Decreased serpin C1 in extracellular vesicles predicts response to methotrexate treatment in patients with pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology primarily affecting the lungs. Treatment is needed when disease symptoms worsen and organ function deteriorates. In pulmonary sarcoidosis, prednisone and methotrexate (MTX) are the most common anti-inflammatory therapies. However, there is large inter-patient variability in response to treatment, and predictive response markers are currently lacking. OBJECTIVE: In this study, we investigated the predictive potential of biomarkers in extracellular vesicles (EVs) isolated from biobanked serum of patients with pulmonary sarcoidosis stored prior to start of therapy. METHODS: Protein concentrations of a four-protein test panel of inflammatory proteins were measured in a discovery (n = 16) and replication (n = 129) cohort of patients with sarcoidosis and 47 healthy controls. Response to therapy was defined as an improvement of the absolute score of > 5% forced vital capacity (FVC) and/or > 10% diffusion lung of carbon monoxide (DLCO) after 24 weeks compared to baseline (before treatment). RESULTS: Serum protein levels differed between EV fractions and serum, and between sarcoidosis cases and controls. Serpin C1 concentrations in the low density lipid particle EV fraction were lower at baseline in the group of patients with a good response to MTX treatment in both the discovery cohort (p = 0.059) and in the replication cohort (p = 0.032). EV Serpin C1 showed to be a significant predictor for response to treatment with MTX (OR 0.4; p = 0.032). CONCLUSION: This study shows that proteins isolated from EVs harbor a distinct signal and have potential as new predictive therapy response biomarkers in sarcoidosis.

Diagnosis of Pulmonary Sarcoidosis.

Diagnosis of sarcoidosis depends on a compatible clinical and imaging presentation, histologic finding of non-necrotizing granulomatous inflammation, and exclusion of alternative causes of granulomatous diseases. This study has reviewed the diagnostic algorithms and approaches of sarcoidosis.

Predictors of Mortality in Sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder that affects individuals of all racial/ethnic origins and occurs at any time of life. Spontaneous remission is frequent and may occur in 2 of 3 patients, while the remaining cases have chronic, progressive disease, with some patients presenting with organ- and life-threatening involvements. Many reports have investigated which features may be related to poor outcomes in patients with sarcoidosis. Pulmonary hypertension and respiratory failure from pulmonary fibrosis are the most common complications associated with the cause of death in sarcoidosis. Other major causes of death include cardiac, neurologic, hepatic involvement, and hemoptysis from aspergilloma.

Role of Bronchoscopy in Diagnosis of Sarcoidosis.

Sarcoidosis is a multisystem inflammatory disorder with unclear etiology and can often pose a diagnostic challenge. A tissue diagnosis is often necessary to illustrate the non-caseating granulomas on histopathology. This review aims to synthesize current evidence related to tissue diagnosis of sarcoidosis using various bronchoscopic techniques. We start by discussing standard bronchoscopic techniques which have remained the cornerstone of diagnostic workup such as bronchoalveolar lavage (BAL), endobronchial biopsy (EBB), conventional transbronchial needle aspiration (cTBNA) and transbronchial lung biopsy (TBLB) followed by newer modalities that incorporate real-time image guidance using endobronchial and endoscopic ultrasound. Although BAL, EBB, and TBLB have been employed as a diagnostic tool for several decades, their sensitivity and diagnostic yield is inferior to ultrasound-based endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). More recently, convincing evidence has also emerged to support the diagnostic accuracy and tissue yield of transbronchial lung cryobiopsy which will also be discussed in this review. These advances in bronchoscopic equipment and techniques over the last 2 decades have made it possible to obtain tissue samples using minimally invasive techniques thus avoiding invasive open lung biopsy and the risks that inherently follow. Up-to-date knowledge of these modalities is imperative for ensuring evidence-based medicine and improving patient-centric outcomes.

Sarcoidosis-Associated Pulmonary Hypertension.

Pulmonary hypertension is a life-threatening complication of advanced sarcoidosis. Many mechanisms can cause an elevation of pulmonary pressure in sarcoidosis, leading to precapillary or postcapillary pulmonary hypertension. Sarcoidosis-associated pulmonary hypertension contributes to severe exertional dyspnea, reduced exercise capacity, and notably compromised the survival. Despite the critical functional and prognostic implications of pulmonary hypertension in sarcoidosis, there is a scarcity of specific guidelines on the management of these patients due to a lack of evidence. Hence, further research is required to identify subgroups of patients who may benefit from pulmonary arterial hypertension-targeted therapies and/or immunosuppressive therapies.

Fibrotic Pulmonary Sarcoidosis.

Fibrotic pulmonary sarcoidosis (fPS) affects about 20% of patients. fPS carries a significant morbidity and mortality. However, its prognosis is highly variable, depending mainly on fibrosis extent, functional impairment severity, and the development of pulmonary hypertension. Moreover, fPS outcomes are also influenced by several other complications, including acute exacerbations, and infections. fPS natural history is unknown, in particular regarding the risk of progressive self-sustaining fibrosis. The management of fPS is challenging, including anti-inflammatory treatment if granulomatous activity persists, rehabilitation, and in highly selected patients antifibrotic treatment and lung transplantation.

Monitoring of Sarcoidosis.

This article focuses on the monitoring of pulmonary sarcoidosis. The monitoring of sarcoidosis is, in part, focused on serial change in major organ involvement but also includes diagnostic re-evaluation and review of change in quality of life. Recent criteria for progression of fibrotic interstitial lung disease are adapted to pulmonary sarcoidosis. The frequency and nature of monitoring are discussed, integrating baseline risk stratification and strategic treatment goals. Individual variables used to identify changes in pulmonary disease severity are discussed with a focus on their flaws and the need for a multidimensional approach. Other key monitoring issues are covered briefly.

Sarcoidosis: Evaluation and Treatment.

Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown etiology that can involve any organ. Ongoing dyspnea and dry cough in a young to middle-aged adult should increase the suspicion for sarcoidosis. Symptoms can present at any age and affect any organ system; however, pulmonary sarcoidosis is the most common. Extrapulmonary manifestations often involve cardiac, neurologic, ocular, and cutaneous systems. Patients with sarcoidosis can exhibit constitutional symptoms such as fever, unintentional weight loss, and fatigue. The early recognition and diagnosis of sarcoidosis are challenging because there is no diagnostic standard for testing, initial symptoms vary, and patients may be asymptomatic. Consensus guidelines recommend a holistic approach when diagnosing sarcoidosis that focuses on clinical presentation and radiographic findings, biopsy with evidence of noncaseating granulomas, involvement of more than one organ system, and elimination of other etiologies of granulomatous disease. Corticosteroids are the initial treatment for active disease, with refractory cases often requiring immunosuppressive or biologic therapies. Transplantation can be considered for advanced and end-stage disease depending on organ involvement.

Dexamethasone alleviates pulmonary sarcoidosis by regulating the TGF-ß/Smad3 signaling to promote Th17/Treg cell rebalance.

Pulmonary sarcoidosis is an immune-mediated disorder closely related to Th17/Treg cell imbalance. Dexamethasone has been shown to regulate inflammation and immune responses in sarcoidosis patients. However, the underlying mechanisms of dexamethasone regulating Th17/Treg balance in sarcoidosis remain elusive. Herein, we elucidated the function role of TGF-ß/Smad3 signaling in pulmonary sarcoidosis development and explored the underlying mechanism of dexamethasone in treating pulmonary sarcoidosis. We found that the TGF-ß/Smad3 pathway was inactivated in pulmonary sarcoidosis patients. Propionibacterium acnes (PA) induced mouse model was generated to investigate the function of TGF-ß/Smad3 signaling in vivo. Data indicated that IL17A inhibition with neutralizing antibody and activation of TGF-ß/Smad3 signaling with SRI-011381 alleviated granuloma formation in the sarcoidosis mouse model. Moreover, we revealed that the Th17/Treg cell ratio was increased with PA treatment in mouse bronchoalveolar lavage fluid (BALF) and peripheral blood. The concentration of cytokines produced by Th17 cells (IL-17A, IL-23) was up-regulated in the BALF of PA-treated mice, while those produced by Tregs (IL-10, TGF-ß1) presented significant reduction. The treatment of IL-17A neutralizing antibody or SRI-011381 was demonstrated to rescue the PA-induced changes in the concentration of IL-17A, IL-23, IL-10, and TGF-ß1. Additionally, we demonstrated that dexamethasone treatment activated the TGF-ß/Smad3 signaling in the lung tissues of pulmonary sarcoidosis mice. Dexamethasone was also revealed to promote the rebalancing of the Th17/Treg ratio and attenuated the granuloma formation in pulmonary sarcoidosis. In conclusion, dexamethasone activates the TGF-ß/Smad3 signaling and induces Th17/Treg rebalance, alleviating pulmonary sarcoidosis, which suggests the potential of dexamethasone in treating pulmonary sarcoidosis.

Sarcoidosis cardíaca como causa muy infrecuente de muerte súbita en pacientes jóvenes asintomáticos / Cardiac sarcoidosis as an infrequent cause of sudden death in asymptomatic young patients

La afectación cardíaca en la sarcoidosis ha sido descrita tanto en presencia de síntomas como en su ausencia. Este trabajo ayuda a comprender la sarcoidosis y su presentación clínico-morfológica. Presentamos dos pacientes jóvenes (37 y 27años), con muerte súbita, a quienes se les realizó la autopsia completa con estudio toxicológico. El hombre de 37años presentaba una sarcoidosis pulmonar generalizada, en ganglios mediastínicos y granulomas sarcoideos intramiocárdicos en el ventrículo izquierdo, que producían un espesor de pared de 14mm. Esto derivó en una miocardiopatía dilatada secundaria que debutó como muerte súbita. El segundo caso, un varón de 27años, presentaba sarcoidosis con importante afectación pulmonar y mediastínica. La presencia de granulomas en el tabique cardíaco sobre un fondo fibrótico podría ser el origen de un mecanismo arritmogénico de muerte súbita. La autopsia clásica y el examen del sistema de conducción cardíaco son cruciales en la muerte súbita.(AU)

Cardiac involvement in sarcoidosis has been described in both symptomatic and asymptomatic patients. The aim of this report is to further the understanding of sarcoidosis and its clinical presentation. We report the autopsy and toxicology results of two cases of sudden death in young men. A 37-year-old male had generalized sarcoidosis, in mediastinal glands and intramyocardial sarcoid granulomas in the left ventricle, which had caused a 14mm thickening of the ventricular wall and a secondary dilated myocardiopathy causing sudden death. A 27-year-old male had extensive sarcoidosis of the lungs and mediastinum. Granulomas with a fibrotic background were found in the cardiac wall which could have originated an arrhythmogenic mechanism causing sudden death. Post-mortem study including careful examination of cardiac conduction pathways are vital to ascertain the cause of sudden death.(AU)

The role of serum and bronchoalveolar lavage fluid chitotriosidase activity on diagnosis, disease characteristics and prognosis of sarcoidosis.

Introduction: Sarcoidosis is a multisystem granulomatous disease with an unpredictable clinical course. Chitotriosidase is a chitinase mainly expressed by activated macrophages. Increased chitotriosidase activity has been reported in serum and bronchoalveolar lavage (BAL) of sarcoidosis patients compared to healthy controls. This study aims to evaluate the role of serum and BAL chitotriosidase activity on diagnosis, disease characteristics, and prognosis of sarcoidosis. Materials and Methods: Patients referred with suspected sarcoidosis or other interstitial lung disease were prospectively included in the study. All patients underwent bronchoscopy with BAL. Serum and BAL chitotriosidase activity, BAL differential cell counts, and lymphocyte phenotypes were determined. Sarcoidosis patients were followed up regularly. Result: Forty-two sarcoidosis and 28 non-sarcoidosis patients were included in the study. Serum chitotriosidase activity was higher in sarcoidosis group 247.5 (2.78-461) vs 108 (2.78-272) nmol/h/mL (p< 0.001). BAL chitotriosidase activity tended to be higher in sarcoidosis group 11 (2-308) vs 6.95 (2.27-44) nmol/h/mg but was not found to be statistically significant (p= 0.11). Serum and BAL chitotriosidase activities were correlated with each other (p= 0.023, r= 0.355). No significant difference was found between the diagnostic performance of BAL CD4/CD8 ratio and serum chitotriosidase activity (p= 0.079). Serum chitotriosidase and ACE activities were correlated with each other (p= 0.004, r= 0.457). No significant difference was found between serum or BAL chitotriosidase activity and stage or extrapulmonary involvement. Serum chitotriosidase activity was higher in patients who needed systemic therapy at diagnosis (p= 0.046). However, no significant difference was found between serum or BAL chitotriosidase activities and disease progression (p= 0.395 and p= 0.723, respectively). Conclusions: Serum chitotriosidase activity can be helpful in the differential diagnosis of sarcoidosis with a similar diagnostic performance with BAL CD4/CD8 ratio. Although serum chitotriosidase activity at diagnosis does not predict progressive disease, it is associated with the need for systemic therapy at diagnosis. Serial chitotriosidase measurements may be useful in monitoring disease progression during follow-up.

Clinical manifestations and associated factors of uveitis in patients with pulmonary sarcoidosis: a case control study.

Sarcoidosis, an idiopathic and inflammatory disease, affects various organs and can manifest as uveitis. Due to limited evidence, researchers investigated the risk factors associated with uveitis in patients with pulmonary sarcoidosis. A retrospective study was conducted on 71 pulmonary sarcoidosis patients, including 19 with uveitis and 52 without. Data on involved organs, imaging findings, spirometry, and analyses from blood and bronchoalveolar lavage fluid were collected. Logistic regression models were used for multivariate analysis. Among the 71 newly diagnosed pulmonary sarcoidosis patients, uveitis was observed in 19 patients (26.8%). No significant differences were found in clinical characteristics between patients with and without uveitis. Fewer patients with uveitis presented lung parenchymal lesions (P = 0.043). In multivariate analysis, skin lesions (aOR 7.619, 95% CI 1.277-45.472, P = 0.026) and ophthalmic symptoms (aOR 4.065, 95% CI 1.192-13.863, P = 0.025) were associated with uveitis. Absence of uveitis was related to lung parenchymal lesions (aOR 0.233, 95% CI 0.062-0.883, P = 0.032). Approximately one-quarter of patients with an initial diagnosis of pulmonary sarcoidosis were diagnosed with uveitis. Presence of skin lesions, ophthalmic symptoms, and absence of lung parenchymal lesions were related to uveitis. These results need to be clarified by further studies to confirm the clinical role of early ophthalmologic screening for pulmonary sarcoidosis patients with these factors.

An Artificial Intelligence Platform for the Radiologic Diagnosis of Pulmonary Sarcoidosis: An Initial Pilot Study of Chest Computed Tomography Analysis to Distinguish Pulmonary Sarcoidosis from a Negative Lung Cancer Screening Scan.

PURPOSE: To determine the reliability of an artificial intelligence, deep learning (AI/DL)-based method of chest computer tomography (CT) scan analysis to distinguish pulmonary sarcoidosis from negative lung cancer screening chest CT scans (Lung Imaging Reporting and Data System score 1, Lung-RADS score 1). METHODS: Chest CT scans of pulmonary sarcoidosis were evaluated by a clinician experienced with sarcoidosis and a chest radiologist for clinical and radiologic evidence of sarcoidosis and exclusion of alternative or concomitant pulmonary diseases. The AI/DL based method used an ensemble network architecture combining Convolutional Neural Networks (CNNs) and Vision Transformers (ViTs). The method was applied to 126 pulmonary sarcoidosis and 96 Lung-RADS score 1 CT scans. The analytic approach of training and validation of the AI/DL method used a fivefold cross-validation technique, where 4/5th of the available data set was used to train a diagnostic model and tested on the remaining 1/5th of the data set, and repeated 4 more times with non-overlapping validation/test data. The probability values were used to generate Receiver Operating Characteristic (ROC) curves to assess the model's discriminatory power. RESULTS: The sensitivity, specificity, positive and negative predictive value of the AI/DL method for the 5 folds of the training/validation sets and the entire set of CT scans were all over 94% to distinguish pulmonary sarcoidosis from LUNG-RADS score 1 chest CT scans. The area under the curve for the corresponding ROC curves were all over 97%. CONCLUSION: This AL/DL model shows promise to distinguish sarcoidosis from alternative pulmonary conditions using minimal radiologic data.

RISK FACTORS FOR GC-RESISTANT PULMONARY SARCOIDOSIS.

OBJECTIVE: The aim: The study aimed to conduct a retrospective analysis of unfavorable outcome rate and to search for clinical and anamnestic criteria for predicting glucocorticoid-resistant pulmonary sarcoidosis. PATIENTS AND METHODS: Materials and methods: There were examined 37 women and 31 men with stage II to III pulmonary sarcoidosis from 2018-2022. The mean patients' age was (35.7±6.6) years. All patients underwent a chest computed tomography scan on the Toshiba Aquilion Prime CT scanner before the start of treatment and after the three-month glucocorticoid therapy. Anamnestic, age- and gender related factors of unfavorable treatment outcomes were studied. RESULTS: Results: Dyspnea (86%), coughing (67%), general weakness and fatigue (29%) on the background of maintaining the indicators of lung tissue density at the level of -893.5 Hounsfield units and above according to the chest computed tomography imaging represented the three-month treatment failure. Glucocorticoid-resistant sarcoidosis was most diagnosed in patients with stage III disease; the mean patients' age was (44.3±3.2) years; B positive men prevailed; 85% of patients developed extrapulmonary manifestations; in 43% of cases, concomitant cardiovascular pathology was diagnosed. CONCLUSION: Conclusions: Age, gender, comorbid conditions, extrapulmonary lesions, and blood type can be used as predictive criteria for GC-resistant sarcoidosis.