ARTICLE
Scleroderma is a chronic disease of unknown aetiology in which sclerosis
of the skin develops with or without involvement of internal organs. Based
on the presence or absence of systemic disease, scleroderma is divided
into very distinct clinical categories: systemic scleroderma or systemic
sclerosis (SSc), and localized scleroderma (LS) or morphea. The latter
may be further subdivided into the following major types: (a) plaque morphea;
(b) generalized morphea; and (c) linear scleroderma. However, other less
common or exceedingly rare variants of LS are seen [1]. Children are more
likely than adults to develop LS, particularly linear scleroderma [2].
Furthermore, the pediatric population more frequently shows extracutaneous
changes, most notably orthopedic, ocular and neurologic abnormalities.
We examined, retrospectively, 239 patients (113 adults and 126 children)
with various forms of LS, with the aim of defining the prevalence and
type of laboratory abnormalities, and extracutaneous manifestations. More
intriguingly, we attempted to characterize the differences between the
adult and pediatric groups, with relation to the clinical and biological
parameters mentioned above.
Patients and methods
We evaluated, by using a retrospective method, 239 patients suffering
from LS, seen at our department from 1980 up to 2001. All the patients
were diagnosed as having different clinical variants of LS, according
to the classification system proposed by Peterson et al. [1]. Clinical
parameters evaluated were: age, sex, type of skin lesions, systemic symptoms
and signs, duration of disease, follow-up, and associated disorders. To
class a patient in the adult group versus the childhood group, the age
of onset cut-off was considered by ourselves to be 15 years. All
patients were re-evaluated by clinical examination at the moment of performing
this study.
Complete remission was defined as clinically proven lack of inflammation
and/or complete absence of residual sclerosis in typical skin lesions.
The severity of skin sclerosis was evaluated by a semiquantitative scale
(0 = normal skin; 1 = mild sclerosis; 2 = moderate
sclerosis; 3 = severe sclerosis) in different lesions, according
to a method previously used by ourselves [3] and expressed as the mean
value of scores.
Relapse was defined as occurrence, in an apparently stationary stage of
disease, of a new skin lesion and/or new inflammation or sclerosis signs
in a pre-existing lesion and, in the forms of deep morphea, new involvement
of deeper tissue and muscle.
We considered the following laboratory findings: routine laboratory examinations,
including blood cell counts, erythrocyte sedimentation rate (ESR) and
rheumatoid factor (RF), immunoglobulin (Ig) serum levels, namely IgG,
IgM, and IgA, antinuclear antibodies (ANA) and anticentromere antibodies
(ACA), as determined by indirect immunofluorescence (IIF) studies on Hep-2 cells,
anti dsDNA by IIF on Crithidia luciliae, and various circulating autoantibodies,
as demonstrated by IIF or enzyme-linked immunosorbent assay (ELISA). ANA
positivity was considered significant when a titer of 1:160 or higher
was found. Pulmonary function tests with diffusion capacity for carbon
monoxyde (DLCO) were made in all adult patients and in 42 of 126 children,
showing adequate compliance. Staging procedures also included capillaroscopy,
esophageal manometry and electromyogram in those cases complaining of
Raynaud's phenomenon, dysphagia, and myalgia and/or weakness, respectively.
Both electroencephalography (EEG) and magnetic resonance imaging (MRI)
of the brain were performed in the subjects diagnosed as having progressive
facial hemiatrophy (Parry-Romberg syndrome) or linear scleroderma en coup
de sabre, independently from the development of neurologic symptoms and
signs.
Results
The clinical findings in the group of adults with LS are summarized in
the Tables I-IV. This
group included 113 patients with a mean age of 52 years; the
mean age at the disease onset was 46 years. The mean duration of
disease was 5.8 years, while the mean of follow-up was of 4.8 years.
The prevalence of different variants of LS in the above group is reported
in Table II. All of the patients were alive and in good general
health and in 104 of the 113 patients the disease was in complete
clinical remission. In contrast, in 9 cases, most notably including
subjects with generalized morphea or with morphea profunda, the condition
showed a chronic course with several recurrences. In regard to the main
systemic symptoms and signs (Table III), an impaired pulmonary
function, as demonstrated by a reduction of DLCO and/or of vital capacity
(VC), was seen in 9% of the cases (10 patients). Among the aforesaid
patients, 5 were affected by plaque morphea and 3 by generalized
morphea while the other 2 were suffering from linear scleroderma
and morphea profunda, respectively. However, in all the above cases an
high-resolution computed tomography (CT) scan of the lung was performed,
ruling out interstitial pulmonary fibrosis. Other visceral involvement
by scleroderma was also excluded after a median follow-up of 7 years.
Raynaud's phenomenon, usually associated with nail-fold capillaroscopic
abnormalities suggestive of connective tissue disease, was observed in
7% of the patients (8 cases). Within this group of patients, 5 were
suffering from plaque morphea, 2 from generalized morphea and the
last one from morphea profunda. The range of capillaroscopic changes included
elongation and/or tortuosity and/or coiling; aneurysmal dilatations with
varying degrees of bleeding and/or atrophy and absorption of nail-fold
capillaries were more rarely seen. Also in these patients progression
to systemic disease was ruled out after a mean follow-up of 7 years.
Orthopedic complications, such as subcutaneous tissue and muscle atrophy,
impaired joint motility and severe joint contractures, were rarely seen
in the group of adults with LS. However, these complications were rather
common in several variants of LS, particularly in generalized morphea
(4 out of 9 cases) and morphea profunda (2 out of 4 cases).
As for the routine laboratory tests (Table IV), increased ESR was
found in around 10% of patients, whatever the variant of LS and disease
activity. Interestingly, blood eosinophilia, although seen only in about
6%, was much more common in generalized morphea and morphea profunda and
it appeared to be associated with an active disease or herald a relapse.
From an immunological point of view (Table IV), ANA positivity
was found in 45% of patients, however not correlating with disease activity.
Furthermore, various serum autoantibodies were present in 20% of cases.
It is noteworthy that antibodies to topoisomerase I, namely scl-70 antibodies,
regarded as a serologic marker of SSc [4], were present at high titer
in one subject who also developed Raynaud's phenomenon associated with
capillaroscopic abnormalities suggesting connective tissue disease. However,
in this case progression to SSc did not occur after a follow-up period
of 5 years. Interestingly, ACA, said to be a marker of CREST (calcinosis,
Raynaud's phenomenon, esophageal dismotility, sclerodactyly, telangectasias)
syndrome [5], were positive in 6 cases, 4 of whom having Raynaud's
phenomenon and capillaroscopic changes. Also in the 4 aforesaid cases,
we failed to demonstrate systemic disease after 7 years of follow-up.
The clinical findings in the group of children
with LS are summarized in Tables
I-IV. This group included 126 patients, with a mean age of 24 years
at the time of writing of the study. The mean age at disease onset was
10.5 years. The mean duration of disease was 13.5 years, the
mean follow-up 9 years. The prevalence of the different variants
of LS is reported in Table II. In 117 of the 126 patients
the disease was in complete clinical remission, although in around one
third of these cases relapses had previously developed. On the other hand,
in 9 cases the disease was still active and complicated by orthopedic
(5 patients), neurologic (3 patients) and gastrointestinal (one
patient) abnormalities. As regards for the main systemic symptoms and
signs, Raynaud's phenomenon in combination with capillaroscopic abnormalities
was seen in 2% of patients. Pulmonary function tests documented a reduction
of DLCO only in 3 children (around 7%); both in these last and in
those presenting with Raynaud's phenomenon progression to systemic disease
was ruled out over a 7-year follow-up period.
Orthopedic complications occurred in 12% of total pediatric patients but
in around 45% (10 out of 22 patients) of children suffering
from linear scleroderma. Patients with acral linear scleroderma showed
growth defects with shortening of the affected extremities. Distressing
complications, most notably seen in the case of "disabling pansclerotic
morphea", included fat tissue and muscle atrophy, joint immobilization
and sometimes bone involvement. Scoliosis was another common clinical
finding (5% of children but 18%, namely 4 patients out of those with
linear scleroderma).
Ocular changes occurred only in children having craniofacial linear scleroderma,
namely Parry-Romberg syndrome (4 cases) or linear scleroderma en
coup de sabre (one case), or mixed forms (3 cases) presenting as
craniofacial linear scleroderma associated with plaque morphea or linear
scleroderma on other sites, their prevalence being of around 47% (8 out
of 17 patients). The clinical findings included: exophthalmos (2 cases),
ptosis (2 cases), resorption of orbital bone resulting in displacement
of the outer canthus (3 cases), uveitis (one case).
Oral changes were also seen only in the aforesaid variants with a prevalence
of around 41% (7 out of 17 patients); namely, 2 children
showed dental abnormalities, another 3 presented with malocclusion,
2 had tongue changes.
Neurologic abnormalities were found in around 47% (8 out of 17) of
children with craniofacial linear scleroderma or the mixed forms mentioned
above. As for the impairment of the neurologic function, brain MRI abnormalities
were demonstrated in 6 patients, three of whom also showed neurologic
symptoms, including seizures, hemiparesis and muscle weakness episodes,
respectively. 2 other children complained of neurologic disturbances,
such as migraine headaches and trigeminal neuralgia, respectively.
In the only case of "disabling pansclerotic morphea", namely a 16 year-old
girl, small bowel vascular changes leading to recurrent intestinal bleeding
were associated; mesenteric angiography was performed revealing telangiectasias
of jejunum circulation [6].
Routine laboratory tests (Table IV) documented increased ESR only
in 2% of patients. Blood eosinophilia was detected in around 7% of children,
most frequently in those suffering from generalized morphea or linear
scleroderma with more severe and extensive disease. ANA positivity was
documented in around 26% of children, whereas various serum autoantibodies
were present in around 7% of children, as indicated in Table IV.
Scl-70 antibodies were found in 3 children but none of them
developed systemic disease over a 7-year follow-up period.
Discussion
We reexamined retrospectively 239 patients suffering from LS to highlight
the analogies and differences between adults and children.
The prevalence of the various subtypes of LS differed between the two
groups.
Morphea en plaque was the most common form of LS among the adult patients
as well as in the pediatric group, confirming previous reports [1]. However,
linear scleroderma affected children much more frequently than adults.
Furthermore, the forms that we called "mixed" represented a peculiar variant
of LS in children, only rarely seen in adults. This subset was characterized
by an overlap among different variants of LS, occurring simultaneously
or developing subsequently during disease course. The usual clinical presentation
was the association between single or multiple typical plaques of morphea,
most commonly involving the trunk, and one or several band-like sclero
derma lesions on the extremities. Orthopedic complications of linear scleroderma
represented the most distressing problem in these patients.
Interestingly, the cases characterized by a combination of multiple plaques
and one or several band-like lesions (40% of children having "mixed" forms,
namely 7 subjects) showed a more prolonged course with a large number
of relapses. More rarely (20% of children displaying "mixed" forms, namely
4 patients), plaque morphea or linear scleroderma were associated
with craniofacial linear scleroderma. Neurologic abnormalities might represent
severe complications in these patients [7]. It is noteworthy
that in almost all children having "mixed" forms with multiple lesions
and/or craniofacial involvement ANA positivity was found (60% of cases,
namely 11 patients); this finding seems to suggest that ANA positivity
may characterize the "mixed" forms following a more protracted and complicated
course. It may be hypothesized that the pathophysiologic mechanisms of
scleroderma, such as vascular damage and immune system dysfunction, involve
both the skin and deep tissues at different anatomical sites, leading
to such a "mixed" clinical presentation, but the pivotal causes of it
remain unknown.
The forms of linear scleroderma with craniofacial involvement, classically
named scleroderma en coup de sabre and Parry-Romberg syndrome, represent,
taken together, the other subset characteristic of childhood. Although
the issue of Parry-Romberg syndrome differing from linear scleroderma
is still debated, in agreement with the majority of investigators [8-10]
we consider these entities as parts of a clinicopathological spectrum
that also includes cases with features of both diseases [7].
As regards the relation between SSc and localized form, it has been compared
with that of discoid to systemic lupus erythematosus; however, in lupus
erythematosus such coexistence is more frequent whereas progression of
LS to SSc is exceedingly rare both in adults and in children [2, 10-15].
In our series, we did not find any patient clearly diagnosed as having
a transitional form of LS leading to SSc; on the other hand, a relatively
high proportion of cases exhibiting ANA in association with specific markers
of SSC, such as Scl-70 and ACA antibodies, was detected. Thus, although
the presence of systemic markers is not always a sign of systemic disease,
such patients should be throughly examined for visceral, vascular, muscle
and bone involvement and followed up until regression of the disease,
as also suggested by others [14]. Finally, considering that internal involvement
in LS is regarded as extremely uncommon by almost all the investigators
[2, 10-15], we believe that systemic studies are indicated only in symptomatic
patients and/or in the presence of immune markers for SSc or other connective
tissue diseases. To evaluate possible lung involvement, we systematically
performed pulmonary function tests in all our adult patients and in one
third of children, revealing an impaired DLCO in 9% and 7% of cases, respectively.
However, it is noteworthy that in all cases mentioned above neither a
relation to distinct subsets of LS nor an association with significant
seroimmunologic abnormalities were found. Thus, the significance of these
pulmonary abnormalities remains controversial, as previously suggested
[16].
In contrast, the findings on Raynaud's phenomenon in the adult group seem
to be more intriguing. Raynaud's phenomenon was found in 7% of adult patients,
87.5% of whom showed also ANA positivity. Furthermore, presence of ACA
was demonstrated in 50% of these cases. Thus, although SSc was excluded
over a 7-year follow-period, we believe that further checking of these
patients is mandatory and regard Raynaud's phenomenon as a risk factor
for developing systemic disease.
The complications of LS closely depend on both the affected anatomical
sites and the depth of involvement, that notably differ in the distinct
subsets of LS. Therefore, considering that the prevalence of different
forms of LS varied between adult and pediatric groups in our series, the
extracutaneous complications represented the most noteworthy clinical
feature distinguishing between the two groups. In fact, various neurological,
ophthalmological and oral abnormalities were observed in craniofacial
linear scleroderma, that is considered as characteristic of childhood,
as previously reported [2, 7, 10, 17-21]. Furthermore, orthopedic complications
were common in linear scleroderma involving the limbs, which affected
children much more frequently than adults. On the other hand, orthopedic
changes were also seen among adults with deep morphea.
From an immunological point of view, presence of ANA did not correlate
with disease's activity neither in the adult nor in pediatric group. However,
ANA positivity seems to characterize the "mixed" forms of children following
a more prolonged and complicated course, as mentioned above. We found
various serum autoantibodies in both groups, but in a much higher percentage
among adult subjects. However, we failed to demonstrate a specific antibody
correlating with disease activity and/or being associated with distinctive
subsets of LS. Intriguingly, ACA seem to identify a group of adult patients
complaining of Raynaud's phenomenon, considered by ourselves as at risk
of progression to SSc.
CONCLUSION
In summary, children and adults develop LS with analogous clinical and
immunological characteristics. LS exists in a series of variants the prevalence
of which significantly differs between the adult and pediatric populations,
leading to different extracutaneous complications. In both populations
the relation of LS to SSc should be viewed as a spectrum with very little
chance of progressing from one to another.
We wish to acknowledge the Italian Group of Immunodermatology which
provided some of the cases and Dr. R. Arco for statistical assistance.
Article accepted on 17/1/2003
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