• Systemic sclerosis
• acute heart failure
• prevention
• prosthetic heart valves
• valvular heart disease

• Autoimmunity
• Environmental pollutants
• Phosphoinositide signaling

• Humans
• Autoimmunity
• Environmental Pollutants/toxicity
• Autoimmune Diseases/etiology
• Autoimmune Diseases/pathology
• Environmental Pollution
• Signal Transduction

• R35 GM134955 NIGMS NIH HHS

• CALIPER
• Ground glass
• Interstitial lung disease
• Systemic sclerosis
• Th2 cytokines

• Humans
• Cytokines
• Interleukin-13
• Interleukin-4
• Interleukin-5
• Lung Diseases, Interstitial/etiology
• Lung/pathology
• Scleroderma, Systemic

• Università degli Studi di Roma La Sapienza

• Cell Biology
• Fibrosis
• Pericytes
• Skin

Compelling evidence shows the involvement of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc) pathogenesis. This study investigated whether microRNAs (miRNAs) are involved in the dysregulation of pDCs in SSc patients already at early stages. RNA from circulating pDCs was isolated from two independent cohorts of SSc patients with different disease phenotypes, and individuals with Raynaud’s phenomenon, for microRNA profiling and RNA-sequencing analysis. Proteomic analysis was exploited to identify novel direct miRNA targets at the protein level. Twelve and fifteen miRNAs were differentially expressed in at least one group of patients compared to healthy controls in discovery cohort I and II, respectively. Of note, miR-126 and miR-139-5p were upregulated in both preclinical and definite SSc patients and correlated with the expression of type I interferon (IFN)-responsive genes. Toll-like receptor 9 (TLR9) stimulation of healthy pDCs upregulated the expression of both miRNAs, similarly to what was observed in patients. The proteomic analysis identified USP24 as a novel target of miR-139-5p. The expression level of USP24 was inversely correlated with miR-139-5p expression in SSc patients and induced by TLR9 stimulation in healthy pDCs. These findings demonstrated that the miRNA profile is altered in pDCs of SSc patients already at early stages of the disease and indicate their potential contribution to pDC activation observed in patients.

• microRNAs (miRNAs)
• plasmacytoid dendritic cells
• systemic sclerosis

• TLR
• connective tissue disease
• expression
• interferon
• pathogenesis

To assess the safety and efficacy of lenabasum in diffuse cutaneous systemic sclerosis (dcSSc).

A randomized, double‐blind, placebo‐controlled, phase II study was conducted at 9 SSc clinics in the US. Adults with dcSSc of ≤6 years’ duration who were receiving stable standard‐of‐care treatment were randomized to receive lenabasum (n = 27) or placebo (n = 15). Lenabasum doses were 5 mg once daily, 20 mg once daily, or 20 mg twice daily for 4 weeks, followed by 20 mg twice daily for 8 weeks. Safety and efficacy were assessed at weeks 4, 8, 12, and 16.

Adverse events (AEs) occurred in 63% of the lenabasum group and 60% of the placebo group, with no serious AEs related to lenabasum. Compared to placebo, lenabasum treatment was associated with greater improvement in the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score and other efficacy outcome measures that assessed overall disease, skin involvement, and patient‐reported function. The median CRISS score increased in the lenabasum group during the study, reaching 0.33, versus 0.00 in the placebo group, at week 16 (P = 0.07 by 2‐sided mixed‐effects model repeated‐measures analysis). Gene expression in inflammation and fibrosis pathways was reduced, and inflammation and fibrosis were improved on histologic evaluation of skin biopsy specimens, in the lenabasum group compared to the placebo group (all P ≤ 0.05).

Despite a short trial duration in a small number of patients in this phase II study in dcSSc, our findings indicate that lenabasum improves efficacy outcomes and underlying disease pathology with a favorable safety profile.

• Fibrosis
• IL-17
• Inflammation

Self/foreign discrimination by the innate immune system depends on receptors that identify molecular patterns as associated to pathogens. Among others, this group includes endosomal Toll-like receptors, among which Toll-like receptors (TLR) 3, 7, 8, and 13 recognize and discriminate mammalian from microbial, potentially pathogen-associated, RNA. One of the discriminatory principles is the recognition of endogenous RNA modifications. Previous work has identified a couple of RNA modifications that impede activation of TLR signaling when incorporated in synthetic RNA molecules. Of note, work that is more recent has now shown that RNA modifications in their naturally occurring context can have immune-modulatory functions: Gm, a naturally occurring ribose-methylation within tRNA resulted in a lack of TLR7 stimulation and within a defined sequence context acted as antagonist. Additional RNA modifications with immune-modulatory functions have now been identified and recent work also indicates that RNA modifications within the context of whole prokaryotic or eukaryotic cells are indeed used for immune-modulation. This review will discuss new findings and developments in the field of immune-modulatory RNA modifications.

• RNA modifications
• Toll-like receptors
• innate immunity
• methylation

Rheumatic diseases are disorders characterized by joint inflammation, in which other organs are also affected. There are more than two hundred rheumatic diseases, the most studied so far are rheumatoid arthritis, osteoarthritis, spondyloarthritis, systemic lupus erythematosus, and systemic sclerosis. The semaphorin family is a large group of proteins initially described as axon guidance molecules involved in nervous system development. Studies have demonstrated that semaphorins play a role in other processes such as the regulation of immunity, angiogenesis, bone remodeling, apoptosis, and cell migration and invasion. Moreover, semaphorins have been related to the pathogenesis of multiple sclerosis, asthma, Alzheimer, myocarditis, atherosclerosis, fibrotic diseases, osteopetrosis, and cancer. The aim of this review is to summarize current knowledge regarding the role of semaphorins in rheumatic diseases, and discuss their potential applications as therapeutic targets to treat these disorders.

• rheumatic diseases
• semaphorins
• therapeutic targets

• Animals
• Humans
• Immune System Diseases/metabolism
• Models, Biological
• Rheumatic Diseases/metabolism
• Semaphorins/metabolism

Mounting evidence indicates that inflammatory mechanisms drive systemic sclerosis (SSc) vasculopathy and fibrosis, especially early in the disease. Therefore, patients with very early SSc could benefit from early treatments targeting inflammation. Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. Several studies have demonstrated a mixed response to treatment with glucocorticoids in SSc, probably because it is seldom initiated at very early stages of the disease. We hypothesise that by inhibiting the inflammatory process driving SSc disease progression, glucocorticoid treatments will induce remission in patients with very early SSc.

This study is a 12-week, randomised, double-blind, placebo-controlled trial analysing the effects of high-dose intravenous methylprednisolone in very early SSc. Thirty patients who fulfil the criteria for very early SSc will be randomly assigned in a 2:1 ratio to receive either intravenous methylprednisolone or a placebo on three consecutive days over three consecutive months. In this study, the primary endpoint will be the change in capillary density between the baseline and after 12 weeks of treatment. The secondary outcomes of this study are a change in selected biomarkers, other changes in the nailfold capillaries, signs of established SSc and changes in physical function, general health and utilities, as reported through questionnaires.

This trial is the first aiming to treat very early SSc and is promising because it targets the very early stages of the disease process by using an inexpensive and relatively safe treatment known to be highly effective against inflammation. The use of vasculopathy and inflammatory biomarkers as well as clinical signs and symptoms as the endpoints in our study enables us to meet the patient need for markers of disease activity. If it is possible to prevent clinically significant disease in patients with very early SSc by using a safe treatment, this will cause a paradigm shift in scleroderma care and research.

ClinicalTrials.gov Identifier: NCT03059979. Registered on 20 February 2017.

The online version of this article (10.1186/s13063-018-2798-x) contains supplementary material, which is available to authorized users.

• Methylprednisolone
• Nailfold capillaroscopy
• Randomised controlled trial
• Systemic sclerosis
• Very early diagnosis of systemic sclerosis

To investigate T-cell activation, the percentage of peripheral T regulatory cells (Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis (SSc).

We enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc (dcSSc, n = 13) or limited cutaneous SSc (lcSSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease - early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activation capacity of T-lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin (IL)-6, IL-10, tissue growth factor-β1 (TGF-β1), and IL-17A.

We identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls (13.35% ± 2.90% vs 37.03% ± 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls (6.30% ± 0.68% vs 9.36% ± 1.08%, P = 0.016). Regarding the forms of the disease, dcSSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects (5.95% ± 0.89% vs 9.36% ± 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls (18.13% ± 1.55% vs 13.73% ± 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lcSSc subset against controls (20.46% ± 2.41% vs 13.73% ± 1.21%, P = 0.025), nevertheless no difference was found between dcSSc and lcSSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dcSSc patients compared to controls (10.94% ± 1.65% vs 6.88% ± 0.91, P = 0.032). Regarding the peripheral cytokine profile, we detected raised levels of IL-6 [2.10 (1.05-4.60) pg/mL vs 0.00 pg/mL, P < 0.001], TGF-β1 (19.94 ± 3.35 ng/mL vs 10.03 ± 2.25 ng/mL, P = 0.02), IL-10 (2.83 ± 0.44 pg/mL vs 0.68 ± 0.51 pg/mL, P = 0.008), and IL-17A [6.30 (2.50-15.60) pg/mL vs 0 (0.00-0.05) pg/mL, P < 0.001] in patients when compared to healthy controls. Furthermore, we found increased circulating IL-10, TGF-β, IL-6 and IL-17A in the lcSSc subset vs control subjects, as it follows: IL-10 (3.32 ± 0.59 pg/mL vs 0.68 ± 0.51 pg/mL, P = 0.003), TGF-β1 (22.82 ± 4.99 ng/mL vs 10.03 ± 2.25 ng/mL, P = 0.031), IL-6 [2.08 (1.51-4.69) pg/mL vs 0.00 pg/mL, P < 0.001], and IL-17A [14.50 (8.55-41.65) pg/mL vs 0.00 (0.00-0.05) pg/mL, P < 0.001]. Furthermore, circulating IL-17A was higher in lcSSc as opposed to dcSSc subset (31.99 ± 13.29 pg/mL vs 7.14 ± 3.01 pg/mL, P = 0.008). Within the dcSSc subset, raised levels of IL-17A and IL-6 were detected vs healthy controls: IL-17A [2.60 (0.45-9.80) pg/mL vs 0.00 (0.00-0.05) pg/mL, P < 0.001], IL-6 [2.80 (1.03-7.23) pg/mL vs 0.00 pg/mL, P < 0.001]. Regarding the stages of the disease, TGF-β1 serum levels were increased in early stage against late stage, independently from the SSc phenotype (30.03 ± 4.59 ng/mL vs 13.08 ± 4.50 ng/mL, P = 0.017).

It is likely that the altered percentage of Th17 and CD4+CD25-FoxP3+ cells along with the peripheral cytokine profile in patients with SSc may play a key role in the pathogenesis of the disease.

• Systemic sclerosis
• T-cell activation
• Th17
• Tregs
• CD4+CD25-Foxp3+ cells
• Interleukin-17
• Tissue growth factor-β
• Interleukin-10
• Interleukin-6

• Fibroblast
• Inflammation
• Systemic sclerosis

• age-related macular degeneration
• interleukin-13
• retinal pigment epithelial cell

Thymoquinone (TQ) is a bioactive component of black seed (Nigella sativa) volatile oil and has been shown to have anti-oxidative, anti-inflammatory, and anti-cancer properties. In the present study, we explored the molecular mechanisms that underlie the anti-inflammatory effect of TQ and its target proteins using lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 and human monocyte-like U937 cells, together with LPS/D-galactosamine (GalN)-induced acute hepatitis and HCl/EtOH-induced gastritis mouse models. TQ strongly inhibited the production of nitric oxide (NO) and repressed NO synthase (iNOS), tumor necrosis factor (TNF)-α, cyclooxygenase (COX)−2, interleukin (IL)−6, and IL-1β expression in LPS-activated RAW264.7 cells. Treatment of LPS/D-GalN–induced hepatitis and EtOH/HCl–induced gastritis mouse models with TQ significantly ameliorated disease symptoms. Using luciferase reporter gene assays, we also showed that the nuclear levels of transcription factors and phosphorylation patterns of signaling proteins, activator protein (AP)−1, and nuclear factor (NF)-κB pathways were all affected by TQ treatment. Finally, we used additional kinase and luciferase validation assays with interleukin-1 receptor-associated kinase 1 (IRAK1) to show that IRAK1 is directly suppressed by TQ treatment. Together, these findings strongly suggest that the anti-inflammatory actions of TQ are caused by suppression of IRAK-linked AP-1/NF-κB pathways.

• Autoimmune disease
• Immune response
• Therapeutic application
• Toll-like receptor

• a recombinant immunotoxin
• antifibrotic effect
• folate receptor β
• macrophage
• skin fibrosis

• ADP Ribose Transferases
• Animals
• Bacterial Toxins
• Bleomycin
• Exotoxins
• Fibrosis/chemically induced
• Fibrosis/metabolism
• Fibrosis/pathology
• Fibrosis/therapy
• Folate Receptor 2/immunology
• Folate Receptor 2/metabolism
• Immunotoxins
• Macrophages/immunology
• Macrophages/metabolism
• Macrophages/pathology
• Male
• Mice
• Skin Diseases/chemically induced
• Skin Diseases/metabolism
• Skin Diseases/pathology
• Skin Diseases/therapy
• Virulence Factors
• Pseudomonas aeruginosa Exotoxin A

• Autoimmunity
• Immune thrombocytopenia
• Immunogenetics
• Single nucleotide polymorphism
• Tumor necrosis factor-alpha

• SSc
• cytokines
• diffuse SSs
• early phase trial
• imatinib
• proof of concept

• CREST syndrome
• anticentromere antibody
• primary biliary cirrhosis
• systemic sclerosis

• Adult
• Animals
• Biomarkers/blood
• Cytokines/metabolism
• Dendritic Cells/metabolism
• Familial Primary Pulmonary Hypertension
• Female
• Humans
• Hypertension, Pulmonary/blood
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Platelet Factor 4/blood
• Platelet Factor 4/metabolism
• Proteome
• Pulmonary Fibrosis/blood
• RNA, Messenger/metabolism
• Scleroderma, Systemic/blood
• Scleroderma, Systemic/etiology
• Skin/pathology

• T32 AR007598 NIAMS NIH HHS
• K23 AR061436 NIAMS NIH HHS
• IP50AR060780 NIAMS NIH HHS
• R01 AR042334 NIAMS NIH HHS
• P50 AR060780 NIAMS NIH HHS
• P30 AR061271 NIAMS NIH HHS
• R01 AR055258 NIAMS NIH HHS
• R03 AR062721 NIAMS NIH HHS
• R01 AR051089 NIAMS NIH HHS

• Adult
• Aged
• Antigens, CD/blood
• Cadherins/blood
• Female
• Humans
• Interleukin-23/blood
• Interleukins/blood
• Male
• Middle Aged
• Neovascularization, Pathologic/blood
• Raynaud Disease/blood
• Scleroderma, Systemic/blood
• Vascular Endothelial Growth Factor A/blood
• Interleukin-22

The aim of this study was to test the naturally occurring organosulfur compound dipropyltetrasulfide (DPTTS), found in plants, which has antibiotic and anticancer properties, as a treatment for HOCl-induced systemic sclerosis in the mouse.

The prooxidative, antiproliferative, and cytotoxic effects of DPTTS were evaluated ex vivo on fibroblasts from normal and HOCl mice. In vivo, the antifibrotic and immunomodulating properties of DPTTS were evaluated in the skin and lungs of HOCl mice.

H₂O₂ production was higher in fibroblasts derived from HOCl mice than in normal fibroblasts (P < 0.05). DPTTS did not increase H₂O₂ production in normal fibroblasts, but DPTTS dose-dependently increased H₂O₂ production in HOCl fibroblasts (P < 0.001 with 40 μM DPTTS). Because H₂O₂ reached a lethal threshold in cells from HOCl mice, the antiproliferative, cytotoxic, and proapoptotic effects of DPTTS were significantly higher in HOCl fibroblasts than for normal fibroblasts. In vivo, DPTTS decreased dermal thickness (P < 0.001), collagen content in skin (P < 0.01) and lungs (P < 0.05), αSMA (P < 0.01) and pSMAD2/3 (P < 0.01) expression in skin, formation of advanced oxidation protein products and anti-DNA topoisomerase-1 antibodies in serum (P < 0.05) versus untreated HOCl mice. Moreover, in HOCl mice, DPTTS reduced splenic B-cell counts (P < 0.01), the proliferative rates of B-splenocytes stimulated by lipopolysaccharide (P < 0.05), and T-splenocytes stimulated by anti-CD3/CD28 mAb (P < 0.001). Ex vivo, it also reduced the production of IL-4 and IL-13 by activated T cells (P < 0.05 in both cases).

The natural organosulfur compound DPTTS prevents skin and lung fibrosis in the mouse through the selective killing of diseased fibroblasts and its immunomodulating properties. DPTTS may be a potential treatment for systemic sclerosis.

Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease with protean clinical manifestations. Recent advances in understanding the pathogenic mechanisms have led to development of target-oriented and vasomodulatory drugs which play a pivotal role in treating various dermatological manifestations. An exhaustive literature search was done using Medline, Embase, and Cochrane library to review the recent concepts regarding pathogenesis and evidence-based treatment of salient dermatological manifestations. The concept of shared genetic risk factors for the development of autoimmune diseases is seen in SSc. It is divided into fibroproliferative and inflammatory groups based on genome-wide molecular profiling. Genetic, infectious, and environmental factors play a key role; vascular injury, fibrosis, and immune activation are the chief pathogenic factors. Vitamin D deficiency has been documented in SSc and correlates with the severity of skin involvement. Skin sclerosis, Raynaud's phenomenon (RP) with digital vasculopathies, pigmentation, calcinosis, and leg ulcers affect the patient's quality of life. Immunosuppressives, biologicals, and hematopoietic stem cell transplantation are efficacious in skin sclerosis. Endothelin A receptor antagonists, calcium-channel blockers, angiotensin receptor inhibitors, prostacyclin analogs, and phosphodiesterase type 5 (PDE-5) inhibitors are the mainstay in RP and digital vasculopathies. Pigmentation in SSc has been attributed to melanogenic potential of endothelin-1 (ET-1); the role of ET 1 antagonists and vitamin D analogs needs to be investigated. Sexual dysfunction in both male and female patients has been attributed to vasculopathy and fibrosis, wherein PDE-5 inhibitors are found to be useful. The future concepts of treating SSc may be based on the gene expression signature.

• Endothelin receptor antagonists
• PDE-5 inhibitors
• fibrosis
• immune activation
• immunosuppressives
• systemic sclerosis
• vascular injury

• Myositis
• Myositis specific antibodies
• Sjogren’s syndrome
• Systemic Lupus Erythematosus
• antiphospholipid antibody syndrome
• new therapies in connective tissue disorders
• scleroderma

• Autoimmune diseases
• Human specific genes
• MicroRNAs
• Non-coding RNA
• Sjögren's Syndrome
• Systemic Sclerosis

Systemic sclerosis (SSc) is an inflammatory disease of unknown etiology characterized by widespread organ dysfunction due to fibrosis and ischemia. Its nebulous pathogenic background and the consequent absence of an etiological therapy prevent the adoption of satisfying treatment strategies, able to improve patients’ quality of life and survival and stimulate researchers to identify a unifying pathogenic target. Platelets show a unique biological behavior, lying at the crossroads between vascular function, innate and adaptive immunity, and regulation of cell proliferation. Consequently they are also emerging players in the pathogenesis of many inflammatory diseases, including SSc. In the setting of SSc platelets are detectable in a persistent activated state, which is intimately linked to the concomitant presence of an injured endothelium and to the widespread activation of the innate and adaptive immune system. As a consistent circulating source of bioactive compounds platelets contribute to the development of many characteristic phenomena of SSc, such as fibrosis and impaired vascular tone.

• HMGB1
• autoimmunity
• collagen
• inflammation
• platelets
• serotonin
• systemic sclerosis
• vascular injury

• Cell Transdifferentiation
• Fibroblasts/immunology
• Fibroblasts/metabolism
• Fibroblasts/pathology
• Fibrosis/genetics
• Fibrosis/metabolism
• Fibrosis/pathology
• Genome-Wide Association Study
• Humans
• Immunity, Innate
• Scleroderma, Systemic/genetics
• Scleroderma, Systemic/metabolism
• Scleroderma, Systemic/pathology
• Signal Transduction/immunology

• R01 AR042309 NIAMS NIH HHS
• R01 AR049025 NIAMS NIH HHS
• R56 AR042309 NIAMS NIH HHS
• AR 42309 NIAMS NIH HHS

• LPA
• S1P
• autoimmunity
• fibrosis
• vasculopathy

• Adult
• Case-Control Studies
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/immunology
• Europe
• Female
• France
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Germany
• HLA-DQ beta-Chains/genetics
• HLA-DQ beta-Chains/immunology
• Humans
• Italy
• Linkage Disequilibrium
• Major Histocompatibility Complex
• Male
• Polymorphism, Single Nucleotide
• Proteins/genetics
• Proteins/immunology
• Scleroderma, Systemic/genetics
• Scleroderma, Systemic/immunology
• rhoB GTP-Binding Protein/genetics
• rhoB GTP-Binding Protein/immunology