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. METHODS: We performed a retrospective longitudinal study utilizing the Northwestern Scleroderma Program Patient Registry and Biorepository. Serum levels of CTRP9 were measured in 110 SSc patients at baseline, and demographic, clinical, and pulmonary function test data were collected in 12-month intervals to 48 months. Longitudinal trajectory of forced vital capacity percent predicted (FVC%) was used as a primary outcome measure. We utilized a mixed model to compare trajectories of lung function by CTRP9 groups and performed latent trajectory analysis to accommodate for heterogeneity. RESULTS: In cross-sectional analysis, elevated circulating CTRP9 was associated with significantly lower FVC% at baseline (72% ± 17 versus 80% ± 18; P = 0.02) and 48 months (68 ± 19 versus 84 ± 18; P = 0.001). In mixed model analysis, high CTRP9 was associated with worse lung function but not with a different trajectory (P = 0.23). In contrast, low CTRP9 identified patients with stability of lung disease with reasonable accuracy (sensitivity 73%). Latent trajectory analysis confirmed the association of lower CTRP9 with higher FVC%. CONCLUSION: Higher circulating CTRP9 associated with worse pulmonary function, while low CTRP9 identified patients with lung disease stability over time. These findings suggest that CTRP9 may be a potential biomarker in SSc-associated ILD.

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. Short-term treatment of mice with a potentially novel nanoparticle, poly(lactic-co-glycolic) acid (PLG), which is composed of a carboxylated, FDA-approved, biodegradable polymer and modulates activation and trafficking of MARCO+ inflammatory monocytes, markedly attenuated bleomycin-induced skin and lung inflammation and fibrosis. Mechanistically, in isolated cells in culture, PLG nanoparticles inhibited TGF-dependent fibrotic responses in vitro. Thus, MARCO+ monocytes are potent effector cells of skin and lung fibrosis and can be therapeutically targeted in SSc using PLG nanoparticles.

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. METHODS: Pulmonary vascular changes in rabbits immunized with human COLV were extensively characterized by a combination of histology, electron microscopy and immunohistochemistry. Physiologic changes induced by COLV in explanted pulmonary artery rings were evaluated. The pattern of histopathologic alterations and gene expression induced in immunized rabbits were compared to those in SSc patients. RESULTS: COLV immunization was accompanied by striking pulmonary vascular abnormalities, characterized by reduced capillary density, perivascular inflammation, endothelial cell injury and collagen accumulation, that closely phenocopy changes seen in SSc patients. Moreover, pulmonary arteries from immunized rabbits showed impaired ex vivo vascular relaxation. Expression of COL5A2 was significantly increased in the lungs from immunized rabbits (p = 0.02), as well as in patients with SSc (P = 0.02). CONCLUSION: COLV immunity in rabbits is associated with marked vascular remodeling in the lung that phenocopies early-stage human SSc-associated pulmonary vascular disease. COLV immunization therefore represents a novel approach to model SSc pulmonary vascular pathology. Moreover, our findings suggest that COLV might represent a novel pathogenic autoantigen in SSc and future studies with the present model should be developed for possible association with PAH.

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. Boosting NAD+ via genetic or pharmacological CD38 targeting or NAD+ precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. In mechanistic experiments, CD38 was found to reduce NAD+ levels and sirtuin activity to augment cellular fibrotic responses, while inhibiting CD38 had the opposite effect. Thus, we identify CD38 upregulation and resulting disrupted NAD+ homeostasis as a fundamental mechanism driving fibrosis in SSc, suggesting that CD38 might represent a novel therapeutic target.

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. AMT is a newly appreciated and highly relevant process in multiple forms of fibrosis. Targeting AMT may serve as a novel method of treating fibrosis.

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. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.

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-ß (TGF-ß) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-γ in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-γ activity and suppresses adipogenesis. METHODS: An NCoR-regulated gene signature was measured in the SSc skin transcriptome. Experimental skin fibrosis was examined in mice with adipocyte-specific NCoR ablation. RESULTS: SSc skin biopsies demonstrated deregulated NCoR signaling. A 43-gene NCoR gene signature showed strong positive correlation with PPAR-γ signaling (R = 0.919, p < 0.0001), whereas negative correlations with TGF-ß signaling (R = - 0.796, p < 0.0001) and the modified Rodnan skin score (R = - 0.49, p = 0.004) were found. Mice with adipocyte-specific NCoR ablation demonstrated significant protection from experimental skin fibrosis and inflammation. The protective effects were mediated primarily through endogenous PPAR-γ. CONCLUSIONS: Our results implicate, for the first time, to our knowledge, deregulated NCoR/PPAR-γ pathways in SSc, and they support a role of adipocyte modulation of skin fibrosis. Pharmacologic restoration of NCoR/PPAR-γ signaling may represent a novel strategy to control skin fibrosis 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. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169. RESULTS: Dasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313). CONCLUSIONS: In patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT00764309.

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. METHODS: Multiplex assays were used to measure circulating adipokine levels in 198 patients with SSc and 33 healthy controls. Data were evaluated for correlations between serum adipokine levels and demographic and clinical features, including pulmonary arterial hypertension (PAH). To assess the relevance of adipsin, an adipokine involved in complement pathway activation, in SSc, we analyzed publicly available genetic and transcriptomic data. RESULTS: Levels of adiponectin and adipsin differed significantly between controls and patients. Adipsin was significantly elevated in patients with limited cutaneous SSc (odds ratio [OR] 28.3 [95% confidence interval (95% CI) 7.0-113.8]; P < 0.0001), and its levels were associated with serum autoantibody status, pulmonary function and cardiovascular parameters, and PAH (OR 3.3 [95% CI 1.3-8.7]; P = 0.02). Elevated adipsin was more strongly associated with PAH than B-type natriuretic peptide was. Moreover, in SSc patients, adipsin gene single-nucleotide polymorphisms were associated with PAH. Transcriptome data set analysis demonstrated elevated adipsin expression in patients with SSc-related PAH. CONCLUSION: We identify adipsin as a novel adipose tissue-derived marker of SSc-related PAH. Circulating adipsin levels might serve as predictive biomarkers in SSc. Mechanistically, adipsin might represent a pathogenic link between adipocyte dysfunction and complement pathway activation and play an important role in the pathogenesis of SSc-related PAH.

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

OBJECTIVE: Although transforming growth factor ß (TGFß) 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. METHODS: Expression and localization of TLR9 were evaluated in SSc skin biopsy specimens and explanted skin fibroblasts. Fibrotic responses elicited by type A CpG oligonucleotide and mitochondrial DNA (mtDNA) were examined in human skin fibroblasts by a combination of real-time quantitative polymerase chain reaction, Western blot analysis, transient transfection, immunofluorescence microscopy, and functional assays. Expression of TLR9 was examined in 2 distinct mouse models of experimental fibrosis. RESULTS: Skin biopsy specimens obtained from 2 independent cohorts of SSc patients showed up-regulation of TLR9, and myofibroblasts were the major cellular source. Moreover, SSc skin biopsy specimens showed evidence of TLR9 pathway activation. CpG induced robust TLR9-dependent fibrotic responses in explanted normal fibroblasts that could be blocked by bortezomib and were mediated through the action of endogenous TGFß. Mice with experimental fibrosis showed a time-dependent increase in TLR9 localized primarily to myofibroblasts in the dermis. CONCLUSION: In isolated fibroblasts, TLR9 elicits fibrotic responses mediated via endogenous TGFß. In patients with SSc, mtDNA and other damage-associated TLR9 ligands in the skin might trigger localized activation of TLR9 signaling, TGFß production, and consequent fibroblast activation. Disrupting this fibrotic process with inhibitors targeting TLR9 or its downstream signaling pathways might therefore represent a novel approach to SSc therapy.

A candidate gene study reveals association between a variant of the Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) gene and systemic sclerosis.

INTRODUCTION: The multifunctional nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) has potent anti-fibrotic effects, and its expression and activity are impaired in patients with systemic sclerosis (SSc). We investigated PPAR-γ gene (PPARG) single nucleotide polymorphisms (SNPs) associated with SSc. METHODS: Tag SNPs spanning PPARG were genotyped in a European ancestry US discovery cohort comprising 152 SSc patients and 450 controls, with replication of our top signal in a European cohort (1031 SSc patients and 1014 controls from France). Clinical parameters and disease severity were analyzed to evaluate clinical associations with PPARG variants. RESULTS: In the discovery cohort, a single PPARG intronic SNP (rs10865710) was associated with SSc (p=0.010; odds ratio=1.52 per C allele, 95% confidence interval 1.10-2.08). This association was replicated in the French validation cohort (p=0.052; odds ratio=1.16 per C allele, 95% confidence interval 1.00-1.35). Meta-analysis of both cohorts indicated stronger evidence for association (p=0.002; odds ratio=1.22 per C allele, 95% confidence interval 1.07-1.40). The rs10865710 C allele was also associated with pulmonary arterial hypertension in the French SSc cohort (p=0.002; odds ratio=2.33 per C allele, 95% confidence interval 1.34-4.03). CONCLUSIONS: A PPARG variant is associated with susceptibility to SSc, consistent with a role of PPAR-γ in the pathogenesis of SSc.

The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor ß 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. The effects of SIRT1 on modulating fibrotic responses, as well as the underlying mechanisms, were examined in human and mouse fibroblasts in culture and in an experimental fibrosis model in the mouse. RESULTS: Analysis of transcriptome data revealed a selective reduction of SIRT1 messenger RNA (mRNA) levels in SSc skin biopsy samples as well as a negative correlation of SIRT1 mRNA with the skin score. Cellular SIRT1 levels were suppressed in normal fibroblasts exposed to hypoxia or platelet-derived growth factor and were constitutively down-regulated in SSc fibroblasts. Activation of SIRT1 attenuated fibrotic responses in skin fibroblasts and skin organ cultures, while genetic or pharmacologic inhibition of SIRT1 had profibrotic effects. The antifibrotic effects of SIRT1 were due in part to decreased expression and function of the acetyltransferase p300. In mice, experimentally induced skin fibrosis was accompanied by reduced SIRT1 expression in lesional tissue fibroblasts, and both fibrosis and loss of SIRT1 in these mice were mitigated by treatment with a SIRT1 activator. CONCLUSION: SIRT1 has antifibrotic effects, and its reduced tissue expression in patients with SSc might have a direct causal role in progression of fibrosis. Pharmacologic modulation of SIRT1 in these patients therefore might represent a potential treatment strategy.

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. Modulation of adipocytic phenotypes ex vivo was investigated in adipose tissue-derived cells in culture. RESULTS: A striking loss of intradermal adipose tissue and its replacement with fibrous tissue were consistently observed in mice with bleomycin-induced fibrosis. Loss of adipose tissue and a decline in the expression of canonical adipogenic markers in lesional skin preceded the onset of dermal fibrosis and expression of fibrogenic markers. Ex vivo, subcutaneous adipocytes were driven by transforming growth factor ß to preferentially undergo fibrogenic differentiation. Cell fate mapping studies in mice with the adiponectin promoter-driven Cre recombinase transgenic construct indicated that adiponectin-positive progenitors that are normally confined to the intradermal adipose tissue compartment were distributed throughout the lesional dermis over time, lost their adipocytic markers, and expressed myofibroblast markers in bleomycin-treated mice. CONCLUSION: These observations establish a novel link between intradermal adipose tissue loss and dermal fibrosis and demonstrate that adiponectin-positive intradermal progenitors give rise to dermal myofibroblasts. Adipose tissue loss and adipocyte-myofibroblast transition might be primary events in the pathogenesis of cutaneous fibrosis that represent novel potential targets for therapeutic intervention.

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. The diagnosis of mild Rickettsiosis was established by sequential immunological analysis in serum and synovial fluid, using the indirect immunofluorescence (IF) assay for antibodies reactive with Rickettsia parkeri and Rickettsia rickettsii. The mild Rickettsiosis is an emerging zoonosis, that must be investigated by physicians, including rheumatologists, in patients that present macular rash, fever and eventually arthritis, after visiting the southern coastal Atlantic rainforest region in Brazil.

Primeiro caso de febre maculosa brasileira branda associada à artrite / First report of mild Brazilian spotted fever associated to arthritis

Descrevemos o primeiro caso brasileiro de Riquetsiose branda, agravada por monoartrite em joelho, em adulto jovem picado por carrapato na perna esquerda na região de Camburi, localizada no município de São Sebastião, sul da região costeira do estado de São Paulo, Mata Atlântica, Brasil. O paciente apresentou uma escara de inoculação no local da picada do carrapato, associada ao aumento ganglionar em virilha esquerda, febre, poliartralgia, cefaleia e erupção macular. Vinte dias após o episódio da picada de carrapato, o paciente apresentou monoartrite em joelho direito. O diagnóstico de Riquetsiose branda foi estabelecido pela análise imunológica sequencial em amostras de soro e líquido sinovial, tendo sido empregada a técnica de imunofluorescência (IF) indireta para anticorpos reativos contra Rickettsia parkeri e Rickettsia rickettsii. A Riquetsiose branda é uma zoonose emergente, que deve ser investigada pelos médicos, incluindo reumatologistas, em pacientes que apresentem erupção macular, febre e, eventualmente, artrite, após visita ao sul da região costeira da Mata Atlântica no Brasil.

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. The diagnosis of mild Rickettsiosis was established by sequential immunological analysis in serum and synovial fluid, using the indirect immunofluorescence (IF) assay for antibodies reactive with Rickettsia parkeri and Rickettsia rickettsii. The mild Rickettsiosis is an emerging zoonosis, that must be investigated by physicians, including rheumatologists, in patients that present macular rash, fever and eventually arthritis, after visiting the southern coastal Atlantic rainforest region in Brazil.

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. Patients were classified as ssSSc if they presented with RP, positive ANAs and at least one visceral involvement typical of SSc in the absence of skin thickening. Demographics, clinical and laboratory data were obtained by chart review. Literature review was performed by searching available original studies up until June 2012. RESULTS: Among the 947 consecutive patients with SSc, 79 (8.3%) were classified as ssSSc. Oesophagus was the most frequently affected organ (83.1%), followed by pulmonary involvement (63.2%). Compared with the limited cutaneous form of SSc, telangiectasia was the only variable significantly different after multivariate logistic regression analyses (odds ratio 0.46; 95% CI 0.27, 0.81). Compared with the diffuse cutaneous form of SSc, multivariate analyses revealed that ssSSc patients were less likely to be male (odds ratio 0.15; 95% CI 0.04, 0.57), have digital ulcers (odds ratio 0.26; 95% CI 0.13, 0.51) or anti-Scl70 antibodies (odds ratio 0.19; 95% CI 0.07, 0.55) and less frequently treated with CYC (odds ratio 0.23; 95% CI 0.12, 0.43). These features were comparable to those in the published literature. CONCLUSION: In this series, patients with ssSSc had a relatively mild disease with good prognosis.

Decreased high-density lipoprotein cholesterol levels in polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To investigate the prevalence of dyslipoproteinemia in a homogeneous cohort of polyarticular juvenile idiopathic arthritis patients. METHODS: Based on the National Cholesterol Education Program, fasting lipoprotein levels and risk levels for coronary artery disease were determined in 28 patients with polyarticular juvenile idiopathic arthritis. The exclusion criteria included diabetes, thyroid dysfunction, smoking, proteinuria, lipid-lowering drugs, and hormone/diuretic therapy. Disease activity, disease duration, and therapy with corticosteroids and/or chloroquine were defined at the time of lipid measurements. RESULTS: Dyslipoproteinemia was identified in 20 of the 28 (71%) patients with polyarticular juvenile idiopathic arthritis. The primary lipoprotein risk factor was decreased high-density lipoprotein cholesterol (57%), followed by elevated levels of low-density lipoprotein cholesterol (18%), triglycerides (14%), and total cholesterol (7%). The male patients had decreased high-density lipoprotein cholesterol levels than the female patients (p<0.05). The incidence of decreased high-density lipoprotein cholesterol levels did not seem to be affected by disease activity or therapy because the incidence was similar in patients with active or inactive disease, with or without corticosteroid use and with or without chloroquine use. In addition, the frequency of decreased high-density lipoprotein cholesterol levels was similar in patients with short (≤5 years) vs. long (>5 years) disease duration. CONCLUSIONS: Dyslipoproteinemia is highly prevalent in patients with polyarticular juvenile idiopathic arthritis and is primarily related to decreased high-density lipoprotein cholesterol levels; therefore, early intervention is essential.

Decreased high-density lipoprotein cholesterol levels in polyarticular juvenile idiopathic arthritis

OBJECTIVES: To investigate the prevalence of dyslipoproteinemia in a homogeneous cohort of polyarticular juvenile idiopathic arthritis patients. METHODS: Based on the National Cholesterol Education Program, fasting lipoprotein levels and risk levels for coronary artery disease were determined in 28 patients with polyarticular juvenile idiopathic arthritis. The exclusion criteria included diabetes, thyroid dysfunction, smoking, proteinuria, lipid-lowering drugs, and hormone/diuretic therapy. Disease activity, disease duration, and therapy with corticosteroids and/or chloroquine were defined at the time of lipid measurements. RESULTS: Dyslipoproteinemia was identified in 20 of the 28 (71 percent) patients with polyarticular juvenile idiopathic arthritis. The primary lipoprotein risk factor was decreased high-density lipoprotein cholesterol (57 percent), followed by elevated levels of low-density lipoprotein cholesterol (18 percent), triglycerides (14 percent), and total cholesterol (7 percent). The male patients had decreased high-density lipoprotein cholesterol levels than the female patients (p<0.05). The incidence of decreased high-density lipoprotein cholesterol levels did not seem to be affected by disease activity or therapy because the incidence was similar in patients with active or inactive disease, with or without corticosteroid use and with or without chloroquine use. In addition, the frequency of decreased high-density lipoprotein cholesterol levels was similar in patients with short (≤5 years) vs. long (>5 years) disease duration. CONCLUSIONS: Dyslipoproteinemia is highly prevalent in patients with polyarticular juvenile idiopathic arthritis and is primarily related to decreased high-density lipoprotein cholesterol levels; therefore, early intervention is essential.

Estudo da vasculopatia pulmonar no modelo experimental de esclerodermia induzido pelo colágeno do tipo V / Study of pulmonary vasculopathy in the collagen V-induced systemic sclerosis experimental model

A esclerodermia sistêmica (ES) é caracterizada por fibrose da pele e órgãos internos, ativação imunológica e vasculopatia. Os modelos animais de ES sofrem com a falta de uma prova definitiva para o envolvimento vascular observado na doença humana. Um novo modelo induzido por colágeno do tipo V (COLV) reproduz muitas características da ES como fibrose e fenômenos imunológicos. No entanto, o estudo da vasculopatia ainda não foi abordado. O objetivo desse estudo foi investigar as alterações estruturais e funcionais das células endoteliais das artérias pulmonares do modelo de ES induzido pelo COLV, assim como determinar a doença pulmonar com ênfase especial no depósito de colágeno e síntese de RNAm de colágenos. Coelhos fêmeas Nova Zelândia (n = 8) foram imunizados com COLV humano emulsificado em adjuvante de Freund ou apenas com adjuvante de Freund (controle; n = 8). Após 7, 75 e 210 dias, os animais foram sacrificados e os pulmões foram analisados por microscopia eletrônica, hematoxilina e eosina, e marcações especiais incluindo imunomarcação para neovascularização (CD31), apoptose de células endoteliais (induzida pela caspase-3) e atividade endotelial (endotelina-1 e VEGF). A resposta vascular a acetilcolina (Ach) foi estudada em anéis de artéria pulmonar isolada. Para determinar o conteúdo de colágeno, expressão RNAm dos colágenos I, III e V e quantidade de colágeno (hidroxiprolina aminoácido específico), os pulmões foram submetidos a imunofluorescência, PCR em tempo real e análise bioquímica. Foi observado que os coelhos imunizados com COLV apresentaram um aumento progressivo de apoptose e atividade das células endoteliais a partir de 7 dias quando comparados aos coelhos controle (p 0,01). Em contrapartida, apenas aos 210 dias os coelhos imunizados com COLV apresentaram aumento significativo na neovascularização quando comparados com o grupo controle (p < 0,001). Coincidente com esses achados, a microscopia eletrônica mostrou alterações das células...

The hallmarks of systemic sclerosis (SSc) are fibrosis of skin and internal organs, immune activity and vasculopathy. Animal models of SSc suffer from lack of a definitive evidence for vascular involvement observed in human disease. A novel model induced by collagen type V (COLV) reproduces many features of SSc, however vascular study has not been addressed. The aim of the present study was therefore evaluate pulmonary arteries for structural and functional alterations in endothelial cells in the COLV-induced SSc model, as well as determine the lung disease with special emphasis on collagen deposition and mRNA collagen synthesis. Female New Zealand rabbits (n = 8) were immunized with human COLV/Freund´s adjuvant or Freund´s adjuvant alone (control; n = 8). After 7, 75 and 210 days, the animals were sacrificed and the lungs were examined by electron microscopy, hematoxylin&eosin and special stains including immunostaining for neovascularization (CD31), endothelial cells apoptosis (caspase-3 induced) and endothelial activity (endothelin-1 and VEGF). Vascular response to acetylcholine (Ach) on isolated pulmonary artery rings was evaluated. To determine collagen content, mRNA expressions of COL I, III and V, and the quantity of collagen-specific amino acid hydroxyproline, the lungs were submitted to immunofluorescence, real-time qPCR and biochemical examination. The COLV rabbits demonstrated an endothelial cells apoptosis and activity compared to control rabbits starting at day-7 (p 0.01). A significant increase in neovascularization was observed only in the COLV-rabbits at day-210 (p < 0,001). Coincident with these findings, the electron microscopy revealed extensive endothelial cells abnormalities characterized by apoptosis, degenerative organelle changes and cytoplasmic tumefaction. Endothelial cells appeared to be detached from the basement membrane. Ach dose required to achieve 50% maximum relaxation (EC50) of pulmonary artery rings was increased in COLV...

[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. Human blood-suckers Ixodes ricinus complex ticks were absent at risk areas; the disease is recurrent in the country; Borrelia burgdorferi was never isolated in Brazil and specific serologic tests have shown little positivity with inconsistent results. Furthermore, peripheral blood analysis of patients on electron microscopy exhibited structures resembling Mycoplasma spp, Chlamydia spp and spirochete-like microorganisms. In fact, they were assumed to be latent forms of spirochetes (L form or cell wall deficient bacteria) adapted to survive at inhospitable conditions in vertebrate and invertebrate hosts. For these reasons, the Brazilian zoonosis was named Baggio-Yoshinari Syndrome (BYS) and defined as: "Exotic and emerging Brazilian infectious disease, transmitted by ticks not belonging to the Ixodes ricinus complex, caused by latent spirochetes with atypical morphology, which originates LD-like symptoms, except for occurrence of relapsing episodes and auto-immune disorders".