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.
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.
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.
•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.
•The identification of disease clusters opens the door to a better stratification and classification of patients, beyond the traditional limited and diffuse cutaneous forms.•Recent randomized ...controlled trials have yielded encouraging results with new drugs targeting inflammatory/immunological and fibrotic pathways.•Further studies on the combination therapy of an antifibrotic with an immunosuppressant are needed to explore this very promising strategy in SSc.•One of the main unmet needs remains the early identification of patients at high mortality risk, for whom aggressiveness of therapies ought to be determined.•Recent data suggest that lung and cardiac transplantation may be taken into account in some carefully selected patients.
Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse microangiopathy and immune dysregulation which ultimately result in widespread fibrosis of skin and internal organs. Although the 2013 EULAR/ACR criteria have allowed to improve the sensitivity for SSc diagnosis, it has recently come to light that the traditional subclassification into limited and diffuse cutaneous forms does not appear to fully capture the different phenotypes of the scleroderma spectrum. In this regard, a recent large cluster analysis-based study and other ongoing projects are trying to achieve a better stratification of SSc patients, as the disease course remains largely unpredictable to date. Recent preclinical studies and randomized controlled trials have yielded encouraging results with new drugs targeting inflammatory/immunological and fibrotic pathways. One of the main unmet needs in SSc remains the early identification of patients at high mortality risk, for whom aggressiveness of therapies ought to be determined and weighed against disease prognosis. Furthermore, lung and cardiac transplantation may also be taken into account in some carefully selected patients. Though the prognosis of SSc remains poor, an optimized stratification of patients along with the recent and ongoing advances in therapies could greatly impact the natural course of the disease in the near future. Moreover, it is envisioned that there will be an increasing need in the future to further develop combination therapies to better fight against this complex disease. In this review we discussed new insights into organ involvements and therapeutic options.
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