Prospects for Stratified and Precision Medicine in Systemic Sclerosis Treatment

Curr Treat Options in Rheum DOI 10.1007/s40674-019-00124-y Scleroderma (C Denton, Section Editor) Prospects for Stratified and Precision Medicine in Systemic Sclerosis Treatment Kristina E. N. Clark, BA, MBBS, MRCP1 Emma Derrett-Smith, PhD, MRCP1,2,* Address *,1 Centre for Rheumatology and Connective Tissue Diseases, University College London Division of Medicine, London, U.K. Email: 2 University Hospitals Birmingham NHS Foundation Trust, Birmingham, U.K. * The Author(s) 2019 This article is part of the Topical Collection on Scleroderma Keywords Systemic sclerosis I Scleroderma I Stratification I Biomarkers I Gene expression Abstract Purpose of review Precision medicine is an evolving field stemming from Oncology research, with an increasingly important role in autoimmune diseases. The heterogeneity, both of clinical presentations of systemic sclerosis and differing response to treatment, emphasises the importance of developing means of patient stratification to ensure that the correct patients are managed with the most appropriate treatments at a disease duration when this will have meaningful impact on disease course and resolution. This review aims to discuss the different means explored so far in stratifying patients with systemic sclerosis. We highlight recent clinical trials which have applied stratification techniques in order to provide a form of precision medicine in the management of systemic sclerosis. Recent findings Advances have focused on utilising gene expression techniques on whole skin biopsies or fibroblasts to understand which groups of patients are more likely to respond to which treatments. This technique has been used successfully to understand the effect of tocilizumab, abatacept, and fresolimumab on systemic sclerosis, and helped identify those that are more likely to respond to treatment. Summary Utilising high output platforms to stratify patients for targeted treatment is still in its infancy but has huge potential for ensuring the patients most likely to respond to a specific therapy are put forward to trials. It has already been shown to be successful in those with a high IL-6 profile and will most likely prove hugely informative in the future. Scleroderma (C Denton, Section Editor) Introduction Precision medicine is an evolving approach to patientcentred care. Pioneered by cancer medicine, it aims to integrate individual genomics, proteomics, pharmacogenomics, and immunogenomics information to tailor personalised therapy, optimise efficacy, and minimise drug toxicity [1]. By identifying key patient groups, this allows for individualised targeted therapies with increased efficacy and/or reduced toxicity. Systemic sclerosis (scleroderma; SSc) is a heterogeneous disease characterised by autoimmunity, vasculopathy and fibrosis. Traditionally considered a disease primarily of the skin, the significant internal organ manifestations including lung fibrosis, pulmonary arterial hypertension, gastrointestinal disease, and myositis are responsible for the high case-specific mortality and morbidity in this condition. Disease stratification within SSc has been primarily by extent of skin involvement (limited vs diffuse), by autoantibodies [2] or by organ manifestation. More modern approaches focus on the individual disease process, which targets treatment to either immune activation, vascular disease, or fibrosis, thus aiding with potential targeted therapies. Biomarkers are a means to aid stratification. The NIH define a biomarker as Ba characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention^ [3]. So far, there is no validated molecular biomarker that meets these criteria in SSc, but there are molecular markers and imaging which correlates with different aspects and stages of the disease. Lessons learned from the use of targeted treatments in rheumatology and other immunological diseases, combined with the heterogeneity of SSc, suggest that only certain subgroups of patients will benefit from this approach. Emphasis on advancing stratification and precision medicine has never been greater. Given the diverse clinical characteristics of this disease, many clinical trials fail: They are either underpowered or have failed due to the challenges of interpreting any clinical changes. Ensuring the right patients who are likely to benefit from a therapy are entered into the appropriate clinical trial is vital if we are to prove efficacy of specific treatment in SSc. This may be disease subset, stage, or organ manifestation specific, and as advancements in molecular identification continue, this will also include specific biomarkers and genomics hopefully to allow us to fine tune these findings further. In this article, we look at the different means of stratifying SSc, and how this can be used for personalised therapy. We will cover stratification by organ manifestation, individual biomarkers, and then the natural evolution to microarray and groups of biomarkers. Stratification by organ manifestation Active skin disease The degree of skin involvement has historically been the main clinical tool used to stratify patients in SSc, with limited systemic sclerosis (lcSSc) patients having skin involvement limited to below the elbow and knee, and diffuse SSc (dcSSc) being defined as above the elbow and knee including chest. The modified Rodnan skin score (mRSS) is the most frequently used outcome measure, providing a semi-quantitative evaluation of skin thickness [4]. Rapid increase in mRSS in patients with dcSSc is often associated with new or worsening internal organ involvement, and correlates with increased mortality [5]. The considerable inter-observer variability means that skin score is not a reliable enough predictor of disease severity, trajectory, or response to enable useful stratification alone. The European Scleroderma Observational Study aimed to derive a prediction model for skin progression in early dcSSc based on clinical characteristics. They identified progressors (defined as an increase in 9 5 units and 25% increase in mRSS over 12 months) as having a shorter disease duration at time of recruitment, and lower mRSS (although over 45% had an mRSS of 9 22). The interaction with autoantibody status also played a significant role with anti-RNA polymerase III patients having the highest peak skin score, and peaked earlier compared to other autoantibody subtypes [6]. Incorporating initial skin score, with disease duration and autoantibodies improved the accuracy of the model in identifying high-risk patients for skin progression. Interstitial lung disease Clinically significant interstitial lung disease (ILD) affects up to 60% of patients with SSc [7]. Diagnosis relies on lung function tests and high-resolution chest tomography (HRCT). Those with anti-topoisomerase I Prospects for Stratified and Precision Medic (...truncated)