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Lupus Er Ythematosus: Epidemiology
Lupus Er Ythematosus: Epidemiology
Lupus Er Ythematosus: Epidemiology
Lupus Erythematosus 41
Lela A Lee and Victoria P Werth
EPIDEMIOLOGY
Systemic lupus erythematosus (SLE) is a common disease with signif-
Key features cant morbidity and mortality. The strongest actor a ecting risk or
There are several variants o cutaneous lupus, de ned in part by lupus is gender: women with systemic lupus outnumber men by at least
the location and depth o the infammatory in ltrate 6 to 113. Since lupus occurs most commonly in women during their
Acute cutaneous lupus involves primarily the epidermis and upper childbearing years, it is likely that hormonal actors in uence suscep-
dermis and is usually associated with systemic disease tibility to lupus. Consistent with the importance o sex steroids in the
Subacute cutaneous lupus involves primarily the epidermis and expression o disease, lupus is rare in prepubertal children. With regard
upper dermis and is associated with anti-Ro/SSA autoantibodies to patients who have only cutaneous lesions, there appears to be a
and photosensitivity; the majority o patients do not have somewhat lower emale-to-male ratio (perhaps 3 : 1) but there is still a
signi cant systemic disease emale predominance.
Ethnicity is also a major risk actor, and its e ect in some populations
Discoid lesions o lupus involve the epidermis, upper and lower is almost as strong as that o gender. For example, the prevalence o
dermis, and adnexal structures, and they can scar; the majority o SLE is our old higher in A rican-American women as compared to
patients do not have signi cant systemic disease Caucasian American women (4 in 1000 vs 1 in 1000)13. In addition,
Lupus erythematosus tumidus involves the dermis but there is no A rican-Americans tend to develop disease at an earlier age and have a
prominent epidermal or adnexal involvement higher mortality rate. A long-term study o a multi-ethnic cohort o
Lupus panniculitis involves the subcutaneous tissue and may 587 SLE patients rom Texas, Alabama and Puerto Rico ound that
result in dis guring depressed scars 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
INTRODUCTION sometimes even a problem with data rom within the same country,
Lupus erythematosus is a multisystem disorder that prominently due in part to di erences in case identifcation and validation (reviewed
a ects the skin. Cutaneous lesions are a source o disability and, on in re . 15). It is likely that Caucasian populations in Europe have a
many occasions, an indicator o internal disease. 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
HISTORY study rom a single county in Minnesota indicated that the incidence
The term “lupus erythemateaux” was frst used by Cazenave in the o cutaneous LE, excluding patients who also had SLE, was similar to
mid-1800s1. Cazenave and others helped to articulate the di erence the incidence o SLE15.
between lupus erythematosus (LE) and lupus vulgaris, a clinical variant
o cutaneous tuberculosis. Due in part to observations o Hutchinson, PATHOGENESIS
Osler and Jadassohn, it was recognized that cutaneous lesions o LE
may be associated with signifcant internal abnormalities, including The pathogenesis o cutaneous LE is complex, and it involves an inter-
arthritis, nephritis, serositis, cytopenias and neurologic disease. In action between genetic and environmental actors. The latter include
1964 and during the ollowing years, Dubois developed the concept o ultraviolet radiation (UVR), medications, and possibly viruses. This
lupus as a spectrum o disease, ranging rom isolated cutaneous lesions interplay triggers a complex in ammatory cascade o cytokine, chemo-
to li e-threatening, multiorgan disease. Gilliam also developed the kine and in ammatory cell responses that include cells residing within
concept o a spectrum o disease, and, in 1979, he, Sontheimer and as well as recruited to the skin. Overall, the lichenoid tissue reaction,
Thomas described a subset o cutaneous disease, which they termed defned as epidermal basal cell damage and a band-like lymphocytic
“subacute” cutaneous lupus 2. The description was virtually identical to infltrate in the upper dermis, characterizes most subsets o cutaneous
that o “ANA-negative” lupus (see Ch. 40), reported by Maddison, LE. It involves activation o keratinocytes, endothelial cells and skin
Provost and Reichlin in 19813. dendritic cells plus the production o type I inter erons (IFNs), ollowed
Important diagnostic advances included discovery o the LE cell phe- by the recruitment and activation o CD4+ and CD8+ cytotoxic T cells.
nomenon by Hargraves, Richmond and Morton in 19484; the ANA by The end result is cytotoxic keratinocyte damage.
Friou in 19575; the lupus band by Burnham, Neblett and Fine in 19636; Genes that can a ect overall immunoreactivity include those whose
and the association o specifc clinical mani estations o lupus with protein products are involved in B- and T-cell unction, innate immu-
specifc autoantibodies by a variety o investigators7–9. With regard to nity, immune complex clearance, apoptosis, ubiquitination, DNA
skin disease, the associations o anti-Ro (also known as anti-SSA) methylation or cellular adhesion16. Examples rom all these gene
autoantibodies with neonatal lupus by Weston et al. in 198110 and with classes, in addition to genes with unknown unction, have been impli-
subacute cutaneous lupus (SCLE) by Sontheimer et al. in 198211 are cated in some way in human or animal models o SLE (Table 41.1; see
noteworthy milestones. Ch. 4).
Antimalarial therapy in the orm o quinine was used or cutaneous Both genetic background based upon ancestry and mutations in spe- 615
lupus by Payne in 189412. By the late 1950s, synthetic antimalarials 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), system, ollowing immune complex ormation.
as well as C2 and C4 defciencies18. Genes previously associated with Both ultraviolet B (UVB) and ultraviolet A radiation have been impli-
SLE, e.g. TYK2, IRF5 and CTLA4, also con er an increased risk or cated in exacerbation o cutaneous LE, although UVB is a more e fcient
developing DLE and SCLE19, while mutations in TREX1, which encodes cause o photo-induced changes in the skin23. UVR induces apoptosis,
a DNA exonuclease, are associated with amilial chilblain lupus20. In which leads to translocation o cellular and nuclear antigens 24, and
the latter patients, dys unction o the exonuclease leads to an accumu- there may also be a reduction in the clearance o apoptotic cells 25. In
lation o IFN-stimulatory nucleic acids. addition, UVR increases keratinocyte production o Ro5226.
Autoantibodies clearly play a role in SCLE and neonatal lupus, where A number o proin ammatory cytokines, including tumor necrosis
anti-Ro (more specifcally, anti-Ro60 and anti-Ro52) and anti-La actor (TNF)-α, interleukin (IL)-1, HMGB1 (high-mobility group box
autoantibodies are requently observed (see Ch. 40); in the case o 1), and IL-1827–29, are induced by UVR. Following UV irradiation o
neonatal lupus, these antibodies are transmitted transplacentally. keratinocytes, a complex array o chemokines, including chemokine
Blocking the unction o either Ro60 or Ro52 presumably predisposes (C-C moti ) ligand 5 (CCL5), CCL20, CCL22, and chemokine (C-X-C
one to these diseases. O note, Ro60 plays an important role in cell moti ) ligand 8 (CXCL8), is produced. O note, there is an increase in
survival ollowing UVR, possibly via binding to mis olded non-coding these chemokines within lesions o cutaneous LE, likely leading to
RNAs and targeting them or degradation, and mice which lack Ro60 leukocyte recruitment to the skin30. These e ects require adhesion
develop a lupus-like syndrome21. Ro52 has a known regulatory role in molecules, with activation o endothelial cells (increased expression o
in ammation, targeting both inter eron regulatory actor 3 (IRF3) ICAM-1, VCAM-1 and E-selectin) and induction o ICAM-1 on basal
and IRF8 or degradation22; thus, antibodies to Ro52 may be keratinocytes (Fig. 41.1A)31,32.
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.
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
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 O the various orms o chronic cutaneous LE, discoid lesions (o ten
observed. Dyspigmentation is to be expected in longstanding lesions, re erred to as DLE) are the most common (see Table 41.2). Patients
typically with hypopigmentation in the central area and hyperpigmen- with only discoid lesions may have associated arthralgias, but, over
tation at the periphery (Fig. 41.5), but sometimes with vitiligo-like time, only 5–15% o these patients eventually develop clear-cut
depigmentation. Rarely, squamous cell carcinoma develops in a long- SLE44–46a. The risk may be higher in patients with widespread (dissemi- 619
standing discoid lesion. 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) In some instances, lesions o SCLE have appeared in patients receiv-
7 and can be a common presenting mani estation o SLE. ing certain medications, in particular hydrochlorothiazide and terbin-
RHEUMATOLOGIC DERMATOLOGY
An unusual variant o DLE is hypertrophic DLE, characterized by afne, but also calcium channel blockers, nonsteroidal anti-in ammatory
thick scaling overlying the discoid lesion or occurring at the periphery drugs (e.g. naproxen), griseo ulvin and antihistamines. The lesions may
o the discoid lesion. The intensely hyperkeratotic lesions are o ten or may not clear once the medication is discontinued.
prominent on the extensor arms (see Fig. 41.4H), but the ace and upper The long-term prognosis o patients who have SCLE is not com-
trunk may also be involved. Frequently, there are typical discoid lesions pletely known, largely because this subset o cutaneous LE only recently
present in other locations. has been widely recognized. It is clear that a certain percentage o
patients, perhaps 10–15%, will over time develop signifcant internal
Subacute cutaneous lupus erythematosus disease, including nephritis 44. Since anti-Ro autoantibodies are associ-
SCLE is typically photosensitive, with lesions confned to sun-exposed ated with Sjögren’s syndrome as well as SCLE, it is not surprising that
skin. It is notable that the mid acial skin is usually spared, while the some patients have eatures o both conditions, and some may have
sides o the ace, upper trunk and extensor aspects o the upper extremi- serious internal mani estations o Sjögren’s syndrome such as pulmo-
ties are commonly involved (Fig. 41.6; see Fig. 41.3)47. In some patients, nary or neurologic disease.
the disease may be mild, with only a ew small scaly patches appearing An important eature o SCLE, rom the standpoint o understanding
a ter sun exposure. the pathogenesis o lupus, is its regular association with the anti-Ro
Lesions o SCLE may have an annular confguration, with raised red autoantibody (see Ch. 40). Although investigators di er in their opin-
borders and central clearing (Fig. 41.7), or a papulosquamous presenta- ions as to the prevalence o anti-Ro in SCLE, it is likely that a
tion with an eczematous or psoriasi orm appearance. SCLE lesions substantial majority o patients with this condition (approximately
characteristically have a relatively sparse, superfcial in ammatory 70% in a large series, reported range o 60–100%) have anti-Ro
infltrate, and, consequently, there is usually no induration. Lesions antibody47,48.
o ten result in dyspigmentation, particularly hypopigmentation or even
depigmentation, but do not scar. 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. 41.5 Discoid lupus lesions with
dyspigmentation and scarring
alopecia. Hypopigmentation o ten
develops centrally with
hyperpigmentation at the periphery. Fig. 41.6 Subacute
Courtesy, Joyce Rico, MD.
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.
620 A B
CH AP T E R
antibodies and lupus nephritis has been proposed and is plausible44, same as the “urticarial plaques” described in lupus patients. However,
although some patients with a malar rash have neither anti-dsDNA these fxed plaques should not be con used with urticarial vasculitis 41
Lupus Erythematosus
antibodies nor lupus nephritis. Patients presenting with this type o (see Ch. 24). Some authors state that the lesions are most common on
eruption must be evaluated care ully or evidence o internal disease. the ace, although they can be quite common on the trunk (Fig. 41.11).
The morphology o the lesions ranges rom mild erythema to intense Morphologically, the lesions are similar to those o Jessner’s lym-
edema. The presence o telangiectasias, erosions, dyspigmentation and phocytic infltrate and may have central clearing (see Ch. 121); some
epidermal atrophy (i.e. poikiloderma) may help to distinguish the malar believe that Jessner’s lymphocytic infltrate and LE tumidus are either
erythema o ACLE rom that o common acial eruptions such as sebor- very closely related or one and the same50.
rheic dermatitis and the vascular type o rosacea. Occasionally, there is Both the very low prevalence o SLE and the relatively low prevalence
a papular component, and occasionally lesions develop scaling (see Fig. o immunoglobulin deposition within the cutaneous lesions in patients
41.8C). The duration may range rom a ew hours to several weeks. reported to have LE tumidus have made it di fcult to determine whether
The ace, particularly the malar area, is most commonly a ected, but LE tumidus is actually a variant o LE or an independent entity.
sometimes lesions may be more widespread in distribution (Fig. 41.9; However, the presence o LE tumidus lesions in patients with other
see Fig. 41.3). When lesions occur on the hands, the knuckles are typi- specifc types o cutaneous LE is evidence in avor o its being classifed
cally spared. It is not unusual or the acute cutaneous eruption to be as a orm o cutaneous LE. LE tumidus has been reported to be repro-
accompanied by oral ulcerations. ducible by phototesting in the majority o patients51. The lesions tend
Rarely, patients with lupus develop an acute eruption clinically to resolve without scarring or atrophy.
similar to toxic epidermal necrolysis or erythema multi orme major
(Fig. 41.10). The presence o erythema multi orme-like lesions in lupus Lupus panniculitis
patients has been termed Rowell’s syndrome49. These lesions may Intense in ammation in the at leads to indurated plaques that can
represent a severe variant o ACLE or, in some cases, SCLE. evolve into disfguring, depressed areas. Lesions o lupus panniculitis
The three major types o cutaneous LE are not mutually exclusive. have a distinctive distribution, occurring predominantly on the ace,
In a given patient, more than one type o cutaneous lesion may occur. upper arms (Fig. 41.12), upper trunk, breasts, buttocks and thighs (see
Fig. 41.3). Some patients have discoid lesions overlying the panniculi-
Cutaneous Lupus – Additional Variants tis, and, in those cases, the condition is sometimes re erred to as
(see Table 41.2) lupus pro undus. For urther discussion o lupus panniculitis, see
Chapter 100.
Lupus erythematosus tumidus
Some patients with cutaneous LE have lesions characterized by indura- Chilblain lupus
tion and erythema but no scale or ollicular plugging. The epidermis Chilblain lupus (SLE pernio; Fig. 41.13) consists o red or dusky purple
appears to be uninvolved in the disease process, although there is an papules and plaques on the toes, fngers, and sometimes the nose,
intense dermal in ammatory infltrate. LE tumidus lesions may be the elbows, knees and lower legs. The lesions are brought on or exacerbated
A B C
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.
7
RHEUMATOLOGIC DERMATOLOGY
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. 41.12 Lupus panniculitis. Erythematous plaque on the upper arm. The Fig. 41.13 Chilblain lupus. Violaceous plaques, some with scale, on toes. I
lesions may resolve with lipoatrophy. there is a amily history o this disorder, the possibility o mutations in TREX1,
which encodes a DNA exonuclease, can be considered.
by cold, particularly moist cold climates. These lesions may represent mortality rate o approximately 20%, and about two-thirds o children
the concurrence o ordinary chilblains with LE (see Ch. 88), although, require pacemakers53.
with time, the lesions may develop a gross and microscopic appearance Hepatobiliary disease and cytopenias, especially thrombocytopenia,
consistent with a discoid lesion. 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
Neonatal lupus erythematosus liver ailure during gestation or in the neonatal period, as conjugated
A neonatal orm o SCLE may occur in in ants whose mothers have hyperbilirubinemia during the frst ew weeks o li e, or with mild eleva-
anti-Ro autoantibodies. In babies who have neonatal lupus erythema- tions o aminotrans erases at 2–3 months o li e.
tosus (NLE), the SCLE-like lesions are histologically identical to those It is common or babies with NLE to exhibit only one o the above
o SCLE in adults, and there is a strong association with anti-Ro anti- clinical mani estations, and thus many children with cutaneous NLE
bodies. Indeed, almost 100% o babies with NLE have anti-Ro antibod- have no other signifcant clinical fndings. However, children who have
ies52. Unlike SCLE in adults, lesions have a predilection or the ace, skin signs o NLE should be evaluated or internal mani estations with
especially the periorbital region and scalp (Fig. 41.14). Photosensitivity a physical examination in addition to an electrocardiogram, complete
is very common in NLE, but sun exposure is not required or lesions blood count, and liver unction tests, when indicated.
to orm, as it is possible or lesions to be present at birth. Neonatal
lupus skin lesions typically resolve without scarring, although dyspig- Other Variants
mentation may persist or many months, and some children have In the clinical setting o lupus, bullous lesions may appear or several
residual telangiectasias. reasons. On occasion, bullous or crusted lesions occur simply as a result
Children who have the cutaneous lesions o NLE may also exhibit o the intensity o the basal cell damage in lesions o ACLE or SCLE
internal mani estations. The major extracutaneous fndings are con- (see Fig. 41.7A) or, possibly, DLE. Rarely, a dramatic, acute eruption
genital heart block (with or without cardiomyopathy), hepatobiliary similar to erythema multi orme major or toxic epidermal necrolysis
disease and thrombocytopenia. The heart block is almost always (TEN) may occur in patients with preexisting ACLE or SCLE, or it may
present by birth, but on rare occasions has developed a ter birth. Clini- appear de novo. Blisters occurring within ACLE and SCLE lesions and
cally signifcant cardiomyopathy occurs concurrently in a small per- erythema multi orme-like and TEN-like cutaneous lupus ft within the
centage o babies who have heart block. Usually, the cardiomyopathy category o lupus-specifc skin lesions.
622 is apparent in the neonatal period, but it is possible or it to become The term bullous eruption o SLE, or bullous SLE, has been used to
apparent only a ter several months have elapsed. Cardiac NLE has a describe a blistering eruption that consists o vesicles and bullae whose
CH AP T E R
histopathology o ten resembles dermatitis herpeti ormis, with a primar- pericarditis, proteinuria, cellular casts in the urine, seizures, psychosis,
ily neutrophilic infltrate and microabscesses within the dermal papillae hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia). 41
(Fig. 41.15)55. In some patients, the clinical and histologic eatures may
Lupus Erythematosus
However, it should be remembered that these systemic eatures have
resemble bullous pemphigoid or epidermolysis bullosa acquisita. been selected as criteria due to their use ulness in distinguishing SLE
Immunoreactants are o ten ound at the basement membrane zone and rom other rheumatic diseases. They are not necessarily the most
antibodies to type VII collagen have been detected in several patients56. common systemic eatures o SLE, and certainly do not represent a
This eruption may represent the concurrence o lupus with an autoim- comprehensive listing o possible organ involvement. Signs and symp-
mune blistering disease due to autoantibodies to a component o the toms such as ever, weight loss, atigue, myalgias and lymphadenopathy
basement membrane zone. There are also a number o case reports o are exceedingly common, i nonspecifc, and may be use ul indicators
other autoimmune bullous diseases appearing in patients with lupus o increased risk or SLE in patients who present with cutaneous lesions.
(reviewed in re . 57). Although ACLE is the cutaneous phenotype with the strongest associa-
A lupus/lichen planus overlap syndrome has been described, in which tion with systemic disease, patients with any type o cutaneous LE may
lesions have eatures o both conditions (see Ch. 11). develop internal involvement.
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.
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.
CH AP T E R
ollicular plugging, deep dermal infltrate, or scarring 61. LE tumidus has authors reserve the term “lupus band” to describe antibody deposits in
prominent dermal mucin deposition and lymphocytic infltrates with normal-appearing skin. It has been proposed that, i this terminology 41
Lupus Erythematosus
a lack o epidermal change. While changes o lupus panniculitis are is used, the investigator should modi y the term “lupus band” by a
most prominent in the subcutis, an overlying discoid lesion can be preceding adjective o “lesional” or “non-lesional”, so that the subject
ound in many cases62. o discussion is clearly identifed37. The antibody and complement
deposits at the dermal–epidermal junction are usually described as
Immunopathology of Lesional Skin granular, although some experienced observers have identifed subtypes
o deposits, variously classifed as fbrillar, thready, stippled, shaggy,
Examination o the skin or deposits o immunoreactants is called
linear, lumpy-bumpy or homogeneous 65.
direct immuno uorescence (DIF). DIF o lesional skin does not replace
Weak, discontinuous deposits may be seen in persons who do not
routine histologic staining as the method o choice or establishing a
have LE, including healthy adults, particularly when chronically sun-
diagnosis o cutaneous LE. DIF is not even necessary as an adjunctive
exposed skin is examined. For this reason, many investigators do not
diagnostic test i the histopathology and clinical presentation are defni-
consider a non-lesional lupus band test to be positive unless the depo-
tive. In those cases where the routine histopathology is equivocal, DIF
sition o immunoreactants is strong and continuous. A true positive
can be a valuable asset in establishing a diagnosis.
non-lesional lupus band test occurs in three-quarters or more o
The most characteristic DIF fnding in cutaneous LE is antibody
patients with SLE i sun-exposed skin is examined, and in about one-
deposition at the dermal–epidermal junction and around hair ollicles6.
hal o patients with SLE i sun-protected skin is examined66. A posi-
These deposits are typically granular, and they are composed primarily
tive non-lesional lupus band test is unlikely to occur in patients who
o IgG and/or IgM (Fig. 41.17), although IgA can also occasionally be
do not have SLE, but there are instances where the non-lesional lupus
seen. In addition, deposits o complement proteins are to be expected.
band test has been positive in patients with other autoimmune
Some investigators have reported that in SCLE, granular deposits o
diseases.
IgG and IgM are observed primarily within the epidermis rather than
In most cases, clinical evaluation and serologic testing or specifc
at the dermal–epidermal junction63. There is evidence that the epider-
autoantibodies provides the required in ormation, and the non-lesional
mal deposits are due to anti-Ro autoantibodies depositing directly
lupus band test is super uous. In cases where the clinical presentation
within the skin64.
or laboratory fndings are atypical, the non-lesional lupus band test may
In ACLE, SCLE and DLE, DIF o lesional skin is positive in the
have diagnostic value.
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 DIFFERENTIAL DIAGNOSIS
requency o positive DIF in LE tumidus. Many reports have noted The di erential diagnosis varies considerably with the subtype o cuta-
nonspecifc fndings. In lupus panniculitis, DIF may show immuno- neous LE under consideration. Some o the major entities in each o
reactants around dermal vessels, but granular deposits at the dermal– the di erential diagnoses are outlined in Table 41.5.
epidermal junction are not uni ormly present. In evaluating a patient with cutaneous lesions, lesional biopsy or
H&E is, in general, the most valuable diagnostic test. An approach to
Immunopathology of Normal-Appearing Skin the diagnosis o cutaneous LE is shown in Figure 41.18. In an occa-
In normal-appearing skin, the presence o antibody deposits at the sional situation, such as that o a patient with known SLE who has
dermal–epidermal junction correlates reasonably well with systemic transient acial lesions that appear to be ACLE, the clinician may orego
disease. The antibody deposits are sometimes re erred to as a “lupus a biopsy because o the high likelihood o obtaining nonspecifc fndings
band”, and examination or them as the “lupus band test”. The termi- and the cosmetic sequela o a scar on the ace. Thus, the diagnostic
nology is con using, because some authors use the term “lupus band” tree presented is not intended to be ollowed strictly or each situation,
to apply to the antibody deposits at the dermal–epidermal junction, but rather is meant as a general overview o the diagnostic approach,
whether the skin tested is normal-appearing or lesional, and other 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
Fig. 41.17 Direct immuno uorescence of cutaneous lupus. Granular deposits that defned the SLE criteria were patients with rheumatoid arthritis.
o IgM are present at the dermal–epidermal junction within lesional skin.
Antibody deposits at the dermal–epidermal junction are the most
There ore, the criteria are especially use ul in distinguishing SLE rom
characteristic immunohistologic nding in lesions o cutaneous lupus and other conditions that a ect joints, and they are quite use ul as a means
normal skin o patients with systemic lupus erythematosus. Courtesy, Janet Fairley, o standardizing patient groups or experimental protocols. However, 625
MD. 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
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.
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- Hydroxychloroquine sul ate is the most commonly chosen antimalarial,
sional triamcinolone, o ten given in a concentration o 4–5 mg/ml, can as it is usually well tolerated. Chloroquine and quinacrine (mepacrine)
be very e ective. The injections may be repeated monthly while the are alternatives. In patients who are not responsive to hydroxychloro-
lesions are active. There are anecdotal reports o the use o new topical quine sul ate, quinacrine may be added to the regimen69a. Quinacrine
immunomodulators (e.g. tacrolimus) or cutaneous lesions. 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
Systemic Therapy 6.5 mg/kg ideal body weight/day, eye toxicity is quite unlikely70. For
Antimalarial therapy has been used or more than a hal -century or chloroquine, the usual dose is 125–250 mg/day, with the eye toxicity- 627
cutaneous LE, and it remains the gold standard or systemic therapy. 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
Dapsone has been used, but usually with little success except in the
LOCAL THERAPY rare subset o bullous eruption o SLE. Both retinoids and thalidomide
Sun protection (2) are potent teratogens, making them di fcult choices in women o
Topical and intralesional corticosteroids (2) childbearing potential. Thalidomide also requently causes a peripheral
Topical calcineurin inhibitors (2) neuropathy. For that reason, some clinicians have advocated giving
Topical retinoids (3) thalidomide in low or intermittent dosing in an attempt to minimize
SYSTEMIC ANTIMALARIAL THERAPY toxicity. In the uture, immune response modifers (such as rituximab,
Hydroxychloroquine (200 mg po qd–bid in adults; up to 6.5 mg/kg ideal body and anti-B-lymphocyte stimulator [BlyS], -IL-6 and -IL-10 antibodies)
weight/day) (2) may play an important role in the treatment o cutaneous LE.
Chloroquine (125–250 po qd in adults; up to 3.5–4 mg/kg ideal body weight/day) In patients with systemic LE but no major organ involvement (i.e.
(2) potentially li e-threatening involvement o visceral organs), treatment
Quinacrine (100 mg po qd) (2) or mild disease includes NSAIDs, while corticosteroids and immuno-
Combination o hydroxychloroquine or chloroquine and quinacrine (2) suppressives (e.g. azathioprine, le unomide, mycophenolate mo etil)
SYSTEMIC THERAPY FOR ANTIMALARIAL RESISTANT CUTANEOUS DISEASE are usually prescribed or moderate to severe disease. When there is a
mild degree o major organ involvement, corticosteroids are the primary
Retinoids (e.g. acitretin, isotretinoin) (2)
Thalidomide (50–100 mg po qd or clearing and, i necessary, 25–50 mg po
treatment, but or moderate to severe involvement, pulse cyclophos-
qd–twice weekly or maintenance) (2) phamide +/− pulse corticosteroids are o ten recommended. Immune
Dapsone (primarily or bullous eruption o SLE) (2) response modifers (biologic therapies) are reserved or re ractory disease
Immunosuppressive agents (e.g. mycophenolate mo etil, azathioprine) (2) (see Table 41.8)72. For a recent more comprehensive review, the reader
Sul asalazine (2) is re erred to re erence 73.
Clo azimine (3)
Systemic corticosteroids (3)
Immune response modi ers (e.g., rituximab, abatacept,* belimumab, anti-IL-6 Ab, Adjunctive Therapy
anti-IL-10 Ab) (3)
*Not more e ective than placebo in non li e-threatening SLE. Sun protection is a vital part o therapy or many patients because the
sun exacerbates or initiates their skin lesions. For others, sun protec-
Table 41.8 Therapy of cutaneous lupus. Key to evidence-based support: tion is important or cancer prevention, particularly in hypopigmented
(1) prospective controlled trial; (2) retrospective study or large case series; skin or in chronic discoid lesions, where the risk o skin cancer develop-
(3) small case series or individual case reports. bid, twice daily; qd, daily. 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
day70. Quinacrine is thought by most not to cause eye toxicity. For be emphasized, even in persons whose skin lesions are not induced or
patients on hydroxychloroquine sul ate or chloroquine, eye examina- exacerbated by sun exposure.
tions should be done by a physician knowledgeable in antimalarial eye Sunscreens should be applied to exposed skin daily, and more o ten
toxicity. i sun sensitivity is great or sun exposure is intense or prolonged. Broad-
The response to antimalarials is relatively slow. It may take 2 or 3 spectrum, high-SPF sunscreens are pre erred (see Ch. 132). In some
months or e fcacy to be appreciated, and sometimes several more cases, the addition o a physical sunblock such as titanium dioxide or
months to achieve maximal e fcacy. Consequently, or patients who zinc oxide is use ul. Protective clothing is important to emphasize, as
are beginning therapy or cutaneous LE, topical or intralesional therapy the proper protective clothing is o ten signifcantly more e ective than
should usually be given along with antimalarial therapy. It has been sunscreens. Sun avoidance is even more e ective than protective chem-
observed that there is a larger than expected percentage o cigarette icals and clothing. Midday sun is particularly high in UVB, a spectrum
smokers among patients who present with cutaneous lupus, and that o UV radiation to which many patients are susceptible. It is more di -
smokers may have more extensive cutaneous disease. It has also been fcult to minimize UVA exposure, as UVA is present in substantial
observed that smokers do not respond as well to antimalarial therapy quantities throughout the day and can penetrate some types o window
as do non-smokers. Thus, smoking cessation may be a use ul adjunc- glass. Education on the optimal use o sunscreens and protective cloth-
tive therapy in some individuals. ing and e ective approaches to sun avoidance is important or most
Some patients do not respond either to single antimalarial therapy patients with lupus. Care ul attention should be given to vitamin D
or to the combination o quinacrine with either hydroxychloroquine and calcium intake.
sul ate or chloroquine. Disease that is re ractory to antimalarials For some patients, cosmetic cover-up is the most help ul therapeutic
is o ten re ractory to other therapies as well. Nonetheless, it is reason- intervention (see Ch. 153). Particularly in situations where the disease
able to seek a therapy that will work well, i the risks o therapy are activity has subsided but dyspigmentation remains, cosmetic camou-
deemed to be worth the potential benefts. In antimalarial-resistant age o the hyperpigmentation or hypopigmentation may be the best
patients, therapeutic options include oral retinoids, thalidomide, approach.
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1999;113:196–201. and their relationship to prognosis in discoid lupus erythematosus. Arthritis Rheum. 1982;25:1271–7.
28. Wang D, Drenker M, Eiz-Vesper B, et al. Evidence or a erythematosus: a long-term ollow-up study o 92 69. Updating the American College o Rheumatology
pathogenetic role o interleukin-18 in cutaneous lupus patients. Arch Dermatol. 1979;115:1055–8. revised criteria or the classi cation o systemic lupus
erythematosus. Arthritis Rheum. 2008;58:3205–15. 46a. Grönhagen CM, Fored CM, Granath F, Nyberg F. erythematosus. American College o Rheumatology
29. Popovic K, Ek M, Espinosa A, et al. Increased expression Cutaneous lupus erythematosus and the association website. http://www.rheumatology.org/publications/
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group box chromosomal protein 1 in skin lesions o cohort o 1088 patients in Sweden. Br J Dermatol. 69a. Chang AY, Piette EW, Foering KP, et al. Response to
patients with lupus erthematosus. Arthritis Rheum. 2011;164:1335–41. antimalarial agents in cutaneous lupus erythematosus: A
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radiation-induced injury, chemokines, and leukocyte 48. Lee LA, Roberts CM, Frank MB, et al. The autoantibody 70. Ochsendor FR. Antimalarials. In: Kuhn A, Lehmann P,
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RHEUMATOLOGIC DERMATOLOGY SECTION 7
Dermatomyositis 42
Joseph L Jorizzo and Ruth Ann Vleugels
Cutaneous Disease
The most important diagnostic eature o the cutaneous eruption
o dermatomyositis is poikiloderma. This eature occurs both in PATHOGENESIS OF DERMATOMYOSITIS
patients with dermatomyositis, where it is characterized by a pink–
violet color, and in patients with lupus erythematosus, where the GENETICS13–15
poikiloderma is red. Poikiloderma includes eatures o hyperpigmenta- • Monozygotic twins a ected
tion, hypopigmentation, telangiectasias and epidermal atrophy, and • Associated human leukocyte antigens (HLA)
these eatures are common to both diseases. I the clinician misses the – HLA-DR3 and -B8 (juvenile dermatomyositis)
poikiloderma, the eruption o dermatomyositis may occasionally be – HLA-DR52 (patients with anti-Jo-1 antibodies)
misdiagnosed as psoriasis because some lesions can present as well- – HLA-DR7 and -DRw53 (patients with anti-Mi-2 antibodies)
marginated plaques on the elbows and knees and be covered with ne – HLA-B14 and -B40 (adults with dermatomyositis overlap)
silvery scale. – HLA-DRB1*15021 (Japanese with juvenile dermatomyositis)
Additional clinical clues to the diagnosis o dermatomyositis are a • TNF-α 308A allele polymorphism
photodistribution and nail old changes. Photodistributed poikiloderma CELLULAR IMMUNITY/APOPTOSIS16–22
involving the “V” o the chest and the upper back is o ten re erred to • Histopathologic ndings in skin and muscle (CD8+ lymphocytes)
as the “shawl sign”. Cuticular dystrophy (i.e. “ragged” cuticles) is quite • 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
REVISED CLASSIFICATION SYSTEM FOR THE IDIOPATHIC INFLAMMATORY • Elevated expression of COX-1, COX-2 and 5-LOX mRNA in a ected muscle
DERMATOMYOPATHIES tissues
HUMORAL IMMUNITY23
Dermatomyositis
Adult-onset • Association with autoimmune diseases (Hashimoto’s thyroiditis, Graves’ disease,
Classic DM myasthenia gravis, type I diabetes mellitus, primary biliary cirrhosis, dermatitis
Classic DM with malignancy herpetiformis, vitiligo, and other autoimmune connective tissue diseases)
Classic DM as part of an overlapping connective tissue disorder • Myositis-speci c antibodies versus antibodies against aminoacyl-tRNA
Clinically amyopathic DM* synthetases, non-synthetases, cytoplasmic antigens, and nuclear antigens.
Examples include: antisynthetase, anti-Jo-1 (lung disease) and anti-Mi-2 (most
Amyopathic DM
speci c for dermatomyositis)
Hypomyopathic DM
Juvenile-onset INFECTIOUS PRECIPITANTS24,25
Classic DM • Seasonal variation
Clinically amyopathic DM • Picornavirus substrate for aminoacyl-tRNA synthetases
Amyopathic DM • Escherichia coli, muscle protein and a capsid protein of a picornavirus that
Hypomyopathic DM induces mouse myositis all have some homology in amino acid sequences with
Polymyositis Jo-1
Isolated polymyositis • Echovirus infection in patients with hypogammaglobulinemia
Polymyositis as part of an overlapping connective tissue disorder • Coxsackievirus-9 myositis
Polymyositis associated with internal malignancy (?) † • AIDS myositis
Inclusion body myositis
DRUG AND VACCINE PRECIPITANTS26–31
*Both adult-onset and juvenile-onset amyopathic DM and hypomyopathic DM can be
further subcategorized as “provisional” and “con rmed” when patients have biopsy- • Hydroxyurea, D-penicillamine, TNF-α inhibitors, nonsteroidal anti-in ammatory
con rmed hallmark cutaneous manifestations of DM without muscle weakness and with drugs, lipid-lowering drugs (statins > gem brozil), cyclophosphamide, BCG
normal muscle enzymes for ≥6 months (provisional) or 24 months (con rmed). vaccine; single case reports of phenytoin, alfuzosin (α-agonist for BPH),
† 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 articaine, sulfacetamide sodium ophthalmic drops
have questioned whether such a relationship exists for polymyositis.
MALIGNANCY ASSOCIATION (ADULTS) 32,33
Table 42.1 Revised classi cation system for the idiopathic in ammatory Table 42.3 Pathogenesis of dermatomyositis. BCG, Bacillus Calmette-Guérin;
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
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
Dermatomyositis
Autoantibodies Target antigen function Clinical phenotype Autoantibody frequency, %
Adult DM Juvenile DM
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
Fig. 42.1 Dermatomyositis cuticular dystrophy and nail fold common cutaneous ndings would be signs o overlap with systemic
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. 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
or lupus erythematosus and does not include dermatomyositis in the cutaneous mani estations o dermatomyositis but no muscle disease.
di erential diagnosis. Care ul patient evaluation and longitudinal assessment will demon-
The eatures that are most characteristic, and that distinguish der- strate that some o these patients have skin disease alone (amyopathic
matomyositis rom lupus erythematosus, are the violaceous hue o dermatomyositis) while others eventually evolve into ull-blown der-
the poikiloderma and the tendency o lesions to be distributed around matomyositis (with muscle disease) or they develop hypomyopathic
the eyes (the heliotrope sign) and on extensor sur aces. However, the dermatomyositis, i.e. no muscle weakness clinically, but myositis by 633
SECTION
7
RHEUMATOLOGIC DERMATOLOGY
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 C
the muscle disease begins, it is indistinguishable clinically rom that
seen in patients with polymyositis. The myopathy a ects proximal Fig. 42.3 Dermatomyositis Gottron’s papules. A The at-topped (lichenoid)
papules overlying the proximal interphalangeal (IP) and metacarpophalangeal
muscle groups, especially the extensor groups (triceps and quadriceps), (MCP) joints are subtle and were misdiagnosed as verrucae vulgaris in this
in a symmetric ashion. In advanced disease, all muscle groups can be child. B Obvious accentuation of skin lesions over the MCP joints, with
a ected. Patients may be unable to complete simple tasks such as coalescence of pink–violet lichenoid papules. C Papulosquamous plaques with
combing their hair or rising to their eet rom a sitting position. The a somewhat linear con guration proximally; clues against psoriasis are the
634 a ected muscle groups are o ten tender to palpation in more advanced Gottron’s papules of the distal IP joints, cuticular dystrophy and nail fold
disease. Muscle strength should be graded on sequential visits by telangiectasias. A, B, Courtesy, Julie V Schafer, MD.
CH AP T E R
Fig. 42.4
Dermatomyositis 42
Gottron’s sign. Thin
Dermatomyositis
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.
• 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
Dermatomyositis
The characteristic changes seen in skin biopsy specimens rom patients evolve into classic dermatomyositis, or remain as amyopathic dermato-
with dermatomyositis can be very subtle (Fig. 42.7) and include epider- myositis44. Additional baseline investigations or pulmonary disease
mal atrophy, basement membrane degeneration, vacuolar alteration o (o ten predicted by anti-Jo-1 antibodies; see Table 42.6), or cardiac
basal keratinocytes, and dermal changes consisting o interstitial mucin disease, or symptomatic esophageal disease (barium swallow or man-
deposition and a sparse lymphocytic in ltrate. In some cases, a col- ometry) and or eatures o overlap connective tissue disease should be
loidal iron stain may help to highlight the presence o mucin. The per ormed at this stage, prior to the institution o systemic therapy
histopathologic changes may be indistinguishable rom those seen in unless immediate therapy is warranted to halt rapidly progressive
specimens rom patients with poikilodermatous lesions o LE. Gottron’s disease. Adult patients should have screening or occult malignancy
papules show a lichenoid in ltrate but have acanthosis rather than annually or at least 2–3 years, or more requently based upon symp-
epidermal atrophy58. toms. A detailed history, review o symptoms, and complete physical
Muscle biopsy specimens also show characteristic changes. The com- examination should be per ormed at regular intervals o 4–6 months.
bination o type II muscle ber atrophy, necrosis, regeneration, and Adult patients with amyopathic dermatomyositis should have similar
hypertrophy with centralized sarcolemmal nuclei, plus lymphocytes in evaluations or malignancy and associated systemic disease.
both a peri ascicular and a perivascular distribution, is classic 59. It is The classic muscle enzymes that should be assessed at baseline and
best or the clinician to request that the surgeon sample triceps muscle at regular intervals throughout the treatment period are creatine kinase
rather than the usually biopsied deltoid muscle because the latter is (CK) and aldolase. Aspartate and alanine transaminases and lactate
o ten spared until late in the disease. Another option, especially or dehydrogenase are o ten elevated as well, since they also are released
patients with mild involvement, is to choose the biopsy site based upon rom damaged muscle tissue. It has been estimated that 95% o patients
MRI ndings (see below). with dermatomyositis have an elevated CK at some point during their
−
Amyopathic
dermatomyositis
7
RHEUMATOLOGIC DERMATOLOGY
A B
TREATMENT
A therapeutic ladder or the treatment o patients with dermatomy-
ositis is summarized in Table 42.8. As with many rare dermatologic
Fig. 42.10 T2-weighted MR images of the proximal thigh in a patient with diseases, double-blind, placebo-controlled trials are lacking. However,
dermatomyositis. Note the increased signal density, primarily in the extensor
a dermatology-based case series supported the belie that a number
muscles (white color, arrows). The increased signal correlates with
in ammation. o patients (75–85%) can become muscle disease- ree, o treatment,
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
illness8. Urine creatine is elevated in some patients who have a normal or the skin disease is clearly inadequate, with many patients exprienc-
serum CK, but this test is not routinely per ormed. Myoglobin, another ing persistent cutaneous disease and pruritus, especially o the scalp,
protein released by damaged muscle, can be detected in the serum even which can become a major complaint once the muscle disease is
in patients with mild muscle disease. Its detection in urine is a cause under control. Aggressive topical therapy and systemic therapy (e.g.
or concern, and, rarely, severe myoglobinuria can result in acute renal antimalarials or weekly methotrexate) added speci cally or the skin
ailure. disease o ten do not provide adequate relie . It is clear however, that,
Electromyography (EMG) is a sensitive but nonspeci c test in patients except in adult patients with an advanced malignancy, the prognosis
with dermatomyositis. Over 90% o patients have abnormal EMG or corticosteroid-treated dermatomyositis in children and in adults
results. The combination o an abnormal electromyogram with classic is excellent, especially when compared with a mortality o up to 50%
cutaneous lesions (clinically and histologically) makes the diagnosis o in the pre-corticosteroid era66.
dermatomyositis very likely. EMG ndings are less help ul in patients The treatment o dermatomyositis must take into account the dis-
with polymyositis because there is overlap with other myopathies in cordance between the response o the muscle disease and that o the
the di erential diagnosis63. dermatologic disease to systemic therapy. The search or muscle
In the absence o classic cutaneous lesions, the muscle biopsy is a involvement must be thorough, even in the patient with normal serum
very important test or con rming the diagnosis and excluding other muscle enzymes. Two positive objective tests documenting muscle
infammatory myopathies. Surgeons will usually biopsy the deltoid disease (e.g. EMG and muscle biopsy, or one o these plus MRI or
muscle or convenience, but this muscle is relatively spared until late muscle ultrasound) should trigger the initiation o systemic cortico-
638 in the disease; there ore, the surgeon should be directed to per orm a steroid therapy in doses aimed at control o the muscle disease
triceps muscle biopsy. (i.e. generally prednisone 1 mg/kg/day). Patients with dermatologic
CH AP T E R
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
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
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Acad Dermatol. 1998;38:397–404. 2000;7:693–7. speci c autoantibodies: their clinical and pathogenic
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( rst of two parts). N Engl J Med. 1975;292:344–7. expression on muscle cells of polymyositis and (Oxford). 2009;48:607–12.
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6. Sontheimer RD. Would a new name hasten the detection as a diagnostic tool in noninformative muscle management of juvenile dermatomyositis results in
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(dermatomyositis sine myositis) as a distinctive subset (DM). Neuropathol Appl Neurobiol. 2003;29:546–52. calcinosis. J Am Acad Dermatol. 2002;47:505–11.
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2002;46:626–36. dermatomyositis. J Rheumatol. 2004;31:605–9. 39. Hundley JL, Carroll CL, Lang W, et al. Cutaneous
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RHEUMATOLOGIC DERMATOLOGY SECTION 7
Systemic Sclerosis (Scleroderma) and
Related Disorders
M Kari Connolly
43
Chapter Contents Epidemiology
SSc has a worldwide distribution and affects all races. The annual
Systemic sclerosis 643 incidence and prevalence rates in the US are approximately 20 and 250
Eosinophilic asciitis 651 cases per million population, respectively1. Women are affected three
Nephrogenic systemic fbrosis 652 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
Sti skin syndrome 654 years. Black patients have an earlier mean age of onset and a higher
Sclerodermoid syndromes induced by exogenous substances 654 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
SYSTEMIC SCLEROSIS 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.
Synonyms: Systemic sclerosis: � Scleroderma � Progressive systemic
sclerosis Pathogenesis
The pathogenesis of SSc is unknown. Key pathogenic abnormalities in
Subtypes of clinical involvement: � Di use � Limited (includes CREST
the skin and internal organs are vascular dysfunction, immune activa-
syndrome) tion with autoantibody production, and tissue brosis characterized
by deposition of collagen and other extracellular matrix proteins
(Fig. 43.1)4–6.
Key features
An autoimmune connective tissue disease o unknown etiology Vascular dysregulation
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 event in the pathogenesis of SSc6. The blood vessels affected range from
Raynaud’s phenomenon is common and digital ulcers develop the smallest capillaries within the proximal nail fold to the large pul-
monary arteries. Endothelial cell injury occurs early (before brosis is
Internal organ involvement is requent and a ects the lungs,
evident), based on changes seen by electron microscopy, such as perivas-
gastrointestinal tract, heart and kidneys; lung involvement is the
cular leak and edema7. Surrounding smooth muscle cells are also
leading cause o death
affected and have altered production of and responsiveness to vasocon-
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 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
Introduction proliferation and luminal obstruction. Scleroderma renal crisis and
Systemic sclerosis (SSc, scleroderma) is an autoimmune connective pulmonary artery hypertension are manifestations of large vessel
tissue disease (AI-CTD) of unknown etiology that affects the skin, dysregulation.
blood vessels and internal organs. The name systemic sclerosis is
meant to convey the systemic nature of the disease, which has two Immune dysregulation
major clinical subtypes: limited and diffuse. Limited SSc is character-
Patients with SSc produce speci c, and therefore diagnostic, autoanti-
ized by brotic skin changes that are limited to the ngers, hands and
bodies (e.g. anticentromere, anti-topoisomerase I [Scl-70]; see Ch. 40),
face and includes the CREST syndrome. In diffuse SSc, generalized and these autoantibodies also have prognostic implications 9,10. Com-
brotic skin changes are seen and they usually start in the ngers and plexes containing topoisomerase I autoantibody, when bound to the
hands but spread to involve the forearms, arms, trunk, face and lower
surface of broblasts, have been found to stimulate monocyte adhesion
extremities. Because SSc is not invariably progressive, the word “pro- and activation. In addition, anti-endothelial cell antibodies from SSc
gressive” has been dropped from the terminology for this condition. patient sera can trigger endothelial cell apoptosis. One group described
The diagnosis of SSc is based on clinical ndings and laboratory stimulatory autoantibodies against the platelet-derived growth factor
abnormalities 1. The differential diagnosis of symmetric and widespread (PDGF) receptor in SSc sera which induced reactive oxygen species and
cutaneous induration includes SSc as well as generalized morphea,
expression of type I collagen by normal human broblasts11. However,
eosinophilic fasciitis, scleromyxedema, nephrogenic systemic brosis, two subsequent studies were unable to con rm these ndings12.
and scleredema (favors neck and upper trunk) (Table 43.1). Lymphocytic in ltrates have been observed in both the skin and lungs
of SSc patients before the development of brosis. Oligoclonal T-cell
History expansion has been identi ed in lesional skin, indicating an antigen-
The rst reported case of SSc (in 1754) was a young Italian woman driven response, and T cells demonstrate a Th2-predominant pro le
who developed progressive induration of her skin. From the clinical with increased production of pro brotic cytokines such as interleukin
description, it is impossible to determine whether she had true SSc or (IL)-4 and IL-13. More recently, Th17 cells and IL-17 have been impli- 643
another sclerodermoid disorder. 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
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.
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
Cutaneous features
Many patients with SSc experience an early edematous phase, which
often features pitting edema of the digits (Fig. 43.4). The skin
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.
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)§
* 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
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
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.
650
CH AP T E R
Treatment systemically and is no longer used. Photopheresis has been shown to
SSc is a challenging disease to treat. Therapeutic interventions focus
have a marginal effect on skin scores. PUVA and UVA1 may also have 43
a role in SSc therapy29a,29b.
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
43
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 disabled. It resulted from the ingestion of aniline-degraded and reproc-
7 The lesions of NSF are refractory to treatment with corticosteroids and
essed rapeseed oil, which led to a speci c immune response in geneti-
RHEUMATOLOGIC DERMATOLOGY
655
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RHEUMATOLOGIC DERMATOLOGY SECTION 7
Morphea and Lichen Sclerosus 44
Martin Röcken and Kamran Ghoreschi
Morphea and lichen sclerosus are in ammatory skin diseases that HISTORY
ultimately evolve into two distinct modes o scar ormation. Morphea
a ects primarily the dermis and may extend to subcutaneous struc- A condition o thickened skin was frst mentioned by Hippocrates
tures. Lichen sclerosus is most o ten a disease o the genital mucosa around 400 BC. The term “scleroderma” is derived rom the Greek
(but may also involve extragenital sites) and it a ects both the epider- words skleros (hard or indurated) and derma (skin). The frst descrip-
mis and the superfcial dermis. Neither one leads to involvement o tion o a generalized “hardness” o the skin in a young woman was by
internal organs other than occasionally the underlying muscle or bone. an Italian physician, Carlo Curzio, in 1753, and the French physician
While an individual patient may have both disorders simultaneously, Gintrac coined the term “sclérodermie” in 1847. Thomas Addison has
they are addressed separately because o their multiple dissimilarities. been credited with the frst detailed description (in 1854) o morphea,
Therapy o these two diseases will be discussed together. 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.
MORPHEA O’Leary and Nomland4 elaborated the distinctive eatures o systemic
sclerosis versus morphea in 1930.
Subtypes/synonyms: � Plaque-type morphea – localized
scleroderma, circumscribed scleroderma � Linear morphea – linear EPIDEMIOLOGY
scleroderma � Morphea en coup de sabre – scleroderma en coup de
Even though morphea has been long recognized as a well-defned entity,
sabre � Deep morphea – morphea profundus
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
Key features this period, the annual incidence rate was 27 per million inhabitants.
According to this study, 56% o patients had plaque-type, 20% linear,
Asymmetric sclerotic plaques, usually 2–15 cm in diameter
13% generalized, and 11% deep morphea. Overall, the incidence appears
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 500 and 2200 per million at ages 18 and 80 years, respectively2. The
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 exception o linear morphea, which has no gender pre erence. Data
There is no associated systemic disease published on the incidence and prevalence o morphea probably re ect
an underestimation, as they critically depend on clinical recognition
Often progresses for several years, then regresses; the linear and diagnosis.
subtype is usually persistent 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
INTRODUCTION patients, substantial disability occurred. This is o particular concern
since disability occurs primarily with linear morphea, and the latter
Morphea is a clinically distinct in ammatory disease, primarily o the o ten has its onset be ore age 18 years (approximately two-thirds o
dermis and subcutaneous at, which ultimately leads to a scar-like patients)5.
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 PATHOGENESIS
be distinguished clinically. Morphea has an asymmetric patchy or linear
distribution, whereas systemic sclerosis usually begins as symmetric Autoantibodies are usually as prevalent in morphea as in the general
tightening o the hands and fngers that extends progressively toward population, with two exceptions: (1) an increased prevalence o anti-
the proximal upper extremities. Although generalized morphea may single strand DNA (ssDNA), -topoisomerase IIα, -phospholipid,
resemble early di use scleroderma, the presence in the latter condition -fbrillin-1 and -histone antibodies in patients with morphea (see Ch.
o Raynaud’s phenomenon, digital sclerosis, and involvement o the 40); and (2) high titers o antinuclear antibodies (ANA) in juvenile
gastrointestinal tract and the lung generally allows separation o sys- patients with linear morphea and individuals with generalized morphea.
temic sclerosis rom morphea. Distinguishing between deep morphea Autoantibodies that activate receptors on fbroblasts, in particular the
and eosinophilic asciitis can prove more di fcult. platelet-derived growth actor receptor (PDGFR), and presumably trigger
Morphea has associated morbidity and impacts quality o li e as a a cascade that leads to increased collagen synthesis have not been
result o symptoms such as pain, skin tightness or decreased range o described in patients with morphea (see Ch. 43).
motion o joints1. In ~10% o patients, scar ormation may lead not Neither histology nor immunohistology o a single lesion will distin-
just to the usual disfgurement but also to signifcant contractures or guish between morphea and systemic sclerosis. In most clinicopatho-
growth retardation, handicapping the a ected individual or li e 2. Thus, logic reviews, it is assumed that the two diseases are triggered by
prompt treatment (e.g. UVA1, PUVA) is indicated when morphea distinct events. However, the development o sclerosis ollowing the 657
a ects more than the superfcial dermis. 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, While IL-4 is the most potent orce in driving Th2-cell di erentiation
closely connected components: vascular damage, activated T cells, and (see Fig. 4.10 )11, it is also produced by Th2 lymphocytes. Because IL-4
altered connective tissue production by fbroblasts (Fig. 44.1)6. enhances pathologic collagen production by fbroblasts and induces
recruitment o eosinophils, it is believed that immune responses domi-
Vascular Changes nated by IL-4- as well as IL-13- and TGF-β-producing cells are critically
A prominent eature o advanced sclerosis is a reduction in the number involved in the development o skin sclerosis. This concept is supported
o capillaries. Studies per ormed in systemic sclerosis suggest that by clinical and experimental data:
microvascular injury is a very early – and perhaps even the primary – l In situ analysis o progressing in ammatory margins o skin
event. Endothelial cell markers such as soluble adhesion molecules and sclerosis has revealed predominantly IL-4 expression 12.
l Th2-associated cytokines IL-13 and IL-33 have been shown to
vascular endothelial growth actor (VEGF) are elevated in the sera o
patients with systemic sclerosis, indicating endothelial activation. The promote skin fbrosis experimentally in mice and early treatment
morphologic changes principally a ect capillaries and small arterioles o scleroderma-developing mice with anti-IL-4 antibodies
50–500 microns in diameter. The initial changes include expression o prevented scleroderma13,14.
adhesion molecules and endothelial swelling, ollowed by thickening o 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.
A Note the “pseudo- pink papulonodules
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.
Fig. 44. 7
Parry–Romberg
A syndrome.
Hyperpigmentation and
loss of subcutaneous fat,
leading to facial
asymmetry. Courtesy, Julie V
Schafer, MD.
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
B
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
Centrally, it can acquire a shiny white color, and peripherally, a viola- consider it to be a separate entity in the di erential diagnosis o
ceous or “lilac” ring. Postin ammatory hyperpigmentation o ten domi- “burnt-out” morphea (see Ch. 99). Hyperpigmented patches are
nates over the white sclerosis as the lesions mature (Fig. 44.4). seen most commonly on the posterior trunk; occasionally, lesions
Skin structures such as hairs and sweat glands are requently lost. ollow Blaschko’s lines (linear atrophoderma o Moulin).
Some patients complain o itch, perhaps due to associated xerosis. Once l Deep morphea re ects an in ammation and sclerosing process
the “lilac” ring vanishes, the lesion’s progression also halts. Although that a ects primarily the deep dermis and subcutaneous at
this in ammatory margin may be di fcult to appreciate, especially in and may even involve underlying structures (e.g. the ascia)
linear sclerosis, it is an important component o the physical examina- (Fig. 44.5A). Patients normally develop a single or ew hard deep
tion as it is an indicator o clinical activity. plaques that may impair motility o the skin; ultimately, lesions
The plaques o morphea most commonly develop on the trunk and may calci y, leading to deep osteoma cutis. Because o the location
are between 2 and 15 cm in diameter. They are usually multiple and o the sclerosis, individual lesions can share some clinical eatures
asymmetric, but marked variation exists. Individual lesions may enlarge with eosinophilic asciitis (Fig. 44.5B and see Ch. 43).
signifcantly or remain stable in size. l In nodular or keloidal morphea, in ammation within the dermis
The course o morphea is also variable. In most patients, morphea leads to thick, keloid-like nodules (Fig. 44.6) or streaks. It is
progresses over 3–5 years, then arrests and eventually resolves sponta- clinically indistinguishable rom indurated keloids.
660 neously. However, residual atrophy and/or dyspigmentation are com- l In rare patients, especially those where sclerosis o the skin is
monly observed. Rarely, patients have relapsing disease or more than associated with di use, rapidly progressive edema, lymphoceles
CH AP T E R
Fig. 44.8 Fig. 44.9 Morphea en
Linear morphea of the coup de sabre. Linear 44
leg. The di erential depressions and sclerosis
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 B
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.
En coup de sabre morphea can also involve the underlying muscles
and osseous structures. Rarely, the in ammation and sclerosis progress
Linear Morphea and Parry–Romberg Syndrome to involve the meninges and even the brain, creating a potential ocus
Linear morphea is di erent rom plaque morphea, with respect to age or seizures. Alternatively, very slowly progressing in ammation, indis-
o onset, distribution, clinical outcome and serologies. Morphea en tinguishable rom the in ammatory process o linear morphea, leads
coup de sabre (meaning stroke or blow with a single-edged sword) is a to gradual involution o the skin, atty tissues and underlying bones.
term used or linear morphea o the orehead and scalp. Hemi acial
atrophy, or Parry–Romberg syndrome, is probably a very severe variant Generalized Morphea
o linear morphea, but it may be a phenotype or more than one entity.
Rarely, plaque-type morphea is rapidly progressive, where multiple
There is a progressive loss o subcutaneous at, but little or no sclerosis
enlarging plaques appear simultaneously and coalesce until they involve
(Fig. 44.7). The entire distribution o the trigeminal nerve, including
the eye and the tongue, may be a ected. nearly the entire integument. Rather, this variant normally begins
insidiously on the trunk as plaque morphea. An individual lesion is
Linear morphea may present initially as a linear, erythematous
indistinguishable rom classic plaque morphea, except that it does not
(in ammatory) streak, but more requently it begins as a harmless-
appearing lesion o plaque-type morphea that extends longitudinally as 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
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 the nipples. The sclerosis may involve the extremities down to the
hands (presenting initially as pu y edema). As the cutaneous sclerosis
morphea tends to involve the underlying ascia, muscle and tendons.
This leads not only to muscle weakness but also to a shortening o the progresses, it may result in disabling constrictions that even cause di -
muscles and ascia that impairs joint motility. Linear morphea is espe- fculty in breathing due to impaired thorax mobility and in ammation
cially dangerous when extending over joints, as this almost invariably o the intercostal muscles. Although an aggressive therapeutic approach
is recommended, the disease is usually persistent given its o ten limited
results in disabling joint immobilization. In some patients, involve-
response.
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 Morphea in Childhood
the head (Fig. 44.9). It is normally unilateral and extends rom the About 20% o those with morphea are children and teenagers. The
orehead into the rontal scalp. It may start either as a linear streak or emale-to-male ratio or plaque-type morphea is about 2:1, with a mean
as a row o small plaques that coalesce. A paramedian location is more age o disease onset o 7 years26. Linear morphea is more o a problem,
common than a median location. Like plaque morphea, it may initially as two-thirds o all patients with this variant are younger than 18 years
be surrounded by a discrete lilac ring that extends longitudinally and o age when it develops. Also, in young children and adolescents, linear
may reach the eyebrows, nose and even the cheeks. The waning in am- morphea o ten leads to growth retardation o the a ected limb. Thus,
mation leaves a linear, hairless crevice that in some patients is more i le t untreated, linear morphea may result not only in decreased range 661
sclerotic, while in others is more atrophic. 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.
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) 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
Key features remain speculative.
Perhaps with the exception o autoantibodies against extracellular
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 been identifed in patients’ sera that clearly correlate with either risk
Most commonly a ects female or male genitalia, less often o disease or disease activity. IgG autoantibodies against ECM-1 are
extragenital skin ound in 80% o patients with lichen sclerosus and the latter may act
May cause scarring of the vaginal introitus or phimosis as an autoantigen39. Oxidative stress may also play a role in the patho-
genesis o lichen sclerosus, based upon analysis o lesional skin that
Severe pruritus may occur
showed lipid peroxidation o epidermal basal cell layers, oxidative DNA
No systemic manifestations damage and oxidative protein damage.
44
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
665
SECTION
lichen sclerosus invariably leads to phimosis (di fculty in retracting the vacuolar degeneration o the basal layer. Hyperkeratosis is especially
7 oreskin to uncover the glans), with the additional risk o paraphimosis pronounced at ollicular openings and may lead to plugging. The vacu-
RHEUMATOLOGIC DERMATOLOGY
(when a oreskin retracted behind the glans can not be returned to its olar degeneration at the dermal–epidermal inter ace and the attening
original position); the latter represents a urologic emergency. Many boys o the rete ridges predisposes to the development o blisters, which may
and men frst present when the phimosis impairs repositioning o the become hemorrhagic. The most important changes are ound in the
oreskin; in these situations, diagnosis depends on histology. Progres- superfcial dermis, where the pale staining re ects homogenized dermal
sive disease can be associated with poorly healing ulcers o the glans. collagen (Fig. 44.16B) or edema (early stage). Loss o elastic fbers is
While circumcision is clearly a frst-line therapy, lichen sclerosus may typical or lichen sclerosus but is not observed in morphea. Cle ting
recur at the site o a circumcision. and hemorrhage within the homogenized papillary dermis is o ten seen.
An open question is whether genital lichen sclerosus is a precancer- During the early phases, the in ammatory infltrate is especially
ous condition. Interpretation and comparison o the data are compli- pronounced along the zone o hyalinization and consists o lymphocytes
cated by two actors: some o the patients reported as developing cancer (CD3+, CD4+, CD8+), macrophages and mast cells. In older lesions, the
had previously received X-ray therapy or the disease or had previous mononuclear infltrate is reduced and sparse, and patchy islands o
dysplasia due to human papillomavirus (HPV) in ection. It is there ore mononuclear cells are dispersed within the hyalinized dermis.
very di fcult to establish a use ul meta-analysis. Most data suggest that Ultrastructural studies reveal shortened collagen fbers.
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.
DIFFERENTIAL DIAGNOSIS
The most important entity in the di erential diagnosis o extragenital
PATHOLOGY lichen sclerosus is morphea, and or genital lichen sclerosus in girls
and boys, it is sexual abuse 40. In adults, genital lichen sclerosus may
Lichen sclerosus has a specifc histologic pattern. Initially, superfcial mimic erythroplasia o Queyrat or erosive lichen planus (see Ch. 73).
dermal edema is associated with a band-like lymphocytic infltrate (Fig. Distinction o ten requires histologic examination. Biopsies may also be
44.16A). The epidermis is thinned, with orthohyperkeratosis and 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.
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
B least 60% o patients45 (Fig. 44.17). Further advantages o phototherapy,
and especially UVA1, include clinical improvement in all skin types46
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. ultrasound (Fig. 44.18) or by histology44,48,49. Both phototherapies seem
CH AP T E R
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
Fig. 44.18 High-frequency ultrasound (20 MHz) of a
7 morphea plaque. Before (A) and after PUVA bath
photochemotherapy (B), showing reduction of
RHEUMATOLOGIC DERMATOLOGY
corium thickness and hyperechoic bands of
connective tissue.
A B
A B
photodynamic therapy or vulvar lichen sclerosus pointed to signifcant reducing in ammation in superfcial active lesions. Similarly, intrale-
relie o symptoms, similar results were not observed in more recent sional injection o triamcinolone into the margins may reduce or
studies. prevent progression. Topical corticosteroids are ine ective in resolving
sclerosis.
Topical Therapies Calcineurin inhibitors
Corticosteroids The macrolide immunosuppressants pimecrolimus (1% cream) and
Retrospective and prospective studies have clearly documented that tacrolimus (0.1% ointment) have been used as topical treatments or
ultrapotent topical corticosteroids are highly e ective in the treatment vulvar lichen sclerosus. Several case reports and initial trials involving
o genital lichen sclerosus. In the majority o these studies, clobetasol limited numbers o patients suggest that these therapies are e ective56.
propionate 0.05% cream was applied or 12–24 weeks54. Clinical Concerns have been raised as to the possibility o increasing the risk
improvement was confrmed by histopathology. Both sa ety and e fcacy o developing SCC or reactivating HPV ollowing the use o topical
o clobetasol in the treatment o genital lichen sclerosus were docu- calcineurin inhibitors or vulvar lichen sclerosus. Long-term sa ety and
mented or all age groups and in both sexes. Nearly all the patients e fcacy studies as well as randomized trials comparing these agents
with vulvar lichen sclerosus responded to ultrapotent topical cortico- with clobetasol are needed. With regard to morphea, improvement ol-
steroids, and amongst those who improved, about 20% experienced lowing topical tacrolimus (0.1% ointment) has been reported in case
complete clearance 55. However, topical corticosteroids do not cure the series, especially in patients with early in ammatory lesions57,58. Again,
disease and relapses may occur. prospective, double-blind, randomized trials are needed.
Major side e ects were not reported, even with long-term and main-
tenance use o clobetasol. There ore, potent topical corticosteroids rep- Vitamin derivatives
resent frst-line therapy or genital lichen sclerosus, including in Derivatives o vitamin D and vitamin A are still under study in
children (Fig. 44.19). Alternatively, corticosteroids such as triamcin- morphea. In vitro, calcipotriol inhibits the proli eration o cultured
olone can be injected intralesionally. O note, vulvar SCC appeared to fbroblasts and topical calcipotriene (0.005% ointment) has been used
develop primarily in untreated or irregularly treated lesions o vulvar or the treatment o morphea59. Single reports have described improve-
lichen sclerosus. ment o both vulvar lichen sclerosus and morphea when treated with
668 The beneft o topical corticosteroids in the treatment o morphea is topical vitamin A derivatives. All o these observations require confr-
questionable. Ultrapotent topical corticosteroids may be use ul or 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
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