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Volume 2 Number 5
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Review for the Generalist: Cutaneous
manifestations of juvenile systemic lupus erythematosus and juvenile
dermatomyositis Arianna Vitale, Lucia
Trail, Enrico Felici, Francesco Traverso, Alberto Martini, Angelo Ravelli Dipartimento di Pediatria, Università di Genova, Unità Operativa Pediatria
II, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini,
Correspondance: Angelo
Ravelli, MD Pediatria
II, Istituto G. Gaslini Largo
G. Gaslini, 5 16147
Genova, Italy Tel.:
+39-010-5636386 Fax: +39-010-5636211 or +39-010-393324 |
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INTRODUCTION Cutaneous manifestations are among the most important
clinical hallmarks of juvenile systemic lupus erythematosus (JSLE) and
juvenile dermatomyositis (JDM). In both diseases, skin lesions are of
great diagnostic help. Indeed, dermatologic features constitute 4 of
the 11 the classification criteria for SLE (discoid rash, malar rash,
photosensitivity, and oral/nasal mucocutaneous ulcerations) [1], and
the presence of the typical skin rash is an essential requirement to
diagnose JDM by the Bohan and In this paper, we review the distinctive cutaneous
features of JSLE and JDM as well as the most recent advances in their
management. JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS Skin disease is common in JSLE both at disease onset
and during disease exacerbations and is extremely heterogeneous [4,5]
(Table 1). The most characteristic manifestation is the classic “butterfly”
or malar rash (Figure 1), which is observed at onset in 30 to 50% of
patients. Although not pathognomonic (as discussed below, a similar
rash may occur in JDM), the malar rash is highly suggestive of SLE.
It is characterized by symmetrical erythema and edema that is typically
centered over the malar eminences and over the bridge of the nose, and
sometimes extends to the forehead and the V area of the neck; the nasolabial
folds are typically spared. The rash is usually confluent and well demarcated,
and may be slightly raised. In most cases it is maculopapular with fine
scales, but rarely results in scarring. Occasionally, the rash begins
on the face as small, discrete macular and/or papular lesions that later
become confluent and hyperkeratotic. The malar rash may be precipitated
by exposure to sunlight (photosensitivity).
Table 1- Cutaneous manifestation of SLE
A number of other dermatologic manifestations can occur
in JSLE. Maculopapular rashes resulting from vasculitis or perivasculitis
may be seen anywhere in the body, particularly on sun-exposed areas,
such as the face and the upper-anterior chest (Figure 2). These lesions
are sometimes painful and may also involve the palms and soles. In most
patients they heal without scarring or hyperpigmentation. More rarely,
cutaneous disease may present as a more widespread morbilliform or exanthematous
eruption or in an extremely acute form that can simulate toxic epidermal
necrolysis. Discoid lupus (Figure 3) occurs rarely in pediatric
patients [6]. It has been reported that only 2 to 3% of cases of discoid
lupus have disease onset before the age of 15 years [7]. The discoid
lesions consist of areas of flat or slightly elevated, sharply demarcated,
red-purple, papulosquamous patches with adherent scales and follicular
plugging, which most commonly occur in sun-exposed areas, such as the
scalp and the limbs, in an asymmetric distribution. These lesions most
commonly evolve into larger, coin-shaped (i.e. discoid) plaques, that
can enlarge and merge to form larger, confluent, disfiguring plaques.
They often leave atrophic scarring and alterations of skin pigmentation.
Discoid lupus is more common in black children than in other ethnic
groups. It is estimated that 7% of patients with discoid lupus will
progress to systemic lupus over a period of 5 years [6] .
Alopecia is a common feature of JSLE. It is associated
with disease activity and is usually characterized by diffuse hair thinning,
which initially affects frontal hairs. The hairs become brittle and
kinky and are prone to breaking off. This phenomenon is generally referred
by the child or the parents as an excessive hair falling on the pillow,
in the comb, or after shampooing. This alopecia is usually non-scarring
and more often causes limited upset. In contrast, irreversible scarring
alopecia from permanent follicular destruction is rare. Dystrophic nail
changes may be seen in patients with long-standing disease. Other uncommon cutaneous manifestations of JSLE
are urticarial and bullous (pemphigoid-like) lesions. Finger, toes or
face red-purple patches and plaques that are precipitated by cold exposure
and are reminiscent of simple chilblains or pernio lesions are occasionally
observed in children. Diffuse hyperpigmentation, usually most prominent
on the light-exposed and extensor surfaces of the body, is another important,
though rare, dermatologic feature of JSLE. The accumulation of excessive
dermal mucin early in the course of a cutaneous lupus lesion can result
in the development of succulent, edematous, urticarial-appearing plaques
of “lupus tumidus”. Lupus panniculitis is characterized by inflammatory
lesions in the lower dermis and subcutaneous tissue, which usually presents
with deep, firm, 1- to 3-cm diameter nodules, often with normal-appearing
overlying skin. As the lesion mature, the skin becomes attached to the
nodular lesions and is drawn inward to produce deep depressions. Confluent
involvement can simulate a lipoatrophy. The so-called “subacute cutaneous lupus” begins with erythematous macules
or papules that subsequently evolve into annular/polycyclic lesions
with raised edges. They are localized on the trunk, limbs and face and may
assume a scaly, hyperpigmented or atrophic appearance, but are nonscarring.
Photosensitivity is common as well. Shallow, painful ulcers of the lips,
gums, palate, and nasal mucosa occur in 10-15% of patients and frequently
occur during disease exacerbations. Similar lesions are seen occasionally
on the vulvar surface [8]. A number of skin changes that may develop in patients
with lupus have been associated with the presence of circulating antiphospholipid
antibodies [9]. They include leg ulcers, livedo reticularis, cutaneous
necrosis, gangrene of the digits or extremities, thrombophlebitis, necrotizing
purpura, and nailfold infarcts. Leg ulcers, which occur more often in
the lower limbs, are painful and sharply marginated; they have a necrotic
center or base and leave a white atrophic scar on healing. Livedo reticularis
has been related to the stagnation of blood in dilated superficial capillaries
and venules and affects primarily the skin of the tights, shins, and
forearms. Deposition of immunoglobulins, usually of the IgG or
IgM isotype, at the dermal/epidermal junction has long been recognized
in lupus. For unknown reasons, these immunoglobulins may be identified
in areas of skin than are not light-exposed, such as the buttocks, and
in which there is no rash. This phenomenon is at the basis of the so-called
lupus band test. Complement components may also be found at the dermal/epidermal
junction. JUVENILE DERMATOMYOSITIS A clear recognition of cutaneous features is essential
for prompt diagnosis of JDM, especially in cases in which these manifestations
are the initial or only findings (Table 2). Although dermatitis may
precede the onset of myositis by several months of even a few years,
it usually becomes evident in the first few weeks after the occurrence
of muscle involvement. In some patients, skin disease can be the most
active or severe disease complaint, failing to respond to therapeutic
interventions that are adequate for myositis or other systemic involvement. Table 2 –Cutaneous manifestations
of JDM
In
three-fourths of JDM patients, skin abnormalities are highly characteristic,
whereas in the remainder a less characteristic rash is present [5,10].
The rash is photosensitive in up to 30% of patients. The three most
typical, and most common, cutaneous manifestation of JDM are heliotrope
discoloration of the upper eyelids, Gottron’s papules, and periungueal
erythema with capillary loop abnormalities. The heliotrope rash occurs
over the upper eyelids and the periorbital region as a dusky, violaceous-reddish
purple erythema, which may be associated with a malar rash resembling
that of JSLE in its distribution, though less well demarcated, or to
a more confluent erythema involving the entire face. The malar rash
of JDM is also distinguished from that of JSLE by the involvement of
nasolabial folds that is typically absent in lupus. In the acute phase,
the heliotrope rash is often accompanied by edema of the eyelids or
the face or both, resulting in sensation of tightness. Capillary teleangectasias
along the lid margin may persist long after the other sign and symptoms
of disease activity have resolved (Figure 4).
Gottron’s papules (Figure 5) are pink-red to violaceous,
flat-topped papules and plaques that are located most commonly over
the extensor surfaces of the proximal interphalangeal joints of the
hands and less so over the metacarpophalangeal and distal interphalangeal
joints. The skin over the thumbs is rarely, if ever, affected. The extensor
surfaces of the elbows and knees and, less frequently, the malleoli
and the vertebral apophyses may be involved as well. These papules may
evolve over time to develop depressed atrophic, porcelain-white centers
with prominent teleangectasias. Occasionally, the lesions appear to
be thickened and pale early in the disease course (hence the name “collodion
patches”). Gottron’s sign refers to the macular erythematous patches
in a distribution similar to that seen for Gottron’s papules. A photosensitive
macular erythematous or violaceous eruption may involve discrete areas
of the body, producing specific signs: the “V-sign” for the V of the
neck and upper chest; the “shawl-sign” for the nape of the neck, upper
back, and posterior aspect of the shoulders. In the most active and
severe forms of JDM, the cutaneous rash may extend considerably and
eventuate in total body erythema (erythrodermia). Pruritus is a common
but underrecognized complaint of JDM patients, and is often associated
with secondary skin findings of excoriations and erosions.
Nailfold capillary abnormalities due to a widespread
capillary vasculopathy, which is the underlying pathologic lesion of
JDM [10], and periungueal erythema (figure 6)
are detectable in 50 to 100% of patients with JDM. Careful examination
with a water-soluble gel and a magnifying glass, an ophthalmoscope,
or a stereomicroscope allows documentation of the presence of nailfold
teleangiectasias. The most common abnormalities are capillary dropouts,
dilatation of isolated loops, thrombosis and hemorrhage, and arborized
clusters of giant capillary loops, which are secondary to post-ischemic
neovascularization and are distinctive of JDM. These changes have been
correlated with a more severe disease course or with the development
of cutaneous ulceration or calcinosis, and have been found to abate
with disease remission [5,11]. Cuticular dystrophy, that leads to overgrowth
of the cuticle is also well described in JDM and may reflect disease
activity. Occasionally, teleangiectasias similar to those seen in the
periungual beds may occur on the anterior gingival margin. The development of cutaneous ulceration has been well-recognized
in JDM. The ulcers are thought to be vasculitic in nature and may locate
at the corners of the eyes, in the axillae, in the upper part of hips,
over the elbows or pressure points and over stretch marks (Figure 6).
These lesions likely mean more severe vascular pathology, and may herald
serious internal organ involvement, such as intestinal ulceration or
perforation. Some authors believe that their presence may constitute
an indication to treatment with intravenous cyclophosphamide [10]. It
has been reported that children who develop a generalized rash and skin
ulcerations may have the poorest prognosis, although this may not always
be true [5]. “Vasculitic” ulcers must be distinguished from those caused
by the extrusion of calcium deposits in patients with calcinosis.
Late in the course of JDM, other cutaneous and subcutaneous
changes may occur. A persistent rash may eventuate into poikiloderma,
which is characterized by mottled hypo- and hyperpigmentation, fine
teleangiectasias and atrophy, with or without scale. Mechanic’s hand,
which is rarely observed in JDM, consists of hyperkeratosis, scaling
and fissuring of the fingers and palms of both hands; it can be mistaken
for contact dermatitis. The existence of an “amyopathic” form of JDM (dermatomyositis
sine myositis) [12] is still controversial and, in particular, it is
still unclear whether it represents a distinct entity or is simply at
one end of a spectrum of disease severity. Furthermore, although some
patients may present with rash alone, or muscle disease may not be initially
documented, some authors believe that these children eventually develop
myositis if followed for long enough [5]. There are, however, a few
children with JDM who have persistently normal levels of serum muscle
enzymes. Lipodystrophy has been reported to occur in as many as
20% of JDM patients [5]. It can be generalized, partial, or localized
and is characterized by a progressive, slow, and symmetrical loss of
subcutaneous fatty tissue, which is often most noticeable over the face
and the limbs (Figure 7). Lypodistrophy is often associated with other
manifestations resulting from metabolic derangement, such as hirsutism,
acanthosis nigricans, clitoral enlargement, hepatomegaly, insulin-resistance,
and hypertriglyceridemia. The loss of subcutaneous fat over the masseter
area and the arms and legs allows clear definition of muscle groups,
giving a false impression of muscle hypertrophy. Abdominal muscle tone
may be quite reduced and, therefore, the child may have difficulty in
sitting-up, even if muscle strength is normal elsewhere [13]. The loss
of abdominal muscle tone is associated with increased abdominal fat,
leading to the development of a “pot belly”. Insulin-resistance in patients
with JDM has been related to muscle damage, probably because skeletal
muscles are the main site of insulin-mediated glucose disposal [14].
Calcinosis is one of the most important sequelae of JDM,
which occurs in approximately one-third of patients. Since this complication
has been discussed in an excellent review, which appeared recently in
the Pediatric Rheumatology Online Journal [15], it will not be addressed. MANAGEMENT The treatment of skin disease in SLE and JDM is similar
and, therefore, the two diseases will be discussed together. The goal
of management is to improve the patients’ appearance and to prevent
development of scars, atrophy, or pigmentation changes [5,16,17]. Because
skin lesions are photosensitive in many patients, adequate protection
from sunlight must be advised. A cornerstone of therapy is represented
by the sunscreen, which should have a broad spectrum and be water-resistant.
Unfortunately, no sunscreen is able to block all UVR that might exacerbate
cutaneous rash and, therefore, patients should also be encouraged to
use other sun-protective measures, including wearing clothes, hats and
sun-glasses that protect the sun-exposed areas of the body from UVR. Topical corticosteroids are sometimes prescribed, particularly
in patients with discoid lupus, although the experience with their use
is probably much greater in adults than in children. An appropriate
topical corticosteroid is selected based on the area of the body to
be treated as well as on the type of lesions that are present. Facial
lesions should be treated with low- to mid-potency agents, whereas trunk
and arm lesions deserve mid-potency agents; rashes located on the palms
or soles and hypertrophic lesions must be managed with the most powerful
topical corticosteroids. In general, ointments are more potent and are
possibly more effective than creams. Intralesional injections of corticosteroids
are often effective in patients with rashes that are refractory to topical
corticosteroids. Again, these procedures may be indicated in adult patients
with the most severe and disfiguring lesions, whereas their use in children
is at least very limited. In some patients with lupus or dermatomyositis,
including a few children, who displayed cutaneous lesions that were
refractory to conventional therapies, tacrolimus ointment was tested
with some success [18-21]. When
skin lesions are not controlled with topical agents, are associated
with visceral involvement or are particularly severe or vasculitic in
nature, systemic therapy is indicated. Beside treatment for the underlying
disease, which can be itself effective on skin disease, the first-line
therapy of dermatitis is often represented by the use of hydroxychloroquine,
which reaches its maximal efficacy in 4 to 8 weeks. Because hydroxychloroquine
may cause ocular toxicity, including irreversible retinopathy, patients
must undergo an ophthalmologic screening at baseline and then every
6 months. This side effect is, however, very rare when the drug is used
in a dose of less than 6.5 mg/kg/day [16,17].
In patients with urticarial vasculitis
or bullous lesions there are reports of successes using dapsone. In
recent years, thalidomide has been increasingly used for cutaneous lupus
disease that is refractory to traditional therapies. The mechanism of
action of this drug, which should be taken at bedtime, is believed to
involve the inhibition of inflammatory mediators, particularly tumor
necrosis factor alpha [22]. Evidence has been provided that up to 90%
of patients who are able to tolerate the drug experience significant
improvement [16]. The most important side effects of thalidomide are
the neuropathy that may be reversible but may also progress despite
stopping the drug, and the teratogenicity. Therefore, all patients receiving
thalidomide must be questioned about the appearance of numbness, tingling
or pain in both hands and feet and have the sensory nerve action potential
amplitudes and, perhaps, nervous conduction velocity checked every 6
months. Furthermore, female with childbearing potential should practice
adequate contraception and men must always use latex condoms during
sexual intercourse because it is unknown whether thalidomide is present
in the ejaculate [22]. Pregnancy tests should be done monthly. In patients
with “recalcitrant” skin involvement, various immunosuppressant medications,
including methotrexate, azathioprine, cyclosporine, intravenous immunoglobulins,
and mofetil-mycophenolate have been tried with conflicting results.
The role of the new biologic agents (e.g. tumor necrosis factor antagonists,
rituximab) has not yet been defined. |
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Sontheimer RD, McCauliffe DP. Cutaneous manifestations of lupus erythematosus
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Cassidy JT, Petty RE. Textbook of Pediatric Rheumatology. Fourth Edition,
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Klein-Gitelman M, Reiff A, Silverman ED. Systemic lupus erythematosus in
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Yoshimasu T, Ohtani T, Sakamoto T, et al. Topical FK506 (tacrolimus) therapy
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Hollar CB, Jorizzo JL. Topical tacrolimus 0.1% ointment for refractory
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Kanekura T, Yoshii N, Terasaki K, et al. Efficacy of topical tacrolimus
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Ossandon A, Cassarà EAM, Priori R, Valesini G. Thalidomide: focus on its
employment in rheumatologic disease. Clin Exp Rheumatol 2002; 20: 709-718. |
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