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BACKGROUND: Sarcoidosis staging primarily has relied on the Scadding chest radiographic system, although chest CT imaging is finding increased clinical use. RESEARCH QUESTION: Whether standardized chest CT scan assessment provides additional understanding of lung function beyond Scadding stage and demographics is unknown and the focus of this study. STUDY DESIGN AND METHODS: We used the National Heart, Lung, and Blood Institute study Genomics Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cases of sarcoidosis (n = 351) with Scadding stage and chest CT scans obtained in a standardized manner. One chest radiologist scored all CT scans with a visual scoring system, with a subset read by another chest radiologist. We compared demographic features, Scadding stage, and CT scan findings and the correlation between these measures. Associations between spirometry results and Dlco, CT scan findings, and Scadding stage were determined using regression analysis (n = 318). Agreement between readers was evaluated using Cohen's κ value. RESULTS: CT scan features were inconsistent with Scadding stage in approximately 40% of cases. Most CT scan features assessed on visual scoring were associated negatively with lung function. Associations persisted for FEV1 and Dlco when adjusting for Scadding stage, although some CT scan feature associations with FVC became insignificant. Scadding stage was associated primarily with FEV1, and inclusion of CT scan features reduced significance in association between Scadding stage and lung function. Multivariable regression modeling to identify radiologic measures explaining lung function included Scadding stage for FEV1 and FEV1 to FVC ratio (P < .05) and marginally for Dlco (P < .15). Combinations of CT scan measures accounted for Scadding stage for FVC. Correlations among Scadding stage and CT scan features were noted. Agreement between readers was poor to moderate for presence or absence of CT scan features and poor for degree and location of abnormality. INTERPRETATION: CT scan features explained additional variability in lung function beyond Scadding stage, with some CT scan features obviating the associations between lung function and Scadding stage. Whether CT scan features, phenotypes, or endotypes could be useful for managing patients with sarcoidosis needs more study.
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RATIONALE: Sarcoidosis is a systemic granulomatous disorder associated with hypergammaglobulinemia and the presence of autoantibodies. The specific antigens initiating granulomatous inflammation in sarcoidosis are unknown and there is no specific test available to diagnose sarcoidosis. To discover novel sarcoidosis antigens, we developed a high-throughput T7 phage display library derived from the sarcoidosis cDNA and identified numerous clones differentiating sarcoidosis from other respiratory diseases. After clone sequencing and homology search, we identified two epitopes (Cofilinµ and Chain A) that specifically bind to serum IgGs of sarcoidosis patients. OBJECTIVES: To develop and validate an epitope-specific IgG-based immunoassay specific for sarcoidosis. METHODS: We chemically synthesized both immunoepitopes (Cofilinµ and Chain A), and generated rabbit polyclonal antibodies against both neoantigens. After extensive standardization, we developed a direct peptide ELISA and measured epitope-specific IgG in sera of 386 subjects including, healthy controls (n=100), three sarcoidosis cohorts (n=186), pulmonary tuberculosis (n=70) and lung cancer (n=30). MEASUREMENTS AND MAIN RESULTS: To develop a model to classify sarcoidosis from other groups, data were analyzed using five-fold cross-validation when adjusting for confounders. The Cofilinµ IgGs model yielded a mean sensitivity, specificity, and positive and negative predictive value (PPV, NPV) of 0.97, 0.9, 0.9 and 0.96, respectively. Those same measures for Chain A IgG antibody were 0.9, 0.83, 0.84 and 0.9 respectively. Combining both biomarkers improved AUC, sensitivity, specificity, PPV and NPV. CONCLUSIONS: These results provide a novel immunoassay for sarcoidosis. The discovery of two neoantigens facilitates the development of biospecific drug discovery and the sarcoidosis-specific model.
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Sarcoidosis is a complex systemic disease. Our study aimed to (1) identify novel alleles associated with sarcoidosis susceptibility; (2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility and (3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1335 sarcoidosis cases and 1264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1487 cases and 1504 controls). The EA and AA cohort was recruited from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. Forty-nine SNPs in the HLA region in HLA-DRA, -DRB9, -DRB5, -DQA1 and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101 and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage from subjects and lung tissue and whole blood from GTEx. We identified six novel SNPs (out of the seven SNPs representing the 49 significant SNPs) and nine HLA alleles associated with sarcoidosis susceptibility in the largest EA population. We also replicated our findings in an AA population. Our study reiterates the potential role of antigen recognition and/or presentation HLA class II genes in sarcoidosis pathogenesis.
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Estudio de Asociación del Genoma Completo , Sarcoidosis , Humanos , Predisposición Genética a la Enfermedad , Cadenas alfa de HLA-DR/genética , Leucocitos Mononucleares , Sarcoidosis/genética , Cadenas HLA-DRB1/genética , AlelosRESUMEN
INTRODUCTION: Sarcoidosis is a pulmonary and systemic granulomatous disease with a wide range of potential outcomes, from spontaneous resolution to end-stage organ damage and death. Currently, clinicians have no easy-to-use risk stratification tools for important clinical outcomes in sarcoidosis, such as progressive lung disease. This study will address two clinical practice needs: (1) development of a risk calculator that provides an estimate of the likelihood of pulmonary progression in sarcoidosis patients during the follow-up period and (2) determine the optimal interval for serial clinical monitoring (eg, 6, 12, 18 months) using these risk prediction tools. METHODS AND ANALYSIS: The Risk Indicators of Sarcoidosis Evolution-Unified Protocol study is a National Institutes of Health-sponsored, longitudinal observational study of adults with pulmonary sarcoidosis who will be enrolled at five US tertiary care centres. Participants will be evaluated at approximately 6-month intervals for up to 60 months with collection of lung function, blood samples and clinical data. The target sample size is 557 and the primary objective is to determine which clinical features measured during a routine clinic visit carry the most prognostic information for predicting clinical progression of pulmonary sarcoidosis over the follow-up period. The primary outcome measure will be quantified by a clinically meaningful change in forced vital capacity, forced expiratory volume in 1 s or diffusing capacity of the lung for carbon monoxide. The secondary objective is to determine if blood biomarkers measured during a routine clinic visit can improve the risk assessment modelling for progression of pulmonary sarcoidosis over the follow-up period. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Review Boards at each centre and the reliance Institutional Review Board overseeing the study (WCG, Protocol #20222400). Participants will provide informed consent prior to enrolment. Results will be disseminated via publication in a relevant peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05567133.
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Sarcoidosis Pulmonar , Sarcoidosis , Adulto , Humanos , Sarcoidosis Pulmonar/diagnóstico , Pulmón , Factores de Riesgo , Capacidad VitalRESUMEN
The contribution and regulation of various CD4+ T cell lineages that occur with remitting vs progressive courses in sarcoidosis are poorly understood. We developed a multiparameter flow cytometry panel to sort these CD4+ T cell lineages followed by measurement of their functional potential using RNA-sequencing analysis at six-month intervals across multiple study sites. To obtain good quality RNA for sequencing, we relied on chemokine receptor expression to identify and sort lineages. To minimize gene expression changes induced by perturbations of T cells and avoid protein denaturation caused by freeze/thaw cycles, we optimized our protocols using freshly isolated samples at each study site. To accomplish this study, we had to overcome significant standardization challenges across multiple sites. Here, we detail standardization considerations for cell processing, flow staining, data acquisition, sorting parameters, and RNA quality control analysis that were performed as part of the NIH-sponsored, multi-center study, BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints (BRITE). After several rounds of iterative optimization, we identified the following aspects as critical for successful standardization: 1) alignment of PMT voltages across sites using CS&T/rainbow bead technology; 2) a single template created in the cytometer program that was used by all sites to gate cell populations during data acquisition and cell sorting; 3) use of standardized lyophilized flow cytometry staining cocktails to reduce technical error during processing; 4) development and implementation of a standardized Manual of Procedures. After standardization of cell sorting, we were able to determine the minimum number of sorted cells necessary for next generation sequencing through analysis of RNA quality and quantity from sorted T cell populations. Overall, we found that implementing a multi-parameter cell sorting with RNA-seq analysis clinical study across multiple study sites requires iteratively tested standardized procedures to ensure comparable and high-quality results.
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ARN , Transcriptoma , Citometría de Flujo/métodos , Separación Celular , Estándares de ReferenciaRESUMEN
Rationale: United States veterans represent an important population to study sarcoidosis. Their unique history of environmental exposures, wide geographic distribution, and long-term enrollment in a single integrated healthcare system provides an unparalleled opportunity to understand the incidence, prevalence, and risk factors for sarcoidosis. Objectives: To determine the epidemiology, patient characteristics, geographic distribution, and associated risk factors of sarcoidosis among U.S. veterans. Methods: We used data from the Veterans Health Administration (VHA) electronic health record system between 2003 and 2019 to evaluate the annual incidence, prevalence, and geographic distribution of sarcoidosis (defined using the International Classification of Diseases codes). We used multivariate logistic regression to examine patient characteristics associated with sarcoidosis incidence. Results: Among more than 13 million veterans who received care through or paid for by the VHA, 23,747 (0.20%) incident diagnoses of sarcoidosis were identified. Compared with selected VHA control subjects using propensity score matching, veterans with sarcoidosis were more likely to be female (13.5% vs. 9.0%), of Black race (52.2% vs. 17.0%), and ever-tobacco users (74.2% vs. 64.5%). There was an increase in the annual incidence of sarcoidosis between 2004 and 2019 (from 38 to 52 cases/100,000 person-years) and the annual prevalence between 2003 and 2019 (from 79 to 141 cases/100,000 persons). In a multivariate logistic regression model, Black race (odds ratio [OR], 4.49; 95% confidence interval [CI], 4.33-4.65), female sex (OR, 1.64; 95% CI, 1.56-1.73), living in the Northeast compared with the western region (OR, 1.57; 95% CI, 1.48-1.67), history of tobacco use (OR, 1.36; 95% CI, 1.31-1.41), and serving in the Army, Air Force, or multiple branches compared with the Navy (OR, 1.08; 95% CI, 1.03-1.13; OR, 1.10; 95% CI, 1.04-1.17; OR, 1.27; 95% CI, 1.16-1.39, respectively) were significantly associated with incident sarcoidosis (P < 0.0001). Conclusions: The incidence and prevalence of sarcoidosis are higher among veterans than in the general population. Alongside traditionally recognized risk factors such as Black race and female sex, we found that a history of tobacco use within the Veterans Affairs population and serving in the Army, Air Force, or multiple service branches were associated with increased sarcoidosis risk.
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Personal Militar , Sarcoidosis , Veteranos , Humanos , Femenino , Estados Unidos/epidemiología , Masculino , United States Department of Veterans Affairs , Sarcoidosis/epidemiología , Factores de Riesgo , Salud de los VeteranosRESUMEN
Sarcoidosis is a systemic granulomatous disease of unknown etiology with significant heterogeneity in organ manifestations and clinical course. Subjects with sarcoidosis share several features such as, non-necrotizing granuloma, hypergammaglobulinemia, increased local and circulating inflammatory cytokines. Macrophage migration inhibitory factor (MIF) is a pluripotent chemokine modulating cellular function. Study included healthy controls (n = 28) and sarcoidosis patients (n = 65). Sera and BAL of sarcoidosis patients were collected and patients were followed longitudinally for 3 years, and demographics, stages, pulmonary function tests, and organ involvements were recorded. We evaluated MIF in the serum and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients in association with clinical features and cytokines, IL-18, IL-10, IL-6, IFN-γ. We found serum MIF had a positive correlation with IL-10 and IFN-γ and % predicted total lung capacity (%TLC). Serum IL-18 had a significant positive correlation with serum lysozyme, but a negative correlation with %TLC and %DLCO. We identified two groups of sarcoidosis subjects with distinct clinical and cytokine features. A group with prominent extrapulmonary involvement, and low serum MIF, IL-10 and IFN-γ and a group with elevated serum MIF, IL-10 and IFN-γ levels. Our work provides understanding of phenotypic diversity in association with heterogeneity in cytokine landscape in sarcoidosis.
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Factores Inhibidores de la Migración de Macrófagos , Sarcoidosis , Líquido del Lavado Bronquioalveolar , Citocinas , Humanos , Interleucina-10 , Interleucina-18 , Interleucina-6 , MuramidasaRESUMEN
INTRODUCTION: Sarcoidosis is a multiorgan granulomatous disorder thought to be triggered and influenced by gene-environment interactions. Sarcoidosis affects 45-300/100 000 individuals in the USA and has an increasing mortality rate. The greatest gap in knowledge about sarcoidosis pathobiology is a lack of understanding about the underlying immunological mechanisms driving progressive pulmonary disease. The objective of this study is to define the lung-specific and blood-specific longitudinal changes in the adaptive immune response and their relationship to progressive and non-progressive pulmonary outcomes in patients with recently diagnosed sarcoidosis. METHODS AND ANALYSIS: The BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints study is a US-based, NIH-sponsored longitudinal blood and bronchoscopy study. Enrolment will occur over four centres with a target sample size of 80 eligible participants within 18 months of tissue diagnosis. Participants will undergo six study visits over 18 months. In addition to serial measurement of lung function, symptom surveys and chest X-rays, participants will undergo collection of blood and two bronchoscopies with bronchoalveolar lavage separated by 6 months. Freshly processed samples will be stained and flow-sorted for isolation of CD4 +T helper (Th1, Th17.0 and Th17.1) and T regulatory cell immune populations, followed by next-generation RNA sequencing. We will construct bioinformatic tools using this gene expression to define sarcoidosis endotypes that associate with progressive and non-progressive pulmonary disease outcomes and validate the tools using an independent cohort. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Review Boards at National Jewish Hospital (IRB# HS-3118), University of Iowa (IRB# 201801750), Johns Hopkins University (IRB# 00149513) and University of California, San Francisco (IRB# 17-23432). All participants will be required to provide written informed consent. Findings will be disseminated via journal publications, scientific conferences, patient advocacy group online content and social media platforms.
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Sarcoidosis Pulmonar , Sarcoidosis , Líquido del Lavado Bronquioalveolar , Broncoscopía , Humanos , Estudios Multicéntricos como Asunto , Estudios Observacionales como Asunto , Linfocitos T Reguladores , Células Th17RESUMEN
Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.
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Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Sarcoidosis/diagnóstico , Sarcoidosis/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/etiología , Enfermedades del Sistema Nervioso Central/fisiopatología , Humanos , Sarcoidosis/etiología , Sarcoidosis/fisiopatologíaRESUMEN
BACKGROUND: Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits. METHODS: RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well-characterised patients with pulmonary sarcoidosis enrolled in the multicentre Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted gene co-expression network analysis and nonparametric statistics were used to analyse genome-wide BAL transcriptome. Validation of results was performed using a microarray expression dataset of an independent sarcoidosis cohort (Freiburg, Germany; n=50). RESULTS: Our supervised analysis found associations between distinct transcriptional programmes and major pulmonary phenotypic manifestations of sarcoidosis including T-helper type 1 (Th1) and Th17 pathways associated with hilar lymphadenopathy, transforming growth factor-ß1 (TGFB1) and mechanistic target of rapamycin (MTOR) signalling with parenchymal involvement, and interleukin (IL)-7 and IL-2 with airway involvement. Our unsupervised analysis revealed gene modules that uncovered four potential sarcoidosis endotypes including hilar lymphadenopathy with increased acute T-cell immune response; extraocular organ involvement with PI3K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan involvement, with increased IL-1 and IL-18 immune and inflammatory responses. We validated the occurrence of these endotypes using gene expression, pulmonary function tests and cell differentials from Freiburg. CONCLUSION: Taken together, our results identify BAL gene expression programmes that characterise major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes.
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Sarcoidosis Pulmonar , Sarcoidosis , Lavado Broncoalveolar , Líquido del Lavado Bronquioalveolar , Humanos , Sarcoidosis Pulmonar/genética , TranscriptomaRESUMEN
Background: Interferon-gamma (IFN-γ) is a key mediator of sarcoidosis-related granulomatous inflammation. Previous findings of IFN-γ-producing Th17 cells in bronchoalveolar lavage fluid from sarcoidosis patients invokes the transition of Th17.0 cells to Th17.1 cells in the disease's pathogenesis. Since the T-bet transcription factor is crucial for this transition, the goal of this study was to determine if T-bet expression in Th17.0 cells reflects the extent of granulomatous inflammation in sarcoidosis patients as assessed by clinical outcomes. Methods: Using a case-control study design, we identified two groups of sarcoidosis subjects (total N = 43) with pulmonary function tests (PFTs) that either (1) changed (increased or decreased) longitudinally or (2) were stable. We used flow cytometry to measure the transcription factors T-bet and RORγt in Th1, Th17.0, and Th17.1 cell subsets defined by CCR6, CCR4 and CXCR3 in blood samples. We compared the percentages of T-bet+ cells in RORγt+Th17.0 cells (defined as CCR6+CCR4+CXCR3-) based on subjects' PFT group. We also assessed the relationship between the direction of change in PFTs with the changes in %T-bet+ frequencies using mixed effects modeling. Results: We found that T-bet expression in subjects' RORγt+Th17.0 cells varied based on clinical outcome. The T-bet+ percentage of RORγt+Th17.0 cells was higher in the cases (subject group with PFT changes) as compared to controls (stable group) (27 vs. 16%, p = 0.0040). In comparisons before and after subjects' PFT changes, the T-bet+ frequency of RORγt+Th17.0 cells increased or decreased in the opposite direction of the PFT change. The percentage of these T-bet+ cells was also higher in those with greater numbers of involved organs. Serum levels of interferon-γ-induced chemokines, CXCL9, CXCL10, and CXCL11, and whole blood gene expression of IFN-γ-related genes including GBP1, TAP1, and JAK2 were independently positively associated with the T-bet+ frequencies of RORγt+Th17.0 cells. Conclusions: These data suggest that expression of T-bet in Th17.0 cells could reflect the extent of granulomatous inflammation in sarcoidosis patients because they represent a transition state leading to the Th17.1 cell phenotype. These findings indicate that Th17 plasticity may be part of the disease paradigm.
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Pulmón/metabolismo , Sarcoidosis Pulmonar/inmunología , Sarcoidosis Pulmonar/metabolismo , Proteínas de Dominio T Box/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Estudios de Casos y Controles , Femenino , Humanos , Interferón gamma/metabolismo , Pulmón/inmunología , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Pronóstico , Sarcoidosis Pulmonar/fisiopatologíaRESUMEN
PURPOSE OF REVIEW: Sarcoidosis is a systemic disease characterized by granulomatous inflammation of unknown cause. There is extensive heterogeneity between patients with respect to the number and types of organs involved, disease course, and response to therapy. Recent research in the field has leveraged 'omics' techniques such as transcriptomics to identify important 'molecular profiles' in the disease. These tools may help in identifying clinically useful biomarkers and targets for therapy. RECENT FINDINGS: Several studies have used gene expression profiling of predesignated lists or the entire genome to find genes and markers that differentiate sarcoidosis from healthy controls, but only a few have compared sarcoidosis patients based on disease phenotypes and organ involvement. The common gene pathways that have been repeatedly identified include those related to the interferon response, T-cell receptor signaling, and the major histocompatibility complex. SUMMARY: While the molecular profiling studies to date offer the ability to compare sarcoidosis and health as well as across tissues, further longitudinal studies that include sarcoidosis patients with varying outcomes with respect to organ involvement and response to treatment are needed to identify clinically important phenotypes in the disease that can then be differentiated based on molecular features.
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Perfilación de la Expresión Génica , Sarcoidosis/genética , Biomarcadores/metabolismo , Progresión de la Enfermedad , Redes Reguladoras de Genes , Genómica , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Metabolómica , MicroARNs , Microbiota , Fenotipo , Proteómica , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Sarcoidosis/inmunología , Sarcoidosis/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure.Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability.Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality.Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.
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Cardiomiopatías/diagnóstico , Enfermedades Renales/diagnóstico , Hepatopatías/diagnóstico , Sarcoidosis Pulmonar/diagnóstico , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Aspartato Aminotransferasas/sangre , Biopsia , Broncoscopía , Calcio/sangre , Cardiomiopatías/sangre , Cardiomiopatías/fisiopatología , Creatinina/sangre , Ecocardiografía , Electrocardiografía , Electrocardiografía Ambulatoria , Endosonografía , Oftalmopatías/diagnóstico , Oftalmopatías/fisiopatología , Humanos , Hipercalcemia/sangre , Hipercalcemia/diagnóstico , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Enfermedades Renales/sangre , Hepatopatías/sangre , Ganglios Linfáticos/patología , Linfadenopatía , Imagen por Resonancia Magnética , Mediastino , Tomografía de Emisión de Positrones , Neumología , Sarcoidosis/sangre , Sarcoidosis/diagnóstico , Sarcoidosis/patología , Sarcoidosis/fisiopatología , Sarcoidosis Pulmonar/sangre , Sarcoidosis Pulmonar/patología , Sarcoidosis Pulmonar/fisiopatología , Sociedades Médicas , Vitamina D/sangreRESUMEN
The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure. Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability. The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and best practice statement. All evidence was very low quality.The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.
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Humanos , Sarcoidosis/prevención & control , Enfermedades Raras/prevención & control , Granuloma/prevención & control , Hipertensión Pulmonar/prevención & control , Enfermedades Pulmonares/prevención & controlRESUMEN
BACKGROUND: Sarcoidosis is a granulomatous inflammatory disease with limited blood markers to predict outcomes. The interferon-gamma (IFN-γ)-inducible chemotactic cytokines (chemokines), CXCL9 and CXCL10, are both increased in sarcoidosis patients, yet they possess important molecular differences. Our study determined if serum chemokines correlated with different aspects of disease severity. METHODS: We measured CXCL9 and CXCL10 serum levels at initial study visits and longitudinally in sarcoidosis subjects using ELISA. We examined these chemokines' relationships with pulmonary and organ involvement outcomes, their gene expression, peripheral blood immune cell populations, and immunosuppression use. RESULTS: Higher CXCL10 levels negatively correlated with FVC, TLC, and DLCO at subjects' initial visit and when measured repeatedly over two years. CXCL10 also positively correlated with longitudinal respiratory symptom severity. Additionally, for every log10(CXCL10) increase, the risk of longitudinal pulmonary function decline increased 8.8 times over the 5-year study period (95% CI 1.6-50, p = 0.014, log10(CXCL0) range 0.84-2.7). In contrast, CXCL9 levels positively correlated with systemic organ involvement at initial study visit (1.5 additional organs involved for every log10(CXCL9) increase, 95% CI 1.1-2.0, p = 0.022, log10(CXCL9) range 1.3-3.3). CXCL10, not CXCL9, positively correlated with its own blood gene expression and monocyte level. Immunosuppressive treatment was associated with lower levels of both chemokines. CONCLUSIONS: In sarcoidosis subjects, serum CXCL9 levels correlated with systemic organ involvement and CXCL10 levels strongly correlated with respiratory outcomes, which may ultimately prove helpful in clinical management. These differing associations may be due to differences in cellular regulation and tissue origin.
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Quimiocina CXCL10/sangre , Quimiocina CXCL9/sangre , Estudios de Asociación Genética , Sarcoidosis Pulmonar/genética , Adulto , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
Background Long-term corticosteroid therapy is the standard of care for treatment of cardiac sarcoidosis (CS). The efficacy of long-term corticosteroid-sparing immunosuppression in CS is unknown. The goal of this study was to assess the efficacy of methotrexate with or without adalimumab for long-term disease suppression in CS, and to assess recurrence and adverse event rates after immunosuppression discontinuation. Methods and Results Retrospective chart review identified treatment-naive CS patients at a single academic medical center who received corticosteroid-sparing maintenance therapy. Demographics, cardiac uptake of 18-fluorodeoxyglucose, and adverse cardiac events were compared before and during treatment and between those with persistent or interrupted immunosuppression. Twenty-eight CS patients were followed for a mean 4.1 (SD 1.5) years. Twenty-five patients received 4 to 8 weeks of high-dose prednisone (>30 mg/day), followed by taper and maintenance therapy with methotrexate±low-dose prednisone (low-dose prednisone, <10 mg/day). Adalimumab was added in 19 patients with persistently active CS or in those with intolerance to methotrexate. Methotrexate±low-dose prednisone resulted in initial reduction (88%) or elimination (60%) of 18-fluorodeoxyglucose uptake, and patients receiving adalimumab-containing regimens experienced improved (84%) or resolved (63%) 18-fluorodeoxyglucose uptake. Radiologic relapse occurred in 8 of 9 patients after immunosuppression cessation, 4 patients on methotrexate-containing regimens, and in no patients on adalimumab-containing regimens. Conclusions Corticosteroid-sparing regimens containing methotrexate with or without adalimumab is an effective maintenance therapy in patients after an initial response is confirmed. Disease recurrence in patients on and off immunosuppression support need for ongoing radiologic surveillance regardless of immunosuppression regimen.
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Adalimumab/uso terapéutico , Antiinflamatorios/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Glucocorticoides/administración & dosificación , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Prednisona/administración & dosificación , Sarcoidosis/tratamiento farmacológico , Arritmias Cardíacas/fisiopatología , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/fisiopatología , Deprescripciones , Quimioterapia Combinada , Electrocardiografía , Femenino , Fluorodesoxiglucosa F18 , Humanos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Radiofármacos , Recurrencia , Estudios Retrospectivos , Sarcoidosis/diagnóstico por imagen , Sarcoidosis/fisiopatología , Resultado del TratamientoRESUMEN
BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology that affects the lungs in 90% of patients, but has a wide range of disease manifestations and outcomes including chronic and progressive courses. Noninvasive biomarkers are needed to assess these outcomes and guide decisions for long term monitoring and treatment. Interferon-gamma (IFN-γ)-inducible chemotactic cytokines (chemokines), CXCL9, CXCL10 and CXCL11, show promise in this regard because they have been implicated in the pathogenesis of and reflect the burden of granulomatous inflammation. CXCL11 has been reported to have unique functional properties in modulating adaptive immunity in model systems so our goal was to examine serum levels of CXCL11 in relation to clinical outcomes in a heterogeneous cohort of sarcoidosis subjects. METHODS: CXCL19, CXCL10, and CXCL11 serum levels were measured in sarcoidosis and healthy subjects using ELISA assay. We determined relationships between CXCL11 and standard clinical inflammatory markers, expression of IFN-γ-related genes in whole blood, organ involvement, dyspnea scores, and measures of pulmonary function. RESULTS: In a cross-sectional analysis of 104 sarcoidosis subjects, serum CXCL11 was significantly elevated compared to 49 healthy controls (pâ¯<â¯0.001). CXCL11 was positively correlated with CXCL9 and CXCL10 (pâ¯<â¯0.001), sedimentation rate (pâ¯<â¯0.01), and mean expression of three IFN-γ-related genes in whole blood (GBP1, STAT1, and STAT2) (pâ¯<â¯0.001). CXCL11 was inversely correlated with FVC %predicted (%pred) and FEV1 %pred and higher levels were associated with higher patient-reported dyspnea scores. We found positive correlations between CXCL11 and number of organs involved. Using survival analyses, we found that CXCL11 levels were predictive of future pulmonary function test (PFT) decline (log rank <0.001 and HR of log10(CXCL11)â¯=â¯5.1, 95% CI 1.2-21, pâ¯=â¯0.026). CONCLUSIONS: The pattern of expression of serum CXCL11 in sarcoidosis patients suggests that this blood measure could be helpful in identifying patients that need longer-term monitoring for progressive thoracic and extra-thoracic sarcoidosis.
Asunto(s)
Quimiocina CXCL10/sangre , Quimiocina CXCL11/sangre , Quimiocina CXCL9/sangre , Sarcoidosis/metabolismo , Adulto , Biomarcadores/metabolismo , Costo de Enfermedad , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Interferón gamma/sangre , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pruebas de Función Respiratoria/métodos , Sarcoidosis/mortalidad , Sarcoidosis/patología , Sarcoidosis/fisiopatología , Análisis de SupervivenciaRESUMEN
INTRODUCTION: Sarcoidosis is a systemic inflammatory disease associated with myriad symptoms, including fatigue. It can affect physiological processes like sleep, leading to poor sleep quality and excessive daytime sleepiness. We hypothesized that sarcoidosis patients would report more severe sleep disturbance than healthy controls and that relationships would be found with sleep disturbance and the severity of other symptoms. METHODS: We enrolled 84 sarcoidosis patients and 30 healthy controls and recorded demographic and clinical characteristics. Self-report measures were used to assess sleep disturbance, psychosocial symptoms, and quality of life at enrollment and longitudinally. Relationships between different self-report outcomes were analyzed using correlation statistics. RESULTS: Using the General Sleep Disturbance Scale, 54% of sarcoidosis patients reported frequent and occasional sleep disturbance compared to only 17% of healthy controls (pâ¯<â¯0.0001). This significant increase in sleep disturbance found in sarcoidosis patients strongly correlated with multiple psychosocial symptoms, including fatigue, depression, and cognitive dysfunction, and negatively impacted quality of life (pâ¯<â¯0.01). Traditional measures of sarcoidosis disease severity or activity were not associated with sleep disturbance. Sleep disturbance scores remained stable at follow-up (mean time between first and last administration of questionnaire was 17.3 months) in 56 of the sarcoidosis patients. CONCLUSIONS: Sarcoidosis patients experienced significant sleep disturbance that correlated with higher levels of fatigue, depression, and cognitive dysfunction, and poorer quality of life. These associations were present regardless of disease severity or activity and result in decrements in quality of life and mental health.