Etiology and Pathogenesis of Scleroderma in children
Francesco Zulian, MD
2006

Juvenile Systemic Sclerosis

The cause of Juvenile Systemic Sclerosis (JSSc) is unknown despite significant advances in the understanding of the pathogenetic mechanisms.

The disease onset and persistence is essentially due to three main alterations: immune system, endothelium and fibroblasts. These three elements are mutually involved in a complex process characterized prominently by fibrosis of the skin or internal organs.

Cellular immunity, that usually is deputed to defend us from infections, plays a major role in the initiation of scleroderma. This is clearly supported by the presence, in early lesions, of mononuclear cells that release various substances such as cytokines, chemokines and growth factors. These mediators act as messengers between different varieties of cells, maintaining inflammation and in turn have effects on both endothelial cells and fibroblasts.

Endothelial cells, that normally represent the inner layer of the vessel, become activated and proliferate leading to fibrosis and narrowing of the vascular lumen. This results in circulation defects and eventually ischemic damage.

Fibroblasts are cells that usually produce a certain amount of collagen, a substance that acts as support for various structures such as vessel, muscles and even bones. Under the influence of  cytokines and chemokines, fibroblasts increase the synthesis of extracellular matrix components and promote fibrosis. Specific cytokines, such as TNF, promote fibrosis others, such as IFN-γ, are potent suppressors of collagen synthesis and this can be useful for the development of innovative treatments with biological agents.  

Microchimerism as a possible cause of scleroderma was postulated from studies of scleroderma in adults.  Microchimerism is defined by the presence within an individual of a very low level of cells derived from different individuals. Common situations in which microchimerism occurs are women who had previous pregnancies, individuals who have had blood transfusions or children with cells either from their mothers or a twin.

It is known that maternal cells can persist in an offspring even in adult life.  Fetus-derived hemopoietic cells can persist in maternal circulation for many years postpartum. Although microchimerism can be identified in normal subjects, it has been proposed as a possible factor in the production of autoimmune diseases.  In scleroderma, chimeric cells are increased in number and are more similar to the maternal cells compared to normals.  Quantitative analysis of microchimerism in mothers with scleroderma documented high persistent concentrations of male DNA in cells of the vascular department years after giving birth to a son.  Although this theory of a chronic graft-versus-host reaction is attractive, studies offer no data to explain the occurrence of scleroderma in women who have never had children or in men.

Juvenile Localised Scleroderma

The etiology of the juvenile localized scleroderma (JLS) is unknown. As in JSSc, the focus of much investigation is on abnormalities of regulation of fibroblasts, production of collagen and immunologic abnormalities. Autoimmunity, environmental factors, infection, and trauma have all been associated with localized disease.

It seems certain that autoimmunity is important in etiology, given the presence of abnormal serum antibodies such as antinuclear antibodies occurring in 42% of the patients, rheumatoid factor in 16% or anti cardiolipin in 13%.

In a recent multicenter study from our group in Padua, we observed that 13.3% of 750 patients with JLS reported specific events which occurred very close to the disease onset and were thus considered significant triggers by both parents and reporting physicians.

 Mechanical events accounted for 67% of these factors, followed by infections (25%), drugs (5%) and psychological distress (3%). Local mechanical factors, including accidental trauma, insect bite and vaccination were reported in approximately 10% of the patients. Although interesting, the mechanism by which a physical trauma may contribute to the development of scleroderma is unclear. Again, the role of some cytokines such as endothelin-1, normally involved in the process of wound healing, has been suggested by some authors but other studies are needed to fully elucidate the pathogenetic process.

A number of drugs and environmental toxins have resulted in scleroderma-like reactions, including bleomycin, bromocriptine, pentazocine, carbidopa and vitamin K.

Some investigators have examined the possibility of an association between scleroderma and Borrelia Burgdorferi, a micro organism responsible for the Lyme disease. Since 1985, serum antibodies against B. Burgdorferi have been found in patients with JLS living in endemic area. More recently this association has been denied and seems to be a coincidence more than a causative event. For this reason serologic testing for Lyme disease is not likely to be helpful per se, in the evaluation of patients with JLS, unless they have been in an endemic area.

Finally, a positive family history for rheumatic or autoimmune diseases was reported in around 12% of children with JLS, indicating that a familial predisposition can partially be responsible as co-factor in the development of the disease.

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