Morphea
Salient features
|
·
Occurs
in children and adults. ·
Linear
subtype predominates in children. ·
Limited
and generalized subtypes predominate in adults. ·
A
self-limited or chronically relapsing autoimmune disorder targeting the skin
with the following major features: ·
Inflammatory,
sclerotic, atrophic phases. ·
Thickened
sclerotic skin. ·
Differentiated
from scleroderma by lack of acrosclerosis/sclerodactyly. ·
Complications
may cause significant irreversible cosmetic and functional impairment
including the following: ·
Atrophy
of dermis, fat, and subcutaneous structures. ·
Contracture. ·
Limb
length discrepancy. ·
Bony
abnormalities. ·
Treatment
based on the following: ·
Disease
subtype. ·
Depth
of involvement. ·
Stage
(inflammatory, sclerotic, atrophic). ·
Potential
for complications. |
Introduction
Morphea, also known
as localized scleroderma, is a clinically distinct
inflammatory disease, primarily of the dermis and subcutaneous fat, which
ultimately leads to a scar-like sclerosisis. It is a disorder
characterized by excessive collagen deposition leading to thickening of the
dermis, subcutaneous tissues, or both. The small
vessel changes, inflammatory infiltrate, and ultimate structural modifications
are identical in morphea and systemic sclerosis (SSc), but the two diseases are
distinct entities that can easily be distinguished clinically. Morphea has an
asymmetric patchy or linear distribution. In contrast, SSc begins either as
symmetric tightening of the fingers and hands that extend progressively toward
the forearms (limited cutaneous SSc [lcSSc]) or as symmetrically
extending sclerosis of the trunk and proximal upper extremities (diffuse cutaneous SSc [dcSSc]). Rarely,
generalized morphea may resemble early dcSSc. Unlike systemic sclerosis, morphea
lacks features such as sclerodactyly, Raynaud phenomenon, nailfold
capillary changes, telangiectasias, and progressive internal organ involvement.
As in SSc, there is an early,
inflammatory, active phase, followed by a sclerotic and then atrophic damage
phase.
The disorder occurs
primarily in children and young adults with 3: 1 female-to-male ratio.
Morphea
can cause significant morbidity as a result of pain, skin tightness or impaired
joint mobility. In ~10% of patients with morphea, sclerosis leads to
significant contractures, growth retardation and even micromelia, resulting in
long-term functional disability.
Epidemiology
The
prevalence of morphea increases with age, occurring in approximately 500 and
2200 per million at ages 18 and 80 years, respectively. The
disorder occurs primarily in children and young adults with 3: 1 female-to-male
ratio.
Pathophysiology
Morphoea
is a chronic autoimmune disease characterized by varying degrees of sclerosis
and atrophy primarily
of the dermis and subcutaneous tissues, sometimes
extending deeply into fascia, muscle and bone. Overproduction of
collagen, particularly types I and III collagen, by fibroblasts in affected
tissues is common to all forms of morphea. An autoimmune component is supported
by the frequent presence of auto antibodies in affected individuals, as well as
the association of morphea with other autoimmune diseases, including systemic
lupus erythematosus, vitiligo, type 1 diabetes, and autoimmune thyroiditis.
Predisposing factors
The aetiology of morphoea is poorly
understood. Trauma, radiation, medications and infection have all been proposed
to act as triggering events in its development in susceptible individuals. It
seems likely that an environmental ‘signal’, on a background of genetic
susceptibility, triggers a sequence of events including vascular activation,
inflammation and subsequent fibrosis.
Immunopathology
It
has been proposed that Th1 and Th17 cytokines are activated during the early
inflammatory stages of morphoea, whereas Th2 cytokines correlate with later fibrotic
stages.
Proposed conceptual model of localized scleroderma:
transition from Th1/Th17 to Th2 response.
·
Endothelial
cell injury and activation is the earliest features involved in the
pathogenesis of morphea and fibrosis is thought to result from a combination of
increased collagen deposition by fibroblasts and reduced extracellular matrix
turnover in morphoea.
Pathogenesis
Auto
antibodies are usually as prevalent in morphea as in the general population,
with two exceptions: (1) an increased prevalence of anti-single strand DNA
(ssDNA), -topoisomerase IIα, -phospholipid,
-fibrillin-1, and -histone antibodies (AHA) in patients with morphea; and (2)
high titres of antinuclear antibodies (ANA) in juvenile patients with linear
morphea and individuals with generalized morphea. In patients with linear
morphea, the presence of ssDNA antibodies or AHA seems to be associated with
increased risk of functional impairment.
Currently, sclerosis of the skin is thought to involve three major,
closely connected components: vascular
injury leading to recruitment and activation of lymphocytes and mononuclear
cells, secretion of pro‐inflammatory mediators and fibroblast activation leading to
eventual fibrosis and damage.
·
Vascular changes
A prominent feature of advanced sclerosis is a
reduction in the number of capillaries. It is suggest
that hypoxia resulting from endothelial injury is a very early and the primary
event. Endothelial cells respond to various stimuli, including vascular
endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and
transforming growth factor-β (TGF-β). In the sera of patients with SSc, markers
indicative of endothelial cell activation (e.g. soluble adhesion molecules,
VEGF) are elevated. Morphologic changes principally affect capillaries and
small arterioles 50–500 microns in diameter and the initial changes
in SSc include expression of adhesion molecules and endothelial swelling,
followed by thickening of the basement membrane and intimal hyperplasia.
Control of fibroblast function by
T-cell-derived cytokines
Fibroblasts isolated from sclerotic tissue produce increased amounts of
collagen (types I, II and III) and other extracellular matrix proteins and this
enhanced production is induced by T-cell-derived cytokines,
especially interleukin (IL)-4, IL-13 and TGF-β.
IL-4 is produced by CD4+ T helper
type 2 (Th2) lymphocytes and can directly enhance TGF-β production.
In contrast, production of collagen and other extracellular matrix proteins can
be significantly suppressed by interferons that are associated with Th1
lymphocytes. TGF-beta
also decreases production of proteases, inhibiting collagen breakdown. Connective-tissue
growth factor is a soluble mediator that enhances and perpetuates the
profibrotic effects of TGF-beta.
IL-4 is the most potent force in driving
Th2-cell differentiation. Because IL-4 enhances pathologic collagen production
by fibroblasts and induces recruitment of eosinophils, it is believed that
immune responses dominated by IL-4- as well as IL-13- and TGF-β-producing cells are critical in the initiation of
skin sclerosis
The ultimate result of the endothelial injury and
inflammatory cascade is increased collagen and extracellular matrix deposition.
Autoimmunity plays an important role in the pathogenesis of
morphea. Similar to SSc, pathogenesis involves endothelial cells, fibroblasts,
and inflammatory cells. Injury of vascular endothelium which could be due
to trauma, infection (with Borrelia burgdorferi), and hypoxia or radiation
therapy could be an early event. This is followed by up regulation of
expression of adhesion molecules and chemotactic cytokines and increased
angiogenesis. Subsequently, there is recruitment and infiltration of monocytes,
macrophages, eosinophils, and CD4+ T cells in the reticular dermis of the skin.
The endothelial and inflammatory cells release growth factors such as
transforming growth factor beta 1, connective tissue growth factor, and
cytokines such as IL-1, IL-4, IL-6, and IL-8 which lead to proliferation of
fibroblast and increased collagen deposition.
Clinical manifestations
Individual lesions of morphoea
generally begin as insidious onset of a slightly elevated erythematous, oedematous, inflammatory phase that undergoes centrifugal
expansion (inflammatory stage). The central portion of the progressing lesion
starts to transform into sclerotic, scar-like tissue associated with a change in skin colour and texture to
thickened, waxy, shiny, yellowish white (sclerotic stage). Depending
on the depth of the sclerosis, the skin becomes progressively indurated. Skin
structures such as hairs and sweat glands are frequently lost. Some patients
complain of itch, perhaps due to associated xerosis. This central sclerotic area may be surrounded by an
erythematous to violaceous so‐called ‘lilac ring’, that reflect ongoing active disease. Once the “lilac” ring vanishes,
the lesion’s progression also halts. Although this inflammatory margin may be
difficult to appreciate, especially in linear sclerosis, it is an important
component of the physical examination as it is an indicator of clinical
activity. Over months to years, the sclerotic
plaque softens and becomes atrophic with hyper or hypo pigmentation (atrophic
stage). In some cases, no sclerotic phase is seen and lesions progress straight
to the atrophic hyper pigmented stage. The atrophic stage is associated with
cigarette paper wrinkling (papillary dermis), cliff drop (dermal), or deep
indentions (subcutis or deeper).
Proposed modified classification of morphoea
and subtype characteristics
|
Main division |
Subtype |
Description |
|
Limited type |
Limited
plaque morphoea |
Single
or multiple round to oval lesions >1 cm in diameter in up to two
anatomical regions. Involves epidermis and dermis |
|
|
Guttate
morphoea |
Multiple
small <1 cm round to oval lesions, usually on the trunk. Involves the
papillary and superficial dermis |
|
|
Atrophoderma
of Pasini–Pierini |
Multiple,
round to oval, non‐indurated, sharply demarcated, depressed patches, ‘cliff‐drop’
edge, and usually hyperpigmented. Involves the superficial reticular dermis |
|
|
||
|
|
Limited
deep morphoea |
Solitary
or multiple lesions in up to two anatomical sites. Poorly defined, thickened
and bound down, sometimes with cobblestone or peaud'orange appearance.
Involves deep dermis and subcutis ± fascia and muscle. |
|
Generalized type |
Disseminated
plaque morphoea |
Occurrence of multiple plaques of
morphoea at three or more anatomical sites a Isomorphic pattern: plaques
coalesce in the inframammary area and bra‐line, waistband and around the
hips and inguinal regions at sites of repeated minor trauma from clothing Non‐isomorphic
pattern: multiple individual plaques occur in a usually symmetrical
distribution on the trunk and limbs. |
|
|
Pansclerotic
morphoea |
Circumferential
involvement to
all depths of skin, extending from dermis to the bone, of the majority of body surface areas with sparing of
fingers, toes and nipples. |
|
Linear type |
|
|
|
Trunk/limb
variant |
Linear
morphoea |
Blaschkoid
linear induration of the limbs or trunk involving the dermis, subcutaneous
tissue ± underlying muscle and bone |
|
|
||
|
|
||
|
Head/neck
variant |
Morphoea
en coup de sabre |
Blaschkoid
linear induration affecting the face and scalp, may involve underlying
muscle, bone, eye and brain |
|
|
Progressive
hemifacial atrophy |
Non‐indurated
skin with atrophy on one side of the face. Probable Blaschkoid distribution.
May involve the dermis, subcutaneous tissue, muscle, bone, eye and brain |
|
Mixed type |
|
A
combination of two or more of the above subtypes, most often linear and
plaque |
|
Morphoea–lichen sclerosus overlap |
|
Morphoea
and extragenital lichen sclerosus lesions may occur at the same site. Small
patches of lichen sclerosus may arise within a larger plaque of morphoea.
Usually truncal but may be widespread. Evidence of genital lichen sclerosus
should be sought |
|
a |
The
seven anatomical sites include the head–neck, right and left upper limbs,
right and left lower limbs, anterior trunk and posterior trunk. |
2.
Limited type
Limited
plaque morphoea
This commonest form of morphoea presents with round to oval
lesions >1 cm in diameter, in up to two of seven anatomical regions
(head–neck, each limb, anterior trunk, posterior trunk). Plaques are most
frequently located on the trunk and in general are between 2 and
15 cm in diameter, poorly
defined, round or oval, often better felt than seen. They
are usually multiple and asymmetric, but marked variation exists. Individual
lesions may enlarge significantly or remain stable in size. The breasts are often involved, but the nipples and areolae
are uniformly spared. This type is also referred to as circumscribed
superficial morphoea, so histopathological changes are usually limited to
reticular dermis. Patients with limited morphea should be closely followed, as
both linear and generalized morphea may begin with circumscribed lesions.
Guttate
morphoea
This is a rare variant, similar to
plaque morphoea, in which multiple, small (<1 cm) erythematous or yellowish
white mildly indurated sharply demarcated plaques, primarily involve the neck and the upper
portion of the trunk. Lesions
are superficial and may have a shiny, crinkled surface, clinically resembling
extragenital lichen sclerosus. It may be difficult to distinguish guttate morphoea
from extragenital lichen sclerosis on clinical and histopathological grounds
and some consider guttate morphoea to be a type of lichen sclerosis associated
with morphoea. In contrast to extragenital lichen sclerosus, however, lesions
generally resolve leaving hyper pigmentation. Involves the papillary and superficial
reticular dermis.
Atrophoderma of Pasini–Pierin
It is thought to represent a superficial variant of plaque-type morphea and
resembles "burnt-out" morphea. Multiple,
round to oval, non‐indurated, sharply demarcated, hyper pigmented, depressed patches,
with a ‘cliff‐drop’ border, symmetrically distributed, most commonly found on the
posterior trunk. In old lesions, the centre of the depressed
area may feel slightly indurated. In the superficial reticular dermis, collagen
bundles are thickened and tightly packed. In addition, indurated areas may show
homogenous hyalinised collagen bundles.
In atrophoderma of Pasini–Pierin,
the atrophy comes first and the sclerosis possibly appears later, whereas in
morphea, the sclerosis comes first and the atrophy appears later.
Keloidal/nodular
morphoea
|
|
Inflammation within the dermis
leads to thick, keloid-like nodules or bands, usually on the trunk. It can
be clinically indistinguishable from indurated keloids. |
Limited
deep morphoea
The
term ‘deep morphoea’ describes a variant in which inflammation and sclerosis
affects primarily the deep dermis and subcutaneous fat and may even involve
underlying structures (e.g. the fascia)and even muscles (synonym morphoea profunda). Deep
involvement can occur in all subtypes of morphoea. Patients normally develop a
single or few ill‐defined, indurated and deeply tethered
hard plaques giving a peaud'orange appearance and bound down feeling involving
the upper trunk; ultimately, lesions may calcify, leading to deep osteoma cutis. The
"groove sign" (a depression along the course of a vein, between
muscle groups, or both) may be evident later in the course of disease. The
lesions are frequently hyper pigmented. Histology shows significant hyalinization and thickening of
collagen bundles in the deep dermis, in the septa of subcutaneous fat and in
the fascia.
Generalized morphea
Generalized
morphea normally begins insidiously on the trunk as plaque morphea. An
individual lesion is indistinguishable from classic plaque morphea, except that
it does not stop expanding. >4 plaques, each >3 cm in diameter, involving
at least 3 of 7 anatomic areas: head/neck, right and left upper extremities,
right and left lower extremities, anterior and posterior trunk
Disseminated
plaque morphoea
Isomorphic pattern: plaques coalesce at sites of repeated minor trauma from
clothing such as in the inframammary area and bra‐line, waistband and around the hips
and inguinal regions.
Non‐isomorphic pattern: multiple individual plaques occur in a usually symmetrical
distribution on the trunk and limbs.
Pansclerotic morphea
Pansclerotic
morphoea is defined as the presence of circumferential involvement of near
total body surface area with sparing of the fingers and toes and nipples with
onset of lesions on the trunk with rapid centrifugal spread and abrupt cut‐off
at the metacarpo‐ and
metatarsophalangeal joints. It affects all depths of skin, extending from
dermis to the bone. No internal organ fibrosis.
Disabling
pansclerotic morphea of children is a rare variant, usually affecting
girls from 1 to 14 years in which deep fibrosis progresses rapidly to involve
fascia, muscle and underlying bone. The disease tends
to cause lifelong severe disability due to persistent atrophy of the underlying
muscles and contractures of the involved joints and is frequently
complicated chronic ulceration and the development of squamous cell carcinoma.
Linear type
Linear morphea is different from
plaque morphea, with respect to age of onset, distribution, clinical outcome
and serologies. Linear morphea often qualifies as deep morphea (albeit in
a linear pattern), involving the deep dermis, subcutaneous fat, fascia, muscle,
tendons and bone. It may be subdivided into limb/trunk and head variants. The
limb/trunk variant occurs twice as often as the head variant. It is quite
common for the upper and lower limb on the same side to be affected. Although
mostly unilateral, bilateral involvement occurs in 5–25% of cases. Linear
morphoea appears to follow Blaschko lines in the majority of cases suggesting
that genetic mosaicism is important in pathogenesis. Roughly a quarter of
patients with linear disease have another form of morphoea elsewhere (mixed
subtype) and most often this is plaque morphoea.
Head/neck
variant
This variant includes morphoea en
coup de sabre (ECDS) and progressive hemifacial atrophy (PHA), also known as
Parry–Romberg syndrome. ECDS lesions are commoner than PHA. They usually begin
in childhood but occasional adult‐onset cases.
(1) Morphoea
en coup de sabre (meaning stroke or blow with a single-edged sword)
This type of morphea represents linear morphea of the head. It is
normally unilateral and extends from the forehead into the frontal scalp in a
paramedian distribution and follows Blaschko's lines. It may start either
as a linear streak, which may initially mimic a port-wine stain, or as a
row of small plaques that coalesce to form a linear indurated band. Like plaque
morphea, it may exhibit varying degrees of erythema, sclerosis, atrophy and
hyper pigmentation and may initially be surrounded by
a discrete lilac ring. Sclerosis is thought to involve the skin and
subcutis first and then later extend to the underlying fascia, muscle and bone.
The band may extend to involve the eyebrows, nose and
even the cheeks. Scarring alopecia of the eyelashes, eyebrows and scalp
occur if they are involved in the band. Linear depressions in the skull bones
are a common consequence. Rarely, the inflammation and sclerosis progress to
involve the meninges and even the brain, creating a potential focus for
seizures.
(2) Progressive
hemifacial atrophy
Hemifacial
atrophy, or Parry–Romberg syndrome, is probably a very severe variant of linear
morphea, but it may be a phenotype for more than one
entity. It is a unilateral, progressive, primary atrophic disorder of
the skin, subcutaneous tissue, muscle and underlying cartilage and bone, but
little or no sclerosis. The entire distribution of
the trigeminal nerve, including the eye and the tongue, may be affected. A
progressive facial asymmetry develops as a result of a gradual loss of fat and
muscle, and atrophy of the frontal, maxillary and/or mandibular bones. The
mouth and nose become deviated towards the affected side. Enophthalmos is
caused by a combination of progressive fat atrophy, shrinkage of the eyeball
and thinning of the extraocular muscles. Neurological complications with
headache and epilepsy are being the most common.
Comparison of PFH and Morphea "en coup de sabre"
|
Findings |
PFH |
Morphea "en coup de
sabre" |
|
Face |
Unilateral atrophy |
Unilateral, frontoparietal sclerotic band |
|
|
Minimal or absent induration or previous
inflammation |
Usually preceded by skin induration |
|
|
Cutaneous atrophy (normal hair and absent sclerosis) |
Usually does not extend below the eyebrow |
|
|
Associated with dysplasia of the underlying bone,
tongue, gingiva and unilateral palate |
Important, depressed, hyper pigmented, shiny
cutaneous sclerosis involving the scalp |
|
|
|
Frequently causes deformity and contractures |
|
|
|
Softening of lesions takes place over time |
Trunk/limb
variant
Linear morphea may begin as a linear, erythematous (inflammatory) streak, but more
frequently begins as a row of small plaques that
extend longitudinally that then join to form a linear indurated band. As in morphoea ECDS, linear bands seem to follow Blaschko's
lines and may exhibit varying degrees of erythema, sclerosis, atrophy and hyper
pigmentation. Linear
morphea tends to involve the
dermis, subcutis, underlying fascia, muscle, tendons and bone.
Linear
scleroderma involving an extremity is associated with a risk of undergrowth,
both linear and circumferential, of the affected limb resulting in limb girth
asymmetry and limb length discrepancy. Impaired joint mobility and contractures
are additional risks when the sclerodermatous area overlies a joint.
Linear
atrophoderma of Moulin
Patients
present with unilateral, depressed, hyper pigmented Blaschkoid plaques on the
trunk and limbs. Linear atrophoderma of Moulin appears to lie within the morphoea
spectrum and be akin to a linear Blaschkoid form of atrophoderma of
Pasini–Pierini. Histologically, perivascular inflammation and thickening of
collagen fibres in the superficial reticular dermis constituted a significant
overlap with atrophoderma of Pasini–Pierini and morphoea.
Linear
deep atrophic morphoea
This is a linear primary atrophic morphoea with no preceding
clinical inflammation or sclerosis, involving the deep dermis and subcutis, and
resembling PHA on a limb.
Mixed type
Mixed morphoea describes the
coexistence of more than one subtype of morphoea. The commonest combination is
linear limb/trunk and plaque morphoea, but any combination can occur.
In most patients, untreated plaque
type morphea normally progresses over 3–5 years, then arrests and eventually
resolves spontaneously. Lesions of linear scleroderma tend to last longer, even
having long periods of quiescence followed by reactivation. Virtually all
patients show residual persistent atrophy and dyspigmentation.
Morphea in Childhood
Approximately
20% of individuals with morphea are children and teenagers. The female-to-male
ratio for plaque-type morphea in this age group is about 2: 1, with a mean age
at disease onset of 7 years. In two-thirds of patients with linear morphea,
disease onset is prior to age 18 years, providing an explanation for the
possibility of growth retardation of the affected limb. Thus, if left
untreated, linear morphea may result not only in decreased range of motion of
joints but also in permanent limb asymmetry from unilateral hypoplasia.
Related Physical Findings
Extracutaneous manifestations develop in
22%–56% of morphea patients. Articular and muscular involvement (arthritis,
myalgias, neuropathies, and carpal tunnel syndrome) is the most common finding
(12%) and can occur unrelated to skin lesions. Cutaneous disease itself
produces limited range of motion, limb length discrepancy, joint deformity, and
contracture (45%–56% linear morphea). Patients with lesions crossing joint
lines are most at risk. ECDS is associated with neurologic and ocular
complications (3.6%) including seizures, headaches, adnexal abnormalities
(eyelids, eyelashes), uveitis, and episcleritis. Facial morphea may produce
dental malocclusion, altered dentition, and atrophy of the tongue and salivary
glands.
Complications
Children with morphea can have significant morbidity
related to morphea, including effects on growth, function, and quality of life.
Muscle weakness may occur in affected extremities or face. Behavioral changes,
learning disabilities, and seizure (sometimes preceding cutaneous lesions) have
been reported in children with (and without) facial involvement. In addition,
disfigurement and physical symptoms (fatigue, pain, and itch) associated with
morphea affect psychosocial development and play a substantial role in the
quality of life for patients with morphea.
Pansclerotic morphea has been associated with an
increased risk of squamous cell carcinoma due to chronic ulcers. The resulting
sclerosis of the skin can cause significant contracture, and produces
restrictive pulmonary defects and dysphagia. Circumferential sclerosis of the
arms or legs may also produce compartment syndrome, bullae, and ulcers.
Morphea may coexist with other autoimmune diseases
(systemic lupus erythematosis, vitiligo, primary biliary sclerosis, autoimmune
hepatitis, Hashitmoto's thyroiditis, and myasthenia gravis). In particular,
generalized morphea has been associated with an increased rate of autoimmune
disease.
Prognosis and Clinical
Course
Although morphea causes functional and aesthetic
impairment, it is rarely life-threatening. Morphea may be self-limited, but
frequently has a remitting relapsing or chronic course producing significant
disease burden over time.
Investigations
The diagnosis of
morphea is usually made by the clinical appearance of the lesions. Histological
examination may aid therapeutic decision-making because it is sometimes
difficult to determine the degree of activity or depth of involvement by
clinical examination alone. Biopsy of the advancing edge of a lesion may
provide insight into both. An
incisional ellipse through the violaceous/inflammatory edge of a lesion, into
the sclerotic centre and extending down into the subcutis, should be taken.
Pathology
In most situations, morphologic changes are
best seen at the border between the dermis and subcutaneous fat. All subtypes of morphoea share similar findings of an early
active inflammatory phase, in which newer lesions demonstrate a lymphocytic
infiltrate, with a variable number of plasma cells and eosinophils. As lesions
evolve, the numbers of inflammatory cells are reduced as collagen bundles
thicken and skin sclerosis increases in the later fibrotic phase.
Early inflammatory, intermediate, and
late sclerotic stages exist. In the early inflammatory stage, found
particularly at the violaceous border of enlarging lesions, oedema and a dense perivascular infiltrate of lymphocytes,
plasma cells and occasionally eosinophils, is present in the papillary and upper
reticular dermis. The infiltrate may extend into the lower reticular dermis,
around the eccrine glands, into the fibrous trabeculae of the
subcutaneous tissues and beyond.
The reticular dermis shows swollen collagen bundles running parallel to the
skin surface. Trabeculae subdividing the subcutaneous fat are thickened
because of the presence of an inflammatory infiltrate and deposition of new
collagen. Large areas of subcutaneous fat are replaced by newly formed
collagen, which is composed of fine, wavy fibres rather than bundles. Vascular
changes in the early inflammatory stage generally are mild both in the dermis
and in the subcutaneous tissue and consist of endothelial swelling and edema
of the walls of the vessel walls.
In
the sclerotic stage, as seen in the center of
old lesions, the inflammatory infiltrate wanes and ultimately
disappears completely, except in some areas of the subcutaneous fat. The
epidermis is basically normal in appearance, but the rete ridges may be
diminished, leaving a flattened dermal–epidermal junction. Edema is no longer visible in the dermis and upper
subcutis. At this stage, there is homogenization of papillary dermis and
sclerosis extending to the reticular dermis (or beyond depending on the depth
of involvement). Collagen bundles in the reticular dermis appear broad and
thick and closely packed, and hypocellular and
stain more deeply eosinophilic than in normal skin, and are aligned
parallel to the dermal–epidermal junction. The
underlying subcutis is homogenized and hyalinized.
The eccrine glands appear markedly atrophic,
have few or no adipocytes surrounding them, and appear surrounded by newly
formed collagen. In addition, instead of lying near the dermal-subcutaneous
junction as in normal skin, they seem to lie higher in the dermis as a result
of the replacement of most of the subcutaneous fat by newly formed
collagen. Few blood vessels are seen
within the thickened hyalinized (sclerotic) collagen; they often have a
fibrotic wall and a narrowed lumen. In deep morphea the deep reticular dermis,
subcutis, and fascia show similar changes.
Deep morphea affects primarily
the deep
reticular dermis and subcutaneous tissue. Following
the inflammatory phase, extensive sclerosis and hyalinization extend into the
underlying fascia. Involvement of the underlying fascia is obligatory in deep
morphea and is also frequently observed in linear and generalized types of
morphea. In these patients, the fascia and even the underlying muscle
(frequently vacuolated) are involved in the process of progressive sclerosis,
characterized by replacement of the differentiated tissue by collagen bundles.
The atrophic phase is characterized by loss
of inflammatory cell infiltrate, lessening of sclerosis, and absence of
appendegeal structures. Telangiectasia may occur.
Reports of lichen-sclerosus–like changes (edematous,
homogenized collagen) in the papillary dermis have been described in lesions of
morphea.
Imaging Studies
MRI provides a complete assessment of the
extent of disease, including depth of involvement and disease activity. This is
especially helpful when deep involvement is suspected.
Ultrasonography (US) is a sensitive tool to evaluate or
monitor tissue thickness, loss of subcutaneous fat and muscle, or other
architectural alterations. Disease activity can be correlated with the
detection of hyperemia and echogenicity. Discussion with the radiologist
performing the MRI or US studies is crucial to adequately detect and evaluate
change related to the morphea.
Laboratory
Findings
Laboratory
abnormalities are not a prominent feature of morphea, except for generalized
and linear morphea. The ESR and serum protein levels are usually normal, but
eosinophilia may occur, especially during early active phases of the disease. High
titers of antinuclear antibodies (ANA) in juvenile patients with linear morphea
and individuals with generalized morphea, but are uncommon in adults with
plaque-type morphea.
Evaluation and
Treatment
A. Algorithm for the
evaluation of patients with morphea.
B.
Therapeutic algorithm for morphea based on existing evidence. Superficial
involvement is defined by histological evidence of papillary and upper
reticular dermal involvement. Deep involvement is defined as inflammation and
sclerosis of the deep dermis, subcutis, fascia, or muscle. Histological
examination and/or MRI are encouraged to evaluate lesions for depth of
involvement and, likewise, determine appropriate treatment as well as
evaluation of therapeutic efficacy.
Patient Evaluation
In determining which therapy is appropriate, the following
must be considered:
Assessment of Activity of Disease
 |
|
Disease Activity and Damage
Existing studies
indicate that early, active disease is most responsive to any therapy.
Indicators of active disease include development of new lesions or extension of
existing lesions (photographs are critical), erythema and/or induration of the
advancing edge of the lesion, patient reported symptoms such as itch or
tingling. Disease damage (reversible or irreversible) includes pigmentary
change, induration of the lesion center (controversial), atrophy (dermal,
subcutaneous, muscle), contracture, limb length discrepancy, and scarring
alopecia. Disease damage is much more difficult to treat and therapy should be
aimed at preventing disease damage. Further, patients with active disease at
risk for significant damage (facial lesions, PFH, lesions crossing joint lines,
large BSA involvement, rapid progression) likely need aggressive therapy
(phototherapy and/or systemic immunosuppressive).
Depth of Involvement
Morphea involving the
superficial to mid-dermis (relatively thin on palpation or with sclerosis and
inflammation in the papillary and superficial reticular dermis) would logically
be amenable to topical therapy or phototherapy; however, involvement of the
deep dermis and beyond should be treated systemically. Deep involvement can
occur in all subtypes of morphea, but is especially prominent among linear and
some generalized patients.
Disease Progression
Many generalized and linear morphea patients are initially diagnosed with circumscribed morphea, but progress to have much more extensive disease. Therefore, patients who initially present with 1–3 plaques (which may be amenable to localized therapy) should be closely followed. If these patients progress, therapy should then be aimed at preventing further progression (i.e., phototherapy or systemic
therapy).
Disease Subtype
Patients with linear
and generalized (particularly those with rapid onset of confluent plaques) are
likely at risk for severe, extensive disease and should be treated aggressively
either with phototherapy or systemic immunosuppressives depending on the depth
of involvement.
Specific
treatments
Treatment
choices should be based on the subtype of morphoea, the level of disease
activity, depth of disease and, to some degree, on the age of the patient and
patient symptoms.
Morphoea treatments and
levels of evidence (in brackets) a
 |
Topical Treatments
Limited
superficial forms of morphea can generally be treated topically. The
benefit of topical corticosteroids in the treatment of morphea is questionable. Ultrapotent topical
corticosteroids may be useful for reducing inflammation in superficial active
lesions. Asymptomatic
plaques should probably be left alone to resolve spontaneously. Class 1 topical
steroids and occlusion may induce slight improvement. They should be used in
the active phase of the disease and their application should be restricted to 3
months. Inducing atrophy by infiltrating with triamcinolone acetonide (10
mg/ml) may be useful in areas where skin thickening causes limitation of
motion, particularly in linear forms. The injection should be performed into
the active margins. Topical corticosteroids are
ineffective in resolving sclerosis.
Calcipotriene inhibits the proliferation of fibroblasts. Calcipotriene
ointment is the topical treatment of choice and has been shown to stop the
progression of morphea when used early in the course, twice daily, without
occlusion in the morning but with occlusion at night. The effects of the
application are evident by 1 month. Calcipotriene should be used when sclerosis
is superficial. Calcipotriol-betamethasone dipropionate have also shown
benefit.
Tacrolimus
0.1% ointment (ointment applied twice daily to a target plaque, occluded)
showed improvement in 1 month. There is greater improvement in early, active
lesions.
The combination of physiotherapy, massage, warm baths, and
exercise are often helpful for patients with linear morphea in whom the
involvement overlies a joint because of the risk of contractures.
Phototherapy
If there is no deep
involvement, disseminated plaque morphea can be treated with phototherapy,
preferably UVA‐1 or bath PUVA. Following 30–36 treatments of bath PUVA therapy (at slightly sub-erythematous
doses) or UVA1 (60 J/cm2), morphea
resolves or markedly improves in at least 60% of patients.
Advantages
of phototherapy, and especially UVA1, include clinical improvement in all skin
types and sustained remissions. Recurrence of morphea plaques after
successful phototherapy has been reported, but primarily in patients with a
prolonged period of disease prior to initiation of phototherapy. The dose of
UVA1 phototherapy (medium versus high) does not appear to correlate with risk
of recurrence.
Both
photo chemotherapy and UVA1 induce expression of matrix metalloproteinase 1, a
collagenase that reduces procollagen and collagen within the skin. The
regression of morphea can be objectively documented by measuring skin thickness
by 20 MHz ultrasound. Both photo therapies seem to be effective in all types of
morphea except for morphea profunda. In
the case of photo chemotherapy, it has been administered primarily as bath PUVA
therapy; less commonly as cream PUVA or systemic PUVA.
UVA wavelengths
(320–400 nm) penetrate deeper into the dermis than UVB (280–320 nm). UVA‐1 have all shown
efficacy, significantly reducing skin thickness and stiffness in adults and
children with all forms of morphea. Early inflammatory and sclerotic lesions
appear to respond most favorably, and cases with deep involvement least
favorably.
Medium doses (60
J/cm2)appear more effective than low‐dose UVA‐1 (20 J/cm2) based on ultrasound
measurements of skin thickness and may give better long‐term results. The current recommendation,
where available, is to use medium‐dose UVA‐1 (60 J/cm2) 3–5 times weekly for a total of 40
sessions. Importantly, in responding patients, lesions of morphea continue
to improve beyond the end of the therapy. Thus, therapy can be terminated after
36 treatments, even if the sclerosis has not yet completely resolved. The only
exception appears to be linear morphea, which may require up to 60 treatments. Nevertheless, low‐dose UVA‐1 therapy may still have a role, particularly if combined
with topical modalities such as vitamin D analogues.
Selected patients who fail to respond to one
mode of phototherapy may benefit from a switch to the other, i.e. if a patient
does not improve within 4 months with one type of phototherapy (e.g. bath
PUVA), a new therapy cycle should be initiated utilizing another mode of
phototherapy (e.g. UVA1). In contrast to the therapeutic success reported with
UVA1 or bath PUVA, NB-UVB has no major impact on the clinical course of
morphea.
Before initiating UV phototherapy, it should be considered
that UV only penetrates into the dermis but not deeper structures(fat tissue,
fascia, muscle or bone),so the subtypes of deep morphea must not be treated
with phototherapy.
Systemic
Treatments
The first-line systemic therapy for severe forms of morphea
(linear, generalized and deep subtypes); lesions producing functional
impairment; rapidly progressive or widespread active disease; and patients who
have failed phototherapy is the combination of methotrexate and systemic corticosteroids.
Monthly
pulsed intravenous (1 g, 3 days per month, for 6 months in the adults and 30
mg/kg/day, 3 days per month, for 3 months in children) and methotrexate at
doses of 0.3–1 mg/kg/week (maximum dose 25 mg) in children and 15 mg/week in
adults.
Oral corticosteroids alone (methyl prednisolone or prednisone
1–2 mg/kg/day) may also be helpful during the inflammatory stages of morphea,
especially in those patients with rapidly progressive linear or disabling
morphea in both children and adults. However, systemic corticosteroids do not
improve established sclerosis and disease activity may rebound following
discontinuation.
In resistance cases, both methotrexate and corticosteroids can be
combined with either UVA1 or bath PUVA.
Among
systemic treatments, the best evidence exists for the use of methotrexate. The
rational is MTX inhibits cytokines that play a central role in sclerotic skin
changes (IL-2, L-4, and IL-6).
Mycophenolate
mofetil has more recently been used in individuals who have failed to respond
to steroids and methotrexate or in combination with methotrexate for greater
effect.
The
treatments discussed thus far are aimed at switching off active disease and
preventing damage. Once damage such as dyspigmentation, atrophy or bony
asymmetry has occurred, treatment should aim at improving the cosmetic
appearances, provided that the disease is no longer active. To this end various
techniques of autologous fat grafting alone or in combination with surgery have
gained popularity in the treatment of tissue defects of the face.
