Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.

Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature.

Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year, novel insights into the pathogenesis, diagnosis and treatment of this severe disease are published. Herewith, we provide an overview of the most significant literature contributions published over the last year.

One year in review 2016: systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by three main features: vasculopathy, immune system dysregulation and fibrosis. Long non-coding RNAs (lncRNAs) may play a role in the pathogenesis of autoimmune diseases and a comprehensive analysis of lncRNAs expression in SSc is still lacking. We profiled 542,500 transcripts in peripheral blood mononuclear cells (PBMCs) from 20 SSc patients and 20 healthy donors using Clariom D arrays, confirming the results by Reverse Transcription Polymerase-chain reaction (RT-PCR). A total of 837 coding-genes were modulated in SSc patients, whereas only one lncRNA, heterogeneous nuclear ribonucleoprotein U processed transcript (ncRNA00201), was significantly downregulated. This transcript regulates tumor proliferation and its gene target hnRNPC (Heterogeneous nuclear ribonucleoproteins C) encodes for a SSc-associated auto-antigen. NcRNA00201 targeted micro RNAs (miRNAs) regulating the most highly connected genes in the Protein-Protein interaction (PPI) network of the SSc transcriptome. A total of 26 of these miRNAs targeted genes involved in pathways connected to the three main features of SSc and to cancer development including Epidermal growth factor (EGF) receptor, ErbB1 downstream, Sphingosine 1 phosphate receptor 1 (S1P1), Activin receptor-like kinase 1 (ALK1), Endothelins, Ras homolog family member A (RhoA), Class I Phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase (MAPK), Ras-related C3 botulinum toxin substrate 1 (RAC1), Transforming growth factor (TGF)-beta receptor, Myeloid differentiation primary response 88 (MyD88) and Toll-like receptors (TLRs) pathways. In SSc, the identification of a unique deregulated lncRNA that regulates genes involved in the three main features of the disease and in tumor-associated pathways, provides insight in disease pathogenesis and opens avenues for the design of novel therapeutic strategies.

https://www.mdpi.com/2077-0383/8/3/320/pdf

In Systemic Sclerosis, a Unique Long Non Coding RNA Regulates Genes and Pathways Involved in the Three Main Features of the Disease (Vasculopathy, Fibrosis and Autoimmunity) and in Carcinogenesis.

Scleroderma (or systemic sclerosis, SSc) is a disease caused by excess crosslinking of collagen. The skin stiffens and becomes painful, while internally, organ function can be compromised by the less elastic collagen. Diagnosis of SSc is often only possible in advanced cases by which treatment time is limited. A more detailed analysis of SSc may provide better future treatment options and information of disease progression. Recently, the histological stain picrosirius red showing collagen register has been combined with atomic force microscopy (AFM) to study SSc. Skin from healthy individuals and SSc patients was biopsied, stained and studied using AFM. By investigating the crosslinking of collagen at a smaller hierarchical stage, the effects of SSc were more pronounced. Changes in morphology and Young’s elastic modulus were observed and quantified; giving rise to a novel technique, we have termed “quantitative nanohistology”. An increase in nanoscale stiffness in the collagen for SSc compared with healthy individuals was seen by a significant increase in the Young’s modulus profile for the collagen. These markers of stiffer collagen in SSc are similar to the symptoms experienced by patients, giving additional hope that in the future, nanohistology using AFM can be readily applied as a clinical tool, providing detailed information of the state of collagen.

/pdf/quantitative-nanohistological-investigation-of-scleroderma-1cdq90t0fd.pdf

Quantitative nanohistological investigation of scleroderma: an atomic force microscopy-based approach to disease characterization.

Objective To determine excess productivity losses and costs of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjogren's syndrome (SS) at the population level. Methods Administrative databases from the province of British Columbia, Canada, were used to establish population-based cohorts of SLE, SSc, and SS, and matched comparison cohorts were selected from the general population. Random samples from these cohorts were surveyed about time absent from paid and unpaid work and working at reduced levels/efficiency (presenteeism), using validated labor questionnaires. We estimated excess productivity losses and costs of each diagnosis (over and above nonsystemic autoimmune rheumatic diseases [non-SARDs]), using 2-part models and work disability rates (not employed due to health). Results Surveys were completed by 167 SLE, 42 SSc, and 90 SS patients, and by 375 non-SARDs (comparison group) participants. Altogether, predicted excess hours of paid and unpaid work loss were 3.5, 3.2, and 3.4 hours per week for SLE, SSc, and SS patients, respectively. Excess costs were $86, $69, and $84 (calculated as 2015 Canadian dollars) per week, or $4,494, $3,582, and $4,357 per person annually, respectively. Costs for productivity losses from paid work stemmed mainly from presenteeism (SLE = 69% of costs, SSc = 67%, SS = 64%, and non-SARDs = 53%), not from absenteeism. However, many working-age patients were not employed at all, due to health (SLE = 36%, SSc = 32%, SS = 30%, and non-SARDs = 18%), and the majority of total productivity costs were from unpaid work loss (SLE = 73% of costs, SSc = 74%, SS = 60%, and non-SARDs = 47%). Adjusted excess costs from these unpaid production losses were $127, $100, and $82 per week, respectively, among SLE, SSc, and SS patients. Conclusion In this population-based sample of prevalent SLE, SSc, and SS, lost productivity costs were substantial, mainly from presenteeism and unpaid work impairments.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/acr.23573

Excess Productivity Costs of Systemic Lupus Erythematosus, Systemic Sclerosis, and Sjögren's Syndrome: A General Population-Based Study.

Objectives Reviewing disease activity indices (DAI) in systemic sclerosis (SSc) and reporting their validation status. Methods Literature was systematically reviewed on studies documenting the development of DAI, assessing the validation status of DAI and studies using a DAI in their analysis. The qualitative and quantitative validation status of existing DAI was assessed based on OMERACT and on definitions of the American College of Rheumatology (ACR) committee on quality measures. Results Three DAI in SSc have been proposed in literature: the European Scleroderma Study Group (EScSG) activity index, the 12-point DAI and the Combined Response Index for Systemic Sclerosis (CRISS). The EScSG activity index is yet applied as an outcome measure in 48 different studies. The EScSG activity index and the CRISS are provisional partially validated DAI. Conclusions Future studies are needed to fully validate the EScSG activity index and the CRISS and to assess the validation status of the 12-point DAI.

Disease activity indices in systemic sclerosis: a systematic literature review.

Objective. With this systematic review an overview is given of what is known about work participation in patients with systemic sclerosis (SSc). 
Methods. The databases Pubmed, Cinahl, Nursing and Allied Health and PsychARTICLES have been checked from 1980 onwards. The search string consisted of all combinations of key words for work participation and SSc. Two investigators evaluated the eligibility for the articles. Reference lists were searched for other studies. 
Results. Eight quantitative and one qualitative study were scrutinised in depth. The percentage of patients not working ranges from 18% to 61%. A meta-analysis of the percentage patients not working was performed and a weight mean of 37% was found. The following parameters are associated with the work variable in multivariate analysis (number of studies in which the variable was independently associated with the work variable/number of studies in which the variable was multivariately assessed): global disability (415), health (315), educational level (214), disease duration (313), skin/lung involvement (113), age/fatigue/muscle involvement/hand function (112) and having a decreased income/race/social support/physically demanding job (111). In the qualitative study, management of the work situation, disclosure of limitations at the work force and adaptation of resources in daily life are discussed. 
Conclusion. Most studies concerning work participation are at this very moment quantitative and cross-sectionally designed. Longitudinal studies are needed to assess causality and qualitative research may be opportune to have a more comprehensive view on the topic of work participation in patients with SSc.

Work participation in patients with systemic sclerosis: a systematic review.

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Disease activity indices in systemic sclerosis: a systematic literature review.

Work participation in patients with systemic sclerosis: a systematic review.