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Systemic sclerosis in childhoodClinical and immunologic features of 153 patients in an international database.

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ARTHRITIS & RHEUMATISM
Vol. 54, No. 12, December 2006, pp 3971–3978
DOI 10.1002/art.22207
© 2006, American College of Rheumatology
Systemic Sclerosis in Childhood
Clinical and Immunologic Features of 153 Patients in an International Database
Giorgia Martini,1 Ivan Foeldvari,2 Ricardo Russo,3 Ruben Cuttica,4 Anne Eberhard,5
Angelo Ravelli,6 Thomas J. A. Lehman,7 Sheila Knupp Feitosa de Oliveira,8 Gordana Susic,9
Galina Lyskina,10 Dana Nemcova,11 Robert Sundel,12 Fernanda Falcini,13 Herman Girschick,14
Ana Paula Lotito,15 Antonella Buoncompagni,6 Flavio Sztajnbok,16 Sulaiman M. Al-Mayouf,17
Ilonka Orbàn,18 Clodoveo Ferri,19 Balu H. Athreya,20 Patricia Woo,21 and Francesco Zulian,1
for the Juvenile Scleroderma Working Group of the
Pediatric Rheumatology European Society
Objective. To determine the clinical and immunologic features of systemic sclerosis (SSc) in a large
group of children and describe the clinical evolution of
the disease and compare it with the adult form.
Methods. Data on 153 patients with juvenile SSc
collected from 55 pediatric rheumatology centers in
Europe, Asia, and South and North America were
analyzed. Demographic, clinical, and immunologic
characteristics of children with juvenile SSc at the
onset, at diagnosis, and during the disease course were
evaluated.
Results. Raynaud’s phenomenon was the most
frequent symptom, followed by skin induration in ⬃75%
of patients. Musculoskeletal symptoms were present in
one-third of patients, and the most frequently involved
internal organs were respiratory and gastrointestinal,
while involvement of renal, cerebral, and cardiovascular
systems was extremely rare. Antinuclear antibodies
were present in the sera of 81% of patients. Anti–
topoisomerase I (Scl-70) and anticentromere antibodies
were found to be positive in 34% and 7.1% of patients,
respectively. Involvement of the respiratory, gastrointestinal, and cardiovascular systems was more frequent
and occurred earlier in patients who died than in those
who survived. Compared with the adult form, juvenile
SSc appears to be less severe, with the involvement of
fewer internal organs, particularly at the time of
diagnosis, and has a less characterized immunologic
profile.
Conclusion. This study provides information on
the largest collection of patients with juvenile SSc ever
reported. Juvenile SSc appears to be less severe than in
adults because children have less internal organ involvement, a less specific autoantibody profile, and a
better long-term outcome.
1
Giorgia Martini, MD, PhD, Francesco Zulian, MD: University of Padua, Padua, Italy; 2Ivan Foeldvari, MD: Ak Eilbek, Hamburg,
Germany; 3Ricardo Russo, MD: Hospital de Pediatria Juan P. Garrahan, Buenos Aires, Argentina; 4Ruben Cuttica, MD: Hospital General
de Ninos Pedro de Elizalde, Buenos Aires, Argentina; 5Anne Eberhard, MB, FRACP: Schneider Children’s Hospital, New York, New
York; 6Angelo Ravelli, MD, Antonella Buoncompagni, MD: Istituto di
Ricovere e Cura a Carattere Scientifico (IRCCS) G. Gaslini, Genoa,
Italy; 7Thomas J. A. Lehman, MD: Hospital for Special Surgery, Weill
Medical College of Cornell University, New York, New York; 8Sheila
Knupp Feitosa de Oliveira, MD: Instituto de Puericultura e Pediatria
Martagao Gesteira, Rio de Janeiro, Brazil; 9Gordana Susic, MD:
Institute of Rheumatology, Belgrade, Serbia; 10Galina Lyskina, MD:
Hospital of Childhood Diseases, Moscow, Russia; 11Dana Nemcova,
MD: First Faculty of Medicine and General Faculty Hospital, Prague,
Czech Republic; 12Robert Sundel, MD: Children’s Hospital Medical
Center, Boston, Massachusetts; 13Fernanda Falcini, MD: Ospedale A.
Meyer, Florence, Italy; 14Herman Girschick, MD: Kinderklinik der
Universitat, Wuerzburg, Germany; 15Ana Paula Lotito, MD, Children’s Institut University of Sao Paulo, Pompeia sao Paulo, Brazil;
16
Flavio Sztajnbok, MD: Hospital Universitario Pedro Ernesto, Rio de
Janeiro, Brazil; 17Sulaiman M. Al-Mayouf, MD: King Faisal Specialist
Hospital and Research Center, Riyadh, Saudi Arabia; 18Ilonka Orbàn,
MD: National Institute of Rheumatology and Physiotherapy, Budapest, Hungary; 19Clodoveo Ferri, MD: University of Modena, Modena, Italy; 20Balu H. Athreya, MD: A. I. Dupont Hospital for Children,
Wilmington, Delaware; 21Patricia Woo, FRCP, PhD: Great Ormond
Street Hospital, London, UK.
Address correspondence and reprint requests to Francesco
Zulian, MD, Department of Paediatrics, University of Padua, Via
Giustiniani 3, 35128 Padua, Italy. E-mail: zulian@pediatria.unipd.it.
Submitted for publication February 6, 2006; accepted in
revised form August 9, 2006.
3971
3972
MARTINI ET AL
Systemic sclerosis (SSc) is a rare multisystemic
disease characterized by inflammation, vascular abnormalities, and fibrosis that affects the skin and various
internal organs (1). Approximately 10% of all adults
with SSc report the onset of the disease during childhood, with a mean age at onset of 8 years (2).
Signs and symptoms of organ involvement usually
evolve over years. Therefore it is crucial to identify these
patients early, before classic skin changes occur. Except
for one case collection (3), there are very few published
studies of children with SSc and related disorders. For
this reason, the clinical and serologic features of SSc in
children are still not well known, particularly at the onset
of the disease.
As part of a multiphase project, data on demographic, epidemiologic, clinical, and laboratory features
of patients with juvenile SSc were retrospectively collected from several pediatric rheumatology centers
around the world. In this report, we describe the clinical
and serologic characteristics at the onset of the disease
and at the time of diagnosis and compare these features
with those seen in adult SSc.
PATIENTS AND METHODS
Patients and data collection. Information on demographic, epidemiologic, clinical, and laboratory characteristics
and treatment of patients with SSc with disease onset before
the age of 16 years was solicited from patients seen in 270
pediatric rheumatology centers (166 in Europe, 42 in North
America, 28 in South America, 30 in Asia, 2 in Australia, and
2 in Africa). These centers were obtained from the mailing lists
of the Pediatric Rheumatology European Society and the
Pediatric Rheumatology International Trials Organization. A
special form was developed for collection of data regarding the
following items.
1. Demographic characteristics (sex, age at the first
signs or symptoms of the disease, age at diagnosis).
2. Family history of connective tissue or other autoimmune diseases, based on the history obtained by the individual physicians.
3. Organ involvement at the time of first manifestation
and/or diagnosis, and anytime during the followup. Participants were asked to use the following recommendations to
define organ involvement. Skin involvement was determined
by the presence of skin induration, proximal or distal to
metacarpophalangeal (MCP) joints, edema, or sclerodactyly.
Peripheral vascular system involvement was diagnosed by the
presence of any 1 of the following: Raynaud’s phenomenon
(RP), digital infarcts, digital pitting, or abnormal nailfold
capillaries and capillaroscopy findings (such as megacapillaries
and avascular areas). Lung involvement was defined by the
presence of any 1 among dyspnea, abnormal chest radiography
findings or high-resolution computed tomography (HRCT)
findings, reduced diffusing capacity for carbon monoxide
(DLCO), or reduced forced vital capacity (FVC), according to
the normal values defined at each center. Cardiac disease was
diagnosed by the presence of arrhythmias or pericarditis, heart
failure, or pulmonary hypertension, seen on echocardiogram.
Musculoskeletal involvement was defined by the presence of
muscle weakness, arthritis, arthralgia, or tendon friction rubs.
Gastrointestinal tract involvement was determined by the
presence of dysphagia, gastroesophageal reflux, diarrhea, or
weight loss. Renal disease was identified by the presence of
raised creatinine levels, proteinuria, renal crisis, or persistent
arterial hypertension. Nervous system involvement was determined by the report of seizures, peripheral neuropathy, or
abnormal brain magnetic resonance imaging (MRI) findings.
4. Abnormal laboratory parameters at the time of
diagnosis and/or anytime after diagnosis. They included white
blood cell (WBC) and eosinophil count, hemoglobin count,
platelet level, erythrocyte sedimentation rate (ESR),
C-reactive protein (CRP) level, creatine kinase (CK) level,
lactate dehydrogenase (LDH) level, and levels of IgG, IgA,
IgM, C3 and C4. Abnormal values were determined using the
normal range of laboratory standards at each participating
center as a reference.
5. Serum levels of autoantibodies, including antinuclear antibodies (ANAs), anti–double-stranded DNA (antidsDNA), Scl-70, anticentromere antibodies (ACAs), extractable nuclear antigens (ENAs), anticardiolipin antibodies, lupus
anticoagulant, and rheumatoid factor (RF). Abnormal values
were determined using the normal range of laboratory standards at each participating center as a reference.
6. Type and duration of treatment.
Since patient-identifying information was not included
when clinical information was collected from the charts, institutional review board approval was required only from a
minority of centers, mainly in North America. Data were
stored electronically on a secure computer network according
to locally applicable guidelines at the participating centers.
Since there are no accepted criteria for the classification of juvenile SSc, participants were asked to report the
patients diagnosed as having SSc according to the 1980 American College of Rheumatology (formerly, the American Rheumatism Association) preliminary criteria (4). They include the
presence of 1 major criterion, namely symmetric thickening of
the skin proximal to the MCP or metatarsophalangeal joint, or
ⱖ2 minor criteria, including sclerodactyly, digital pitting scars,
or loss of substance from the finger pad and bibasilar pulmonary fibrosis (1).
Patients with overlap syndromes and mixed connective
tissue disease (MCTD) were excluded from the study. Before
the analysis was completed, we carefully reviewed the characteristics of the patients and, if there was any question regarding
the diagnosis of juvenile SSc, we asked the principal investigators at the participating centers to verify the accuracy of the
classification of their patients in order to minimize the risk of
including patients who did not have juvenile SSc.
A comparison of clinical and laboratory features between patients with juvenile SSc from the present study and
adult patients was performed using published data from a large
multicenter study (5). In order to make our data comparable
with data from previous studies, we asked the participants to
classify patients as having the diffuse or the limited form of the
disease on the basis of skin involvement (6), with skin thickening above the elbows, on the trunk, or above the knees
JUVENILE SYSTEMIC SCLEROSIS
3973
identifying diffuse disease, and skin thickening of the distal
extremities identifying limited disease.
Statistical analysis. Descriptive statistics were used to
report demographic, clinical, and laboratory characteristics of
the patients. Data were evaluated using the chi-square test,
Student’s t-test, or Fisher’s exact test, as appropriate. Statistical
analyses were performed using SAS System Release 8 software
(SAS Institute, Cary, NC). P values less than 0.05 were
considered significant.
RESULTS
General demographic characteristics. This study
was conducted between January 2002 and June 2003. Of
the 270 centers that had been contacted, 138 (51%)
responded. Eighty-three of these centers did not have
patients with SSc to include in the database. Fifty-five
centers (32 European, 8 North American, 11 South
American, and 4 Asian) reported 153 patients with
juvenile SSc. The characteristics of the patients are
summarized in Table 1. One hundred twenty patients
(78.4%) were female and 33 patients (21.5%) were male,
with a female:male ratio of 3.6:1. The onset of the
disease occurred at a mean age of 8.1 years (range
0.4–15.6 years), and the mean time between the first sign
of the disease and the diagnosis was 1.9 years (median 1
year, range 0–12.2 years).
The average followup time was 3.9 years (median
2.5 years, range 0.2–18.8 years). Among the patients
studied, the earliest year of diagnosis was 1971, and the
last followup visit occurred in 2005.
Family history of autoimmune diseases. In 17
families at least 1 first- or second-degree relative of
patients (11.1%) had an autoimmune disease. Five
Table 1. Main demographic features of the 153 patients with juvenile systemic sclerosis
Sex
No. female/no. male
Female:male ratio
Clinical subtype, no. (%)
Limited
Diffuse
Age at onset, years
Mean
Median
Range
Disease duration at diagnosis, years
Mean
Median
Range
Duration of followup, years
Mean
Median
Range
Family history of autoimmune diseases, no. (%)
120/33
3.6:1
14 (9.2)
139 (90.8)
8.1
9.3
0.3–15.6
1.9
1
0–12.2
3.9
2.5
0.2–18.8
17 (11.1)
Figure 1. Symptoms at onset (stippled bars) and at diagnosis (solid
bars) in children with systemic sclerosis. MCP ⫽ metacarpophalangeal
joint; FVC ⫽ forced vital capacity.
patients had first-degree relatives with an autoimmune
disease, 9 had second-degree relatives, and 3 patients
had both first- and second-degree relatives with an
autoimmune disease. Three patients had a relative with
SSc; in 1, it was the mother, and in 2 patients it was the
grandfather. The other reported diseases were rheumatoid arthritis (RA) in 10, systemic lupus erythematosus
(SLE) in 2, psoriasis in 3, and Sjögren’s syndrome (SS),
Crohn’s disease, and autoimmune thrombocytopenia in
1 relative each.
Clinical features at onset and at diagnosis. The
clinical features at disease onset and at the time of
diagnosis are summarized in Figure 1. RP was the first
sign of the disease in ⬃70% of the patients, and in 10%
it was complicated by digital infarcts. Proximal skin
induration was the second most frequent symptom,
being present in 41% of the patients at onset and in 63%
at diagnosis. As expected, the association of RP and skin
changes, eventually with some signs of internal organ
involvement as well, was the key diagnostic feature.
Interestingly, nailfold capillary changes were reported in
10% of patients at the onset of the disease, in 25% at
diagnosis, and in 51% during the overall disease course.
At diagnosis, the most common combination of
signs and symptoms of SSc was the association of RP
with skin induration, in 80 of 153 patients (52.3%), with
20 patients having concomitant respiratory involvement
and 6 patients having gastrointestinal involvement.
Clinical features during the course of the disease.
During the overall course of the disease, RP was the
most frequently reported symptom (84%), followed by
3974
MARTINI ET AL
Table 2. Prevalence of clinical features in juvenile SSc at the time of diagnosis and during the overall course of the disease in comparison with the
adult form*
At diagnosis
Skin
Edema
Sclerodactyly
Skin induration
Calcinosis
Peripheral vascular system
Raynaud’s phenomenon
Digital infarcts
Digital pitting
Abnormal nailfold capillaries
Abnormal capillaroscopy
Respiratory system
Dyspnea
Abnormal chest radiography findings
Abnormal chest HRCT findings
Reduced DLCO
Reduced FVC
Cardiac involvement
Pericarditis/arrhythmias
Heart failure
Pulmonary hypertension
Musculoskeletal system
Muscle weakness
Arthritis
Arthralgia
Tendon friction rubs
Gastrointestinal system
Dysphagia
Gastroesophageal reflux
Diarrhea
Weight loss
Renal system
Raised creatinine/proteinuria
Renal crisis
Hypertension
Nervous system
Seizures
Peripheral neuropathy
Abnormal brain MRI findings
Overall course
Juvenile SSc
(n ⫽ 153),
no. (%)
Adult SSc
(n ⫽ 290),
%†
P
Juvenile SSc
(n ⫽ 153),
no. (%)
Adult dcSSc
(n ⫽ 117),
%†
P
51/145 (35)
70/153 (46)
113/153 (74)
14/151 (9)
54
NA
94
26
⬍0.001
–
⬍0.001
⬍0.001
67/145 (46)
101/153 (66)
116/153 (76)
28/151 (19)
51
NA
95
22
NS
NA
⬍0.001
NS
112/150 (75)
28/149 (19)
42/150 (28)
38/148 (26)
36/146 (25)
92
17
62
NA
NA
⬍0.001
NS
⬍0.001
–
–
128/152 (84)
43/149 (29)
57/150 (38)
60/150 (40)
78/151 (52)
91
22
62
NA
NA
NS
NS
⬍0.001
NA
NA
15/151 (10)
18/149 (12)
7/148 (5)
12/150 (8)
17/150 (11)
62
64
85
51
27
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
27/151 (18)
43/149 (29)
34/148 (23)
40/150 (27)
63/150 (42)
67
72
NA
58
44
⬍0.001
⬍0.001
NA
⬍0.001
NS
8/153 (5)
3/150 (2)
2/153 (1)
21
3
NA
⬍0.001
NS
–
15/153 (10)
11/150 (7)
11/153 (7)
NA
3
NA
NA
NS
NA
18/150 (12)
26/150 (17)
39/148 (26)
8/142 (6)
24
18
52
13
0.003
NS
⬍0.001
0.007
37/152 (24)
41/152 (27)
54/150 (36)
16/142 (11)
27
17
60
23
NS
NS
⬍0.001
⬍0.01
15/151 (10)
12/149 (8)
3/151 (2)
27/150 (18)
NA
79
11
NA
–
⬍0.001
0.002
–
36/152 (24)
45/150 (30)
15/151 (10)
41/151 (27)
NA
NA
10
NA
NA
NA
NS
NA
5/153 (3)
0
2/153 (1)
18
NA
18
⬍0.001
–
⬍0.001
8/153 (5)
1/153 (1)
4/153 (3)
NA
0
17
NA
NS
⬍0.001
1/153 (1)
1/153 (1)
3/153 (2)
NA
NA
NA
–
–
–
4/153 (3)
1/153 (1)
4/153 (3)
NA
NA
NA
NA
NA
NA
* SSc ⫽ systemic sclerosis; dcSSc ⫽ diffuse cutaneous SSc; NA ⫽ not available; NS ⫽ not significant; HRCT ⫽ high-resolution computed
tomography; DLCO ⫽ diffusing capacity for carbon monoxide; FVC ⫽ forced vital capacity; MRI ⫽ magnetic resonance imaging.
† Data obtained from ref. 5.
skin induration in 76% of patients (Table 2). Other signs
of skin involvement included sclerodactyly in 66% of
patients, edema in 46%, and calcinosis in 19%.
Abnormalities on capillaroscopy were identified
in 52% of the patients while signs suggestive of severe
vasculopathy, such as digital infarcts and pitting, were
reported in approximately one-third of patients. Respiratory system involvement was manifested by reduced
FVC (42%) and DLCO (27%). Radiologic signs of lung
fibrosis were revealed in 29% of patients by standard
radiography and in 23% by HRCT. Nonspecific symptoms, such as dyspnea and cough, were reported more
rarely (18% and 12%, respectively).
Cardiac involvement was rarely reported. Ten
percent of patients developed pericarditis, 7% developed pulmonary hypertension, 7% developed heart failure, and 10% developed arrhythmias. Musculoskeletal
symptoms, such as arthralgia (36%), arthritis (27%),
JUVENILE SYSTEMIC SCLEROSIS
and reduced muscle strength (24%), were present in
many children with SSc.
In 30% of patients, 24-hour pH monitoring
and/or gastroscopy showed gastroesophageal reflux,
while gastroesophageal dysmotility, suggested by dysphagia, was described in 24% of patients. Weight loss
was reported in one-third of patients, while diarrhea or
constipation was reported in only 10%.
Scleroderma renal crisis was described in only 1
patient (0.7%), while 8 (5%) had increased urinary
protein excretion, and 7 (5%) had elevated creatinine
levels. Very few patients experienced nervous system
involvement. Seizures were reported in 4 patients (3%),
MRI abnormalities of the brain in 4 (3%), and peripheral neuropathy in 1 patient (1%).
Clinical outcome. Data on clinical outcome were
available for 127 patients with SSc, with the remaining
patients being lost to followup. Fifteen of 127 patients
(11.8%) died. The causes of death were cardiac failure in
10 patients (2 of whom had pulmonary hypertension),
renal failure in 2 (1 also had pulmonary hypertension),
respiratory failure in 2, and septicemia in 1.
The mean age at onset of the disease in patients
who died was 10.4 years (range 5.1–15 years), which was
slightly higher than that in surviving patients (8.4 years
[range 0.3–16 years]), while the time interval between
the onset of the disease and diagnosis was significantly
shorter (mean 8.8 months [range 0–49 months] in those
who died versus 23 months [range 0–149 months] in
survivors; P ⬍ 0.001). This observation suggests that in
patients who died, the clinical manifestations were severe, leading to an earlier diagnosis from the time of
symptom onset. The course of the disease was rapidly
fatal in some patients and slower in others, with deaths
occurring from 4 months to 18.8 years after onset of the
disease (mean 4.5 years, median 3.8 years). Four of the
patients (26.7%) died in the first year after diagnosis,
and 11 of 15 (73.3%) died within 5 years.
Laboratory analysis. All laboratory tests were
performed in ⬎80% of the patients, and the given
percentages are based on the available denominators.
WBC and peripheral blood eosinophil counts were
elevated in 18.6% of patients. Inflammation markers
such as ESR and CRP were elevated in 34.8% and
12.6% of patients, respectively. Increased levels of muscle enzymes such as CK and LDH were reported in
20.2% and 24.7%, respectively. Serum IgG levels were
elevated in one-third of patients, while less frequently,
increases in IgA and IgM were reported. C4 was decreased in 17% of tested patients, and C3 in 8.6%.
As shown in Table 3, results of testing for ANA
3975
Table 3. Serum autoantibody profile in juvenile SSc in comparison
with the adult form*
Serum
autoantibody
Juvenile SSc,
no. (%)
Adult dcSSc,
no. (%)†
ANA
ENA
Scl-70
ACA
Anti-dsDNA
RF
aCL
121/150 (80.7)‡
51/120 (42.5)
36/106 (34)
6/84 (7.1)§
7/122 (5.7)
19/112 (17)
8/54 (14.8)
233/249 (93.6)
NA
116/269 (43.1)
57/253 (22.5)
NA
53/231 (22.9)
22/215 (10.2)
* ANA ⫽ antinuclear antibody; ENA ⫽ extractable nuclear antigen;
NA ⫽ not available; ACA ⫽ anticentromere antibody; anti-dsDNA ⫽
anti–double-stranded DNA; RF ⫽ rheumatoid factor; aCL ⫽ anticardiolipin antibody.
† Data obtained from ref. 5.
‡ P ⬍ 0.001 versus adult diffuse cutaneous systemic sclerosis (dcSSc).
§ P ⬍ 0.01 versus adult dcSSc.
were available in almost all patients (98%). They were
found to be positive in the majority (80.7%). ENAs were
tested in 120 of 153 patients (78.4%) and were positive
in 42.5%. Scl-70 was positive in 36 of 106 tested (34%),
ACAs were positive in 6 of 84 (7.1%), and Sm in 2 of 84
(2.3%). Interestingly, 7 ENA-positive sera showed no
specificity.
Anti-dsDNA antibodies were reported positive in
7 of 122 patients (5.7%) and 2 of these also had
decreased complement levels. None of these patients
had a positive family history of SLE or had developed
signs or symptoms compatible with this disease during a
mean 8.0 years (range 3.5–13 years) of followup.
RF was found to be positive in 19 of 112 patients
(17%). Six of them (31.6%) had arthritis, but no significant correlation was found between the presence of RF
and arthritis or between RF and a family history of RA.
Anticardiolipin antibodies were found in 8 of 54 patients
(14.8%). None of these patients exhibited either thromboembolic symptoms or alterations of the coagulation
panel.
Treatment. Most of the patients (147 of 153,
96.1%) received some form of treatment. Oral corticosteroids were the most frequently used treatment (48.3%
of patients), followed by methotrexate (MTX) in 43.5%
of patients. Cyclophosphamide (CYC) was used intravenously in 12.9% of patients and orally in 9.5%.
D-penicillamine (D-Pen) was used in half of the patients. A decreasing trend in the use of this drug was
observed over time, such that while 79.1% of patients
whose diagnosis was made before 1998 were treated with
D-Pen, only 20.8% of those diagnosed after that date
received D-Pen (P ⬍ 0.0001).
3976
MARTINI ET AL
The large use of combinations of immunosuppressive treatments and the retrospective nature of the
study did not allow us to verify whether a particular
pattern of organ involvement was associated with a
preferential use of selected drugs. The most common
combinations of agents were corticosteroids (intravenous or oral) and D-Pen, which was used in 16.4% of
treated patients, MTX and D-Pen, which was used in
15.6% (half of whom also received corticosteroids),
corticosteroids and MTX (used in 10.2% of patients),
and corticosteroids/D-Pen/MTX/CYC (8.6% of patients).
The most widely used vasodilators were calcium
channel blockers in 54.4% of patients, followed by
angiotensin-converting enzyme inhibitors (8.8%) and
prostanoids (5.4%). H2 antagonists and prokinetics were
used by 7.5% and 2.7% of patients, respectively. Almost
one-fourth (23.1%) of patients took nonsteroidal antiinflammatory drugs.
DISCUSSION
This study represents the largest collection of
data on patients with juvenile SSc reported to date. The
participation of centers from all over the world and the
good response rate make this study the most representative up to now. The information obtained is crucial to
understanding the features of this disease, particularly at
onset, to the identification of prognostic factors, and to
future development of diagnostic and classification criteria.
The previous absence of large studies of pediatric
patients with SSc makes it difficult to make any comparisons. There is 1 earlier study with data on 135 children
with SSc (3). However, that study focused mainly on the
clinical outcome, and organ involvement was based on
the judgment of the referring physician rather than on
objective data. Therefore, all available data for comparison were obtained from adult data collections.
In our study population, as in previous studies of
both adults and children (7–10), juvenile SSc affected
mainly females, with a female:male ratio of 3.6:1. Consistent with the findings of previously published studies
(3,7,8), the mean age at onset was 8.1 years.
Family history of rheumatic or autoimmune disease was reported in 11% of patients with juvenile SSc,
consistent with recent findings in children with localized
scleroderma (11). In particular, 3 patients with juvenile
SSc (2.0%) had a relative with the same disease. In adult
series, cases of SSc occurring in ⬎1 family member have
been reported (12). In 2 population studies, in the US
and Australia, multiple cases of SSc in a family were
uncommon (1.6% and 1.7%, respectively), but familial
aggregation was shown more frequently than expected in
such a rare disease (13,14).
Within the limits of a retrospective study, including self-reported information that might be biased, the
significance of a positive family history of autoimmune
conditions in ⬎1 of 10 patients with juvenile SSc should
be considered. This might support the hypothesis that
inherited genetic factors play a role in susceptibility to
autoimmune diseases, although the low concordance in
twins suggests a lesser role for genetic factors or a
complex trait involving many genes (15).
RP is the first symptom of the disease in ⬃70% of
patients and, in some instances, it precedes other manifestations by years (16). As also found in our juvenile
SSc population, this symptom remained the most frequent later in the disease course, affecting almost 84%
of the patients in the present study. Given the rarity of
this condition in childhood and the high prevalence of
ANAs in juvenile SSc, patients presenting with RP and
positive ANAs must be very carefully followed up even
if they do not show any other clinical features of juvenile
SSc. Duffy et al (16) found that in 27 children with RP,
the concomitant presence of ANA positivity and abnormal findings on nailfold capillaroscopy were highly predictive of the development of a connective tissue disease.
Moreover, LeRoy and Medsger have suggested that
combinations of RP, SSc-type nailfold capillary abnormalities, and SSc-selective autoantibodies, with no sign
of skin sclerosis, characterize a subset of SSc in adults
(17).
The importance of nailfold capillary abnormalities is confirmed by our data, in which half the patients
with SSc had a pathologic pattern during capillaroscopy
and almost 40% had visible capillary abnormalities
suggestive of scleroderma. These results are possibly
biased by the limited availability of nailfold capillary
microscopy in all centers collaborating in the study, but
confirm results of previous studies indicating its utility
both in diagnosis and in followup of connective tissue
diseases such as SSc (16,18).
In our study, the course of the disease was rapidly
fatal in some patients and slower in others. In more than
one-fourth of the deceased patients, death occurred in
the first year after diagnosis, and in 73.3% of patients, it
occurred within 5 years of diagnosis. In a smaller study
(19), a few children had very rapid development of
internal organ failure, particularly cardiac, leading to
severe disability and eventually to death, while other
patients experienced a slow insidious course with lower
JUVENILE SYSTEMIC SCLEROSIS
mortality. An in-depth analysis of the mortality data and
prospective studies are needed to further evaluate these
observations. The only available data on a large number
of pediatric patients are consistent with ours, regarding
both the prevalence and the causes of death (3).
Comparison with adult studies is difficult because
in children the limited cutaneous form of SSc is rare,
whereas it is far more frequent in adults. Furthermore,
our data, within the limits of a retrospective study, show
that none of the clinical and immunologic features that
characterize the limited and the diffuse forms in adults
are expressed at significantly different rates in children
(data not shown). It has been found that in a substantial
number of patients with childhood-onset SSc, the diagnosis is confirmed either during adolescence or as young
adults (20), and it is possible that the limited subset
might be underdiagnosed in younger children because of
the lack of a full clinical picture.
Unfortunately, since there is no validated skin
score for children, the usual parameters for adult skin
scores cannot necessarily be extrapolated to a pediatric
population. Indeed, it has recently been observed that
healthy children have increased values on the modified
Rodnan skin score (21), which is validated in adults with
SSc and used as a primary outcome measure in clinical
trials (22).
We compared the clinical and laboratory characteristics, at the time of diagnosis and during the overall
disease course, of children in our study with those
reported in adults in a large multicenter European study
of 290 patients with SSc (5). Although the different
methodologies of the studies as well as the diversity in
diagnostic tests and treatments among the sites may
limit the results, this analysis provides interesting
thoughts for discussion. The comparison of the clinical
features at the time of diagnosis is most reliable because
it reduces the confounding signs and symptoms (e.g.,
concomitant diseases or unhealthy lifestyle, such as
smoking, obesity, etc.) that are particularly present in
adults and during long-term followup.
As shown in Table 2, at the time of diagnosis
children showed significantly less frequent involvement
of all organs, except for the prevalence of arthritis and
the severity of RP, as shown by digital infarcts. The
differences between adult and juvenile SSc became less
evident during followup. During the overall course of
the disease, children showed signs of interstitial lung
involvement less frequently than adults. This frequency
is lower than in a previous study of 13 patients, in which
pulmonary function test results were abnormal in 12 of
13 patients (23). For other internal organs, a similar
3977
pattern of involvement has been seen in adult and
pediatric patients, with the exception being gastroesophageal dysmotility (which has been reported in ⬃25% of
our patients and in 50–80% of adults with diffuse
cutaneous SSc), arterial hypertension, and musculoskeletal symptoms, which are significantly much more common in adults (5,24). In contrast, in a recent study (20),
muscle inflammation was observed in up to 38% of
children with SSc and was a distinguishing feature from
adult SSc. These results, however, could be influenced
by the fact that the population examined in that study
included patients with overlap syndromes and MCTD,
which have more frequent muscle involvement.
Other differences with SSc in adults (5) can be
seen in the prevalence of arthritis, which is slightly more
common in children, RP, and skin sclerosis, which are
somewhat less frequent in children. It is interesting to
note that in our population the prevalence of renal crisis
was very low despite the relatively frequent use of
corticosteroids, which are known to be associated with
increased risk of this complication. With regard to
immunologic features, adults with SSc seem to have a
significantly higher prevalence of ANAs and ACA positivity than children. No significant difference between
the adult and juvenile forms was found in the frequency
of Scl-70, RF, and ACAs (Table 3).
In conclusion, juvenile SSc appears to be less
severe than the adult form. Children have less internal
organ involvement, a less specific autoantibody profile,
and a better long-term outcome. This study provides
reliable information on the pattern of organ involvement
and the outcome in patients with juvenile SSc, and
represents a starting point for the development of a
more comprehensive and pediatric-specific classification.
ACKNOWLEDGMENTS
The authors are grateful to Dr. Christopher Denton
for his thoughtful comments and to Francesca Loro and Fabio
Vittadello for statistical support.
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