Advances in pathogenesis and treatment of systemic sclerosis

Abstract

Systemic sclerosis is the most severe disease within the scleroderma spectrum and is a major medical challenge with high mortality and morbidity. There have been advances in understanding of pathogenesis that reflect the interplay between immune-inflammatory processes and vasculopathy and fibrosis. It can be regarded as a disease of connective tissue repair and this leads to organ-based complications. However the aetiology and triggering events remain to be elucidated. Treatment is available for many aspects of the disease although the available therapies are not curative and some complications remain very challenging, especially non-lethal manifestations such as fatigue, calcinosis and anorectal dysfunction. Immunosuppression is now established as a beneficial approach but balancing risk and benefit is vital, especially for powerful approaches such as autologous stem cell transplantation.

Keywords: Scleroderma; autoantibodies; fibrosis; pulmonary hypertension; systemic sclerosis.

Fig 1.

Pathology and clinical impact of SSc. The hallmark pathologies of fibrosis, inflammation and vasculopathy in SSc translate into a challenging array of organ-based complications that define the burden and impact of disease. Highlighted in red are those aspects that contribute to high case-specific mortality, mostly due to cardiorespiratory manifestations. SSc = systemic sclerosis.

Fig 2.

Overview of management of SSc. Patients with a confirmed diagnosis of SSc are classified into diffuse or limited subsets and this determines the main focus of therapy although around one fifth of cases have overlap features of another concurrent autoimmune rheumatic disease. In all cases vigilant follow up to identify major complications and general symptomatic approaches are cornerstones of modern management. dc = diffuse systemic sclerosis; GI = gastrointestinal; lcSSc = limited systemic sclerosis; SSc = systemic sclerosis.

Fig 3.

Disease mechanism in SSc: linking pathogenesis to therapeutic targets. Studies of patient samples, genetics and animal models have defined likely processes that determine the pathogenesis of SSc. Within these pathways there are candidate mediators that may be targeted in future therapeutic trials. Some of these such as endothelin axis and IL6 are already in the clinical arena.