Title: Implementing patient stratification in scleroderma through identification of composite index of disease activity
Funder: Department of Health and Social Care

Abstract: Systemic Sclerosis or Scleroderma (SSc) is a rare condition resulting from autoimmunity, tissue fibrosis and vasculopathy (6). Scleroderma has an extremely heterogeneous natural history ranging from extremely benign to be the primary cause of death within 3 years of onset (7). Is essential, therefore, that an effective patient stratification for the risk of developing severe disease is developed to (i) identify those at risk of complications, (ii) provide targeted therapy for these at risk patients and (iii) prevent unnecessary investigations on patients who are not at risk (8,9). The diffuse fibrotic involvement of the skin is a major prognostic marker of severity in SSc and as such is the primary outcome measure in most clinical trials (8). Nevertheless, the gold standard for skin assessment is a semi quantitative clinical score (modified Rodnan skin score or mRSS), which is compromised by a 25% interobserver variability (10) . Recently we have developed a set of non-invasive, quantitative imaging biomarkers of skin fibrosis based on Optical Coherence Tomography (OCT), which show a strong correlation with clinically assessed skin involvement (r=-0.7, p0.9) (1). Beyond the prognostic role of skin involvement, the main cause of morbidity and mortality in SSc is severe pulmonary involvement, including interstitial lung disease, pulmonary artery hypertension or the combination of the two (1113). These manifestations occur overall in less than 40% of SSc patients (14). Given the lack of validated predictive markers of progression towards severe pulmonary involvement, a cardiorespiratory screening is unselectively offered for all patients with SSc, including several investigations and sequential specialist input sought from respiratory and cardiology consultants. This results in unnecessary visits and investigations in more than 60% of patients. Available resources therefore become needlessly limited with possible under-investigation of those patients that warrant more careful monitoring and examination for early detection and intervention. Recently, we and others have demonstrated that a set of three in vitro diagnostics (Tissue inhibitor of Metalloproteases-1, Hyaluronic Acid and Procollagen III N-terminal propeptides), which can be routinely analysed in NHS pathology labs, show a very good correlation with overall fibrosis and disease activity as well as skin and lung fibrosis in SSc (2,1518). Furthermore, several studies have demonstrated the proof of concept validity of a 4th IVD (NT-proBNP) in estimating the severity of pulmonary artery hypertension in scleroderma (1922). Both the imaging and serological biomarkers have shown a sound clinical validity in cross-sectional studies. The clinical utility of these biomarkers in predicting disease progression needs to be determined in longitudinal prospective cohorts. Here we aim to model a diagnostic strategy for effective patient stratification in Scleroderma by addressing two research objectives: Objective 1: To determine whether the quantitative outcome measures of OCT are more sensitive and reliable than the actual gold standard (mRSS) in defining the extent of skin involvement and its prognostic value. Objective 2: To model a composite diagnostic algorithm integrating clinical and serological data from four newly identified biomarkers, to stratify patients for their risk of developing severe pulmonary involvement. We plan to reach these objectives by furthering the biomarker evidence available following the framework outlined in our recently awarded NIHR Diagnostic Evidence Cooperative for biomarker development and clinical application. My CDF project will build on a multicenter inception cohort thoroughly phenotyped for a complete set of clinical outcomes and paired with sequential serum and imaging assessments. Utilising the infrastructure of the DEC platform, the project will rely on robust methodology to determine the clinical validity of the set of biomarkers and will include continuous economic modeling to inform on their clinical utility.

Lay abstract: Scleroderma is a rare fibrotic disease extremely variable among patients, affecting the skin and most of the internal organs. Scleroderma can cause severe disability and death within three years from diagnosis or be completely benign. We are currently unable to predict the course of the disease and for this reason all patients are extensively screened in specialist rheumatology units every six months. Here we propose to determine whether we can build a risk score based on novel biomarkers, to stratify patients requiring intense screening from those that don't and guide therapy accordingly.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM