point to
a role or oxidative stress in the pathogenesis o skin sclerosis20.
Animal Model and Genetics
Currently, the best animal model or studying pathogenic events in
scleroderma is the tight skin (TSK) mouse (Fig. 44.2). A partial duplica-
tion o the fbrillin-1 gene may be responsible or the increased synthe-
sis and accumulation o collagen in the skin and internal organs o TSK
mice. TSK mice not only have increased collagen deposits, but also the
collagen fbers are reduced in length and the amounts o hydroxyproline
are increased in the dermis, as is the case in morphea and systemic
sclerosis. Moreover, the mice have high antibody titers against topo-
isomerase I and fbrillin-1, similar to patients with systemic sclerosis
and morphea, respectively. One major di erence is that blood vessels
remain uninvolved in TSK mice, demonstrating that sclerosis o the
skin can develop in the presence o apparently normal vessels 21. The
phenotype can be trans erred rom diseased animals to healthy syn-
geneic mice via bone marrow cells (see Fig. 44.2).
Fibroblasts rom TSK mice have elevated IL-4 receptor α expression
and back-crossing the TSK mice onto a genetic background that either
can not respond to IL-4 or is defcient in producing TGF-β prevents
skin sclerosis. Moreover, this back-cross normalizes collagen length,
skin thickness and hydroxyproline content and prevents antibody or-
mation to topoisomerase I (see Fig. 44.2)21. Promising therapeutic inter-
ventions include CpG moti -containing oligodeoxynucleotides that
promote Th1 responses (and suppress IL-4 production) and PDGFR-
targeting kinase inhibitors (e.g. imatinib), both o which reduce dermal
thickening and fbrosis in TSK mice22. O note, in case series, imatinib
has led to improvement o cutaneous sclerosis in both fbrotic chronic
GVHD and nephrogenic systemic fbrosis.
Besides the phenotypic similarities, the genetic locus associated with
the TSK phenotype appears to be related to risk o developing sclero-
derma. In humans, this susceptibility locus is on chromosome 15q in
a region o 2-cM that contains the fbrillin-1 gene (mutations in the
fbrillin-1 gene have been implicated in sti skin syndrome)23. Other
genetic variations reported to be associated with scleroderma include
polymorphisms in both STAT4 (see above) and the promotor region o
the gene encoding connective-tissue growth actor (CTGF)9,10,24.
CH AP T E R
Fig. 44.4  Plaque-type
morphea of the back.  44 
Multiple, large 
Morphea and Lichen Sclerosus
hyperpigmented 
plaques, several of which 
have an in ammatory 
border. 
Triggering Events
Most immunologic and metabolic studies were designed to understand
systemic sclerosis, and the question remains as to whether they can
also explain ocal, asymmetric in ammation and sclerosis o the skin.
The major discriminating actor between morphea and systemic scle-
rosis might be the triggering event, with morphea being caused by a
local trigger within the skin and systemic sclerosis being initiated by
triggers with systemic e ects.
These questions initiated the search or potential triggers and studies
o diseases that share clinical eatures with morphea and scleroderma.
One intensively investigated area was the potential role o in ection
with Borrelia burgdorferi. The isolation o B. burgdorferi rom the skin
o some selected patients with morphea originally supported this specu-
lation. However, larger studies by several groups rom di erent coun-
tries ound that morphea lesions normally do not contain mRNA or
B. burgdorferi or related strains and the prevalence o antibodies against
B. burgdorferi is similar in patients with and without morphea25. Thus,
this theory has been abandoned.
CLINICAL FEATURES
Morphea can be subdivided into several subgroups: plaque-type
morphea, linear morphea, generalized morphea, and other less common
variants (e.g. deep, guttate, nodular). There are also in ammatory
syndromes leading to superfcial or deep sclerosis o the skin that
resemble morphea (i.e. morphea orm; see below). Patients with morphea
do not have Raynaud’s phenomenon or involvement o internal organs,
except or underlying ascia, muscle and bone in some patients with
linear morphea. In rare patients with presumptive morphea, clinically
insignifcant fbrosis o the lung or slightly reduced esophageal motility
has been detected radiographically or by scintigraphy. Clinically rele-
vant involvement o internal organs is only observed in certain types
o pseudoscleroderma (see Ch. 43).
Clinical Manifestations
Plaque-type morphea, the most requent variant, is characterized by the
insidious onset o a slightly elevated, erythematous or violaceous,
somewhat edematous plaque that undergoes centri ugal expansion
(Fig. 44.3). It is generally asymptomatic and there ore requently goes
unnoticed by the patient. The central portion o the progressing lesion
starts to trans orm into sclerotic, scar-like tissue. Depending on the 659
depth o the sclerosis, the skin becomes progressively indurated.
SECTION
Fig. 44.5  Comparison of
7 deep morphea and
eosinophilic fasciitis.
RHEUMATOLOGIC DERMATOLOGY
A Note the “pseudo-
cellulite” appearance of  arising within an area of
the involved skin of the  hyperpigmented
thigh in deep morphea.  induration.  Courtesy, Jean L
B In eosinophilic fasciitis,  Bolognia, MD.
the level of  brosis is 
also deep, resulting in a 
similar clinical 
appearance. 
A syndrome.
B
Centrally, it can acquire a shiny white color, and peripherally, a viola-
ceous or “lilac” ring. Postin ammatory hyperpigmentation o ten domi-
nates over the white sclerosis as the lesions mature (Fig. 44.4).
Skin structures such as hairs and sweat glands are requently lost.
Some patients complain o itch, perhaps due to associated xerosis. Once
the “lilac” ring vanishes, the lesion’s progression also halts. Although
this in ammatory margin may be di fcult to appreciate, especially in
linear sclerosis, it is an important component o the physical examina-
tion as it is an indicator o clinical activity.
The plaques o morphea most commonly develop on the trunk and
are between 2 and 15 cm in diameter. They are usually multiple and
asymmetric, but marked variation exists. Individual lesions may enlarge
signifcantly or remain stable in size.
The course o morphea is also variable. In most patients, morphea
progresses over 3–5 years, then arrests and eventually resolves sponta-
660 neously. However, residual atrophy and/or dyspigmentation are com-
monly observed. Rarely, patients have relapsing disease or more than
Fig. 44.6 
Nodular (keloidal)
morphea. Elevated,  rm 
pink papulonodules 
 
 
Fig. 44. 7 
Parry–Romberg
 
Hyperpigmentation and 
loss of subcutaneous fat, 
leading to facial 
asymmetry.  Courtesy, Julie V
Schafer, MD.
5 years. Because many patients are lost to ollow-up, no defnitive long-
term statistical data have been published.
Variants
Various mani estations o morphea have become associated with
specifc names. They do not really re ect unique entities, but rather
di erent morphologic eatures, distribution patterns or depth o involve-
ment. In most patients, morphea seems to be randomly distributed.
However, in some patients, the lesions are unilateral, and they may
ollow dermatomes or Blaschko’s lines.
l Guttate morphea presents primarily as multiple, rather
superfcial, nummular plaques. Even though relatively small, they
may become deeply indurated.
l Atrophoderma of Pasini and Pierini is considered by some to be a
very superfcial variant o plaque-type morphea, while others
consider it to be a separate entity in the di erential diagnosis o
“burnt-out” morphea (see Ch. 99). Hyperpigmented patches are
seen most commonly on the posterior trunk; occasionally, lesions
ollow Blaschko’s lines (linear atrophoderma o Moulin).
l Deep morphea re ects an in ammation and sclerosing process
that a ects primarily the deep dermis and subcutaneous at
and may even involve underlying structures (e.g. the ascia)
(Fig. 44.5A). Patients normally develop a single or ew hard deep
plaques that may impair motility o the skin; ultimately, lesions
may calci y, leading to deep osteoma cutis. Because o the location
o the sclerosis, individual lesions can share some clinical eatures
with eosinophilic asciitis (Fig. 44.5B and see Ch. 43).
l In nodular or keloidal morphea, in ammation within the dermis
leads to thick, keloid-like nodules (Fig. 44.6) or streaks. It is
clinically indistinguishable rom indurated keloids.
l In rare patients, especially those where sclerosis o the skin is
associated with di use, rapidly progressive edema, lymphoceles

Fig. 44.8  Fig. 44.9  Morphea en
Linear morphea of the
leg. The di erential  depressions and sclerosis
diagnosis includes linear  are more frequently
melorheostosis which is  paramedian (rather than
often associated with  midline) and can be wide
underlying candlewax-
like linear hyperostosis.  the prominent veins and
may result rom stasis o lymphatic uid. When the latter develop
into bullae, this is re erred to as bullous morphea. It is more
requently observed in generalized morphea or sclerodermoid
GVHD and is rarely a eature o plaque-type morphea. Bullous
morphea has to be distinguished rom mechanical blisters that
may occur in the central scar and are secondary to impaired
mechanical stability o the dermal–epidermal junction.
Linear Morphea and Parry–Romberg Syndrome
Linear morphea is di erent rom plaque morphea, with respect to age
o onset, distribution, clinical outcome and serologies. Morphea en
coup de sabre (meaning stroke or blow with a single-edged sword) is a
term used or linear morphea o the orehead and scalp. Hemi acial
atrophy, or Parry–Romberg syndrome, is probably a very severe variant
o linear morphea, but it may be a phenotype or more than one entity.
There is a progressive loss o subcutaneous at, but little or no sclerosis
(Fig. 44.7). The entire distribution o the trigeminal nerve, including
the eye and the tongue, may be a ected.
Linear morphea may present initially as a linear, erythematous
(in ammatory) streak, but more requently it begins as a harmless-
appearing lesion o plaque-type morphea that extends longitudinally as
a series o plaques that then join to orm a scar-like band (Fig. 44.8).
This band may severely impair the mobility o the a ected limb. Linear
morphea tends to involve the underlying ascia, muscle and tendons.
This leads not only to muscle weakness but also to a shortening o the
muscles and ascia that impairs joint motility. Linear morphea is espe-
cially dangerous when extending over joints, as this almost invariably
results in disabling joint immobilization. In some patients, involve-
ment is circular rather than linear and results in progressive atrophy
o the limb similar to the Parry–Romberg variant o acial morphea.
The en coup de sabre type o morphea represents linear morphea o
the head (Fig. 44.9). It is normally unilateral and extends rom the
orehead into the rontal scalp. It may start either as a linear streak or
as a row o small plaques that coalesce. A paramedian location is more
common than a median location. Like plaque morphea, it may initially
be surrounded by a discrete lilac ring that extends longitudinally and
may reach the eyebrows, nose and even the cheeks. The waning in am-
mation leaves a linear, hairless crevice that in some patients is more
sclerotic, while in others is more atrophic.
CH AP T E R
coup de sabre. Linear  44 
 
Morphea and Lichen Sclerosus
 
 
 
(A) or narrow (B). Note 
 
loss of the medial 
eyebrow in A.  B, Courtesy,
Julie V Schafer, MD.
B
En coup de sabre morphea can also involve the underlying muscles
and osseous structures. Rarely, the in ammation and sclerosis progress
to involve the meninges and even the brain, creating a potential ocus
or seizures. Alternatively, very slowly progressing in ammation, indis-
tinguishable rom the in ammatory process o linear morphea, leads
to gradual involution o the skin, atty tissues and underlying bones.
Generalized Morphea
Rarely, plaque-type morphea is rapidly progressive, where multiple
enlarging plaques appear simultaneously and coalesce until they involve
nearly the entire integument. Rather, this variant normally begins
insidiously on the trunk as plaque morphea. An individual lesion is
indistinguishable rom classic plaque morphea, except that it does not
stop expanding. Just as in the di use orm o systemic sclerosis, the
plaques rapidly coalesce and a ect the entire trunk, o ten only sparing
the nipples. The sclerosis may involve the extremities down to the
hands (presenting initially as pu y edema). As the cutaneous sclerosis
progresses, it may result in disabling constrictions that even cause di -
fculty in breathing due to impaired thorax mobility and in ammation
o the intercostal muscles. Although an aggressive therapeutic approach
is recommended, the disease is usually persistent given its o ten limited
response.
Morphea in Childhood
About 20% o those with morphea are children and teenagers. The
emale-to-male ratio or plaque-type morphea is about 2:1, with a mean
age o disease onset o 7 years26. Linear morphea is more o a problem,
as two-thirds o all patients with this variant are younger than 18 years
o age when it develops. Also, in young children and adolescents, linear
morphea o ten leads to growth retardation o the a ected limb. Thus,
i le t untreated, linear morphea may result not only in decreased range 661
o motion o joints but also in permanent limb asymmetry rom
SECTION
Fig. 44.10  Linear morphea of the leg
7 in two adolescents. A Extensive 
induration of the left leg with 
RHEUMATOLOGIC DERMATOLOGY

hypoplasia and an obvious  exion 
contracture of the knee; there is also 
involvement of the right foot. B Linear 
distribution of coalescing sclerotic 
plaques on the thigh; note the 
lilac-colored border.  B, Courtesy, Julie V
Schafer, MD.

unilateral hypoplasia (Fig. 44.10). Linear morphea that is indistinguish-

able rom the idiopathic variant can also ollow allogeneic hematopoi-
etic stem cell transplantation.
Disabling pansclerotic morphea of children is similar to generalized
morphea o the adult. It usually starts be ore 14 years o age and tends
to cause li elong severe disability due to persistent atrophy o the under-
lying muscles and contractures o the involved joints. The disease tends
to extend rom the trunk to the hands and eet. Periodontal atrophy
may occur, but there is only slight involvement o the esophagus and
lung. Distinction rom systemic sclerosis may prove challenging.
Importantly, in a large multicenter study o children with morphea
(85% o whom had linear morphea or Parry–Romberg syndrome [PRS]),
22% had extracutaneous fndings that were primarily articular (11%),
neurologic (4%) and ocular (2%)26. The latter were seen primarily in
those with linear morphea o the head or PRS.
LABORATORY FINDINGS
Laboratory abnormalities are not a prominent eature o morphea,
except or generalized and linear morphea. The ESR and serum protein
levels are usually normal, but eosinophilia may occur, especially during
early active phases o the disease. The presence o ANA or antibodies
to ssDNA and histones are unusual in patients with plaque-type
morphea (see Ch. 40). They are more requent in linear and generalized
morphea, where ANA can be ound in high titers in 40–80% o patients.
662 About 40% o children and adolescents with morphea have elevated
ANA titers26,27.
B
Fig. 44.11  Morphea – histologic features. A Overview with thickening of the 
dermis and perivascular in ltrates of lymphocytes and plasma cells (insert).  
B Advanced sclerosis of the entire dermis extending into the fat with thickened 
collagen bundles and “trapped” eccrine glands (arrow). 
PATHOLOGY
The histology o scleroderma depends on two actors: the stage and area
o the lesion sampled (early in ammatory margin or central sclerosis)
and the depth to which the disease extends. In most situations, mor-
phologic changes are best seen at the border between the dermis and
subcutaneous at. Specimens or histology must include subcutaneous
at and it is important to note whether the biopsy specimen is taken
rom the in ammatory border or rom the fbrotic center.
At the in ammatory border, vascular changes are relatively discrete
by light microscopy. Vessel walls show endothelial swelling and edema.
Capillaries and small arterioles are surrounded by an infltrate that
contains primarily CD4+ T cells and sometimes eosinophils, plasma
cells and mast cells (Fig. 44.11A).
In later stages, the in ammatory infltrate wanes and ultimately
disappears completely, except in some areas o the subcutaneous at.

The epidermis is basically normal in appearance, but the rete ridges
may be diminished, leaving a attened dermal–epidermal junction.
Edema is no longer visible in the dermis and upper subcutis. Capillaries
and small vessels are signifcantly reduced in number, and homogene-
ous collagen bundles with decreased space between the bundles replace
most structures. At this stage, collagen bundles in the reticular dermis
appear densely packed, as evidenced by a more intense eosinophilic
staining, and are aligned parallel to the dermal–epidermal junction
(Fig. 44.11B). Eccrine glands appear atrophic and “trapped” within the
thickened dermis. The underlying subcutis is homogenized and
hyalinized.
Deep morphea a ects primarily the deep subcutaneous tissue. Fol-
lowing the in ammatory phase, extensive sclerosis and hyalinization
extend into the underlying ascia. Involvement o the underlying ascia
is obligatory in deep morphea and is also requently observed in linear
and generalized types o morphea. In these patients, the ascia and even
the underlying muscle ( requently vacuolated) are involved in the
process o progressive sclerosis, characterized by replacement o the
di erentiated tissue by collagen bundles.
MORPHEAFORM AND SCLERODERMOID
INFLAMMATORY SYNDROMES
Some entities (e.g. sclerosis secondary to exposure to bleomycin, vinyl
chloride or epoxy resin) that are characterized by acrosclerosis and
Raynaud’s phenomenon have a clinical presentation similar to sclero-
derma (i.e. sclerodermoid or pseudoscleroderma), while others present
with circumscribed plaques similar to morphea (i.e. morphea orm). The
ormer are discussed in Chapter 43 and the latter are discussed below
and presented in Table 44.1. There are also clinical disorders that may
have either type o clinical presentation, such as toxic oil syndrome.
DIFFERENTIAL DIAGNOSIS OF MORPHEAFORM SKIN LESIONS
Morphea (plaque-type, linear, generalized* or deep*)
Chronic graft-versus-host disease*
Lichen sclerosus (may coexist with morphea)
Lipodermatosclerosis*
Sclerosis at injection sites†
•  Vitamin K1 (Texier’s disease) or vitamin B12
•  Silicone or para n implants
•  Interferon-β
•  Glatiramer
•  Enfuvirtide
•  Bleomycin (intralesional therapy)
•  Opioids (e.g. pentazocine, ketobemidone, methadone)
Chemical/toxin exposures
•  Aromatic/chlorinated hydrocarbons (e.g. benzene or toluene at sites of contact  asciitis (see Ch. 52).
with skin)*
•  Nephrogenic systemic  brosis (induced by gadolinium-containing contrast  in Chapter 43.
media)*
•  Toxic oil syndrome (historical)*
Radiation-induced morphea
Porphyria (porphyria cutanea tarda, hepatoerythropoietic porphyria, congenital  DIFFERENTIAL DIAGNOSIS
erythropoietic porphyria)
Muckle–Wells syndrome
Winchester syndrome*
Asymmetric childhood scleredema/sti  skin syndrome*
Linear melorheostosis
Re ex sympathetic dystrophy*
Morpheaform sarcoidosis
Sclerosing congenital melanocytic nevus
Dermato brosarcoma protuberans
Cutaneous metastases (e.g. carcinoma en cuirasse)
*Can overlap with sclerodermoid disorders, which are outlined in Table 43.6; in particular,
deep morphea and eosinophilic fasciitis may have a similar appearance.
† insulin-dependent diabetes with cheiroarthropathy, also re erred to as
Systemic medications for which there have been reports of an association with
morpheaform lesions include bleomycin, taxanes (e.g. paclitaxel, docetaxel),
bromocriptine, ethosuximide, valproic acid, appetite suppressants and penicillamine.
Table 44.1  Di erential diagnosis of morpheaform skin lesions.
CH AP T E R
While a variety o in ammatory diseases ultimately lead to superf-
cial or deep sclerosis o the skin, their exact relationship to morphea 44 
Morphea and Lichen Sclerosus
is enigmatic. Some o these diseases are preceded by or associated
with eosinophilia in blood or tissue. Infltration by eosinophils
may be o unknown etiology, as in eosinophilic asciitis, or it may
re ect an immune reaction to a defned toxic insult or antigenic stim-
ulus, as in the L-tryptophan syndrome (eosinophilia–myalgia syn-
drome), toxic oil syndrome, or GVHD ollowing hematopoietic stem
cell transplantation. Lastly, since certain exogenous drugs or chemi-
cals, endogenous metabolites or X-ray irradiation induce sclerosis at
the site o tissue injury in only a subset o individuals, this suggests
that unique metabolic events and innate or adaptive immune
responses to these compounds determine the individual’s susceptibil-
ity to develop sclerosis.
l Lipodermatosclerosis. Chronic venous insu fciency that persists
or many years leads to sclerosis in association with chronic
hypoxia. Lipodermatosclerosis avors the lower extremities, but
can also involve the pannus; it is discussed in Chapter 100.
l Injections of vitamin K1 (Texier’s disease). Injection o
oil-soluble vitamin K 1 rarely causes a strictly localized, deep
eosinophilic asciitis that is indistinguishable rom deep morphea.
It may ultimately resolve with atrophy o the dermis and/or
subcutis.
l Paraf n and silicone injections or implants. It is suspected that
injection o silicone or liquid para fn during reconstructive surgery
or leakage o silicone implants may cause chronic in ammation
that results in localized morphea-like sclerosis. The belie that
these substances can cause more generalized in ammation and
trigger systemic diseases such as systemic sclerosis, eosinophilic
asciitis or mixed connective tissue disease was not substantiated
when meta-analyses were per ormed28.
l Porphyrias. In adults, porphyria cutanea tarda can lead to
morphea-like sclerosis in UV-exposed sites, such as the ace,
hairless scalp, dorsal aspects o the hands, and the upper chest.
Histology and electron microscopy fndings may resemble morphea
except or the presence o PAS-positive deposits around dermal
blood vessels. Other rare orms o porphyria can also lead to
scarring in UV-exposed sites (see Ch. 49).
l Radiation-induced morphea. This disorder is characterized by
marked sclerosis, erythema and pigmentary changes occurring
within the radiation feld or even beyond it. The incidence o
radiation-induced morphea is about 1 in 500 patients and it is
seen primarily in patients treated or breast carcinoma. Predictive
risk actors or the development o radiation-induced morphea are
unknown and disease onset can even occur several years a ter
radiation therapy. In addition to the changes o radiation
dermatitis, histopathology demonstrates perivascular and
subcutaneous in ammation together with dermal fbrosis and
collagen deposition.
l Chronic GVHD. Patients with chronic GVHD develop lesions
that resemble morphea and lichen sclerosus as well as eosinophilic
l Nephrogenic systemic brosis. This entity is discussed in detail
In addition to the other morphea orm and sclerodermoid conditions
discussed above, the most important entity in the di erential diagnosis
is systemic sclerosis (see Ch. 43). Absence o Raynaud’s phenomenon
and lung or esophageal involvement is characteristic o morphea. The
other common considerations are lichen sclerosus and keloids; however,
the ormer can coexist with morphea. Dupuytren’s contracture and
camptodactyly, a benign ulnar deviation o the ourth and f th fnger,
can be clinically distinguished rom linear morphea.
Scleredema leads to di use woody induration o the upper back and
neck. Symmetric tightness and induration o acral sites can be seen in
waxy skin and sti joints. In children, progeria and premature aging
syndromes need to be distinguished rom Parry–Romberg syndrome,
but the latter is unilateral. Additional entities in the sclerodermoid 663
di erential diagnosis (e.g. scleromyxedema) are listed in Table 43.6.
SECTION
LICHEN SCLEROSUS
7 MHC class II antigen HLA-DQ7 was observed in a relatively large
RHEUMATOLOGIC DERMATOLOGY
Synonyms: � Lichen sclerosus et atrophicus � Kraurosis vulvae �  region o the MHC is underlined by the fnding that the same region
Balanitis xerotica obliterans (lichen sclerosus of the penis)
Key features
  Sclerotic, ivory-white,  at papules and plaques with epidermal  matrix protein 1 (ECM-1), no specifc immunologic parameters have
atrophy and, in extramucosal sites, follicular plugging
  Most commonly a ects female or male genitalia, less often  o disease or disease activity. IgG autoantibodies against ECM-1 are
extragenital skin
  May cause scarring of the vaginal introitus or phimosis
  Severe pruritus may occur
  No systemic manifestations
INTRODUCTION
Lichen sclerosus is a clinically distinct in ammatory disease primarily
o the superfcial dermis or submucosa that leads to ivory-white scar-
like atrophy. Extragenital lichen sclerosus may itch and be cosmetically
disturbing. Genital lichen sclerosus causes both dryness and severe,
persistent pruritus, and it o ten leads to progressive atrophy and unc-
tional impairment. Phimosis or scarring o the vaginal introitus are the
most requent complications.
HISTORY
Francois Henri Hallopeau’s report on a “lichen plan atrophique” in
1887 is considered to be the frst description o lichen sclerosus. The
typical histopathologic changes o lichen sclerosus et atrophicus were
published by Ferdinand Jean Darier in 1892. Unna, Westberg, von
Zumbusch and others elucidated the clinical eatures o lichen sclero-
sus in various case reports 29–31. This contributed to the panoply o
terms, such as white spot disease or lichen albus, an aspect that com-
plicates any literature survey. Lichen sclerosus in the genital area was
frst described in women by Breisky as kraurosis vulvae32 and 40 years
later in men by Stühmer as balanitis xerotica obliterans33. Today, lichen
sclerosus, the term proposed by the International Society or the Study
o Vulvar Disease, is most requently used34,35.
EPIDEMIOLOGY
Lichen sclerosus is relatively uncommon, although the exact prevalence
is unknown. It occurs at all ages and seems to have a similar incidence
in all races; the reported emale-to male-ratio varies widely, depending
upon the study, rom 10 : 1 to 1 : 134,35.
In both sexes, the anogenital area is a ected in at least 85% o
patients. However, the best epidemiologic studies concentrate on vulvar
disease. Since lichen sclerosus o non-genital skin requently causes no
symptoms, it is likely that the prevalence o extragenital lichen sclero-
sus is underestimated.
Prospective and retrospective studies in adult patients suggest that
lichen sclerosus is one o the most common causes o symptomatic
vulvar disease. In two large series, lichen sclerosus was diagnosed in
13% to 19% o patients36 presenting with symptomatic vulvar disease.
In women, the peak incidence is during the f th and sixth decades, and
a second peak occurs in girls between 8 and 13 years o age. Among
prepubertal girls with vulvar disease, the relative requency o lichen
sclerosus is similar to that in adults. Extragenital lichen sclerosus is
rare in children. In boys and men, lichen sclerosus requently leads to
phimosis (seen in 14 o 100 prepubertal boys undergoing circumcision
or phimosis). O 357 male patients attending a dermatology clinic with
genital skin disease, 14% had lichen sclerosus37.
PATHOGENESIS
664 As in most in ammatory diseases, genetic predisposition contributes
to the development o lichen sclerosus, as it may be ound in
monozygotic and raternal twins. In addition, association with the
study38. The existence o a susceptibility gene or sclerosis within this
is associated with an increased risk o autoimmune diseases. Even
though in ammation seems essential or initiation and progression o
lichen sclerosus, the mechanisms leading to subsequent sclerosis
remain speculative.
Perhaps with the exception o autoantibodies against extracellular
been identifed in patients’ sera that clearly correlate with either risk
ound in 80% o patients with lichen sclerosus and the latter may act
as an autoantigen39. Oxidative stress may also play a role in the patho-
genesis o lichen sclerosus, based upon analysis o lesional skin that
showed lipid peroxidation o epidermal basal cell layers, oxidative DNA
damage and oxidative protein damage.
CLINICAL FEATURES
Lichen sclerosus is a disease that can a ect both extragenital skin and
the anogenital region. Lichen sclerosus o the oral cavity, the palms or
soles is rare. In the oral mucosa, bluish white papules up to 5 mm in
diameter may occur on the buccal mucosa or under the tongue. They
can lead to superfcial scar-like atrophy or erosions.
Extragenital lichen sclerosus normally does not cause symptoms
except or dryness and associated pruritus. Lesions avor the trunk
(Fig. 44.12A) and the proximal extremities. More specifc predilection
sites include the neck (Fig. 44.12B), shoulders, exor sur aces o the
wrists, and sites o physical trauma or continuous pressure (e.g. the
shoulder or hip). The periorbital area and scalp are rarely a ected.
It is unusual to see extragenital disease during its early phases when
single lesions begin as polygonal, bluish-white, shiny, slightly elevated,
inter ollicular papules. Over time, these papules o ten enlarge or coa-
lesce into larger plaques. Most patients present with slightly sclerotic,
scar-like papules and plaques that are usually ivory in color and have
a shiny and/or wrinkled sur ace. Occasionally, lesions have a pink or
light violet hue. At sites o continuous pressure, the sur ace may acquire
a parchment-like appearance.
In more advanced stages, telangiectasias or ollicular plugging can be
seen (Fig. 44.13A). The attened inter ace between the epidermis and
dermis results in ragility o the dermal–epidermal junction; as a result,
lichen sclerosus is occasionally complicated by the development o
bullae that tend to become hemorrhagic (Fig. 44.13B).
In women, the vulva and the perianal region are commonly involved,
o ten in a fgure-o -eight confguration (see Ch. 73). Although the
disease may be symptom- ree, it requently causes severe pruritus and
soreness. These symptoms may be considerable and lead to dysuria,
dyspareunia, or pain upon de ecation (o ten mani esting as constipation
in children). Lichen sclerosus o ten begins as a slightly elevated, sharply
demarcated area o erythema, which can be slightly eroded (Fig. 44.14).
Over time, the involved skin becomes shiny, hypopigmented and scle-
rotic, and fssures may develop. Associated scarring can lead to burying
o the clitoris and usion o the labia minora to the labia majora. With
severe disease, loss o the labia minora and signifcant narrowing o the
introitus can occur. Sexual intercourse may become impossible.
Areas o purpura o ten develop within lesions o anogenital lichen
sclerosus and can even aid in clinical diagnosis. However, the hemor-
rhage combined with erosions may be misdiagnosed as sexual abuse.
Care ul examination, perhaps with confrmation o the diagnosis by
histology, is mandatory. The two disorders can coexist and sexual abuse
may (although rarely) trigger the onset o lichen sclerosus as a Koebner
phenomenon. False accusations can be as problematic or traumatic to
the child and amily as overlooking sexual abuse.
In boys and men, acquired phimosis or recurrent balanitis are the
primary presenting eatures, and perianal involvement is very rare.
Itching and soreness are common. On the glans and the inner aspect
o the oreskin, lichen sclerosus starts as sharply demarcated,
sometimes slightly blue–red lesions, occasionally with erosions. This
in ammation tends to evolve into an atrophic white sclerotic scar (Fig.
44.15). The constriction may cause pain on erection and, at advanced
stages, dysuria and urinary obstruction. I the oreskin is a ected,
 CH AP T E R

44 

Morphea and Lichen Sclerosus

A B

Fig. 44.12  Lichen sclerosus. A large shiny, ivory-colored plaque of the lower back (A) and white papules and small plaques on the neck (B). 

Fig. 44.13 
Lichen sclerosus. 
A Follicular plugging in a 
plaque of lichen sclerosus 
on the back of a patient 
with chronic GVHD.  
B Hemorrhagic bullae on 
the leg.  A, Courtesy, Jean L
Bolognia, MD.

A B

Fig. 44.14  Vulvar lichen

sclerosus. Centrally, 
there is erythema with 
super cial erosion and 
purpura. More 
peripherally, white 
plaques with a wrinkled 
surface are seen. Note 
ssuring of the 
perineum. 

Fig. 44.15  Lichen sclerosus of the penis (balanitis xerotic obliterans). Note 

the ivory color, erosion and scarring. 

665
SECTION
lichen sclerosus invariably leads to phimosis (di fculty in retracting the
7 oreskin to uncover the glans), with the additional risk o paraphimosis
RHEUMATOLOGIC DERMATOLOGY
(when a oreskin retracted behind the glans can not be returned to its
original position); the latter represents a urologic emergency. Many boys
and men frst present when the phimosis impairs repositioning o the
oreskin; in these situations, diagnosis depends on histology. Progres-
sive disease can be associated with poorly healing ulcers o the glans.
While circumcision is clearly a frst-line therapy, lichen sclerosus may
recur at the site o a circumcision.
An open question is whether genital lichen sclerosus is a precancer-
ous condition. Interpretation and comparison o the data are compli-
cated by two actors: some o the patients reported as developing cancer
had previously received X-ray therapy or the disease or had previous
dysplasia due to human papillomavirus (HPV) in ection. It is there ore
very di fcult to establish a use ul meta-analysis. Most data suggest that
lichen sclerosus is not intrinsically precancerous, but that it has to be
considered as a chronic scar continuously exposed to a humid milieu,
where carcinogenesis may be promoted34,35.
PATHOLOGY
Lichen sclerosus has a specifc histologic pattern. Initially, superfcial
dermal edema is associated with a band-like lymphocytic infltrate (Fig.
44.16A). The epidermis is thinned, with orthohyperkeratosis and
A based on a single observation or those that require more substantial
B least 60% o patients45 (Fig. 44.17). Further advantages o phototherapy,
Fig. 44.16  Lichen sclerosus – histologic features. A Early lesion with band-like  and long periods o remission47.
in ltrate of lymphocytes in the upper dermis and vacuolar change at the 
dermal–epidermal junction. Mild homogenization of the papillary dermis is  Both photochemotherapy and UVA1 induce expression o matrix
present. B Late lesion with orthohyperkeratosis, thinning of the epidermis and  metalloproteinase 1, a collagenase that reduces procollagen and colla-
homogenization of the upper dermis. There is also hyalinization and sclerosis  gen within the skin. The regression o morphea can be objectively
666 of the papillary dermis, telangiectasias and an interstitial lymphocytic in ltrate.  documented by measuring skin thickness and skin density by 20 MHz
Courtesy, Lorenzo Cerroni, MD.
vacuolar degeneration o the basal layer. Hyperkeratosis is especially
pronounced at ollicular openings and may lead to plugging. The vacu-
olar degeneration at the dermal–epidermal inter ace and the attening
o the rete ridges predisposes to the development o blisters, which may
become hemorrhagic. The most important changes are ound in the
superfcial dermis, where the pale staining re ects homogenized dermal
collagen (Fig. 44.16B) or edema (early stage). Loss o elastic fbers is
typical or lichen sclerosus but is not observed in morphea. Cle ting
and hemorrhage within the homogenized papillary dermis is o ten seen.
During the early phases, the in ammatory infltrate is especially
pronounced along the zone o hyalinization and consists o lymphocytes
(CD3+, CD4+, CD8+), macrophages and mast cells. In older lesions, the
mononuclear infltrate is reduced and sparse, and patchy islands o
mononuclear cells are dispersed within the hyalinized dermis.
Ultrastructural studies reveal shortened collagen fbers.
DIFFERENTIAL DIAGNOSIS
The most important entity in the di erential diagnosis o extragenital
lichen sclerosus is morphea, and or genital lichen sclerosus in girls
and boys, it is sexual abuse 40. In adults, genital lichen sclerosus may
mimic erythroplasia o Queyrat or erosive lichen planus (see Ch. 73).
Distinction o ten requires histologic examination. Biopsies may also be
needed to exclude malignant trans ormation, especially when there is
a superimposed in ection with potentially carcinogenic HPV-16 or
HPV-18. Histologically, lichen sclerosus-associated pseudoepithelioma-
tous hyperplasia has to be distinguished rom squamous cell carcinoma
(SCC). A past history o allogeneic hematopoietic stem cell transplant
points to chronic GVHD.
TREATMENT OF MORPHEA AND
LICHEN SCLEROSUS
Various therapeutic modalities have been reported or lichen sclerosus
and morphea (Table 44.2). Most reports are based on single or limited
observations or, occasionally, larger numbers o patients but without
controls. Well-designed, randomized controlled trials are rare.
Meta-analysis o the literature suggests that some treatments are well
established and e ective in a majority o patients while others seem to
be e ective in only a small number o patients. Well-established treat-
ment options should not be con used with therapeutic suggestions
investigation.
A major problem has been the lack o standardized outcome mea-
sures or assessing the e fcacy o various therapies or morphea and
lichen sclerosus. However, there has been a recent attempt to devise a
reproducible severity index score or morphea41. In addition, 20 MHz
ultrasound measurements o individual plaques (pre- and post-therapy)
can prove help ul.
Phototherapies
Phototherapy or morphea was frst described in 1994 42, and since then,
the e fcacy has been confrmed by more than 30 publications 43,44. Due
to the nature o phototherapy, placebo-controlled studies can not be
per ormed. Nonetheless, little doubt exists as to the e fcacy o this
therapy, as untreated morphea normally progresses over 3–5 years and
then regresses very slowly over years. More rapid spontaneous improve-
ment only occurs in a small minority o patients2. The clinical course
is defnitely di erent in patients receiving either bath PUVA therapy or
UVA1. I 30–36 treatments o bath PUVA therapy (at slightly sub-
erythematous doses) or 30–36 treatments o UVA1 (30–60 J/cm2) are
given, morphea either completely resolves or markedly improves in at
and especially UVA1, include clinical improvement in all skin types46
ultrasound (Fig. 44.18) or by histology44,48,49. Both phototherapies seem
 CH AP T E R

TREATMENT OF MORPHEA AND LICHEN SCLEROSUS 44 

Morphea and Lichen Sclerosus

Treatment modalities Morphea Lichen sclerosus

E cacy Level of evidence E cacy Level of evidence

Local Topical corticosteroids + 3 +++ (ultrapotent) 1
Intralesional corticosteroids + 3 ++ 2
Topical calcineurin inhibitors + (early lesions) 2 ++ 2
Vitamin A analogues + 3 + 2
Vitamin D analogues + 3 + 3
Testosterone No experience 0 1
Progesterone No experience 0 1
Intralesional interferon-γ 0 1 No experience

Systemic Penicillin ++ (approx. 5% of patients) 3 No experience

Hydroxy-/chloroquine No experience + 3
Corticosteroids + 3 + 3
Vitamin A analogues * + 3 ++ 1
Vitamin D analogues 0 1 + 3
Cyclosporine 0 3 No experience
Penicillamine ++ 3 No experience
Methotrexate ++ 2 No experience
Phototherapy Oral photochemotherapy ++ 3 + 3
Bath photochemotherapy +++ 2 ++ 3
Cream photochemotherapy ++ 3 + 3
UVA1 +++ 2 ++ 2
Photodynamic therapy + 3 ++ 3
Extracorporeal photopheresis + 3 No experience
Others CO2 laser No experience ++ 3
Surgery Selected patients Selected patients
Physical therapy Important – –
*e.g. acetretin.

Table 44.2  Treatment of morphea and lichen sclerosus. +++, Highly e ective; ++, e ective; +, moderately e ective; 0, low e cacy or ine ective. 1, prospective 
controlled trial; 2, retrospective study or large case series; 3, small case series or individual case reports.

Fig. 44.17 
Another open question is the ideal dose or UVA1 therapy. Most
Phototherapy of
morphea. Disseminated  initial studies were per ormed with either low (20 J/cm 2) or medium
morphea on the trunk  doses (30–70 J/cm2) o UVA1 and reported similar e fcacy. A recent
before (A) and after  study that utilized 20 MHz ultrasound rather than clinical assessment
PUVA bath  o morphea lesions reported a better response (a ter 30 treatments) with
photochemotherapy (B).  medium-dose (70 J/cm2) than with low-dose (20 J/cm 2) UVA148. In
agreement with these reports, we have observed that 36 treatments
with 30 J/cm2 o UVA1 markedly improved morphea in the majority o
patients45. Importantly, in responding patients, lesions o morphea
continue to improve beyond the end o the therapy. Thus, therapy can
be terminated a ter 36 treatments, even i the sclerosis has not yet
A completely resolved. The only exception appears to be linear morphea,
which may require signifcantly more treatments. In our experience,
selected patients who ail to respond to one mode o phototherapy may
beneft rom a switch to the other, i.e. i a patient does not improve
within 4 months with one type o phototherapy (e.g. bath PUVA), a
new therapy cycle should be initiated utilizing another mode o photo-
therapy (e.g. UVA1). Patients may also beneft rom phototherapy plus
low-dose systemic retinoids as this combination has led to improve-
ment o sclerodermoid GVHD and plaque-type morphea 16,52.
Much less experience exists with regard to phototherapy or lichen
sclerosus. Based upon observations in a small number o patients with
extragenital lichen sclerosus, bath or cream PUVA therapy or UVA1
therapy may improve lesions in some selected patients; similar results
have been reported or genital lichen sclerosus. For example, a prelimi-
B
nary study reported clinical improvement in 10 patients with extrageni-
tal lichen sclerosus ollowing 40 treatments with low-dose UVA1 (20 J/
cm2)53. Based upon our experience with extragenital lichen sclerosus,
phototherapy seems less e ective than in morphea. More detailed
studies are required and phototherapy may be an alternative or selected
to be e ective in all types o morphea except or morphea pro unda. patients with extensive lichen sclerosus who respond poorly to topical
There is less experience with extensive linear or pansclerotic morphea, corticosteroids and/or calcineurin inhibitors.
but these subtypes may also improve with either mode o photother- There are no consistent results rom the use o extracorporeal pho-
apy50. In the case o photochemotherapy, it has been administered tophoresis. The associated costs and the invasiveness are very high,
primarily as bath PUVA therapy16,51 ( ew reports exist on the use o and the e fcacy o UVA1 or photochemotherapy clearly appears to be 667
cream PUVA or systemic PUVA50). superior. Although preliminary data rom a prospective study o
SECTION
7 morphea plaque. Before (A) and after PUVA bath
RHEUMATOLOGIC DERMATOLOGY
A B
A B
photodynamic therapy or vulvar lichen sclerosus pointed to signifcant
relie o symptoms, similar results were not observed in more recent
studies.
Topical Therapies
Corticosteroids
Retrospective and prospective studies have clearly documented that
ultrapotent topical corticosteroids are highly e ective in the treatment
o genital lichen sclerosus. In the majority o these studies, clobetasol
propionate 0.05% cream was applied or 12–24 weeks54. Clinical
improvement was confrmed by histopathology. Both sa ety and e fcacy
o clobetasol in the treatment o genital lichen sclerosus were docu-
mented or all age groups and in both sexes. Nearly all the patients
with vulvar lichen sclerosus responded to ultrapotent topical cortico-
steroids, and amongst those who improved, about 20% experienced
complete clearance 55. However, topical corticosteroids do not cure the
disease and relapses may occur.
Major side e ects were not reported, even with long-term and main-
tenance use o clobetasol. There ore, potent topical corticosteroids rep-
resent frst-line therapy or genital lichen sclerosus, including in
children (Fig. 44.19). Alternatively, corticosteroids such as triamcin-
olone can be injected intralesionally. O note, vulvar SCC appeared to
develop primarily in untreated or irregularly treated lesions o vulvar
lichen sclerosus.
668 The beneft o topical corticosteroids in the treatment o morphea is
questionable. Ultrapotent topical corticosteroids may be use ul or
Fig. 44.18  High-frequency ultrasound (20 MHz) of a
 
photochemotherapy (B), showing reduction of 
corium thickness and hyperechoic bands of 
connective tissue. 
Fig. 44.19  Ultrapotent topical corticosteroids in the
treatment of lichen sclerosus in a 12-year-old girl. 
Before (A) and after topical application of clobetasol 
propionate 0.05% cream daily for 5 months (B). 
reducing in ammation in superfcial active lesions. Similarly, intrale-
sional injection o triamcinolone into the margins may reduce or
prevent progression. Topical corticosteroids are ine ective in resolving
sclerosis.
Calcineurin inhibitors
The macrolide immunosuppressants pimecrolimus (1% cream) and
tacrolimus (0.1% ointment) have been used as topical treatments or
vulvar lichen sclerosus. Several case reports and initial trials involving
limited numbers o patients suggest that these therapies are e ective56.
Concerns have been raised as to the possibility o increasing the risk
o developing SCC or reactivating HPV ollowing the use o topical
calcineurin inhibitors or vulvar lichen sclerosus. Long-term sa ety and
e fcacy studies as well as randomized trials comparing these agents
with clobetasol are needed. With regard to morphea, improvement ol-
lowing topical tacrolimus (0.1% ointment) has been reported in case
series, especially in patients with early in ammatory lesions57,58. Again,
prospective, double-blind, randomized trials are needed.
Vitamin derivatives
Derivatives o vitamin D and vitamin A are still under study in
morphea. In vitro, calcipotriol inhibits the proli eration o cultured
fbroblasts and topical calcipotriene (0.005% ointment) has been used
or the treatment o morphea59. Single reports have described improve-
ment o both vulvar lichen sclerosus and morphea when treated with
topical vitamin A derivatives. All o these observations require confr-
mation by controlled studies.
 CH AP T E R
Hormones Vitamin derivatives
For years, topical testosterone or progesterone preparations were re- Treatment with the oral vitamin A derivatives etretinate or acitretin at
44 

Morphea and Lichen Sclerosus

quently used or the treatment o genital lichen sclerosus. In sharp
contrast to ultrapotent topical corticosteroids, there is no evidence to
support the e fcacy o these agents. Controlled clinical studies have
clearly shown that hormone preparations have no clinical beneft in
lichen sclerosus60. In one study, 2% testosterone propionate was even
less e ective than petrolatum ointment61.
Systemic Treatments
Immunosuppression
Oral corticosteroids (methylprednisolone or prednisone 1–2 mg/kg/day)
may be help ul during the in ammatory stages o morphea, especially
in those patients with rapidly progressive linear or disabling morphea.
However, systemic corticosteroids do not improve established sclerosis
and disease activity may rebound ollowing discontinuation.
Alternatively, 15–20 mg/week o methotrexate seems to be help ul in
the acute phase o morphea62. Based on experience with other autoim-
mune diseases, some authors avor the combination o methotrexate
plus corticosteroids, especially in rapidly progressive disabling types o
morphea63. Clinical data rom a prospective pilot study confrmed the
therapeutic e ectiveness o methotrexate (15 mg/week) combined with
pulsed high-dose intravenous methylprednisolone (1 g 3 days per
month)64. Placebo-controlled studies are still lacking, but the potential
beneft documented in systemic sclerosis suggests that this mode o
immunosuppression, administered or several months to up to 1 year,
may be indicated in selected patients with disabling morphea.
In contrast, cyclosporine has not been shown to be e ective.
Furthermore, cyclosporine should not be combined with any orm o
phototherapy.
Although systemic immunosuppression is normally not indicated
or lichen sclerosus, there is a subset o patients with recalcitrant gen-
eralized disease. In a small series o such patients, a combination o
pulsed high-dose intravenous corticosteroids plus low-dose oral meth-
otrexate led to improvement65.
Penicillin and its derivatives
Regression o morphea or systemic sclerosis during prolonged treat-
ment with penicillin or penicillamine has been observed in adults and
in children66. Penicillin in the range o 30 × 106 IU/day or 3–4 weeks
is help ul in about 5% o patients, as documented by several authors.
In addition, the response is reproducible in those individuals who
relapse ollowing previously success ul penicillin regimens. Penicilla-
mine seems to be similarly e ective but is used less o ten because o
its potential side e ects.
In lichen sclerosus, neither penicillin nor other antibiotics nor peni-
cillamine are help ul.
doses o 10–50 mg/day is e ective in morphea and lichen sclerosus67,68.
Importantly, the response can only be assessed a ter several months o
therapy. The exact mechanism by which retinoids improve sclerosis is
unclear. However, in cultured scleroderma fbroblasts, retinoids can
induce COX-2 and PGE2 while inhibiting the profbrotic actor CTGF
and collagen production (types I and III)69. Moreover, retinoids interact
with TGF-β signaling, one o the key cytokine pathways or promoting
collagen synthesis by fbroblasts (see Fig. 44.1). Retinoids (e.g. etreti-
nate, isotretinoin) are also e ective in certain pseudoscleroderma dis-
orders such as “sclerodermoid” GVHD15,16.
The other vitamin derivative investigated or the treatment o
morphea is calcitriol. 1,25-Dihydroxyvitamin D3 has pronounced anti-
in ammatory e ects, and it modulates fbroblast growth as well as
TGF-β70. Despite promising case reports, a double-blind, placebo-
controlled study did not confrm the clinical e fcacy o oral calcitriol
in morphea71.
Cytokines, TNF-α inhibitors, multi-kinase inhibitors
As IFN-γ and IFN-α normalize pathogenic collagen production by
fbroblasts in vitro, both cytokines have been tested or the treatment
o morphea. However, in controlled studies, neither cytokine reversed
cutaneous sclerosis17. Whether TNF-α has a pathogenic role in morphea
and systemic sclerosis is unclear. In a pilot study o patients with sys-
temic sclerosis, in iximab did not improve skin sclerosis72.
The signaling pathways o growth actors such as TGF-β and PDGF,
which play a role in generating cutaneous sclerosis, represent potential
therapeutic targets. Imatinib is an example o a multi-kinase inhibitor
that can inhibit the PDGF receptor (hence its e ect on dermatofbro-
sarcoma protuberans). In case series, systemic administration o ima-
tinib reduced skin sclerosis in patients with systemic sclerosis22,73.
Surgery
In the case o persistent contractures, reconstructive surgery may be
needed. Similarly, surgical revision may be required in linear or en coup
de sabre morphea. Autologous at transplantation has been used suc-
cess ully or the latter as well as or Parry–Romberg syndrome.
Circumcision is the treatment o choice or genital lichen sclerosus
complicated by phimosis or paraphimosis.
Physical Therapy
Expert and longstanding physiotherapy is obligatory or patients in
whom morphea threatens to impair mobility.

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