Systemic sclerosis in childhoodClinical and immunologic features of 153 patients in an international database.код для вставкиСкачать
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: email@example.com. 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. REFERENCES 1. Black CM, Stephens SC. Systemic sclerosis (scleroderma) and related disorders. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, editors. Oxford textbook of rheumatology. Oxford: Oxford University Press; 1993. p. 771–89. 2. Zulian F. Scleroderma in children. Pediatr Clin N Am 2005;52: 521–45. 3. Foeldvari I, Zhavania M, Birdi N, Cuttica RJ, de Oliveira SK, Dent PB, et al. Favourable outcome in 135 children with juvenile systemic sclerosis: results of a multi-national survey. Rheumatology (Oxford) 2000;39:556–9. 3978 4. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581–90. 5. Della Rossa A, Valentini G, Bombardieri S, Bencivelli W, Silman AJ, D’Angelo S, et al. European multicentre study to define disease activity criteria for systemic sclerosis. I. Clinical and epidemiological features of 290 patients from 19 centres. Ann Rheum Dis 2001;60:585–91. 6. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J Rheumatol 1988;15:202–5. 7. Suarez-Almazor ME, Catoggio LJ, Maldonado-Cocco JA, Cuttica R, Garcia-Morteo O. Juvenile progressive systemic sclerosis: clinical and serologic findings. Arthritis Rheum 1985;28:699–702. 8. Lababidi HM, Nasr FW, Khatib Z. Juvenile progressive systemic sclerosis: report of five cases. J Rheumatol 1991;18:885–8. 9. Steen VD, Oddis CV, Conte CG, Janoski J, Casterline GZ, Medsger TA Jr. Incidence of systemic sclerosis in Allegheny County, Pennsylvania: a twenty-year study of hospital-diagnosed cases, 1963–1982. Arthritis Rheum 1997;40:441–5. 10. Roberts-Thomson PJ, Jones M, Hakendorf P, Kencana Dharmapatni AA, Walker JG, MacFarlane JG, et al. Scleroderma in South Australia: epidemiological observations of possible pathogenic significance. Intern Med J 2001;31:220–9. 11. Zulian F, Athreya B, Laxer R, Nelson AM, Feitosa de Oliveira SK, Punaro MG, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology (Oxford) 2006;45:614–20. 12. Johnson RW, Tew MB, Arnett FC. The genetics of systemic sclerosis [review]. Curr Rheumatol Rep 2002;4:99–107. 13. Arnett FC, Cho M, Chatterjee S, Aguilar MB, Reveille JD, Mayes MD. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum 2001;44:1359–62. MARTINI ET AL 14. Englert H, Small-McMahon J, Chambers P, O’Connor H, Davis K, Manolios N, et al. Familial risk estimation in systemic sclerosis. Aust N Z J Med 1999;29:36–41. 15. Feghali-Bostwick C, Medsger TA Jr, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003;48:1956–63. 16. Duffy CM, Laxer RM, Lee P, Ramsay C, Fritzler M, Silverman ED. Raynaud syndrome in childhood. J Pediatr 1989;114:73–8. 17. LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–6. 18. Spencer-Green G, Schlesinger M, Bove KE, Levinson JE, Schaller JG, Hanson V, et al. Nailfold capillary abnormalities in childhood rheumatic diseases. J Pediatr 1983;102:341–6. 19. Quartier P, Bonnet D, Fournet JC, Bodemer C, Acar P, OuacheeCardin M, et al. Severe cardiac involvement in children with systemic sclerosis and myositis. J Rheumatol 2002;29:1767–73. 20. Scalapino K, Arkachaisri T, Lucas M, Fertig N, Helfrich DJ, Londino AV Jr, et al. Childhood onset systemic sclerosis: classification, clinical and serologic features, and survival in comparison with adult onset disease. J Rheumatol 2006;33:1004–13. 21. Steen VD, Medsger TA Jr, Rodnan GP. D-penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med 1982;97:652–8. 22. Foeldvari I, Wierk A. Healthy children have a significantly increased skin score assessed with the modified Rodnan skin score. Rheumatology (Oxford) 2006;45:76–8. 23. Garty BZ, Athreya BH, Wilmott R, Scarpa N, Doughty R, Douglas SD. Pulmonary functions in children with progressive systemic sclerosis. Pediatrics 1991;88:1161–7. 24. Akesson A, Wollheim FA. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br J Rheumatol 1989;28:281–6.