Background of Systemic Sclerosis

Systemic sclerosis, with a prevalence of approximately 1 in 2,000 of the general population, is an orphan, multi-organ disease affecting the connective tissue of the skin and all internal organs. The disease appears to be driven by alterations of both the immune system and the microvasculature. In contrast to the majority of other rheumatic diseases, the dysregulated activity of the immune system in SSc not only leads to tissue destruction but also to overproduction of connective tissue matrix, resulting in its classical manifestation of tight, thickened skin (scleroderma) as well as fibrosis of many organ systems. Scleroderma is the clinical hallmark of SSc and typically occurs in one of two distribution patterns, (i) diffuse cutaneous SSc (dcSSc) or (ii) limited cutaneous SSc (lcSSc). While in dcSSc the entire skin of the body can be affected by scleroderma, in lcSSc the sclerodermic changes are limited to the distal extremities and face but spare the proximal extremities and the the trunk. A phenotypical subgroup of lcSSc is the CREST syndrome, which is characterised by a combination of calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia.

Annual incidence rates vary between 0.27 to 0.5 per million children. The aetiology of the jSSc is still unclear. A positive family history of SSc is the strongest known risk factor for jSSc. As has been shown by two recent studies evaluating 135 and 153 jSSc cases, respectively, there are several differences between juvenile and adult SSc. The dcSSc subtype is much more common in jSSc (91% vs. 37% in adults), whereas the CREST variant of lcSSc is exceedingly rare (0.7%). Furthermore, the female preponderance is lower children (3.6:1) than in adults (6:1). Affected children also appear to have less internal organ involvement, a less specific autoantibody profile, and a better long-term outcome. The 5-year mortality is around 6% with heart failure being the most frequent cause (63%). Most patients die in the first 2 years of the disease. Similar to SSc in adults, Raynaud’s phenomenon is the most common and earliest manifestation (84%). There is a lower prevalence of ischemic digital ulcers (28.6%) compared to adults (43%). Joint involvement, is the second most frequent clinical manifestation and can be found in up to 79% of cases. While the frequency of arthritis in children does not differ from adults, joint pain and tendon friction rubs are significantly less common. Pulmonary hypertension (7%) and severe heart disease (approximately 10%) are significantly less common in children than in adults (22% and 66%, respectively). As patients with juvenile onset of SSc proceed into adulthood, there is a change of the cutaneous subtype and organ involvement patterns. The organ involvement pattern in adult patients with juvenile onset SSc is equal to that of adult onset SSc patients, only renal involvement remains rare. As juvenile patients become adults, the cutaneous involvement changes from a 91% predominance of dcSSc in childhood to about 40% dcSSc in the adult jSSc population. At present it is unclear whether this may represent a survival bias or may be due to other, yet to be elucidated reasons. Nevertheless, the survival even after a 20-year disease course seems to be more favourable for the juvenile onset patients. 

Fibrosis as well as the microangiopathy are the causes for the multifaceted pathophysiology of both juvenile and adult SSc. This unique pathophysiology is also the reason why at present still neither general strategies nor drugs have been identified to target all aspects of the disease. In both the juvenile and adul onset forms of SSc, the organ-specific manifestations, especially of the hands and the cardiopulmonary system, considerably decrease the quality of life and contribute to the significantly increased morbidity and mortality of SSc. On the other hand, since these manifestations are potentially amenable to specific treatments, they can be used as starting points for novel therapeutic strategies.