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Localized scleroderma progressing to systemic disease. case report and review of the literature

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410
LOCALIZED SCLERODERMA PROGRESSING TO
SYSTEMIC DISEASE
Case Report and Review of the Literature
NINA BIRDI, RONALD M. LAXER, PAUL THORNER, MARVIN J. FRITZLER,
and EARL D. SILVERMAN
We describe a 15-year-old girl with biopsyproven morphea who developed progression to systemic
disease 2 years after initial presentation. In contrast to
other reported patients with localized scleroderma,
some of whom have had mild, nonprogressive systemic
involvement, this patient developed severe, debilitating
disease, with skin tightness, sclerodactyly, esophageal
involvement, restrictive pulmonary disease, and myopathy. From the time of her initial evaluation, the patient
was positive for antinuclear antibodies (ANA), which
were shown to be primarily directed against the Ku
antigens. This observation suggests that ANA may be a
prognostic indicator for progression to systemic disease.
Localized scleroderma is a relatively rare condition in children. However, it does occur more com___
-
From the Division of Rheumatology and the Department of
Pathology, The Hospital for Sick Children, Toronto, Ontario, and
the Division of Rheumatology, Clinical Immunology and Dermatology, University of Calgary, Calgary, Alberta, Canada.
Dr. Birdi is a Fellow of the Arthritis Society. Drs. Laxer
and Silverman are Associates of the Arthritis Society.
Nina Birdi, MD, FRCPC: Division of Rheumatology, The
Hospital for Sick Children, and Assistant Professor of Pediatrics,
Staff Rheumatologist, The Children’s Hospital of Eastern Ontario,
Ottawa, Ontario, Canada; Ronald M. Laxer, MD, FRCPC: Associate Professor of Pediatrics, Head, Division of Rheumatology, The
Hospital for Sick Children; Paul Thorner, MD, PhD, FRCPC:
Associate Professor of Pathology, Staff Pathologist, Department of
Pathology, The Hospital for Sick Children; Marvin J. Fritzler, MD,
PhD, FRCPC: Professor and Head, Division of Rheumatology,
Clinical Immunology, and Dermatology, University of Calgary; Earl
D. Silverman, MD, FRCPC: Associate Professor of Pediatrics and
Immunology, Division of Rheumatology, The Hospital for Sick
Children.
Address reprint requests to Ronald M. Laxer, MD,
FRCPC, Division of Rheumatology, The Hospital for Sick Children,
555 University Avenue, Toronto, Ontario MSG 1x8, Canada.
Submitted for publication March 19, 1992; accepted in
revised form November 3, 1992.
Arthritis and Rheumatism, Vol. 36, No. 3 (March 1993)
monly in the pediatric population than does systemic
sclerosis (SSc). Localized scleroderma may be classified into 3 forms: morphea, generalized morphea, and
linear scleroderma. The course of localized scleroderma is usually benign, with slow resolution of the
skin lesions; progression to the systemic form of the
disease is extremely rare. Localized scleroderma and
SSc have a number of features in common, such as the
pathologic findings in the skin and the presence of
autoantibodies, and they may represent two ends of a
spectrum of disease. The patient described herein had
well-documented progression of her disease during a
period of close observation.
CASE REPORT
Clinical course. The patient, a 12-year-old girl,
presented to the division of dermatology at our institution in October 1987, with a 2-month history of rash
on her face and upper arm. The lesions were not
pruritic, tender, or photosensitive. She was otherwise
asymptomatic. There was no history of Raynaud’s
phenomenon, dysphagia, gastroesophageal reflux,
sicca symptoms, skin tightness, alopecia, photosensitivity, fatigue, weight loss, or fevers. She reported
having infrequent retrosternal chest pains. Other than
having mild asthma, she had previously been well. The
family history was positive for systemic lupus erythematosus in the paternal grandmother, and arthritis in a
maternal aunt.
On examination, she had 4 erythematous nodules involving the right nasolabial fold and the right
upper arm. The remainder of her physical examination
findings were normal. The results of laboratory inves-
SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA
41 1
Table 1. Results of laboratory studies and other tests at presentation and at followup*
Oct. 1987
CBC
Eosinophil count
ESR (mdhour; normal 20)
AST (unitsfliter; normal 45)
ALT (units/liter; normal <45)
CPK (unitsfliter; normal <180)
LE cell preparation
ANA
Anti-dsDNA
Anticentromere
Anti-Ku
RF
Urinalysis
BUNkreatinine
Complement C3, C4
Chest radiography
PFT
Chest CT
Gallium scan
Electrocardiography
2D echocardiography, stress
thallium
Upper GI series,
esophagoscopy
Electromyography
Nerve conduction
Triceps muscle biopsy
Normal
Normal
24
64
Not done
Not done
1:1,280
Negative
Negative
Negative
Positive
1:20 (80 IU)
Negative
Normal
Normal
Not done
Not done
Not done
Not done
Not done
Not done
Nailfold microscopy
Feb. 1988
Normal
Normal
53
58
44
Not done
1:1,280
Negative
Negative
Negative
Positive
1:lO (40 IU)
Negative
Normal
Normal
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Nov. 1989
Normal
Normal
35
160
88
1,850-5,628
1 :1,280
Negative
Negative
Negative
Positive
1:20 (80 IU)
Negative
Normal
Normal
Normal
Restrictive defect
Normal
Uptake lower lobes, both lungs
Occasional PVC
Normal
Severe reflux, jejunal dilatation,
esophageal ulceration
“Myopathic”
Normal
No inflammation, few
regenerating fibers, vessels
normal, no eosinophils
Dropout, dilatation
* CBC = complete blood cell count; ESR = erythrocyte sedimentation rate; AST = aspartate transaminase; ALT = alanine transaminase; CPK
= creatine phosphokinase; LE = lupus erythematosus; ANA = antinuclear antibodies; anti-dsDNA = antiaouble-stranded DNA; RF =
rheumatoid factor; BUN = blood urea nitrogen; P I T = pulmonary function testing; CT = computed tomography; PVC = premature ventricular
contraction; 2D = 2-dimensional; GI = gastrointestinal.
tigations are shown in Table 1. Punch biopsy of a
lesion on the upper arm revealed prominent acellular
collagenous fibrosis involving the full thickness of the
dermis to the level of the subcutaneous tissue, with loss
of skin adnexa (Figure 1). Immunofluorescence staining
was negative for immunoglobulin and complement. The
biopsy findings were consistent with morphea.
Four months later (February 88) she developed
pain in the right wrist, right hip, and lower back. She
took tiaprofenic acid 300 mg twice daily, prescribed by
her family doctor, with no improvement. She had also
developed new skin lesions. Physical examination
revealed a well-looking, normotensive girl. Hyperpigmented, indurated lesions were noted on the right
shoulder, extending anteriorly over the clavicle (Figure 2)* She had
pain
the right wrist,
and low ’lack
with
range Of motion and n’
Pain On full flexion. Radiography revealed spinal dysraphism. She was followed up in the dermatology
Figure 1. photomicrograph of &in biopsy specimen from the patient’s upper arm, showing fibrosis of the dermis with loss of skin
adnexa, consistent with morphea (hematoxylin and eosin stained,
original magnification x 80).
412
Figure 2. Photograph of the patient’s shoulder, showing a slightly
raised, ill-defined, hyperpigmented lesion.
clinic. Her facial lesion resolved, and the shoulder
lesion remained stable with topical betamethasone
treatment.
In February 1989 (1 year later), she presented
with anorexia, fatigue, fever, and tender inguinal adenopathy. Lymph node biopsy revealed perinodal fibrosis
and obliterative changes in the blood vessels. The
adenopathy resolved without treatment. In November
1989, she developed a new plaque involving the left
side of the neck, left arm, and posterior aspect of the
right shoulder. In addition, she now had arthralgias
involving the fingers, wrists, and knees, early morning
stiffness lasting 2 hours, fatigue, myalgias, and muscle
weakness. She had triphasic Raynaud’s phenomenon
and reported dry mouth and tightness of the skin
around her mouth and fingers. She had sharp, retrosternal chest pain that radiated to the left shoulder and
was associated with palpitations. She also reported
heartburn, reflux, and bloating after meals. Physical
examination revealed new skin lesions involving the
left side of the neck and both arms symmetrically, and
sclerodactyly. The skin over the arms, chest, abdomen, and thighs was tight. There was proximal muscle
weakness with no distal weakness and no deficit in
sensation or reflexes. There was no Gottron’s sign or
heliotrope rash. Biopsy of the skin of the upper arm
revealed changes similar to those noted previously.
Immunofluorescence results were again negative. Results of laboratory investigations performed at this
time are shown in Table 1.
A diagnosis of SSc was made based on the
BIRD1 ET AL
sclerodactyly, Raynaud’s phenomenon, dysphagia,
esophageal dysmotility , restrictive pulmonary defect,
arthralgias, and myopathy. Her subsequent course has
been characterized by persistent proximal muscle
weakness with serum creatine phosphokinase levels
ranging from 2,000 units/liter to 3,000 unitsfliter. She
also has had shortness of breath, episodic chest pain,
and worsening dysphagia, and decreased lung volumes
demonstrated on chest radiography. Response to
treatment with high-dose prednisone (60 mglday), penicillamine, and nifedipine has been minimal. The myopathy responded transiently to intravenous pulse
methylprednisone (1 gm daily for 3 days). A 6-month
course of cyclosporin A resulted in softening of her
skin, but no improvement in the muscle weakness.
ANA studies. Antinuclear antibody specificity
was characterized on the basis of indirect immunofluorescence (IIF), double-immunodiffusion, and Western
immunoblotting, using control samples of known specificity (Sm, UI RNP, Ro, La, double-stranded DNA
[dsDNA]), as described previously (1,2). A prototype
anti-Ku serum (a gift from Dr. Eng Tan, Scripps Clinic
and Research Foundation, La Jolla, CA) was used. The
ANA titer as determined by IIF on HEp-2 substrate
(Immuno Concepts, Sacramento, CA) was 2 1: 1,280 in
all samples tested. No anticentromere antibodies were
seen. No antibodies against dsDNA, histone, Sm, U1
RNP, SS-AIRo, SS-B/La, or Scl-70 were detected.
However, double-immunodiffusion studies suggested
the presence of anti-Ku antibodies (results not shown).
This was confirmed by Western immunoblotting using
MOLT-4 whole cell extract separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The 2
protein bands reactive with the patient’s serum were
identical to the 80-kd and 70-kd Ku antigens bound by
the prototype serum (Figure 3). All samples demonstrated the same pattern of reactivity although there
was variability between samples in the titer of anti-Ku,
as implied by the intensity of the reaction.
DISCUSSION
Localized scleroderma can be classified into 3
forms: morphea, generalized morphea, and linear
scleroderma. Although localized scleroderma is not
considered to be a systemic disease, arthralgias, arthritis (3,4), and myopathic changes similar pathologically to those seen underlying an involved area of skin
in juvenile dermatomyositis ( 5 ) can occur. Raynaud’s
phenomenon is rare. An increased incidence of spinal
dysraphism has been reported (4). Laboratory abnor-
SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA
Figure 3. Immunoblotting profile of the patient. MOLT4 whole cell
extract was separated by sodium dodecyl sulfate-polyacrylamide
gel electrophoresis, transferred to nitrocellulose, and probed with
patient serum diluted 1:lOO. Lane 1, Prototype anti-Ku serum.
Lanes 2-6, Sequential samples from the patient, showing reactivity
with the 80-kd and 70-kd Ku proteins. Lane 7, Normal human serum
(NHS). Molecular mass markers are indicated on the left.
malities may include eosinophilia, elevated erythrocyte sedimentation rate (ESR),hypergammaglobulinemia, positive ANA, double-stranded and singlestranded DNA antibodies, positive lupus erythematosus
cell preparation, rheumatoid factor (RF),and positive
Borrelia burgdorferi serology (6-9), but all of these
may also be normal in localized scleroderma. Pathologically, the skin lesions of localized scleroderma are
indistinguishable from those of systemic sclerosis.
413
The course of localized scleroderma is generally benign, with spontaneous resolution of the skin
lesions over several years. Progression to the systemic
form of the disease is considered to be extremely rare
(6). Our patient presented with biopsy-proven morphea and had positive ANA and RF, mild hypergammaglobulinemia, and transiently elevated ESR. Other
than mild arthralgias, she had no evidence of systemic disease until 2 years after her initial presentation. In retrospect, the retrosternal chest pain and
lymphadenopathy may have indicated a systemic disease process.
Progression of localized scleroderma to SSc has
been reported, albeit infrequently. Christianson et a1
(4) reported that 2 of 235 patients with generalized
morphea developed SSc. Curtis and Jansen (10) noted
progression in 6 of 106 patients with localized scleroderma. Some investigators have documented the presence of abnormal esophageal peristalsis and decreased
carbon monoxide diffusing capacity in patients with
localized scleroderma (1 1-13). These patients do not
fulfill criteria for a diagnosis of SSc (14), and the
systemic involvement appears to have a mild and
nonprogressive course. Falanga and colleagues (15)
reported 53 patients with linear scleroderma, none
of whom had signs of systemic progression after a
mean followup time of 10 years. The issue of whether
patients with localized scleroderma are at increased
risk of systemic progression remains unresolved. It
has been suggested that the presence of generalized
morphea, symmetric skin involvement, or Raynaud’s
phenomenon may represent a transitional form of
the disease.
The difficulty in determining the incidence of
systemic progression stems from a number of factors:
Not all patients have had clear documentation of the
presence of sclerodactyly , Raynaud’ s phenomenon, or
dysphagia at the onset of their localized scleroderma.
Systemic involvement, if present, may be asymptomatic.
Localized scleroderma itself may have some mild systemic features in addition to the occasional elevated
ESR, hypergammaglobulinemia,and positive results on
serologic immunologic tests that are not considered to
denote a more serious systemic disease. It is impossible
to distinguish the conditions based on skin pathology.
Localized scleroderma and systemic sclerosis likely
represent two ends of a continuous spectrum of disease. Our patient represents a well-documented case
of progression along this spectrum. In contrast to most
other reported patients with localized scleroderma and
mild systemic features that have generally remained mild
BIRD1 ET AL
414
on followup, this patient’s course evolved to severe,
debilitating systemic disease.
Of interest, early in the patient’s clinical
course, she had autoantibodies directed against the
80-kd and 70-kd Ku antigens. The presence of this
antibody has remained constant throughout her clinical course, with apparent changes in titer as estimated
by the intensity of the immunoblotting reaction.
Anti-Ku antibodies were originally detected in patients
with polymyositislscleroderma overlap (16), but more
recent studies have identified these antibodies in a
wide variety of connective tissue diseases including
systemic lupus erythematosus, scleroderma, myositis,
Sjogren’s syndrome, and mixed connective tissue disease (17). They have not been described in patients
with localized scleroderma (18,19). The importance of
the observation that this patient had anti-Ku antibodies when she presented with localized scleroderma is
twofold. First, similar to reports of anticentromere
antibodies in the CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) variant of scleroderma (20,21), the presence of anti-Ku may be a marker for morphea patients
whose disease will progress to a systemic form. Second, it is possible that the presence of these markers
early in the disease process was an indication of much
more widespread systemic involvement than was
recognized.
We suggest that all patients with localized
scleroderma be carefully evaluated for the presence of
systemic involvement. Patients with evidence of systemic involvement may be at risk for progressive,
severe disease. With thorough clinical and laboratory
monitoring, a better understanding of the eventual
disease course and outcome of localized scleroderma
may be achieved.
ACKNOWLEDGMENTS
The authors thank Dr. Bernice Krafchik for referring
the patient, Edda Laxer for editorial assistance, and Joanne
Blagdon for preparation of the manuscript.
REFERENCES
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RR: Localized scleroderma: a clinical study of two
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characterization of novel DNA-binding proteins recognized by human autoimmune sera. J Exp Med 161:1839, 1985
SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA
18. Yaneva M, Arnett FC: Antibodies against Ku protein in
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