Background
Juvenile systemic sclerosis (JSSc) is a rare connective tissue disease of unknown etiology. Characteristic features include fibrosis of the skin, subcutaneous tissues, and internal organs as well as abnormalities of the vascular and immune systems occurring in children 16 and younger. This disease is one of the most severe rheumatologic conditions diagnosed in children.
Pathophysiology
One of the earliest processes thought to occur in juvenile systemic sclerosis is vascular injury. This results in upregulation of endothelial cell adhesion molecules, which facilitates local platelet aggregation and infiltration of inflammatory cells. This endothelial injury is manifested clinically as Raynaud phenomenon, pulmonary hypertension, and renovascular hypertension. Fibrosis is due to increased organ and dermal infiltration of lymphocytes, macrophages, eosinophils and mast cells.
These inflammatory cells release numerous cytokines, including transforming growth factor beta (TGF-β) and interleukin-1 (IL-1). Among its numerous effects, IL-1 is known to stimulate the release of platelet-derived growth factor, which stimulates fibroblasts to increase production and deposition of extracellular matrix components such as collagen, fibronectin, and glycosaminoglycans. This fibrosis may affect any organ of the body, most commonly the skin, GI tract, lungs, heart, kidneys, and musculoskeletal system.
Little is known about the role of the various autoantibodies, such as ANA, seen in almost all cases of juvenile systemic sclerosis, but their presence is suggestive of an autoimmune process underlying the aforementioned vascular injury and fibrosis. Resistance of lymphocytes to apoptosis seen in these patients is a potential mechanism for the persistence of autoreactive T cells in juvenile systemic sclerosis.
Epidemiology
Frequency
United States
Juvenile systemic sclerosis is a rare childhood disorder. Foeldvari reported an incidence of approximately .05 per 100,000 children.[1] In addition, 5-10% of adult cases of systemic sclerosis arise before age 16 years, meeting the age criterion for juvenile systemic sclerosis. New criteria aimed at more uniformly defining juvenile systemic sclerosis will aid in better estimation of incidence and prevalence of juvenile systemic sclerosis.
Mortality/Morbidity
Mortality rates in juvenile systemic sclerosis are more optimistic than that seen in adult systemic sclerosis. Five year and 20 year survival rates in juvenile systemic sclerosis are 89% and 69-82.5%, respectively.
The greatest morbidity and mortality is seen in those children who develop pulmonary, cardiac, and renal manifestations of the disease. A recently published report reveals that the most significant predictors of mortality at the time of diagnosis are pericarditis, elevated creatinine levels, and fibrosis on chest radiography.[2] The most common cause of early death in patients with juvenile systemic sclerosis is heart failure due to dilated cardiomyopathy, likely related to pulmonary hypertension and myocardial fibrosis.
In a study of 153 patients with juvenile systemic sclerosis, those patients that succumbed to this disease had a significantly shorter time to diagnosis from onset of symptoms (8.8 mo) compared with patients that were still alive at follow-up (23 mo).[3] This demonstrates that those patients who eventually die due to complications of juvenile systemic sclerosis likely have a more progressive form that is more quickly recognized by doctors due to the severity of symptoms. This is consistent with mortality rates of most studies that show most deaths from juvenile systemic sclerosis occur within the first 5 years after diagnosis.
Morbidity from the disease is seen in most patients in the form of fibrosis of the skin, which may lead to contractures and loss of mobility, and Raynaud phenomenon with associated pain and paresthesias, as well as occasional digital ulcers. Arthralgias, arthritis, and muscle weakness may occur in as many as 26% of patients, and a small number may experience dyspnea, weight loss and dysphagia as well.
Race
In the United States, adult systemic sclerosis is more common in blacks than in whites, with a ratio of 2:1. No specific demographic data are available for juvenile systemic sclerosis.
Sex
Females are more commonly affected than males in juvenile systemic sclerosis, with an overall female-to-male ratio of approximately 3.6:1. This is much lower than the 15:1 female-to-male predominance seen in adult systemic sclerosis.
Age
A child must be younger than 17 years at the time of disease onset to the meet the criteria for juvenile systemic sclerosis. The youngest patient documented with juvenile systemic sclerosis was only a few months old at disease onset. The average age of onset is 8.1-8.8 years in the two largest case series published on juvenile systemic sclerosis. Due to the rarity of this childhood disease and the subtle nature by which it can first appear, the average time from symptom onset to diagnosis is 1.9 years, taking as long as 12 years in some cases. Of note, children who died from juvenile systemic sclerosis in these 2 studies were diagnosed almost 2 years later than the average child with juvenile systemic sclerosis.
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