Utility of factor D and other alternative complement factors as biomarkers in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH).

Background: Activation of the complement cascade is thought to play a role in scleroderma vasculopathy. We previously showed that complement factor D was elevated in patients with limited cutaneous SSc and pulmonary arterial hypertension (PAH). In this study, we sought to assess multiple relevant components of the complement cascade to determine if they are altered in SSc-PAH, as well as their potential utility as biomarkers of disease severity and progression.

Clinical and Autoantibody Associations in Antinuclear Antibody-Positive Systemic Sclerosis Lacking Prototypic Autoantibodies.

Background/objectives:: The subset of ANA-positive patients with systemic sclerosis (SSc) who lack prototypic SSc-specific autoantibodies (centromere, topoisomerase, RNA polymerase III, “triple negative SSc”) is poorly characterized. We assessed clinical features and prevalence of additional autoantibodies in these patients.

Methods:: In this case series patients with ANA+ and triple negative SSc antibodies were identified from two independent SSc cohorts (n=280) and demographic and clinical data were obtained over two years.

PLG nanoparticles target fibroblasts and MARCO+ monocytes to reverse multiorgan fibrosis.

Systemic sclerosis (SSc) is a chronic, multisystem orphan disease with a highly variable clinical course, high mortality rate, and a poorly understood complex pathogenesis. We have identified an important role for a subpopulation of monocytes and macrophages characterized by surface expression of the scavenger receptor macrophage receptor with collagenous structure (MARCO) in chronic inflammation and fibrosis in SSc and in preclinical disease models. We show that MARCO+ monocytes and macrophages accumulate in lesional skin and lung in topographic proximity to activated myofibroblasts in patients with SSc and in the bleomycin-induced mouse model of SSc.

Circulating CTRP9 Is Associated With Severity of Systemic Sclerosis-Associated Interstitial Lung Disease.

Objective: While interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc), there remains a paucity of predictive markers to assess disease progression. We previously demonstrated that adipose tissue metabolism and adipokine homeostasis is dysregulated in SSc. The present study was undertaken to determine the association and predictive ability of the novel adipokine C1q/tumor necrosis factor-related protein 9 (CTRP9) for SSc-associated ILD.

Pathological pulmonary vascular remodeling is induced by type V collagen in a model of scleroderma.

Objective: The pulmonary vascular remodeling in systemic sclerosis (SSc) is poorly understood and animal models are lacking. Type V collagen (COLV) is elevated in SSc and is implicated in the pathogenesis, and immunization with human COLV induces SSc-like skin and lung changes in rabbits and mice. Here we tested the hypothesis that COLV immunization will induce pathological and functional changes that phenocopy SSc-associated pulmonary vascular disease.

Targeting CD38-dependent NAD metabolism to mitigate multiple organ fibrosis.

The processes underlying synchronous multiple organ fibrosis in systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in nicotinamide adenine dinucleotide (NAD) that is due to dysregulation of NAD homeostasis and involves the NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular fibrosis signatures, as well as clinical fibrosis scores, while expression of key NAD-synthesizing enzymes is unaltered.

Adipocytic Progenitor Cells Give Rise to Pathogenic Myofibroblasts: Adipocyte-to-Mesenchymal Transition and Its Emerging Role in Fibrosis in Multiple Organs.

Purpose Of Review: Adipocytes have recently been shown to be able to reprogram to a myofibroblastic phenotype in a process termed adipocyte mesenchymal transition (AMT). This review seeks to discuss the relevance of this process to disease and explore its mechanisms.

Recent Findings: AMT occurs in multiple organs and diseases, transdifferentiation goes through a precursor cell and there is a reversible process that can be influenced by metabolic stress, myeloid cells, immune dysregulation, and pharmacological intervention.

The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib.

Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized.

Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration-approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models.

Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis.

Background: A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-γ is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-γ (PPAR-γ) has antifibrotic effects by blocking transforming growth factor-β (TGF-β) and is dysregulated in SSc.

Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

Background: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).

Methods: Primary objectives were safety and pharmacokinetics.

Brief Report: Association of Elevated Adipsin Levels With Pulmonary Arterial Hypertension in Systemic Sclerosis.

Objective: Adipose tissues secrete adipokines, peptides with potent effects modulating fibrosis, inflammation, and vascular homeostasis. Dysregulated adipose tissue biology and adipokine balance have recently been implicated in systemic sclerosis (SSc). This study was undertaken to determine whether altered circulating adipokine levels correlate with SSc disease subsets or clinical manifestations.

Toll-like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor β-Dependent Fibroblast Activation.

Objective: Although transforming growth factor β (TGFβ) is recognized as being a key trigger of fibroblast activation in systemic sclerosis (SSc), prominent innate immunity suggests that additional pathways contribute to disease persistence. Toll-like receptor 9 (TLR9) is implicated in autoimmunity and fibrosis; however, the expression, mechanism of action, and pathogenic role of TLR9 signaling in SSc remain uncharacterized. The aim of this study was to explore the expression, activity, and potential pathogenic role of TLR9 in the context of skin fibrosis in SSc and in mouse models of experimental fibrosis.

The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor β Signaling.

Objective: Persistent fibroblast activation underlies skin fibrosis in systemic sclerosis (SSc), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. In view of the potent influence of acetylation status governing tissue fibrosis, we undertook this study to investigate the expression of the antiaging deacetylase enzyme sirtuin 1 (SIRT1) in SSc and its effects on fibrotic responses in vitro and in vivo.

Methods: Tissue expression of SIRTs was interrogated from publicly available genome-wide expression data sets and by immunohistochemistry.

Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors.

Objective: Accumulation of myofibroblasts in fibrotic skin is a hallmark of systemic sclerosis (SSc; scleroderma), but the origins of these cells remain unknown. Because loss of intradermal adipose tissue is a consistent feature of cutaneous fibrosis, we sought to examine the hypothesis that myofibroblasts populating fibrotic dermis derive from adipocytic progenitors.

Methods: We performed genetic fate mapping studies to investigate the loss of intradermal adipose tissue and its potential role in fibrosis in mice with bleomycin-induced scleroderma.

First report of mild Brazilian spotted fever associated to arthritis.

We describe the first Brazilian case of mild Rickettsiosis, complicated by knee monoarthritis, in young adult bitten by a tick on his left leg in Camburi zone, located in São Sebastião municipality, southern coastal region of the State of São Paulo, in the Atlantic rainforest region, Brazil. The patient developed inoculation eschar at the tick bite site associated with enlarged lymph nodes in the left groin, fever, polyarthralgia, headache and macular rash. Twenty days after tick bite episode, he displayed monoarthritis in his right knee.

Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction.

We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD).

Systemic sclerosis sine scleroderma: distinct features in a large Brazilian cohort.

Objective: Systemic sclerosis sine scleroderma (ssSSc) is an infrequent SSc variant characterized by visceral and immunological manifestations of SSc in the absence of clinically detectable skin involvement. We sought to delineate the characteristics of ssSSc in a cohort of Brazilian patients and contrast them with those in the literature.

Methods: SSc patients seen at two academic medical centres in Brazil were retrospectively analysed.

Brazilian lyme-like disease or Baggio-Yoshinari syndrome: exotic and emerging Brazilian tick-borne zoonosis.

Lyme disease (LD) is a frequent zoonosis found in the Northern Hemisphere and is considered an infectious disease caused by spirochetes belonging sensu lato to the Borrelia burgdorferi complex transmitted by ticks of the Ixodes ricinus group. In 1992, first cases similar to LD were described in Brazil, when brothers, after a tick bite episode developed symptoms , as erythema migrans, general flu-like symptoms and arthritis. Careful analysis of Brazilian LD-like illness casuistry showed that epidemiological, clinical and laboratorial features in the country were very different from those exhibited by North American and Eurasian LD patients.