Current status of systemic sclerosis biomarkers: applications for diagnosis, management and drug development

Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous orphan disease of unknown etiology and no effective therapy. It is characterized by protean manifestations, an unpredictable disease course and variable outcomes. Clinical manifestations reflect underlying autoimmunity, small vessel vasculopathy and progressive multi-organ fibrosis. Predicting disease progression, pattern and severity of complications and response to therapy in SSc remain major challenges both for the management of patients and for the development of effective disease-modifying therapies. This review summarizes contemporary understanding of novel and emerging biomarkers for SSc. We focus on the development of new classification criteria, the utility of SSc-specific autoantibodies as diagnostic and prognostic markers, and on biomarkers for skin and lung involvement. Finally, we review genome-wide expression analysis as a tool to predict therapeutic responses. We anticipate that the development, validation and application of these biomarkers, singly or more likely in combination, will have a transformative impact in SSc, informing early diagnosis, classification and management, as well as the design, execution and interpretation of clinical trials of novel therapeutic agents.

Keywords::

• autoantibodies
• biomarker
• classification criteria
• gene expression
• scleroderma

Acknowledgements

The authors are grateful for helpful discussions with S Bhattacharyya, M Hinchcliff, R Marangoni, K Lakota and R Lafyatis.

Financial & competing interests disclosure

FV Castelino was supported by grant K08 AR062592 from NIAMS and by the Scleroderma Foundation. J Varga was supported by R01 AR42309 from NIAMS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Current approaches to monitoring systemic sclerosis (SSc) include measures of functionality, the modified Rodnan skin score (mRSS) to assess skin fibrosis and various imaging and functional modalities to evaluate pulmonary status.

• • Biomarkers are helpful in predicting disease progression, pattern and severity of complications and response to therapy.

• • SSc-specific autoantibodies aid in identifying preclinical SSc, and in diagnosing and risk-stratifying SSc patients.

• • Newly developed ACR–EULAR classification criteria will allow for more precise sub-classification of SSc patients for clinical trials.

• • Brain natriuretic peptide (BNP) and its N-terminal cleavage product (NT-pro-BNP) have been validated as diagnostic markers for pulmonary artery hypertension (PAH) and are applicable to the diagnosis of SSc-PAH.

• • The advent of transcriptomics and proteomics in SSc research will change the scope of disease assessment and therapeutic management in SSc, allowing for markers to predict response to therapy.

Notes

Data taken from [7].