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1.
Pathol Res Pract ; 220: 153382, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33647866

RESUMO

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.

2.
J Psychosom Res ; 140: 110314, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33271402

RESUMO

INTRODUCTION: No studies have examined factors associated with fear in any group of people vulnerable during COVID-19 due to pre-existing medical conditions. OBJECTIVE: To investigate factors associated with fear of consequences of COVID-19 among people living with a pre-existing medical condition, the autoimmune disease systemic sclerosis (SSc; scleroderma), including country. METHODS: Pre-COVID-19 data from the Scleroderma Patient-centered Intervention Network (SPIN) Cohort were linked to COVID-19 data collected in April 2020. Multivariable linear regression was used to assess factors associated with continuous scores of the 10-item COVID-19 Fears Questionnaire for Chronic Medical Conditions, controlling for pre-COVID-19 anxiety symptoms. RESULTS: Compared to France (N = 156), COVID-19 Fear scores among participants from the United Kingdom (N = 50) were 0.12 SD (95% CI 0.03 to 0.21) higher; scores for Canada (N = 97) and the United States (N = 128) were higher, but not statistically significant. Greater interference of breathing problems was associated with higher fears due to COVID-19 (Standardized regression coefficient = 0.12, 95% CI 0.01 to 0.23). Participants with higher financial resources adequacy scores had lower COVID-19 Fear scores (Standardized coefficient = -0.18, 95% CI -0.28 to -0.09). CONCLUSIONS: Fears due to COVID-19 were associated with clinical and functional vulnerabilities in this chronically ill population. This suggests that interventions may benefit from addressing specific clinical issues that apply to specific populations. Financial resources, health policies and political influences may also be important. The needs of people living with chronic illness during a pandemic may differ depending on the social and political context in which they live.

3.
J Infect Dis ; 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33330902

RESUMO

BACKGROUND: Microbiome sequencing has brought increasing attention to the polymicrobial context of chronic infections. However, clinical microbiology continues to focus on canonical human pathogens, which may overlook informative, but non-pathogenic, biomarkers. We address this disconnect in lung infections in people with cystic fibrosis (CF). METHODS: We collected health information (lung function, age, BMI) and sputum samples from a cohort of 77 children and adults with CF. Samples were collected during a period of clinical stability and 16S rDNA sequenced for airway microbiome compositions. We use Elastic Net regularization to train linear models predicting lung function and extract the most informative features. RESULTS: Models trained on whole microbiome quantitation outperform models trained on pathogen quantitation alone, with or without the inclusion of patient metadata. Our most accurate models retain key pathogens as negative predictors (Pseudomonas, Achromobacter) along with established correlates of CF disease state (age, BMI, CF related diabetes). In addition, our models select non-pathogen taxa (Fusobacterium, Rothia) as positive predictors of lung health. CONCLUSIONS: These results support a reconsideration of clinical microbiology pipelines to ensure the provision of informative data to guide clinical practice.

4.
JAMA Netw Open ; 3(12): e2029917, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33315114

RESUMO

Importance: Patients with autoimmune disease and lung cancer pose a multidisciplinary treatment challenge, particularly with the advent of immunotherapy. However, the association between autoimmune disease and lung cancer survival is largely unknown. Objective: To determine the association between autoimmune disease and lung cancer survival. Design, Setting, and Participants: Retrospective cohort study between 2003 and 2019 at a single academic medical center (Northwestern University). A query of the Northwestern Medicine Enterprise Data Warehouse identified 349 patients with lung cancer and several autoimmune diseases. Types of lung cancers included small cell, adenocarcinoma, squamous cell carcinoma, non-small cell not otherwise specified, and large cell carcinoma. Autoimmune diseases included rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, myositis, and Sjögren syndrome. Inclusion criteria were biopsy-confirmed lung cancer, autoimmune diagnosis confirmed by a rheumatologist, and death or an encounter listed in the electronic medical record within 2 years of study end. A control group of patients with biopsy-proven lung cancer but without autoimmune disease was identified. Data analysis was conducted from March to July 2020. Exposure: Presence of autoimmune disease. Main Outcomes and Measures: Overall survival and progression-free survival in patients with autoimmune disease. The hypothesis was that patients with autoimmune disease would have worse progression-free survival and overall survival compared with patients in the control group. Results: Of the original 349 patients, 177 met inclusion criteria. Mean (SD) age at lung cancer diagnosis was 67.0 (10.0) years and 136 (76.8%) were women. Most common autoimmune diseases were rheumatoid arthritis (97 [54.8%]), systemic sclerosis (43 [24.3%]), and systemic lupus erythematous (15 [8.5%]). Most common lung cancers were adenocarcinoma (99 [55.9%]), squamous cell carcinoma (29 [16.4%]), and small cell lung cancer (17 [9.6%]). A total of 219 patients (mean [SD] age at diagnosis, 65.9 [4.1] years; 173 [79.0%]) were identified as having lung cancer without autoimmune disease and included in the control cohort. Compared with patients in the control group, patients with autoimmune disease experienced no difference in overall survival (log-rank P = .69). A total of 126 patients (69.5%) with autoimmune disease received standard of care vs 213 patients (97.3%) in the control group (P < .001). No individual autoimmune disease was associated with worse prognosis, even among patients with underlying interstitial lung disease. Conclusions and Relevance: Compared with institutional controls, patients with autoimmune disease experienced no difference in survival despite the fact that fewer patients in this group received standard-of-care treatment. No individual autoimmune disease was associated with worse prognosis. Future multicenter prospective trials are needed to further evaluate autoimmune disease and lung cancer survival.


Assuntos
Neoplasias Pulmonares , Pulmão/patologia , Idoso , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/terapia , Autoimunidade , Biópsia/métodos , Biópsia/estatística & dados numéricos , Comorbidade , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Pesquisa Interdisciplinar , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Estadiamento de Neoplasias , Noroeste dos Estados Unidos/epidemiologia , Prognóstico , Estudos Retrospectivos , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/fisiopatologia , Escleroderma Sistêmico/terapia , Padrão de Cuidado/organização & administração , Padrão de Cuidado/estatística & dados numéricos , Análise de Sobrevida
5.
Arthritis Rheumatol ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131208

RESUMO

OBJECTIVE: To provide a large-scale assessment of serum protein dysregulations in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: Baseline serum protein profile of 66 participants with dcSSc enrolled in the Scleroderma: Cyclophosphamide Or Transplant trial and 66 healthy, age- and gender-matched controls was investigated. A panel of 230 proteins, including several cytokines and chemokines was determined. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Mean disease duration was 2.3 years, all had interstitial lung disease (ILD), and none were treated with immunosuppressive agents at baseline visit. Ninety proteins were differentially expressed compared to controls. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion and diapedesis were the top over-represented pathways. Eighteen proteins correlated with modified Rodnan Skin Score (mRSS). Soluble EGFR was significantly down-regulated in dcSSc and showed the strongest negative correlation with mRSS and predicted its course, whereas Alpha 1 Antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with mRSS. Furthermore, higher CA15.3 correlated with more severe ILD, based on lower forced vital capacity and higher high-resolution CT scores. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSIONS: dcSSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells.

6.
J Psychosom Res ; 139: 110262, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070043

RESUMO

INTRODUCTION: No studies have reported mental health symptom comparisons prior to and during COVID-19 in vulnerable medical populations. OBJECTIVE: To compare anxiety and depression symptoms among people with a pre-existing medical condition and factors associated with changes. METHODS: Pre-COVID-19 Scleroderma Patient-centered Intervention Network Cohort data were linked to COVID-19 data from April 2020. Multiple linear and logistic regression were used to assess factors associated with continuous change and ≥ 1 minimal clinically important difference (MCID) change for anxiety (PROMIS Anxiety 4a v1.0; MCID = 4.0) and depression (Patient Health Questionnaire-8; MCID = 3.0) symptoms, controlling for pre-COVID-19 levels. RESULTS: Mean anxiety symptoms increased 4.9 points (95% confidence interval [CI] 4.0 to 5.7). Depression symptom change was negligible (0.3 points; 95% CI -0.7 to 0.2). Compared to France (N = 159), adjusted anxiety symptom change scores were significantly higher in the United Kingdom (N = 50; 3.3 points, 95% CI 0.9 to 5.6), United States (N = 128; 2.5 points, 95% CI 0.7 to 4.2), and Canada (N = 98; 1.9 points, 95% CI 0.1 to 3.8). Odds of ≥1 MCID increase were 2.6 for the United Kingdom (95% CI 1.2 to 5.7) but not significant for the United States (1.6, 95% CI 0.9 to 2.9) or Canada (1.4, 95% CI 0.7 to 2.5). Older age and adequate financial resources were associated with less continuous anxiety increase. Employment and shorter time since diagnosis were associated with lower odds of a ≥ 1 MCID increase. CONCLUSIONS: Anxiety symptoms, but not depression symptoms, increased dramatically during COVID-19 among people with a pre-existing medical condition.

7.
Semin Arthritis Rheum ; 50(6): 1226-1237, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33059296

RESUMO

Numerous drugs and chemical substances are capable of inducing exaggerated tissue fibrotic responses. The vast majority of these agents cause localized fibrotic tissue reactions or fibrosis confined to specific organs. Although much less frequent, chemically-induced systemic fibrotic disorders have been described, sometimes occurring as temporally confined outbreaks. These include the Toxic Oil Syndrome (TOS), the Eosinophilia-Myalgia Syndrome (EMS), and Nephrogenic Systemic Fibrosis (NSF). Although each of these disorders displays some unique characteristics, they all share crucial features with Systemic Sclerosis (SSc), the prototypic idiopathic systemic fibrotic disease, including vasculopathy, chronic inflammatory cell infiltration of affected tissues, and cutaneous and visceral tissue fibrosis. The study of the mechanisms and molecular alterations involved in the development of the chemically-induced systemic fibrotic disorders has provided valuable clues that may allow elucidation of SSc etiology and pathogenesis. Here, we review relevant aspects of the TOS, EMS, and NSF epidemic outbreaks of chemically-induced systemic fibrosing disorders that provide strong support to the hypothesis that SSc is caused by a toxic or biological agent that following its internalization by endothelial cells induces in genetically predisposed individuals a series of molecular alterations that result in the development of SSc clinical and pathological alterations.

9.
Curr Opin Rheumatol ; 32(6): 488-496, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32941246

RESUMO

PURPOSE OF REVIEW: Here we review recent literature on the emerging role of nicotinamide adenine dinucleotide (NAD) metabolism and its dysfunction via the enzyme CD38 in the pathogenesis of rheumatologic diseases. We evaluate the potential of targeting CD38 to ameliorate NAD-related metabolic imbalance and tissue dysfunction in the treatment of systemic sclerosis (SSc), systemic lupus erythematous (SLE), and rheumatoid arthritis (RA). RECENT FINDINGS: In this review, we will discuss emerging basic, preclinical, and human data that point to the novel role of CD38 in dysregulated NAD-homeostasis in SSc, SLE, and RA. In particular, recent studies implicate increased activity of CD38, one of the main enzymes in NAD catabolism, in the pathogenesis of persistent systemic fibrosis in SSc, and increased susceptibility of SLE patients to infections. We will also discuss recent studies that demonstrate that a cytotoxic CD38 antibody can promote clearance of plasma cells involved in the generation of RA antibodies. SUMMARY: Recent studies identify potential therapeutic approaches for boosting NAD to treat rheumatologic diseases including SSc, RA, and SLE, with particular attention to inhibition of CD38 enzymatic activity as a target. Key future directions in the field include the determination of the cell-type specificity and role of CD38 enzymatic activity versus CD38 structural roles in human diseases, as well as the indicators and potential side effects of CD38-targeted treatments.

10.
Curr Rheumatol Rep ; 22(11): 79, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978695

RESUMO

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.

11.
Curr Rheumatol Rep ; 22(10): 73, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32856128

RESUMO

PURPOSE OF REVIEW: Calcinosis is a common complication of systemic sclerosis with no known effective pharmacologic therapy. We reviewed the literature regarding systemic sclerosis-related calcinosis as well as other disorders of biomineralization in order to identify targets of future study for calcinosis. RECENT FINDINGS: Patients with systemic sclerosis-related calcinosis demonstrate systemic abnormalities in mineralization pathways, including decreased levels of the mineralization inhibitor inorganic pyrophosphate. Insights from other mineralization disorders suggest that local and systemic phosphate metabolism pathways involving the ABCC6, ENPP1, and NT5E genes play a critical role in regulation of ectopic calcification. Knockout models of these genes may lead to an appropriate murine model for study of calcinosis. Poly(ADP-ribose) polymerase (PARP) enzymes may also play a critical role in hydroxyapatite nucleation and warrant future study in systemic sclerosis. Study of local and systemic mineralization pathways, particularly phosphate metabolism pathways and PARP enzymes, should provide greater insight into the pathogenesis of systemic sclerosis-related calcinosis.

12.
J Psychosom Res ; 135: 110132, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32521358

RESUMO

OBJECTIVE: Contagious disease outbreaks and related restrictions can lead to negative psychological outcomes, particularly in vulnerable populations at risk due to pre-existing medical conditions. No randomised controlled trials (RCTs) have tested interventions to reduce mental health consequences of contagious disease outbreaks. The primary objective of the Scleroderma Patient-centered Intervention Network COVID-19 Home-isolation Activities Together (SPIN-CHAT) Trial is to evaluate the effect of a videoconference-based program on symptoms of anxiety. Secondary objectives include evaluating effects on symptoms of depression, stress, loneliness, boredom, physical activity, and social interaction. METHODS: The SPIN-CHAT Trial is a pragmatic RCT that will be conducted using the SPIN-COVID-19 Cohort, a sub-cohort of the SPIN Cohort. Eligible participants will be SPIN-COVID-19 Cohort participants without a positive COVID-19 test, with at least mild anxiety (PROMIS Anxiety 4a v1.0 T-score ≥ 55), not working from home, and not receiving current counselling or psychotherapy. We will randomly assign 162 participants to intervention groups of 7 to 10 participants each or waitlist control. We will use a partially nested RCT design to reflect dependence between individuals in training groups but not in the waitlist control. The SPIN-CHAT Program includes activity engagement, education on strategies to support mental health, and mutual participant support. Intervention participants will receive the 4-week (3 sessions per week) SPIN-CHAT Program via videoconference. The primary outcome is PROMIS Anxiety 4a score immediately post-intervention. ETHICS AND DISSEMINATION: The SPIN-CHAT Trial will test whether a brief videoconference-based intervention will improve mental health outcomes among at-risk individuals during contagious disease outbreak.


Assuntos
Ansiedade/prevenção & controle , Infecções por Coronavirus/psicologia , Promoção da Saúde/métodos , Pneumonia Viral/psicologia , Escleroderma Sistêmico/terapia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Humanos , Pandemias/prevenção & controle , Assistência Centrada no Paciente , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Avaliação de Programas e Projetos de Saúde , Projetos de Pesquisa , Medição de Risco , Isolamento Social/psicologia , Comunicação por Videoconferência
13.
Arterioscler Thromb Vasc Biol ; 40(5): 1239-1255, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32212854

RESUMO

OBJECTIVE: Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited. Approach and Results: Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment. CONCLUSIONS: Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.


Assuntos
Bactérias/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Colina/farmacologia , Inibidores Enzimáticos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Liases/antagonistas & inibidores , Metilaminas/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Bactérias/enzimologia , Proteínas de Bactérias/metabolismo , Colina/análogos & derivados , Modelos Animais de Doenças , Fibrose , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Liases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/patologia
14.
Semin Cell Dev Biol ; 101: 146-160, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31859147

RESUMO

Systemic sclerosis (SSc) is a highly challenging chronic condition that is dominated by the pathogenetic triad of vascular damage, immune dysregulation/autoimmunity and fibrosis in multiple organs. A hallmark of SSc is the remarkable degree of molecular and phenotypic disease heterogeneity, which surpasses that of other complex rheumatic diseases. Disease trajectories in SSc are unpredictable and variable from patient to patient. Disease-modifying therapies for SSc are lacking, long-term morbidity is considerable and mortality remains unacceptably high. Currently-used empirical approaches to disease modification have modest and variable clinical efficacy and impact on survival, are expensive and frequently associated with unfavorable side effects, and none can be considered curative. However, research during the past several years is yielding significant advances with therapeutic potential. In particular, the application of unbiased omics-based discovery technologies to large and well-characterized SSc patient cohorts, coupled with hypothesis-testing experimental research using a variety of model systems is revealing new insights into SSc that allow formulation of a more nuanced appreciation of disease heterogeneity, and a deepening understanding of pathogenesis. Indeed, we are now presented with numerous novel and rationally-based strategies for targeted SSc therapy, several of which are currently, or expected to be shortly, undergoing clinical evaluation. In this review, we discuss promising novel therapeutic targets and rationally-based approaches to disease modification that have the potential to improve long-term outcomes in SSc.

15.
Am J Respir Crit Care Med ; 201(6): 650-660, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31841044

RESUMO

Systemic sclerosis (SSc) is a complex, multiorgan, autoimmune disease. Lung fibrosis occurs in ∼80% of patients with SSc; 25% to 30% develop progressive interstitial lung disease (ILD). The pathogenesis of fibrosis in SSc-associated ILD (SSc-ILD) involves cellular injury, activation/differentiation of mesenchymal cells, and morphological/biological changes in epithelial/endothelial cells. Risk factors for progressive SSc-ILD include older age, male sex, degree of lung involvement on baseline high-resolution computed tomography imaging, reduced DlCO, and reduced FVC. SSc-ILD does not share the genetic risk architecture observed in idiopathic pulmonary fibrosis (IPF), with key risk factors yet to be identified. Presence of anti-Scl-70 antibodies and absence of anti-centromere antibodies indicate increased likelihood of progressive ILD. Elevated levels of serum Krebs von den Lungen-6 and C-reactive protein are both associated with SSc-ILD severity and predict SSc-ILD progression. A promising prognostic indicator is serum chemokine (C-C motif) ligand 18. SSc-ILD shares similarities with IPF, although clear differences exist. Histologically, a nonspecific interstitial pneumonia pattern is commonly observed in SSc-ILD, whereas IPF is defined by usual interstitial pneumonia. The course of SSc-ILD is variable, ranging from minor, stable disease to a progressive course, whereas all patients with IPF experience progression of disease. Although appropriately treated patients with SSc-ILD have better chances of stabilization and survival, a relentlessly progressive course, akin to IPF, is seen in a minority. Better understanding of cellular and molecular pathogenesis, genetic risk, and distinctive features of SSc-ILD and identification of robust prognostic biomarkers are needed for optimal disease management.


Assuntos
Biomarcadores/sangue , Currículo , Educação Médica Continuada/organização & administração , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/genética , Escleroderma Sistêmico/etiologia , Escleroderma Sistêmico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Humanos , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Escleroderma Sistêmico/fisiopatologia
16.
Proc Natl Acad Sci U S A ; 117(1): 552-562, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871193

RESUMO

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/genética , Antígenos HLA/genética , Mimetismo Molecular/imunologia , Escleroderma Sistêmico/genética , Afro-Americanos/genética , Alelos , Sequência de Aminoácidos/genética , Antígenos Virais/genética , Antígenos Virais/imunologia , Autoantígenos/imunologia , Biologia Computacional , Conjuntos de Dados como Assunto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Antígenos HLA/imunologia , Humanos , Masculino , Mimiviridae/imunologia , Phycodnaviridae/imunologia , Estrutura Secundária de Proteína/genética , Medição de Risco , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Homologia de Sequência de Aminoácidos
18.
Ann Rheum Dis ; 78(10): 1371-1378, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31391177

RESUMO

OBJECTIVE: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.


Assuntos
Interferons/sangue , Neutrófilos/metabolismo , Escleroderma Sistêmico/genética , Transcriptoma , Condicionamento Pré-Transplante/métodos , Adulto , Ciclofosfamida/uso terapêutico , Regulação para Baixo , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multinível , Agonistas Mieloablativos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/terapia , Transplante Autólogo , Resultado do Tratamento , Regulação para Cima
19.
Curr Opin Rheumatol ; 31(6): 589-594, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31449135

RESUMO

PURPOSE OF REVIEW: Review the current state of knowledge and recent developments in the field of scleroderma-related calcinosis [systemic sclerosis (SSc)-calcinosis], focusing on emerging information related to pathophysiology. RECENT FINDINGS: Recent studies have begun to characterize that factors that regulate ectopic mineralization, and those that underlie the imbalance of promoters and inhibitors of this process in SSc. SUMMARY: Calcinosis cutis due to ectopic mineralization is a common and highly troublesome complication of SSc. Despite its significant prevalence and clinical impact, the pathogenesis is poorly understood and effective treatment is lacking. More research to better understand the pathophysiology is needed for the identification of novel management strategies for this severe complication of SSc.


Assuntos
Calcinose/etiologia , Escleroderma Sistêmico/complicações , Calcinose/diagnóstico , Calcinose/epidemiologia , Cristalização , Saúde Global , Humanos , Prevalência
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