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 1 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.
Genetics in sarcoidosis Spagnolo, Paolo; Maier, Lisa A.
Current opinion in pulmonary medicine,
09/2021, Letnik:
27, Številka:
5
Journal Article
Odprti dostop
Purpose of review
Epidemiological and clinical observations as well as familial clustering support the existence of a genetic predisposition to sarcoidosis. In this article, we review the most recent ...findings in genetics of sarcoidosis and discuss how the identification of risk alleles may help advancing our understanding of disease etiology and development.
Recent findings
Genetic studies of sarcoidosis phenotypes have identified novel and ancestry-specific associations. Gene-environment interaction studies highlighted the importance of integrating genetic information when assessing the relationship between sarcoidosis and environmental exposures. A case-control-family study revealed that the heritability of sarcoidosis is only 49%, suggesting the existence of additional important contributors to disease risk. The application of whole-exome sequencing has identified associations with disease activity and prognosis. Finally, gene expression studies of circulating immune cells have identified shared and unique pathways between sarcoidosis and other granulomatous diseases.
Summary
Sarcoidosis genetic research has led to the identification of a number of associations with both sarcoidoses
per se
and disease phenotypes. Newer sequencing technologies are likely to increase the number of genetic variants associated with sarcoidosis. However, studying phenotypically and ethnically homogeneous patient subsets remains critically important regardless of the genetic approach used.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiac sarcoidosis is difficult to diagnose, often requiring expensive and inconvenient advanced imaging techniques. Circulating exosomes contain genetic material, such as microRNA (miRNA), that are ...derived from diseased tissues and may serve as potential disease-specific biomarkers. We thus sought to determine whether circulating exosome-derived miRNA expression patterns would distinguish cardiac sarcoidosis (CS) from acute myocardial infarction (AMI).
Plasma and serum samples conforming to CS, AMI or disease-free controls were procured from the Biologic Specimen and Data Repository Information Coordinating Center repository and National Jewish Health. Next generation sequencing (NGS) was performed on exosome-derived total RNA (n = 10 for each group), and miRNA expression levels were compared after normalization using housekeeping miRNA. Quality assurance measures excluded poor quality RNA samples. Differentially expressed (DE) miRNA patterns, based upon >2-fold change (p < 0.01), were established in CS compared to controls, and in CS compared to AMI. Relative expression of several DE-miRNA were validated by qRT-PCR.
Despite the advanced age of the stored samples (~5-30 years), the quality of the exosome-derived miRNA was intact in ~88% of samples. Comparing plasma exosomal miRNA in CS versus controls, NGS yielded 18 DE transcripts (12 up-regulated, 6 down-regulated), including miRNA previously implicated in mechanisms of myocardial injury (miR-92, miR-21) and immune responses (miR-618, miR-27a). NGS further yielded 52 DE miRNA in serum exosomes from CS versus AMI: 5 up-regulated in CS; 47 up-regulated in AMI, including transcripts previously detected in AMI patients (miR-1-1, miR-133a, miR-208b, miR-423, miR-499). Five miRNAs with increased DE in CS included two isoforms of miR-624 and miR-144, previously reported as markers of cardiomyopathy.
MiRNA patterns of exosomes derived from CS and AMI patients are distinct, suggesting that circulating exosomal miRNA patterns could serve as disease biomarkers. Further studies are required to establish their specificity relative to other cardiac disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, ...which is upregulated on immune cells in response to lung inflammation.
What is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis?
In this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4 weeks for 24 weeks, randomized patients (2:1) underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16. The primary end point was the incidence of adverse events (AEs); secondary end points included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales.
Thirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected AEs and no dose-dependent AE incidence. Average daily steroid doses through end of study were 6.8 mg, 6.5 mg, and 5.6 mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg groups compared with 7.2 mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. Clinically meaningful improvements were achieved across several patient-reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but nonsignificant trend toward improved lung function also was observed for 3 and 5 mg/kg.
Efzofitimod was safe and well tolerated and was associated with dose-dependent improvements of several clinically relevant end points compared with placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis.
ClinicalTrials.gov; No.: NCT03824392; URL: www.clinicaltrials.gov
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Developmental drugs for sarcoidosis Obi, Ogugua Ndili; Saketkoo, Lesley Ann; Maier, Lisa A. ...
Journal of autoimmunity,
2024-Mar-28
Journal Article
Recenzirano
Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%–30% will develop a chronic ...progressive disease with pulmonary fibrosis leading to significant morbidity and mortality.
Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited.
The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity.
Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.
•Up to 30% of patients with sarcoidosis require prolonged immunosuppressive therapy.•Though recommended as first line therapy, steroids are associated with significant toxicity and reduced quality of life, therefore, steroid-sparing alternatives are imperative.•Drugs and novel therapeutic targets that leverage the complex immunopathogenic basis of sarcoidosis are critical.•Challenges surrounding drug development and clinical trial design abound in sarcoidosis and are discussed.
The effects of chronic inhaled and systemic corticosteroids use on COVID-19 susceptibility and severity are unclear. Since many patients with chronic pulmonary diseases rely on corticosteroids to ...control disease, it is important to understand the risks of their use during the pandemic. We aim to study if the use of inhaled or systemic corticosteroids affects the likelihood of developing COVID-19 infection.
We used the National Jewish Health electronic medical record research database to identify a cohort of all subjects who were tested for suspected COVID-19 between March 11 - June 23, 2020. Testing results, medication use, and comorbidities were obtained from the medical record. Following a comparison of different propensity score weighting methods, overlap propensity score weighting was used to analyze the association between medication use and COVID-19 diagnosis.
The cohort consisted of 928 patients, of which 12% tested positive. The majority (66%) of patients had a history of chronic pulmonary diseases. There was no significant association between inhaled corticosteroid use and testing positive for COVID-19. Interestingly, systemic corticosteroid use was associated with a lower odds ratio (0.95, 95% CI: 0.91–0.99) of testing positive for COVID-19. Similar results were noted when the analysis was restricted to those with any chronic pulmonary diseases, with asthma or with chronic obstructive pulmonary disease (COPD).
Our study supports the recommendation that patients with chronic pulmonary diseases, including asthma and COPD who require treatment with either inhaled or systemic corticosteroids, should continue their use during the COVID-19 pandemic.
•Systemic corticosteroids may lower the likelihood of testing positive for COVID-19.•An analysis of EMR using overlap propensity score weighting methods.•Patients with indications for corticosteroid therapy should continue using them.
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