Pulmonary Sarcoidosis Patients Research Articles

Abstract We067: A meta-analysis of RNA sequencing data to characterize immune cell activation among patients with cardiac sarcoidosis

Introduction: Cardiac sarcoidosis (CS) is a life-threatening auto-immune disorder that causes the formation of non-caseating granulomas in cardiac tissue. Th17.1 cell have been found to be upregulated in patients with pulmonary sarcoidosis (PS) although data is lacking among CS patients. This meta-analysis integrates all publicly available granuloma single-cell and single-nuclei RNA sequencing data to identify patterns in immune cell activation across different granulomatous diseases while focusing on CD4+T cell activation among CS patients. Methods: Five studies were included, spanning cardiac tissue from healthy controls and DCM (Koenig 2022, PMID:35959412), cardiac tissue from ICM and cardiac sarcoidosis (Liu 2022, PMID:36111531), BAL from beryllium sensitized, chronic berylliosis, and PS (Liao 2021, PMID: 33602861), peripheral blood samples from sarcoidosis (Garman 2020, PMID: 33363531), and lesional and nonlesional skin tissue from sarcoidosis (Krausgruber 2023, PMID: 36750099) for a total of 122 patients. All integrative analysis was performed using the R package Seuratv5 on Stanford’s computing cluster, Sherlock. After quality control filtering, a total of 127,335 cells were integrated using Seurat’s reference-based integration. After labeling the UMAP with general immune cells (figure 1A), we subsetted T cells into CD4+ and CD8+ and examined the landscape of CD4+ T cells (figure 1B). Results: We found significantly more Tregs in CS than PS (P=0.013, figure 1C). Additionally, patients with CS had significantly more Th17.1 cells in CS in comparison to PS (P=0.0041). However, significantly less Th2 cells were found in CS than PS patients (P=0.0152). These differences remained statistically significant across various analyses comparing Tregs and Th17.1 cell as a proportion of CD4+, CD3+, and CD45+ cells. Conclusions: In comparison to patients with PS, pathways which differentiate naive CD4+ cells into TH17.1 and Tregs are upregulated among CS patients while the TH2 differentiation pathway is downregulated. Our findings indicate distinct CD4+ T cell patterns among CS and PS patients. Our ongoing work aims to further evaluate T cell proliferation and expression to elucidate mechanistic pathways as potential drug targets for CS.

A Multichannel CT and Radiomics-Guided CNN-ViT (RadCT-CNNViT) Ensemble Network for Diagnosis of Pulmonary Sarcoidosis.

Pulmonary sarcoidosis is a multisystem granulomatous interstitial lung disease (ILD) with a variable presentation and prognosis. The early accurate detection of pulmonary sarcoidosis may prevent progression to pulmonary fibrosis, a serious and potentially life-threatening form of the disease. However, the lack of a gold-standard diagnostic test and specific radiographic findings poses challenges in diagnosing pulmonary sarcoidosis. Chest computed tomography (CT) imaging is commonly used but requires expert, chest-trained radiologists to differentiate pulmonary sarcoidosis from lung malignancies, infections, and other ILDs. In this work, we develop a multichannel, CT and radiomics-guided ensemble network (RadCT-CNNViT) with visual explainability for pulmonary sarcoidosis vs. lung cancer (LCa) classification using chest CT images. We leverage CT and hand-crafted radiomics features as input channels, and a 3D convolutional neural network (CNN) and vision transformer (ViT) ensemble network for feature extraction and fusion before a classification head. The 3D CNN sub-network captures the localized spatial information of lesions, while the ViT sub-network captures long-range, global dependencies between features. Through multichannel input and feature fusion, our model achieves the highest performance with accuracy, sensitivity, specificity, precision, F1-score, and combined AUC of 0.93 ± 0.04, 0.94 ± 0.04, 0.93 ± 0.08, 0.95 ± 0.05, 0.94 ± 0.04, and 0.97, respectively, in a five-fold cross-validation study with pulmonary sarcoidosis (n = 126) and LCa (n = 93) cases. A detailed ablation study showing the impact of CNN + ViT compared to CNN or ViT alone, and CT + radiomics input, compared to CT or radiomics alone, is also presented in this work. Overall, the AI model developed in this work offers promising potential for triaging the pulmonary sarcoidosis patients for timely diagnosis and treatment from chest CT.

Diagnostic Value of Imaging and Serological Biomarkers in Pulmonary Sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease of an unknown aetiology. It can exist in many organs. Pulmonary and intrathoracic lymph nodes are most commonly involved. Lung sarcoidosis is uncommon in Asia. However, due to the large population of our country and the development of bronchoscopy, percutaneous lung puncture, and other medical technologies, the number of pulmonary sarcoidosis patients is on the rise. Pulmonary sarcoidosis patients have no obvious symptoms in the early stage, and the clinical manifestations in the later stage may vary from person to person. Eventually, the disease progresses to life-threatening pulmonary fibrosis. Therefore, patients with pulmonary sarcoidosis should receive a timely diagnosis. In recent years, the imaging features and serologic biomarkers of pulmonary sarcoidosis have been continuously studied. The diagnostic value of imaging and serologic biomarkers for pulmonary sarcoidosis is summarized below.

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.

Dexamethasone alleviates pulmonary sarcoidosis by regulating the TGF-β/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-β/Smad3 signaling in pulmonary sarcoidosis development and explored the underlying mechanism of dexamethasone in treating pulmonary sarcoidosis. We found that the TGF-β/Smad3 pathway was inactivated in pulmonary sarcoidosis patients. Propionibacterium acnes (PA) induced mouse model was generated to investigate the function of TGF-β/Smad3 signaling in vivo. Data indicated that IL17A inhibition with neutralizing antibody and activation of TGF-β/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-β1) 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-β1. Additionally, we demonstrated that dexamethasone treatment activated the TGF-β/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-β/Smad3 signaling and induces Th17/Treg rebalance, alleviating pulmonary sarcoidosis, which suggests the potential of dexamethasone in treating pulmonary sarcoidosis.

Pulmonary sarcoidosis: A comprehensive review: Past to present

Sarcoidosis is a sterile non-necrotizing granulomatous disease without known causes that can involve multiple organs with a predilection for the lung and thoracic lymph nodes. Worldwide it is estimated to affect 2–160/100,000 people and has a mortality rate over 5 years of approximately 7%. For sarcoidosis patients, the cause of death is due to sarcoid in 60% of the cases, of which up to 80% are from advanced cardiopulmonary failure (pulmonary hypertension and respiratory microbial infections) in all races except in Japan were greater than 70% of the sarcoidosis deaths are due to cardiac sarcoidosis.Scadding stages for pulmonary sarcoidosis associates with clinical outcomes. Stages I and II have radiographic remission in approximately 30%–80% of cases. Stage III only has a 10%–40% chance of resolution, while stage IV has no change of resolution. Up to 40% of pulmonary sarcoidosis patients progress to stage IV disease with lung parenchyma fibroplasia, bronchiectasis with hilar retraction and fibrocystic disease. These patients are at highest risk for the development of precapillary pulmonary hypertension, which may occur in up to 70% of these patients. Sarcoid patients with pre-capillary pulmonary hypertension can respond to targeted pulmonary arterial hypertension medications. Stage IV fibrocytic sarcoidosis with significant pulmonary physiologic impairment, >20% fibrosis on HRCT or pre-capillary pulmonary hypertension have the highest risk of mortality, which can be >40% at 5-years.First line treatment for patients who are symptomatic (cough and dyspnea) with parenchymal infiltrates and abnormal pulmonary function testing (PFT) is oral glucocorticoids, such as prednisone with a typical starting dose of 20–40 mg daily for 2 weeks to 2 months. Prednisone can be tapered over 6–18 months if symptoms, spirometry, PFTs, and radiographs improve. Prolonged prednisone may be required to stabilize disease. Patients requiring prolonged prednisone ≥10 mg/day or those with adverse effects due to glucocorticoids may be prescribed second and third line treatements. Second and third line treatments include immunosuppressive agents (e.g., methotrexate and azathioprine) and anti-tumor necrosis factor (TNF) medication; respectively. Effective treatments for advanced fibrocystic pulmonary disease are being explored. Despite different treatments, relapse rates range from 13% to 75% depending on the stage of sarcoid, number of organs involved, socioeconomic status, and geography. ConclusionThe mortality rate for sarcoidosis over a 5 year follow up is approximately 7%. Unfortunately, 10%–40% of patients with sarcoidosis develop progressive pulmonary disease, and >60% of deaths resulting from sarcoidosis are due to advance cardiopulmonary disease. Oral glucocorticoids are the first line treatment, while methotrexate and azathioprine are considered second and anti-TNF agents are third line treatments that are used solely or as glucocorticoid sparing agents for symptomatic extrapulmonary or pulmonary sarcoidosis with infiltrates on chest radiographs and abnormal PFT. Relapse rates have ranged from 13% to 75% depending on the population studied.

Imbalance of Lymphocyte Subsets and CD45RA-Expressing Cells in Intrathoracic Lymph Nodes, Alveolar Compartment and Bloodstream of Pulmonary Sarcoidosis Patients.

Sarcoidosis is a systemic granulomatous disease mainly affecting the lungs and hilomediastinal lymph nodes. It is characterized by non-caseating epithelioid cell granulomas in lymph nodes and lungs. Our study aimed to evaluate and compare T, B and NK cell subsets in the alveolar compartment, lymph nodes and the bloodstream simultaneously in the same patients to elucidate the immune responses associated with the development and progression of sarcoidosis. A secondary aim was to evaluate the distribution of CD45RA-expressing cells in the different anatomical compartments. Patients suspected to have sarcoidosis and who underwent bronchoscopy with bronchoalveolar lavage (BAL), lung-draining lymph node (LLN) biopsy by EBUS-TBNA and peripheral blood (PB) sampling were included in the study. They were monitored at the Regional Referral Centre of Siena University Hospital and the Respiratory Diseases Unit of Perugia Hospital. Multicolour flow cytometry analysis through FASCLyric was performed to assess T, B and NK cell subsets. Thirty-two patients (median age (IQR) 57 (52-58) years) were consecutively and prospectively enrolled. Machine learning analysis created a model which selected CD56dim16bright, CD8, Tfc, Th17, Th12, Tfh17, Tfh2, TcemRA, ThemRA, T naïve, Tc naïve, Breg, CD1d+CD5+, Th-reg, Tfh, Th1 and CD4 cells with an accuracy of 0.9500 (kappa 0.8750). Comparative analysis found 18 cell populations that differed significantly between the three anatomical compartments. The bloodstream was enriched in ThemRA (p = 0.0416), Tfh2 (p = 0.0189), Tfh17 (p = 0.0257), Th2 (p = 0.0212), Th17 (p = 0.0177), Th-naïve (p = 0.0368), CD56dimCD16bright (p < 0.0001), CD8 (p = 0.0319), TcemRA (p < 0.0001) and Tfc cells (p = 0.0004) compared with the alveolar compartment, while Th-reg were lower in PB than BAL (p = 0.0329). The alveolar compartment was enriched in Breg (p = 0.0249) and CD1d+CD5+ (p = 0.0013) with respect to LLN samples and PB. Conversely, Tfh (p = 0.0470), Th1 (p = 0.0322), CD4 (p = 0.0486) and Tc-naïve (p = 0.0009) were more abundant in LLN than in BAL and PB. It has been speculated that changes in the relative contents of PB cells could be related to changes in production and to the selective redistribution of PB cells to granulomatous foci. This study further supports the fact that sarcoidosis is multisystemic in nature. However, the low level of immune cells in peripheral blood of patients with sarcoidosis is concerning. A re-expression of CD45RA on CD4+ and CD8+ cells could result in a reduction in peripheral immune activity. Thus, changes in the spectrum of the bloodstream may reflect both pathogenic and compensatory processes.

S2778 Ulcerative Colitis and Concomitant Pulmonary Sarcoidosis Leading to Colectomy: A Case Series

Introduction: A recent analysis of 24 cases of ulcerative colitis (UC) with concomitant sarcoidosis found a common HLA serotype (Toshiyuki 2021), however its role in disease severity is unknown. We describe 2 pulmonary sarcoidosis patients with rapidly progressing refractory UC needing colectomy. Case Description/Methods: A 45-year-old male presented with 15-20 episodes of hematochezia a day with nocturnal bowel movements. He was diagnosed with UC and started on mesalamine and vedolizumab. He did not respond and was switched to multiple biologics including ustekinumab, adalimumab and infliximab. He ultimately underwent total colectomy within 1 year of diagnosis. He was diagnosed with pulmonary sarcoidosis 10 years prior, presenting with weight loss and chest pain. Prior to his UC diagnosis, he was not taking steroids for his pulmonary disease. His annual pulmonary function tests had been normal. A 52-year-old female presented with 3 months of hematochezia and anemia. She was treated for gastroenteritis but was hospitalized due to minimal improvement. Imaging, endoscopy, and histology confirmed colitis, thought to be Crohn’s disease (CD) but later reclassified as UC. She was started on infliximab but was a primary non-responder. After 1 year of therapy she was switched to vedolizumab but received 3 doses before switching to ustekinumab. Soon after induction, her symptoms warranted hospitalization, and colectomy was performed 3 years after diagnosis. She was diagnosed with pulmonary sarcoidosis 3 years prior to her UC diagnosis and had been on daily low-dose prednisone since then. (Figure) Discussion: Our patients were diagnosed with sarcoidosis well before their UC and had rapidly progressing disease despite biologic therapy requiring colectomy. Most studies address the link between CD and sarcoidosis. Increased CD4/CD8 ratios are specific for sarcoidosis with similar expansion of T cell subsets in patients with CD. Both have been observed more often among siblings and monozygotic twins suggesting a genetic component. A similar analysis has not been performed in UC patients. To date, there is only one case that found specific HLA serotypes associated with both UC and sarcoidosis. In addition, sarcoidosis was thought to lead to less penetrative disease and fewer colectomies. This contrasts with the cases presented here, which both progressed to colectomy within 3 years of diagnosis. Thus, more studies need to be conducted in patients with UC and sarcoidosis to further elucidate the prognosis and potential complications.Figure 1.: Diffuse severe inflammation characterized by erythema, friability and deep ulcerations of the rectum (Fig 1a. and 1b.). Less severe inflammation characterized by erythema of the sigmoid colon (Fig 2a. and 2b.).

Prognostic features of sarcoidosis course in a Brazilian cohort.

ABSTRACTObjective:To identify predictive features associated with the course of sarcoidosis at initial evaluation and to develop a predictive score. Methods:This was a retrospective study involving pulmonary sarcoidosis patients, classified as having a self-limited or persistent course of disease, comparing data between the outcomes by univariate analysis. Features related to persistent disease were selected by multivariate analysis and a prognostic score was designed. Results:The sample comprised 200 patients (mean age = 49 years). The median duration of symptoms to diagnosis was 12 months, and delayed diagnosis (> 12 months) was found in 43% of the cases. The most common radiological stage was II; 37% had reduced FVC. Relevant systemic involvement was detected in 37% of the patients. Treatment for tuberculosis was prescribed in 44 patients prior to sarcoidosis diagnosis. Treatment for sarcoidosis was required in 77% of the sample, and the disease course was persistent in 115 cases. Excluding 40 patients with fibrotic disease, prognostic factors to persistent disease were parenchymal involvement, delayed diagnosis, dyspnea, relevant systemic involvement, and reduced FVC. On the basis of the analysis, a 3-letter scoring system (A, B and C) was developed according to the selected factors. The positive predictive values for persistent course for A (≤ 1 point) and C scores (≥ 4 points) were 12.5% and 81.8%, respectively. Conclusions:A score can be derived by selected features at initial evaluation, allowing the prediction of outcomes in a significant number of sarcoidosis patients.

Фенотипическая пластичность макрофагов воспаления при саркоидозе и туберкулезе легких

Pulmonary macrophages form a heterogenous population of mononuclear cells, which provides systemic defense of an organ from any impairments of structural homeostasis. Functional mobilization of pulmonary macrophages is especially expressed in the development of granulomatous reactions, differentiation of circulating monocytes in pro-inflammatory macrophages, which play the key role in the progression and reparation of inflammatory processes. Phenotypic plasticity of these cells in the context of delayed-type hypersensitivity reaction and developing epithelioid cell granuloma genesis like in pulmonary TB or sarcoidosis represent an important area of research. The present review includes long-term ownstudies of phenotypic plasticity of pulmonary macrophages in TB or sarcoidosis. Biomarkers for verification and differential diagnosis of these diseases have been described. Structural and functional features of the M1 and M2 phenotypes, which differ in the expression of surface markers and cytokine production, were established. It was demonstrated that the M1 phenotype with hypersecretion of epithelioid cells prevailed in pulmonary sarcoidosis patients while the mixed phenotype with active secretion and phagocytosis, i.e. M1/M2 with the predominant M2 phenotype, was typical for disseminated pulmonary TB patients.

Value of echocardiography using knowledge-based reconstruction in determining right ventricular volumes in pulmonary sarcoidosis: comparison with cardiac magnetic resonance imaging

Abstract Background Right ventricular (RV) dysfunction in sarcoidosis is associated with adverse outcomes. Assessment of RV function by conventional transthoracic echocardiography (TTE) is challenging due to the complex RV geometry. Knowledge-based reconstruction (KBR) combines TTE measurements with three-dimensional coordinates to determine RV volumes. Purpose The aim of this study was to investigate the accuracy of TTE-KBR compared to the gold standard cardiac magnetic resonance imaging (CMR) in determining RV dimensions in pulmonary sarcoidosis. Methods Pulmonary sarcoidosis patients prospectively received same-day TTE and TTE-KBR. If performed, CMR within three months after TTE-KBR was used as reference standard. Outcome parameters included RV end-diastolic volume (RVEDV), end-systolic volume (RVESV), stroke volume (RVSV) and ejection fraction (RVEF). Results 282 patients underwent same day TTE and TTE-KBR. In total, 122 patients received a CMR within 90 days of TTE and were included. TTE-KBR measured RVEDV and RVESV showed strong correlation with CMR measurements (R=0.73, R=0.76), while RVSV and RVEF correlated weakly (R=0.46, R=0.46). Bland-Altman analyses (mean bias ±95% limits of agreement), showed good agreement for RVEDV (ΔRVEDVKBR-CMR, 5.67±55.4mL), while RVESV, RVSV and RVEF showed poor agreement (ΔRVESVKBR-CMR, 21.6±34.1mL; ΔRVSVKBR-CMR, −16.1±42.9mL; ΔRVEFKBR-CMR, −12.9±16.4%). Image quality, time to CMR and learning curve showed no impact. Conclusions TTE-KBR is convenient and shows good agreement with CMR for RVEDV. However, there is poor agreement for RVESV, RVSV and RVEF. The use of TTE-KBR does not seem to provide additional value in the determination of RV dimensions in pulmonary sarcoidosis patients. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): ZonMW (The Netherlands Organisation for Health Research and Development) Figure 1. Correlation plotsFigure 2. Bland-Altman plots

Value of echocardiography using knowledge-based reconstruction in determining right ventricular volumes in pulmonary sarcoidosis: comparison with cardiac magnetic resonance imaging.

Right ventricular (RV) dysfunction in sarcoidosis is associated with adverse outcomes. Assessment of RV function by conventional transthoracic echocardiography (TTE) is challenging due to the complex RV geometry. Knowledge-based reconstruction (KBR) combines TTE measurements with three-dimensional coordinates to determine RV volumes. The aim of this study was to investigate the accuracy of TTE-KBR compared to the gold standard cardiac magnetic resonance imaging (CMR) in determining RV dimensions in pulmonary sarcoidosis. Pulmonary sarcoidosis patients prospectively received same-day TTE and TTE-KBR. If performed, CMR within 90 days after TTE-KBR was used as reference standard. Outcome parameters included RV end-diastolic volume (RVEDV), end-systolic volume (RVESV), stroke volume (RVSV) and ejection fraction (RVEF). 281 patients underwent same day TTE and TTE-KBR. In total, 122 patients received a CMR within 90 daysof TTE and were included. TTE-KBR measured RVEDV and RVESV showed strong correlation with CMR measurements (R = 0.73, R = 0.76), while RVSV and RVEF correlated weakly (R = 0.46, R = 0.46). Bland-Altman analyses (mean bias ± 95% limits of agreement), showed good agreement for RVEDV (ΔRVEDVKBR-CMR, 5.67 ± 55.4mL), while RVESV, RVSV and RVEF showed poor agreement (ΔRVESVKBR-CMR, 21.6 ± 34.1mL; ΔRVSVKBR-CMR, -16.1 ± 42.9mL; ΔRVEFKBR-CMR, -12.9 ± 16.4%). The image quality and time between CMR and TTE-KBR showed no impact on intermodality differences and there was no sign of a possible learning curve. TTE-KBR is convenient and shows good agreement with CMR for RVEDV. However, there is poor agreement for RVESV, RVSV and RVEF. The use of TTE-KBR does not seem to provide additional value in the determination of RV dimensions in pulmonary sarcoidosis patients.

Comparative Effectiveness of Methotrexate versus Methylprednisolone in Treatment Naïve Pulmonary Sarcoidosis Patients.

Among those who study granulomatous diseases, sarcoidosis is of tremendous interest, not only because its cause is unknown, but also because it is still as much an enigma today as it was 150 years ago when Jonathan Hutchinson first described the cutaneous form of the disease as “livid papillary psoriasis”. This piece editorializes a comparative effectiveness study of methotrexate versus methylprednisolone in treatment naïve pulmonary sarcoidosis patients for CT-guided clinical responses and drug-related adverse events.

Cases of tuberculous pleurisy in sarcoidosis patients

The article describes 3 clinical cases of tuberculous pleurisy in pulmonary sarcoidosis patients who received courses of glucocorticosteroid therapy in the past. In all cases, the tuberculous etiology of pleurisy was confirmed by microbiological detection of the pathogen in exudate or biopsy specimens.

Detection of cardiac involvement in pulmonary sarcoidosis using high-resolution Holter electrocardiogram.

BackgroundEarly detection of cardiac involvement in patients with sarcoidosis is important but currently unresolved. The aim of this study was to elucidate the utility of frequency domain microvolt T‐wave alternans (TWA), signal‐averaged ECG (SAECG), and heart rate turbulence (HRT) using 24‐hour Holter ECG for detecting cardiac involvement in patients with pulmonary sarcoidosis.MethodsThis study consisted of consecutive 40 pulmonary sarcoidosis patients (11 males, 62 ± 13 years) who underwent 24‐hour Holter monitoring with and without cardiac involvement. All patients underwent frequency domain TWA, SAECG, and HRT using 24‐hour Holter monitoring. Patients with atrial fibrillation pacing or wide QRS electrocardiogram were excluded.ResultsAfter 14 patients were excluded, a total of 26 patients (six males, 59 ± 14 years) were evaluated. Seven patients had cardiac involvement (cardiac sarcoidosis [CS] group). On the Holter SAECG, duration of low‐amplitude signals <40 μV in the terminal filtered QRS complex (LAS40) was significantly higher, and root mean square voltage of the terminal 40 ms of the filtered QRS complex (RMS40) was significantly lower in the CS group compared with the non‐CS group (LAS40: 61.4 ± 35.9 vs 37.6 ± 9.2 ms; P = .018, RMS40: 11.4 ± 10.3 vs 23.6 ± 13.2 ms; P = .023). Prevalence of positive late potential (LP) was also significantly higher in the CS group than that in the non‐CS group (85.7% vs 31.5%; P = .026). The sensitivity, specificity, positive, and negative predictive values of LP for identifying patients with cardiac involvement were 85.7%, 68.4%, 50.0%, and 92.8%, respectively.ConclusionHolter SAECG may be useful for detecting cardiac involvement in patients with pulmonary sarcoidosis.

ЕФЕКТИВНІСТЬ ЗАСТОСУВАННЯ МЕТОТРЕКСАТУ У ЛІКУВАННІ РЕЦИДИВІВ САРКОЇДОЗУ ЛЕГЕНЬ

EFFECTIVENESS OF METHOTREXATE IN MANAGEMENT OF PULMONARY SARCOIDOSIS RELAPSES N. A. Vlasova Abstract Relapses are one of most urgent problems of treatment in pulmonary sarcoidosis patients. There have been demonstrated the correlation between the rate of pulmonary sarcoidosis relapses and previous longterm glucocorticosteroid (GCS) therapy. This makes a feasibility of GCS administration in patients with relapsing disease doubtful. Literature data and author’s clinical experience considering lower incidence of sarcoidosis relapses after the use of immunosuppressive drugs such as methotrexate (MTX) were the rationale for this study. Aim: to study the efficacy of MTX in treatment of patients with the relapses of pulmonary sarcoidosis. Material and methods. We examined 12 patients (5 males and 7 females, 36-54 years of age) with relapses of pulmonary sarcoidosis, revealed within 12 months after successful completion of main course of methylprednisolone (MP) therapy (clinical cure). MTX was prescribed in dose of 15 mg/week under monthly control of white blood cells and platelets count and alanine aminotransferase (ALT) serum level. Therapy has been stopped after the complete cure, confirmed by lung computed tomography (CT). The primary endpoint was the long-term outcomes of MTX use – the rate of repeated relapses during 12 months follow-up period following MTX discontinuation. The control group was comprised of 33 patients (males 14, females 19, 30-58 years of age) with relapses of pulmonary sarcoidosis after completion of GCS therapy, treated with MP at initial dose of 24 mg/day. Therapy has been stopped after the complete cure, confirmed by lung CT. The long-term outcomes were assessed at 6 and 12 months of follow-up. Additionally, incidence of adverse reactions was compared between groups. Exact Fisher’s test was used to determine the differences between studied variables. Results. No significant differences were found in rate of adverse reactions between study groups (16,7 % in МТХ vs 21,2 % in MP group). At the same time the rate of repeated relapses was lower in MTX than in MP group (25 % vs 57,6 %, respectively, p=0,01993). Conclusion. Use of MTX 15 mg/week in patients with relapses of pulmonary sarcoidosis was associated with less frequent repeated relapses in comparison with conventional use of MP at starting dose 24 mg/day. Key words: pulmonary sarcoidosis, relapse, methotrexate, methylprednisolone.

Mortality in a well-defined group of predominantly Caucasian pulmonary sarcoidosis patients

Abstract Background Sarcoidosis is an inflammatory systemic disease. Mortality has often been described in patients with more advanced disease, especially in those awaiting lung transplant. The PULSAR study is a cross sectional study prospectively investigating at least two year follow up on mortality in a large prospective, well-defined cohort of Dutch sarcoidosis patients, newly referred to a tertiary centre for sarcoidosis, including data on echocardiography. Methods All patients underwent prospective screening. Patients with intermediate or high probability for PH where referred for right heart catheterisation (RHC). In accordance to the guideline PH was defined as a mean PAP ≥25mmHg by RHC. Elevated pulmonary artery pressure was defined as &amp;gt;20 and &amp;lt;25mmHg. The absence of PH was defined as a mean PAP &amp;lt;25mmHg or a low PH probability on echocardiography. Survival was defined as absence of mortality or transplantation at the time of evaluation. Results 399 patients were included in the analysis. All patients had follow up of at least 2 years. Five patients had died during fallow up, and none were transplanted. The PH prevalence was 3%. PH and elevated pulmonary artery pressure was associated with worse survival. On echocardiography, high PH probability was associated with worse survival compared to low PH probability (HR 1.78, p=0.01). If measurable, RVSP differed significantly between groups. Conclusion Only high PH probability and RVSP measurement on echocardiography were associated with mortality Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): ZonMW

IMPACT OF RACE, GENDER, AND SOCIOECONOMICS ON CARDIAC SARCOIDOSIS MANAGEMENT

SESSION TITLE: Cardiovascular Disease SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Approximately one quarter of sarcoidosis patients have cardiac involvement which is the second most common cause of mortality in sarcoidosis patients. Among pulmonary sarcoidosis patients, symptoms and access to care have been shown to vary by race. These metrics have not been in examined in a cardiac sarcoidosis (CS) population. Leveraging a racially diverse, urban CS registry at Temple University Hospital, we assessed socioeconomics and potential disparities in disease management and resource allocation. METHODS: Using our electronic medical record, we performed a retrospective review of consecutive CS patients receiving care at our hospital between January 2014 and September 2019. Patient demographics, socioeconomics characteristics, CS related interventions and outcomes were collected. Comparisons were made among race (white vs non-white), gender (male vs female), and household income (low vs medium/high income). Patient’s home ZIP codes were collected as a surrogate for socioeconomic status. Using US census data in 2019, ZIP codes were used to categorize patients based on median annual household income into either low income (<$45,000) or medium/high income group (>$45,000). Outcomes were defined as arrhythmia burden (defined by any atrial tachycardia, non-sustained ventricular tachycardia, or sustained ventricular tachycardia found in intra-cardiac device interrogation), intra-cardiac device placement, and use of steroids and immunomodulators. RESULTS: We identified 49 CS patients, of which 49% were non-white (23 black, 1 Hispanic), 57% were male (n=28), with a mean age of 56±13 years. Whites were more likely to live in a higher income ZIP codes (82% white vs 33% non-white patients, p<0.0001). When comparing among race (white vs non-white), gender (male vs female), or income by ZIP code (low vs medium/high income), there is no statistical significant difference in medical comorbidities (hypertension, hyperlipidemia, diabetes, coronary artery disease, obstructive sleep apnea). Arrhythmia burden and intra-cardiac device placements were similar among comparison groups. There was no difference in steroid use among race (84% white vs 83% non-white, p=0.95), gender (71% female vs 78% male, p=0.57), and income (79% low income vs 70% medium/high income, p=0.45). Similarly, there was no difference in immunomodulator use among race (36% white vs 50% black, p=0.32), gender (52% female vs 56% male, p=0.74), and income (48% low income vs 35% medium/high income, p=0.36). CONCLUSIONS: When comparing CS patients by race, gender, or income by ZIP code, there was no difference in medical comorbidities, prevalence of arrhythmic events, presence of intra-cardiac devices, or steroid or immunomodulator use. CLINICAL IMPLICATIONS: This revelation is promising but needs further examination by collaboration between CS registries and large prospective studies. DISCLOSURES: No relevant relationships by Anuj Basil, source=Web Response No relevant relationships by Matthew Bocchese, source=Web Response No relevant relationships by Crystal Chen, source=Web Response Consultant relationship with Abbott Laboratories Please note: $5001 - $20000 Added 04/11/2020 by Joshua Cooper, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Abbott Medical Please note: $5001 - $20000 Added 04/11/2020 by Joshua Cooper, source=Web Response, value=Consulting fee Consultant relationship with Johnson & Johnson Please note: $20001 - $100000 Added 04/11/2020 by Joshua Cooper, source=Web Response, value=Consulting fee Consultant relationship with Boston Scientific Please note: $5001 - $20000 Added 04/11/2020 by Joshua Cooper, source=Web Response, value=Consulting fee Consultant relationship with Biosense Webster Please note: $5001 - $20000 Added 04/11/2020 by Joshua Cooper, source=Web Response, value=Consulting fee Consultant relationship with Medtronic Inc Please note: $1001 - $5000 Added 04/11/2020 by Joshua Cooper, source=Web Response, value=Consulting fee No relevant relationships by Edmond Cronin, source=Web Response No relevant relationships by chethan gangireddy, source=Web Response No relevant relationships by Richard Greenberg, source=Web Response No relevant relationships by Rohit Gupta, source=Web Response No relevant relationships by Abdullah Haddad, source=Web Response No relevant relationships by Benjamin Rosenfeld, source=Web Response No relevant relationships by Isaac Whitman, source=Web Response No relevant relationships by George Yesenosky, source=Web Response

Whole exome sequencing and analysis of a Chinese family with familial pulmonary sarcoidosis

Objective: To analyze the clinical features and the results of the whole exome sequencing (WES) of a Chinese family containing both pulmonary sarcoidosis patients and healthy members, and to find potent genes and variants that may be involved in the pathogenesis of sarcoidosis. Methods: Three patients with pulmonary sarcoidosis and 1 healthy member was included from a Chinese Han family in the north of China diagnosed in November 2016, which characterized as 2 consecutive generations including 2 males and 1 female, aged from 23 to 69 years old. The proband is Ⅱ-6. Pulmonary sarcoidosis was diagnosed by clinical features, imaging and pathological findings, and clinical data such as family history were collected. Whole blood samples were taken and WES (Illumina NovaSeq S2) was performed. The pathogenicity analysis and gene annotation analysis were performed by ExAC, SIFT, Polyphenv2, Metascape databases. Results: It was found that 27 genes were highly pathogenic in the database filtering result. After gene annotation analysis, we found that ZC3H12A gene can negatively regulate the differentiation of Th17 cells, which may be involved in the onset of pulmonary sarcoidosis. Sanger sequencing confirmed the c.1361 A>G variant in 3 sarcoidosis patients but normal in healthy member. Conclusions: In patients with familial pulmonary sarcoidosis, the genetic background could regulate immune response which is one of the pathogenic mechanisms of sarcoidosis. The whole exome test and gene ontology analysis showed that Ⅱ-2, Ⅱ-6 and Ⅲ-1 pulmonary sarcoidosis patients in this family were all shared the same variant on ZC3H12A gene, which played a pivotal role in differentiation of Th17 cells and is a potent pathogenesis gene in this Chinese pulmonary sarcoidosis family.

Clinical phenotyping: role in treatment decisions in sarcoidosis.

A variety of phenotypic categorisations have been developed for sarcoidosis. Phenotyping has been used for genetics studies and to guide treatment selection. The authors participated in a Delphi expert consensus panel to develop a proposed phenotype categorisation and treatment recommendations for pulmonary sarcoidosis patients. Panellists reached consensus that asymptomatic patients with normal pulmonary function and adenopathy alone or normal chest imaging do not require therapy, while symptomatic patients with impaired pulmonary function or infiltrates should be treated. The panel did not reach consensus on asymptomatic patients with abnormal chest imaging or reduced pulmonary function, or symptomatic patients with normal chest imaging and pulmonary function. The proposed phenotype categories and associated treatment recommendations are asymptomatic (no therapy), acute (disease duration <1-2 years, apparently self-limited, corticosteroids), chronic (antimetabolites and other second-line therapies) and advanced (biologics). Some clinical settings, such as dyspnoea/hypoxaemia at rest, severely impaired or rapidly decreasing pulmonary function tests, and severe cardiac, neurologic, ocular or renal involvement warrant immediate therapy.