Abstract In Rheumatoid arthritis (RA), neoangiogenesis is an early and crucial event to promote the development of the hyperplasic proliferative pathologic synovium. Endothelial cells are critical ...for the formation of new blood vessels since they highly contribute to angiogenesis and vasculogenesis. Current therapies in RA target the inflammatory consequences of autoimmune activation and despite major improvements these last years still refractory patients or incomplete responders may be seen raising the point of the need to identify complementary additive and innovative therapies. This review resumes the mechanisms of synovial neoangiogenesis in RA, including recent insights on the implication of vasculogenesis, and the regulation of synovial neoangiogenesis by angiogenic and inflammatory mediators. In line with the recent development of vascular-targeted therapies used in cancer and beyond, we also discuss possible therapeutic implications in RA, in particular the combination of targeted immunotherapies with anti-angiogenic molecules.
Relevant animal models are essential tools to investigate in depth the pathogenesis of autoimmune disease. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder that affects ...particularly the skin. SSc is characterized by vasculopathy, immune disturbances, and fibrosis. Expression of each of the three pathologic features varies among SSc patients leading to disease heterogeneity and variable organ manifestations. Several animal models of SSc are available; however, some models display inflammation followed by fibrosis, whether some others primarily mimic autonomous fibroblast activation. Here, we describe the mouse model of bleomycin-induced dermal fibrosis, which mimics early and inflammatory stages of SSc, and is widely used in SSc research.
To review susceptibility genes and how they could integrate in systemic sclerosis (SSc) pathophysiology providing insight and perspectives for innovative therapies.
SSc is a rare disease ...characterized by vasculopathy, dysregulated immunity and fibrosis. Genome-Wide association studies and ImmunoChip studies performed in recent years revealed associated genetic variants mainly localized in noncoding regions and mostly affecting the immune system of SSc patients. Gene variants were described in innate immunity (IRF5, IRF7 and TLR2), T and B cells activation (CD247, TNFAIP3, STAT4 and BLK) and NF-κB pathway (TNFAIP3 and TNIP1) confirming previous biological data. In addition to impacting immune response, CSK, DDX6, DNASE1L3 and GSDMA/B could also act in the vascular and fibrotic components of SSc.
Although genetic studies highlighted the dysregulated immune response in SSc, future research must focus on a deeper characterization of these variants with determination of their functional effects. Moreover, the role of these genes or others on specific vasculopathy and fibrosis would provide insight. Establishment of polygenic score or integrated genome approaches could identify new targets specific of SSc clinical features. This will allow physicians to propose new therapies to SSc patients.
•ctd-ild and ipf share common biomarkers suggesting common pathways.•KL-6, SP-D and MMP7 are sensitive but not specific to diagnose lung fibrosis in IPF.•KL-6, SP-D and CCL18 are sensitive but not ...specific for SSc-ILD diagnosis.•KL-6 is the most sensitive circulating biomarker for diagnosis.•KL-6 and CCL18 can predict lung involvement worsening in IPF and SSc-ILD.
Interstitial lung diseases (ILDs) are complex diseases with various courses where personalized medicine is highly expected. Biomarkers are indicators of physiological, pathological processes or of pharmacological response to therapeutic interventions. They can be used for diagnosis, risk-stratification, prediction and monitoring of treatment response. To better delineate the input and pitfalls of biomarkers in ILDs, we performed a systematic review and meta-analysis of literature in MEDLINE and Embase databases from January 1960 to February 2019. We focused on circulating biomarkers as having the highest generalizability. Overall, 70 studies were included in the review and 20 studies could be included in the meta-analysis. This review highlights that ILD associated with connective tissue diseases (CTD-ILD) and idiopathic pulmonary fibrosis (IPF) share common biomarkers, suggesting common pathophysiological pathways. KL-6 and SP-D, could diagnose lung fibrosis in both IPF and CTD-ILD, with KL-6 having the strongest value (OR: 520.95110.07–2465.58, p<0.001 in IPF and OR:26.437.15–97.68, p<0.001 in CTD-ILD), followed by SPD (OR: 33.813.20–357.52, p = 0.003 in IPF and 13.24 3.84–45.71 in SSc-ILD), MMP7 appeared as interesting for IPF diagnosis (p<0.001), whereas in SSc, CCL18 was associated with ILD diagnosis. Both CCL18 and KL-6 were predictive for the outcomes of ILDs, with higher predictive values for CCL18 in both IPF (OR:10.224.72–22.16, p<0.001 and in SSc 2.621.71–4.03, p<0.001). However, disease specific biomarkers are lacking and large longitudinal studies are needed before the translational use of the potential biomarkers in clinical practice. With the recent availability of new effective therapies in ILDs, further studies should assess response to treatment.
Chimeric antigen receptor–T (CAR‐T) cell therapy is based on specific targeting of tumor antigens, leading to lysis and destruction of tumor cells. The high potency of CAR‐T cells in the management ...of B cell malignancies has been demonstrated. Following the success of this therapeutic strategy, new CAR‐T cell–derived constructs that have the ability to eradicate pathogenic B cells or restore tolerance have been developed. The present review discusses how the knowledge and technology generated by the use of CAR‐T cells may be translated and integrated into ongoing therapeutic strategies for autoimmune rheumatic diseases. To this end, we describe the details of CAR‐T cell technology, as well as the meaningful achievements attained with the use of CAR‐T cells in onco‐hematology. In addition, we review the preliminary data obtained with CAR‐T cells and their derivative constructs in experimental models of autoimmune diseases. Finally, we focus on how CAR‐T cell engineering interferes with the pathogenesis of 3 chronic autoimmune rheumatic diseases—rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis—and discuss whether these constructs might yield greater efficacy and be associated with fewer adverse events compared to current treatment strategies.
Objective
Interstitial lung disease (ILD) in systemic sclerosis (SSc) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and ...prognostic performance of 4 candidate serum biomarkers for SSc‐associated ILD.
Methods
Serum samples from a combined cohort of SSc patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme‐linked immunosorbent assay for concentrations of lung epithelial–derived surfactant protein D (SP‐D), Krebs von den Lungen 6 glycoprotein (KL‐6), CCL18, and OX40 ligand (OX40L). Lung fibrosis was measured by high‐resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow‐up 3.2 ± 4.4 years) were investigated.
Results
In SSc patients at baseline, serum levels of KL‐6 correlated with the forced vital capacity (FVC) (r = −0.317, P < 0.001), diffusing capacity for carbon monoxide (r = −0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL‐6 and SP‐D, but not CCL18 and OX40L, were associated with lung fibrosis (odds ratio OR 2.41, 95% confidence interval 95% CI 1.43–4.07 P = 0.001 and OR 3.15, 95% CI 1.81–5.48 P < 0.001, respectively). In SSc patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio HR 2.90, 95% CI 1.25–6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02–13.52; P = 0.048). Matrix‐based logistic regression models for the diagnosis and prognosis of SSc‐associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP‐D (for diagnosis) and serum levels of CCL18 (for progression of disease).
Conclusion
These results show that SP‐D is a relevant diagnostic biomarker for SSc‐associated ILD, whereas KL‐6 could be used to assess the severity of lung fibrosis. CCL18 appears to be a potential predictive marker for progression of ILD in SSc.
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