Controversies: molecular vs. clinical systemic sclerosis classification

Systemic sclerosis (SSc) is a multisystem chronic disease characterized by the three cardinal pathological features, including autoimmunity/inflammation, vasculopathy, and fibrosis, with unknown etiology. Individual patients manifest these three components to variable degrees, resulting in the diverse heterogeneity of clinical presentation. The classification of SSc patients into relatively homogenous subtypes is helpful in the setting of daily clinical practice and the field of clinical and basic research. The classification of SSc has been continuously discussed over four decades based on the clinical and laboratory features, especially the extent of skin sclerosis and disease-related autoantibodies. This clinical classification system enables clinicians to provide general advice regarding prognosis and risk for internal organ disease, but only permits estimates of outcomes informed by population-based studies. On the other hand, the recent decade has seen much progress in the understanding of molecular aspects of SSc complex pathology, raising a discussion on molecular classification of SSc. The development of molecular targeting therapies, especially biologics, further strengthens the importance of molecular classification which aids the identification of potential responders for each treatment. Although a careful validation study is required for molecular classification of SSc due to its large heterogeneity, the advance of molecular classification would introduce a further modification into SSc classification system in the near future. Importantly, clinical and molecular classifications are not mutually exclusive, therefore the combination would facilitate the development of a better classification system of this complex heterogeneous disorder that is useful in both the clinical setting and research studies.