Progression Of Sarcoidosis Research Articles

Exploring the Role of Genetics in Sarcoidosis and Its Impact on the Development of Cardiac Sarcoidosis

Sarcoidosis is a multifaceted and multisystemic inflammatory disorder, the etiology of which remains unknown. However, it has been suggested that an intricate interplay between genetic, environmental, and inflammatory factors may contribute to the development and progression of sarcoidosis. Although 30–50% of patients demonstrate extra-pulmonary manifestations, cardiac involvement is rare, affecting only 2–5% of cases. Diagnosis is often challenging, relying on the careful application of clinical judgment, histopathological evidence, and imaging biomarkers. In this literature review, we aim to provide a comprehensive overview of the current understanding of the genetic basis of sarcoidosis, the contribution to the pathogenesis of the disorder, and discuss the potential link between certain genetic variants and the development of cardiac sarcoidosis.

Pulmonary Recurrence of Colorectal Mucinous Adenocarcinoma and Sarcoidosis on 18 F-FDG PET/CT.

A 67-year-old woman, previously diagnosed with pulmonary sarcoidosis and sigmoid colon mucinous adenocarcinoma with pulmonary metastasis, showed an enlarged pulmonary nodule in routine follow-up. Because of the absence of treatment for either condition over the past 3 years, the nodule raised concerns of cancer recurrence or sarcoidosis progression. Its distinctive 18 F-FDG PET/CT appearance, compared with other pulmonary lesions, suggested a mucinous histology. The diagnosis was confirmed by pathological examination. This emphasizes the importance of knowledge of the 18 F-FDG PET/CT phenotype of neoplastic histological variants to address challenging diagnostic scenarios.

The role of the host-microbiome and metabolomics in sarcoidosis.

Sarcoidosis is a complex inflammatory fibrotic disease that affects multiple organ systems. It is characterised by the infiltration of lymphocytes and mononuclear phagocytes, which form non-caseating granulomas in affected organs. The lungs and intrathoracic lymph nodes are the most commonly affected organs. The underlying cause of sarcoidosis is unknown, but it is believed to occur in genetically predisposed individuals who are exposed to pathogenic organisms, environmental contaminants, or self and non-self-antigens. Recent research has suggested that the microbiome may play a role in the development of respiratory conditions, including sarcoidosis. Additionally, metabolomic studies have identified potential biomarkers for monitoring sarcoidosis progression. This review will focus on recent microbiome and metabolomic findings in sarcoidosis, with the goal of shedding light on the pathogenesis and possible diagnostic and therapeutic approaches.

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.

Lymphocyte Subsets and Pulmonary Nodules to Predict the Progression of Sarcoidosis.

The search for biological markers, which allow a relatively accurate assessment of the individual course of pulmonary sarcoidosis at the time of diagnosis, remains one of the research priorities in this field of pulmonary medicine. The aim of our study was to investigate possible prognostic factors for pulmonary sarcoidosis with a special focus on cellular immune inflammation markers. A 2-year follow-up of the study population after the initial prospective and simultaneous analysis of lymphocyte activation markers expression in the blood, as well as bronchoalveolar lavage fluid (BALF) and lung biopsy tissue of patients with newly diagnosed pulmonary sarcoidosis, was performed. We found that some blood and BAL fluid immunological markers and lung computed tomography (CT) patterns have been associated with a different course of sarcoidosis. We revealed five markers that had a significant negative association with the course of sarcoidosis (worsening pulmonary function tests and/or the chest CT changes)-blood CD4+CD31+ and CD4+CD44+ T lymphocytes, BALF CD8+CD31+ and CD8+CD103+ T lymphocytes and a number of lung nodules on chest CT at the time of the diagnosis. Cut-off values, sensitivity, specificity and odds ratio for predictors of sarcoidosis progression were calculated. These markers may be reasonable predictors of sarcoidosis progression.

Risk Indicators of Sarcoidosis Evolution-Unified Protocol (RISE-UP): protocol for a multi-centre, longitudinal, observational study to identify clinical features that are predictive of sarcoidosis progression

IntroductionSarcoidosis 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...

Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2.

Progressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes. Plasma biomarker levels and biomarker protein expression in lung and lymph nodes tissues (immunohistochemical studies) from sarcoidosis subjects with limited disease and progressive (complicated) sarcoidosis were performed. Gene expression of the protein-coding genes included in this panel was analyzed using RNAseq in sarcoidosis granulomatous tissues from lung and lymph nodes. Except for IL-8, plasma levels of each biomarker-eNAMPT, IL-1RA, IL-6, ANG-2, and HBEGF-were significantly elevated in sarcoidosis subjects compared to controls. In addition, plasma levels of HBEGF were elevated in complicated sarcoidosis, while eNAMPT and ANG-2 were observed to serve as markers of lung fibrosis in a subgroup of complicated sarcoidosis. Genomic studies corroborated HBEGF and NAMPT among the top dysregulated genes and identified cytokine-related and fibrotic pathways in lung granulomatous tissues from sarcoidosis. These findings suggest HBEGF, eNAMPT, and ANG-2 may serve as potential novel indicators of the clinical severity of sarcoidosis disease.

Sarcoidosis: Progression to the chronic stage and pathogenic based treatment (narrative review).

Many factors confirm the autoimmune nature of sarcoidosis and help in determining the strategy of patient management and treatment initiation. However, the causes and the mechanisms of disease progression that result in fibrosis and insufficiency of the affected organ remain unclear. This narrative review aims to analyse the mechanisms and biomarkers of sarcoidosis progression, as well as the pathogenetic basis of sarcoidosis therapy. The following characteristics of progressive chronic sarcoidosis were revealed: the disease develops in patients with a genetic predisposition (SNP in genes GREM1, CARD15, TGF-β3, HLA-DQB1*06:02, HLA-DRB1*07/14/15), which contributes either the decreased ability of antigen elimination or autoimmune inflammation. Various prognostic biomarkers of disease progression (decreased levels of neopterin, elastase, sIL-2R, chitotriosidase, glycoprotein Krebs von den Lungen, Th17 cell count, reduced quantity of TNF-α in peripheral blood or bronchoalveolar lavage fluid) have been described and can potentially be used to determine the group of patients who will benefit from the use of corticosteroids/cytostatic drugs/biologics.

Sarcoidosis. Disease progression based on radiological and functional course: Predictive factors

BackgroundSarcoidosis is a multiorgan granulomatous disease with a variable course. OobjectivesThe purpose of this study is to identify the patients that are more likely to experience disease progression. MethodsA retrospective study in patients ≥18 years. Pulmonary function and radiological stage (Scadding criteria) were assessed at diagnosis, and at 1, 3 and 5 years. Sarcoidosis progression was established based on deterioration of radiological or pulmonary function (decrease ≥10% of FVC and/or ≥15% of diffusing capacity of the lung (DLCO). ResultsThe sample included 277 caucasian patients [mean age, 50±13.6; 69.7% between 31-60 years; 56.3% men]. In total, 65% had stage II sarcoidosis, whereas only 8.3% had stage III/IV disease. Mean pulmonary function (FVC, FEV1, FEV1/FVC and DLCO) at diagnosis was 103±21.8, 96±22.2, 76.2±8 and 81.7±21.7, respectively. The percentage of patients with normal FVC and DLCO was 72.2% and 51.8%, respectively. Radiological stage did not change significantly during follow-up (5 years; p=0.080) and only progressed in 13 patients (5.7%). At 3 years, FVC improved, whereas DLCO exacerbated significantly (p<0.001 for the two). Disease progressed in 34.5% of the patients (57/165) whose pulmonary function and radiological stage were available (both baseline and at 3 years). Age was associated with disease progression [OR=1.04 (95%CI=1.01, 1.06)]. Risk increased by 4% for each year older a patient was at diagnosis. ConclusionsAt 3 years, a third of patients experienced sarcoidosis progression. Age was the only factor associated with disease prognosis.

Expression of S100A9 and KL-6 in common interstitial lung diseases.

By evaluating S100 calcium binding protein A9 (S100A9) and Klebs von den Lungen-6 (KL-6) expression in patients with 4 common interstitial lung diseases (ILDs), we aimed to investigate whether S100A9 or KL-6 can be of any value in the differential diagnosis of these ILDs and simultaneously signal the disease progression.We collected the data of patients diagnosed with the 4 ILDs and underwent fiber-optic bronchoscopy and BAL in the First Affiliated Hospital, China Medical University from January 2012 to December 2020. The data related to BGA, C-reactive protein, pulmonary function test, total number and fraction of cells, T lymphocyte subsets in bronchoalveolar lavage fluid (BALF), and the expression of S100A9 and KL-6 in BALF and serum were collected. We analyzed, whether S100A9 or KL-6 could serve as a biomarker for differential diagnosis between the 4 common ILDs; whether the levels of S100A9 and KL-6 correlated with each other; whether they were correlated with other clinical parameters and disease severity.This study included 98 patients, 37 patients with idiopathic pulmonary fibrosis (IPF), 12 with hypersensitivity pneumonitis, 13 with connective tissue disease-associated ILD, and 36 with sarcoidosis (SAR): stage I (18), stage II (9), stage III (5), and stage IV (4). The expression of KL-6 in BALF was significantly higher in IPF patients than other 3 groups (all P-value < .05). However, there was no significant difference in the levels of S100A9 in BALF and serum between the 4 groups (P-value > .05). The levels of S100A9 in BALF of IPF patients was positively and significantly correlated with KL-6 expression and the percentage of neutrophils in BALF (P-value < .05). Along with the stage increase of SAR patients, the level of S100A9 in BALF gradually increased, which was negatively and significantly correlated with the forced vital capacity/predicted, carbon monoxide diffusing capacity/predicted%, and PaO2 (all P-value < .05).The expression of KL-6 in BALF can be used as a biomarker to differentiate IPF from the other 3 common ILDs. While, this was not the case with expression of S100A9 in BALF and serum. However, the expression S100A9 in BALF is useful to indicate the progression of SAR. Thus, simultaneous measurement of KL-6 and S100A9 levels in BALF makes more sense in differential diagnosing of the 4 common ILDS.

Клинические фенотипы больных саркоидозом в реальной клинической практике

The aim of the research. To identify clinical phenotypes of sarcoidosis using cluster analysis based on clinical and demographic characteristics and the results of laboratory and instrumental analysis of patients in real clinical practice. Material and methods. We retrospectively studied the data of outpatient records of 276 sarcoidosis patients (107 males, 169 females) aged 20-68 years (41 (30; 55) years), who had been observed for more than 2 years. We analysed the gender characteristics of the patients, the forms of sarcoidosis, clinical symptoms, laboratory and functional parameters, X-ray stages, extrapulmonary lesions, and comorbid conditions. Results. A total of 5 clusters were identified using two-step cluster analysis. Cluster 1: female and male patients with acute or chronic form of pulmonary sarcoidosis (PS) and extrapulmonary manifestations; cluster 2: women with chronic asymptomatic PS; cluster 3: females with the chronic form of clinically relevant PS; cluster 4: male patients with the chronic form of asymptomatic PS; cluster 5: men with the chronic form of clinically associated PS. In contrast to cluster 4 patients with the criteria of favorable PS course, the risk of sarcoidosis progression was 7 times higher for cluster 1 patients (OR=7.01; 95% CI 2.53- 22.95; p&lt;0.001), and 5.7-fold higher for cluster 3 patients (OR=5.73; 95% CI 2.25–17.73; p&lt;0.001). Patients of clusters 2 and 5 had no significant differences in laboratory and instrumental parameters compared to cluster 4 patients (p&gt;0.05). Conclusion. Identification of clinical phenotypes of sarcoidosis in patients in clinical practice based on clinical, demographic, laboratory, functional and radiological characteristics, makes it possible to optimise the therapy choice and predict the course of the disease

Development of pulmonary sarcoidosis in Crohn\u2019s disease patient under infliximab biosimilar treatment after long-term original infliximab treatment: a case report and literature review

BackgroundInflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor inhibitors (TNF-I) are effective for the treatment. Recently, biosimilars of TNF-I, such as CT-P13, have been developed and are thought to possess equal efficacy and safety to the original TNF-I. Sarcoidosis is also a systemic granulomatous disease of unknown etiology. In steroid-resistant cases of sarcoidosis, TNF-I have been reported effective for achieving resolution. However, the progression of sarcoidosis due to the TNF-I also has been reported. We herein report a case of pulmonary sarcoidosis with a Crohn’s disease (CD) patient developed after a long period administration (15 years) of TNF-I.Case presentationsA 37-year-old woman with CD who had been diagnosed at 22 years old had been treated with the TNF-I (original infliximab; O-IFX and infliximab biosimilar; IFX-BS). Fifteen years after starting the TNF-I, she developed a fever and right chest pain. Chest computed tomography (CT) revealed clustered small nodules in both lungs and multiple enlarged hilar lymph nodes. Infectious diseases including tuberculosis were negative. Bronchoscopic examination was performed and the biopsy specimens were obtained. A pathological examination demonstrated noncaseating granulomatous lesions and no malignant findings. TNF-I were discontinued because of the possibility of TNF-I-related sarcoidosis. After having discontinued for four months, her symptoms and the lesions had disappeared completely. Fortunately, despite the discontinuation of TNF-I, she has maintained remission.ConclusionsTo our knowledge, this is the first case in which sarcoidosis developed after switching from O-IFX to IFX-BS. To clarify the characteristics of the cases with development of sarcoidosis during administration of TNF-I, we searched PubMed and identified 106 cases. When developing an unexplained fever, asthenia, uveitis and skin lesions in patients with TNF-I treatment, sarcoidosis should be suspected. Once the diagnosis of sarcoidosis due to TNF-I was made, the discontinuation of TNF-I and administration of steroid therapy should be executed promptly. When re-starting TNF-I, another TNF-I should be used for disease control. Clinicians should be aware of the possibility of sarcoidosis in patients under anti-TNF therapy.

SARS-COV-2 PNEUMONIA LEADING TO PROGRESSION OF PULMONARY SARCOIDOSIS

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: The implication of COVID 19 pneumonia on chronic inflammatory disorders is not clearly known. Due to a lack of data, it is difficult to predict the disease course post-COVID 19 pneumonia. Here, we present a case of stable sarcoidosis that progressed rapidly after COVID 19 pneumonia. CASE PRESENTATION: A 43-year-old male, with a history of sarcoidosis, briefly treated with steroids at initial diagnosis and in remission for the last six years, was admitted for dyspnea and hypoxia (room air oxygen saturation 83%) secondary to COVID 19 pneumonia diagnosed a week prior to admission. Chest X-ray on admission showed diffuse bilateral interstitial and airspace opacities. He was treated with dexamethasone and remdesevir. The clinical status of the patient improved after a week, and he was discharged on prednisone taper (10 mg for 5 days). Four weeks later, the patient had a recurrence of dyspnea on exertion with occasional hemoptysis. Computed Tomography (CT) scan of the chest showed honeycombing and reticulations in bilateral upper lobes, interstitial thickening, and worsening hilar and mediastinal lymphadenopathy (sarcoidosis Scadding stage IV). Labs were significant for elevated serum soluble interleukin-2 (IL-2) receptor and calcitriol levels. Pulmonary function test showed a restrictive defect with reduced diffusion capacity. The patient was started on prednisone. Repeat CT scan after three months showed improvement in ground-glass opacities and stable scarring. Fine needle aspiration biopsy of subcarinal lymph node confirmed non-caseating granulomatous inflammation. The patient was started on mycophenolate mofetil, tapered off prednisone, and is being evaluated for a lung transplant. DISCUSSION: The main pathogenesis related to sarcoidosis is the formation of granulomas due to sustained host immune system stimulation from various known and unknown antigens. Activation of the immune system as evidenced by elevated inflammatory makers in viral infections may in turn precipitate the relapse and progression of inflammatory disorders such as sarcoidosis. It is difficult to distinguish between the sequela of COVID 19 pneumonia and sarcoidosis progression. CT scan findings in fibrotic sarcoidosis have upper lobe predilection. However, the distribution of ground-glass opacities and fibrosis in COVID 19 pneumonia is usually peripheral and may have lower lobe predilection. Close monitoring is important to look for activation of sarcoidosis post COVID 19 pneumonia. CONCLUSIONS: Implications of COVID 19 infection on pathogenesis and progression of sarcoid are important to understand, and more research is required so that clinicians can be vigilant about worsening pulmonary function and intervene in a timely manner. REFERENCE #1: Ramdani H, Benelhosni K, Moatassim Billah N, Nassar I. COVID-19 pneumonia in a patient with sarcoidosis: A case report. Clin Case Rep. 2020 Dec 23;9(2):910-913. REFERENCE #2: Tana C, Mantini C, Cipollone F, Giamberardino MA. Chest Imaging of Patients with Sarcoidosis and SARS-CoV-2 Infection. Current Evidence and Clinical Perspectives. Diagnostics (Basel). 2021 Jan 27;11(2):183. DISCLOSURES: No relevant relationships by Salim Daouk, source=Web Response No relevant relationships by Samiksha Gupta, source=Web Response No relevant relationships by Ahmad Hassan, source=Web Response No relevant relationships by SYED HUSSAIN, source=Web Response No relevant relationships by Miloni Parmar, source=Web Response

Elevated IL-15 concentrations in the sarcoidosis lung are independent of granuloma burden and disease phenotypes.

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,6'-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis.

The Role of Multimodality Imaging in Cardiac Sarcoidosis.

The etiology and the progression of sarcoidosis remain unknown. However, cardiac sarcoidosis (CS) is significantly associated with a poor prognosis due to the associated congestive heart failure, arrhythmias (such as an advanced atrioventricular block), and ventricular tachyarrhythmia. Novel imaging modalities are now available to detect CS lesions secondary to active inflammation, granuloma formation, and fibrotic changes. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and cardiac magnetic resonance imaging (CMR) play essential roles in diagnosing and monitoring patients with confirmed or suspected CS. The following focused review will highlight the emerging role of non-invasive cardiac imaging techniques, including FDG PET/CT and CMR.

Serum IL-35 Levels Are Associated With Activity and Progression of Sarcoidosis.

Objective: To investigate the relationship of interleukin (IL)-35 with sarcoidosis.Methods: We enrolled 114 inpatients and outpatients with sarcoidosis at the Shanghai Pulmonary Hospital, and 24 healthy controls between March 2015 and December 2017. Serum and whole blood were collected during the follow-up period. Serum IL-35 levels were detected by ELISA. Proportions of Breg, Tfh, and Treg cells in the peripheral blood were detected using flow cytometry (FCM). The mRNA levels of p35, EBI3, and GAPDH in CD19+ cells and CD4+ cells were detected by real-time PCR. Sarcoidosis granuloma mice models were established with Propionibacterium acnes (PA) and one group was treated with IL-35 antibodies. Proportions of Breg, Tfh, and Treg cells in the peripheral blood and bronchoalveolar lavage fluid (BALF) were detected by FCM.Results: The IL-35 levels and the proportions of Breg and Tfh cells in the peripheral blood of patients with active sarcoidosis were significantly higher compared to patients with stable sarcoidosis and healthy controls. Moreover, the IL-35 level in patients with progressive disease was lower than that found at the initial visit. EBI3 and p35 mRNA levels in CD19+ cells for patients with active sarcoidosis were significantly higher as compared to patients with stable sarcoidosis and healthy controls, while there were no significant differences in p35 and EBI3 mRNA levels in CD4+ cells between the three groups. In the mouse model of sarcoidosis, there were loose granulomata (macrophage accumulation in the bronchial areas and immature granuloma) after intervention with IL-35 antibodies. Meanwhile, the proportions of Breg cells in the peripheral blood and BALF of the model were significantly increased, while the proportion of Treg cells declined significantly. After intervention with IL-35 antibodies, the proportion of Breg cells in the peripheral blood of mice decreased significantly as compared to the mice not exposed to anti-IL-35 antibodies.Conclusion: IL-35 levels increased significantly in the serum of patients with active sarcoidosis, and lower IL-35 levels were correlated with persistent disease. Serum IL-35 levels might be better correlated with Breg cell functions.

Sarcoidosis-related Uveitis: Clinical Presentation, Disease Course, and Rates of Systemic Disease Progression After Uveitis Diagnosis

To document the clinical presentation, treatment, and visual outcome of sarcoid uveitis and to determine the timing and potential risk factors of sarcoidosis progression to symptomatic systemic disease from the time of sarcoid uveitis diagnosis. Retrospective, interventional case series. Subjects: Patients with dual diagnoses of uveitis and presumed/biopsy-proven sarcoidosis. Retrospective review of 143 patient records from the Royal Victorian Eye and Ear Hospital and Eye Surgery Associates in Melbourne, Australia, between October 1990 and April 2014 coded with the dual diagnoses of uveitis and sarcoidosis. Only patients with uveitis and presumed or biopsy-proven sarcoidosis (N= 113) were included. Ascertainment of rate and time (months) to the development of symptomatic systemic sarcoidosis from uveitis onset; comparison of the patient demographics, characteristics of uveitis, treatment, and visual outcome between those who developed systemic sarcoidosis and those who remained systemically asymptomatic. Uveitis was the initial presenting complaint of sarcoidosis in 78.8% (n= 89). Twenty-three patients had concurrent undiagnosed systemic disease at presentation and 29 subsequently developed symptomatic sarcoidosis in an organ uninvolved at uveitis onset. The median time to the development of symptomatic systemic sarcoidosis was 12months. No statistically significant association was ascertained between any particular uveitis characteristic and extraocular sarcoidosis progression. Uveitis was the initial presentation of sarcoidosis in the vast majority of our subjects. Concurrent undiagnosed systemic sarcoidosis was common at the time of uveitis onset. A high index of suspicion for subsequent systemic progression should also be maintained, especially within the first 5 years of the uveitis diagnosis.

DEVELOPMENT OF CHRONIC KIDNEY DISEASE IN WOMEN WITH CHRONIC SARCOIDOSIS

THE AIM: to study the frequency of CKD in women suffering from chronic sarcoidosis. PATIENTS AND METHODS : 160 female patients with sarcoidosis without signs of primary renal pathology and severe cardiovascular pathology were divided into 3 groups depending on the activity of the disease: 1 – chronic progressive sarcoidosis, 2 – chronic sarcoidosis in remission 6-12 months, 3 – chronic sarcoidosis in remission more than 14 months. RESULTS: The negative effect of the progression of sarcoidosis on GFR was revealed. The lowest rGFR and the highest albuminuria were observed in the group of patients with progressive sarcoidosis, a reliable correlation was obtained between the progression of pulmonary fibrosis and renal markers of CKD. CONCLUSION: Progression of chronic sarcoidosis leads to a decrease in kidney function and the formation of chronic kidney disease.

TORmented macrophages spontaneously form granulomas.

Elevated signaling via the metabolic checkpoint kinase mTORC1 in macrophages stimulates spontaneous granuloma formation in mice and is associated with the progression of sarcoidosis in humans.

Annexins family: insights into their functions and potential role in pathogenesis of sarcoidosis.

Annexins are Ca2+-regulated phospholipid-binding proteins that play an important role in the cell life cycle, exocytosis, and apoptosis. Annexin A11 is one of the oldest vertebrate annexins that has a crucial role in sarcoidosis pathogenesis. The mechanism of effect in sarcoidosis granuloma cells may be due to alterations in apoptosis. Immune cells with a specific mutation at protein location 230 are resistant to apoptosis and consequently have continued effects on inflammation and progression of sarcoidosis. The mechanism of action of annexin A11 may be based upon alterations in delivering calcium to two different apoptosis pathways (caspase and P53).