Active Sarcoidosis Research Articles

ACE and chitotriosidase as possible predictive biomarkers for activity of sarcoidosis in correlation with PET/CT findings

Sarcoidosis is a granulomatous disease which can afflict virtually any tissue in human body, most commonly the mediastinal lymph nodes and lungs. Pathohistological confirmation is the gold standard in establishing a diagnosis; however, determining the activity of the disease requires multiple clinical, radiographic and laboratory procedures. PET/CT scan is considered the gold standard for determining the presence of active granuloma, but has several significant limitations (radioactive material, cost, overall access to device). ACE and chitotriosidase are biomarkers used for diagnosis of sarcoidosis, and could have a place in determining the activity of the disease, when compared with the results of PET/CT scan. We have compared the levels of ACE and chitotriosidase with the levels of SUVmax values in patients with sarcoidosis. SUVmax and chitotriosidase level were significantly correlated both at the baseline and after the follow-up period, regardless of gender, age, duration of disease and radiography stage, while SUVmax and ACE level were not. Chitotriosidase had also shown a significant predictive ability of the decrease of the activity of sarcoidosis represented as the decrease of SUVmax as the effect of therapy in comparison with ACE. In the absence of ideal biomarker for sarcoidosis (high sensitivity, specificity and stability), chitotriosidase can be used in determining the activity of disease, as it had shown a significant correlation to the gold standard- PET/CT scan.

The abundance of regulatory T cell subsets is associated with the clinical outcomes of sarcoidosis.

Some patients with sarcoidosis achieve spontaneous remission, whereas others repeatedly experience relapse. We examined differences in the clinical course of active sarcoidosis according to peripheral blood immunophenotypes before treatment. This retrospective study compared peripheral blood immunophenotypes between patients with active sarcoidosis (n=28) and healthy control subjects (n=10). Patients with sarcoidosis were divided into the spontaneous remission group without treatment (n=9), the non-relapsed group after treatment (n=13), and the relapsed group after treatment (n=6) and were compared for peripheral blood immunophenotypes and background characteristics at baseline. Patients with sarcoidosis showed increases in activated T helper (Th) 1 cells, activated Th17 cells, and regulatory T (Treg) cell subsets. The proportion of effector Treg cells was highest in the spontaneous remission group, and the proportion of non-suppressive Treg cells was highest in the relapsed group. No differences were observed in the proportions of other CD4+ T cell subsets. The cut-off values for predicting spontaneous remission and relapse were calculated for the effector Treg/non-suppressive Treg ratio. As a result, A ratio ≥1.469 predicted spontaneous remission (75%), while ≤0.722 predicted relapse (66.7%). Effector and non-suppressive Treg cell proportions before treatment may predict spontaneous remission and relapse in active sarcoidosis.

Ventricular parasystole as a new indicator suggesting ventricular arrhythmias in cardiac sarcoidosis

Abstract Background In cardiac sarcoidosis (CS), it is considered that inflammation occurs in localized areas such as the basal septum. Inflammation has been suggested to be associated with ventricular fibrillation (VF). Meanwhile, ventricular parasystole is strongly associated with VF in non-ischemic cardiomyopathy. However, the relationship between CS and ventricular parasystole remains unclear. Purpose The purpose is to examine the frequency of parasystole in cases of VF and ventricular tachycardia (VT) in CS, and whether there is a correlation between the inflammatory activity of sarcoidosis and the origin of ventricular parasystole. Methods We evaluated ventricular arrhythmias (VA) in a cohort of 213 consecutive cases diagnosed with CS from 1989 to 2021 (median age 69 years, 104 males, median LVEF 36%) in our center. We investigated parasystole in cases that developed VA, using 5,313 electrocardiograms, 94 Holter electrocardiograms, and 3,174 ICD interrogation records. Classic parasystole is defined as three ventricular ectopic beats with the same morphology at a fixed interval but different coupling intervals (CI) in a 10-second continuous ECG. A new definition of parasystole requires two ventricular ectopic beats with a CI difference of more than 120ms. We also investigated the correlation of the inflammation site with ECG morphology. Results VAs were observed in 95 individuals (33.7%), and 22 developed VF (23.2%). In the VF group, parasystole was observed in 12 of 22 individuals (classic: 5, new: 7), and in the VT group observed in 20 of 73 individuals (classic: 5, new: 15), with parasystole being significantly more frequent in the VF group (P=0.018) and classic parasystole (P=0.033). In VF patients with recorded 12-lead ECGs of parasystole, the inflammation site on PET within 3 months of the VA and PVC origin matched in all 4 out of 4 cases, but no VF starting from ventricular parasystole ectopic beats was recorded. Conclusion Ventricular parasystole was detected in 54.5% of CS patients with VF. There is a possibility that the presence of parasystole and the inflammatory activity in the CS can predict the occurrence of VF.

Cardiac Neuroendocrine Tumor Metastases on 68Ga-DOTATATE PET/CT: Identification and Prognostic Significance.

Neuroendocrine tumor (NET) metastases to the heart are found in 1%-4% of NET patients and have been reported primarily in the form of individual cases. We investigated the prevalence, clinical characteristics, imaging features, and outcomes of NET patients with cardiac metastases on 68Ga-DOTATATE PET/CT. Methods: 68Ga-DOTATATE PET/CT of 490 consecutive patients from a single institution were retrospectively reviewed for sites of metastases. The cumulative cardiovascular event rate and overall survival of patients with cardiac NET metastases (CNMs) were compared with those of a control group of metastatic NET patients without cardiac metastases. In patients with CNMs, the cardiac SUVmax with and without normalization to the myocardial background uptake was compared with a separate cohort of 11 patients with active cardiac sarcoidosis who underwent 68Ga-DOTATATE PET/CT for research purposes. Results: In total, 270 patients with metastatic NETs were identified, 9 (3.3%) of whom had CNMs. All 9 patients had grade 1-2 gastroenteropancreatic NETs, most commonly from the small intestine (7 patients). The control group consisted of 140 patients with metastatic grade 1-2 gastroenteropancreatic NETs. On Kaplan-Meier analysis, there was no significant difference in the risk of cardiovascular adverse events (P = 0.91 on log-rank test) or mortality (P = 0.83) between the metastatic NET patients with and without cardiac metastases. The degree of cardiac DOTATATE uptake was significantly higher in CNMs than in patients with cardiac sarcoidosis without overlap, in terms of both cardiac SUVmax (P = 0.027) and SUVmax-to-myocardial background ratio (P = 0.021). Conclusion: Routine 68Ga-DOTATATE PET/CT can be used to identify CNMs in 3% of patients with metastatic NETs. CNMs do not confer added cardiovascular or mortality risk. A distinguishing feature of CNMs is their high degree of DOTATATE uptake compared with focal myocardial inflammation.

A-083 Performance evaluation of Sentinel Diagnostics’ ACE assay on the Abbott Alinity c system and ARCHITECT c16000 System

Abstract Background The analytical performances of the Angiotensin Converting Enzyme (ACE) assay for quantitative determination of ACE activity in human serum and plasma have been evaluated on the Abbott Alinity c system and ARCHITECT c16000 System. ACE (dipeptidyl carboxypeptidase) is a glycoprotein peptidyldipeptide hydrolase that cleaves histidylleucine dipeptide from angiotensin I, a relatively inactive decapeptide. The latter is converted to the potent vasoconstrictor, angiotensin II. ACE also inactivates bradykinin. Elevated levels of ACE activity occur in serum of patients with active sarcoidosis, and occasionally in premature infants with respiratory distress syndrome, in adults with tuberculosis, Gaucher’s disease, leprosy, and in many other pathologic conditions involving lung and liver diseases. Methods ACE hydrolyses urylacryloylphenylalanine-glycylglycine (FAPGG) to furylacryloylphenylalanine (FAP) and glycylglycine. Hydrolysis of FAPGG results in a decrease in absorbance at 340 nm. The ACE activity in the sample is determined by comparing the sample reaction rate to that obtained with the Sentinel ACE calibrator. Performances evaluation have been done following the latest CLSI guidelines protocols available. Results Summary of the analytical performances for the tested assay is reported in table below. Conclusions Analytical performances of Sentinel Diagnostics’ ACE assay demonstrate that quantitative determination of ACE activity in human serum and plasma are suitable for the routine measurement of the analyte on Abbott Alinity c system and ARCHITECT c16000 System.

Scar sarcoidosis: Clinical features and prognostic significance.

Only a few series of patients with scar sarcoidosis (SS) have been reported. Our aim was to analyse the clinical features of SS patients and their relationship to the prognosis of sarcoidosis. Patients with systemic sarcoidosis with SS diagnosed between 1980-2017 at Bellvitge University Hospital, were enrolled. Their clinical charts were reviewed to collect the following data: age, sex, ethnicity, number of lesions, location of SS, origin of the scar, association with erythema nodosum or other specific cutaneous lesions, radiological stage at diagnosis, chronic systemic sarcoidosis activity. Forty two of 728 patients with systemic sarcoidosis presented SS (31 females and 11 males, mean age 47.71±13.747 years). SS was present at the onset of systemic sarcoidosis in 35/42 cases (83.33%). Twelve patients had simultaneously erythema nodosum. In 14 patients SS was the only specific cutaneous lesion of sarcoidosis. Foreign bodies were observed in 16 of 26 biopsied SS lesions (61.54%). Radiological stage at diagnosis was 0 for 2 patients, I for 22, II for 13, III for 4, and IV for 1. The activity of systemic sarcoidosis persisted for more than 5 years in 16/42 patients with SS (38.1%) vs. 186/686 patients with systemic sarcoidosis (27.11%), However the differences were not significant (p=0.154). SS was observed in 5.77% of our patients with systemic sarcoidosis. It is usually present at the onset of the disease and is an useful sign for suspicion of a diagnosis of sarcoidosis, but it carries no prognostic significance.

Increased serum interferon activity in sarcoidosis compared to that in tuberculosis: Implication for diagnosis?

ObjectivesIn this study, we measured serum interferon (IFN) levels and activity in patients with sarcoidosis and tuberculosis (TB) with and without uveitis. We aimed to understand the role of IFN in the pathophysiology of both conditions and explore its potential as a discriminating marker for these clinically similar diseases. MethodsSera from an Indonesian TB and a Dutch sarcoidosis cohort were used in the analysis. IFNα2 and IFNγ concentrations were measured using Simoa® and Luminex assays, respectively. Serum IFN activity was assessed by incubating THP-1 cells with patient serum and measuring IFN-stimulated gene transcription using qPCR. Anti-IFNα2 and IFNγ autoantibodies were detected via Luminex assay and tested for neutralizing capacity using a flow cytometry-based signal transducer and activator of transcription (STAT) 1 phosphorylation inhibition assay. ResultsIFNα2 was detected in 74 % and 64 % of patients with sarcoidosis and pulmonary TB, respectively, while IFNγ was found in 78 % and 23 % of patients with sarcoidosis and TB, respectively. For uveitis cases specifically, IFNα2 was detected in 85 % of sarcoid uveitis (SU) and 33 % of tubercular uveitis (TBU) cases. Similarly, IFNγ was detected in 69 % of SU and 17 % of TBU cases. IFNγ serum concentrations were higher in sarcoidosis than that in TB patients (p < 0.0001). Focusing on patients with uveitis, SU showed increased IFNα2 (p = 0.004) and IFNγ (p < 0.002) serum concentrations compared to that in TBU. Notably, TBU displayed significantly reduced IFNα2 concentrations compared to that in healthy controls (p = 0.006). These results align with the increased interferon stimulated gene (ISG) transcriptional upregulation observed in THP-1 cells stimulated with serum from patients with sarcoidosis. Elevated levels of non-neutralizing anti-IFN autoantibodies were observed in patients with TB; however, these levels were similar to those observed in geographically matched healthy Indonesian controls. ConclusionOur results suggest decreased serum levels and activity of type I and II IFN in TB compared to those in sarcoidosis. This is indicative of distinct pathophysiological processes in these highly clinically similar diseases. We propose that the assessment of serum IFN levels and IFN activity has the potential to distinguish between sarcoidosis/SU and TB/TBU.

Positron emission tomography/computed tomography (PET/CT) as predictor of sarcoidosis activity: A case series

Positron emission tomography/computed tomography (PET/CT) as predictor of sarcoidosis activity: A case series

The active papillary muscle sign in 18F-FDG PET/CT cardiac sarcoidosis exams and its relationship with myocardial suppression.

Papillary muscle (PM) activity may demonstrate true active cardiac sarcoidosis (CS) or mimic CS in 18FDG-PET/CT if adequate myocardial suppression (MS) is not achieved. We aim to examine whether PM uptake can be used as a marker of failed MS and measure the rate of PM activity presence in active CS with different dietary preparations. We retrospectively reviewed PET/CTs obtained with three different dietary preparations. Diet-A: 24-h ketogenic diet with overnight fasting (n = 94); Diet-B: 18-h fasting (n = 44); and Diet-C: 72-h daytime ketogenic diet with 3-day overnight fasting (n = 98). Each case was evaluated regarding CS diagnosis (negative, positive, and indeterminant) and presence of PM activity. MaxSUV was measured from bloodpool, liver, and the most suppressed normal myocardium. Linear mixed-effects models were used to compare these factors between those with PM activity and those without. PM activity was markedly lower in the Diet-C group compared with others: Diet-C: 6 (6.1%), Diet-A: 36 (38.3%), and Diet-B: 26 (59.1%) (p < 0.001). MyocardiumMaxSUV was higher, and MyocardiummaxSUV/BloodpoolmaxSUV, MyocardiummaxSUV/LivermaxSUV ratios were significantly higher in the cases with PM activity (p < 0.001). Among cases that used Diet-C and had PM activity, 66.7% were positive and 16.7% were indeterminate. If Diet-A or Diet-B was used, those with PM activity had a higher proportion of indeterminate cases (Diet-A: 61.1%, Diet-B: 61.5%) than positive cases (Diet-A: 36.1%, Diet-B: 38.5%). Lack of PM activity can be a sign of appropriate MS. PM activity is less common with a specific dietary preparation (72-h daytime ketogenic diet with 3-day overnight fasting), and if it is present with this particular preparation, the likelihood that the case being true active CS might be higher than the other traditional dietary preparations.

Characterisation and management of expected and unexpected urgent findings from positron emission tomography with 18F-fluorodeoxyglucose integrated with computed tomography in cardiovascular disease

BackgroundCardiac 18F-fluorodeoxyglucose (FDG)-PET-CT plays an important role in the assessment of cardiovascular diseases. Effective management of urgent scan findings facilitates optimal patient care. MethodsWe characterised the management of urgent, expected and unexpected findings in patients referred for cardiac [18F]fluorodeoxyglucose integrated with computed tomography (FDG-PET-CT) at the Royal Brompton Hospital (United Kingdom). Urgent findings are escalated by the reporting physicians/radiologists raising RadAlert notifications to the referring clinician. We characterised the indications and time to management (TTM) between the RadAlert and the resulting management. As controls, we characterised the TTM of 33 urgent findings identified before the RadAlert system was implemented. ResultsOf the 1497 consecutive FDG-PET-CT scans screened (April 2021 to February 2023), 93 RadAlerts were suitable for analysis (TTM 7 days [interquartile range: 2–14]). Expected urgent findings included active cardiac sarcoidosis (56%; TTM 8 days [5–18]), heart transplant rejection (12%; 6 ± 4 days), infective endocarditis (9%; 2 days [1–12]), cardiac device infections (5%; 1 day [0–2]), acute myocarditis (2%; 5 and 14 days) and epicardial mass (1%; 1 day). TTM did not differ significantly between indications (P = 0.06). RadAlert cases had significantly shorter TTM than controls without RadAlert, P = 0.001. After the RadAlerts, 81% of patients had clinical reviews, and 55% had escalation of medical/surgical therapies. Unexpected findings (total N = 45; median TTM 6 days [1–10]) included malignancies (N = 3), infections (N = 2), pneumothorax (N = 1), benign diagnosis (N = 30), unclear diagnosis (N = 5) and 4 findings disappeared on repeat imaging. ConclusionsCardiac FDG-PET-CT identifies expected and unexpected findings in a range of cardiovascular diseases. Serious, unexpected findings are rare and can be effectively escalated by the RadAlert system.

Hybrid Magnetic Resonance Positron Emission Tomography Is Associated With Cardiac-Related Outcomes in Cardiac Sarcoidosis

BackgroundImaging with late gadolinium enhancement (LGE) magnetic resonance (MR) and 18F-fluorodeoxyglucose (18F-FDG) PET allows complementary assessment of myocardial injury and disease activity and has shown promise for improved characterization of active cardiac sarcoidosis (CS) based on the combined positive imaging outcome, MR(+)PET(+). ObjectivesThis study aims to evaluate qualitative and quantitative assessments of hybrid MR/PET imaging in CS and to evaluate its association with cardiac-related outcomes. MethodsA total of 148 patients with suspected CS underwent hybrid MR/PET imaging. Patients were classified based on the presence/absence of LGE (MR+/MR−), presence/absence of 18F-FDG (PET+/PET−), and pattern of 18F-FDG uptake (focal/diffuse) into the following categories: MR(+)PET(+)FOCAL, MR(+)PET(+)DIFFUSE, MR(+)PET(−), MR(−)PET(+)FOCAL, MR(−)PET(+)DIFFUSE, MR(−)PET(−). Further analysis classified MR positivity based on %LGE exceeding 5.7% as MR(+/−)5.7%. Quantitative values of standard uptake value, target-to-background ratio, target-to-normal-myocardium ratio (TNMRmax), and T2 were measured. The primary clinical endpoint was met by the occurrence of cardiac arrest, ventricular tachycardia, or secondary prevention implantable cardioverter-defibrillator (ICD) before the end of the study. The secondary endpoint was met by any of the primary endpoint criteria plus heart failure or heart block. MR/PET imaging results were compared between those meeting or not meeting the clinical endpoints. ResultsPatients designated MR(+)5.7%PET(+)FOCAL had increased odds of meeting the primary clinical endpoint compared to those with all other imaging classifications (unadjusted OR: 9.2 [95% CI: 3.0-28.7]; P = 0.0001), which was higher than the odds based on MR or PET alone. TNMRmax achieved an area under the receiver-operating characteristic curve of 0.90 for separating MR(+)PET(+)FOCAL from non-MR(+)PET(+)FOCAL, and 0.77 for separating those reaching the clinical endpoint from those not reaching the clinical endpoint. ConclusionsHybrid MR/PET image–based classification of CS was statistically associated with clinical outcomes in CS. TNMRmax had modest sensitivity and specificity for quantifying the imaging-based classification MR(+)PET(+)FOCAL and was associated with outcomes. Use of combined MR and PET image–based classification may have use in prognostication and treatment management in CS.

Клиническое значение определения sST2 в крови больных кардиосаркоидозом

The results of a pilot study of the serum marker of cardiac damage sST2 in patients with chronic generalized sarcoidosis are presented. Correlations between the activity of sarcoidosis, sST2 levels and the risk of developing heart failure have been demonstrated.

Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trial

Sarcoidosis is an inflammatory condition that can affect various organs and tissues, causing the formation of granulomas and subsequent functional impairment. The origin of sarcoidosis remains unknown and there are few treatment options. Mechanistic target of rapamycin (mTOR) activation is commonly seen in granulomas of patients across different tissues and has been shown to induce sarcoidosis-like granulomas in a mouse model. This study aimed to examine the efficacy and safety of the mTOR inhibitor sirolimus as a treatment for cutaneous sarcoidosis. We did a single-centre, randomised study treating patients with persistent and glucocorticoid-refractory cutaneous sarcoidosis with sirolimus at the Vienna General Hospital, Medical University of Vienna (Vienna, Austria). We recruited participants who had persistent, active, and histologically proven cutaneous sarcoidosis. We used an n-of-1 crossover design in a placebo-controlled, double-blind topical treatment period and a subsequent single-arm systemic treatment phase for 4 months in the same participants. Participants initially received either 0·1% topical sirolimus in Vaseline or placebo (Vaseline alone), twice daily. After a washout period, all participants were subsequently administered a 6 mg loading dose followed by 2 mg sirolimus solution orally once daily, aiming to achieve serum concentrations of 6 ng/mL. The primary endpoint was change in the Cutaneous Sarcoidosis Activity and Morphology Index (CSAMI) after topical or systemic treatment. All participants were included in the safety analyses, and patients having completed the respective treatment period (topical treatment or systemic treatment) were included in the primary analyses. Adverse events were assessed at each study visit by clinicians and were categorised according to their correlation with the study drug, severity, seriousness, and expectedness. This study is registered with EudraCT (2017-004930-27) and is now closed. 16 participants with persistent cutaneous sarcoidosis were enrolled in the study between Sept 3, 2019, and June 15, 2021. Six (37%) of 16 participants were men, ten (63%) were women, and 15 (94%) were White. The median age of participants was 54 years (IQR 48-58). 14 participants were randomly assigned in the topical phase and 2 entered the systemic treatment phase directly. Daily topical treatment did not improve cutaneous lesions (effect estimate -1·213 [95% CI -2·505 to 0·079], p=0·066). Systemic treatment targeting trough serum concentrations of 6 ng/mL resulted in clinical and histological improvement of skin lesions in seven (70%) of ten participants (median -7·0 [95% CI -16·5 to -3·0], p=0·018). Various morphologies of cutaneous sarcoidosis, including papular, nodular, plaque, scar, and tattoo-associated sarcoidosis, responded to systemic sirolimus therapy with a long-lasting effect for more than 1 year after treatment had been stopped. There were no serious adverse events and no deaths. Short-term treatment with systemic sirolimus might be an effective and safe treatment option for patients with persistent glucocorticoid-refractory sarcoidosis with a long-lasting disease-modulating effect. The effect of sirolimus in granulomatous inflammation should be investigated further in large, multi-centre, randomised clinical trials. Vienna Science and Technology Fund, Austrian Science Fund.

Get reliable laboratory findings- how to recognize the deceptive effects of angiotensin-converting enzyme inhibitor therapy in the laboratory diagnostics of sarcoidosis?

Serum angiotensin-converting enzyme (ACE) is the only biomarker routinely used in the laboratory diagnostics of sarcoidosis, and ACE inhibitor (ACEi) drugs are among the most prescribed drugs worldwide. Taking ACEi can mislead medical teams by lowering ACE activity, delaying diagnosis and giving a false impression of disease activity of sarcoidosis. We aimed to develop a simple method to detect the presence of ACEi drugs in samples, to investigate the ACEi medication-caused interference and consequences in a retrospective study. ACE activity and the level of ACE inhibition were determined for 1823 patients with suspected sarcoidosis. These values were compared with the therapeutic information at the first and follow-up visits. A total of 302 patients had biochemical evidence of an ACEi drug effect during diagnostic ACE activity testing. In their case, ACE activity was significantly lower (median(IQR): 4.41 U/L(2.93-6.72)) than in patients not taking ACEi (11.32 U/L(8.79-13.92), p<0.01). In 62 sarcoidosis patients, the ACEi reduced ACE activity to the reference range or below. Only in 40 % of the cases was the medication list recorded in the outpatient chart and only in 3 cases was low ACE activity associated with ACEi use. 67 % of the repeated ACE activity measurements were also performed during ACEi therapy. Our study revealed that the use of ACEi is common in patients with suspected sarcoidosis. The ACE activity lowering effect of ACEi drugs may escape the attention of medical teams which can lead to diagnostic errors and unnecessary tests. Nevertheless, these pitfalls can be avoided by using a method suggested by our team.

Role of serum markers in diagnosis of exacerbations of sarcoidosis

In order to improve the diagnosis of exacerbation and activity of sarcoidosis in patients receiving complex treatment, including corticosteroids, 303 patients with respiratory sarcoidosis were examined at the initial visit (before treatment) and every 2 months of treatment for 2 years. Group 1–193 patients without exacerbation of sarcoidosis; group 2–51 patients with exacerbation of sarcoidosis, who did not take corticosteroids (GCS); group 3–59 patients with exacerbation of sarcoidosis, long-term taking corticosteroids. In order to improve the diagnosis of exacerbation and activity of sarcoidosis in patients receiving complex treatment, including glucocorticosteroids, 303 patients with respiratory sarcoidosis were examined at the initial visit (before treatment) and every 2 months of treatment for 2 years. Group 1–193 patients without exacerbation; group 2–51 patients with exacerbation who did not take corticosteroids (GCS); group 3–59 patients with exacerbation, long-term taking corticosteroids. Conducted clinical and biochemical blood tests, computed tomography of the respiratory organs, spirography, echocardiography, electrocardiography at rest. Changes in the following serum markers were studied: free radicals (RwR), resistance to oxidative stress calculated by trolox equivalent (UcE), angiotensin-converting enzyme (ACE), adenosine deaminase (ADA), the correlation coefficient (CC) was calculated according to the developed formula (patent): CC = ACE/ADA in arbitrary units (KKnorm = 1.2–2.4), markers of lipid metabolism disorders were determined, to assess the activity of endogenous inflammation, the indicator of lipoidosis activity (PAL) was calculated according to the previously developed formula (patent): PAL = TC/LDLxc + TGL. Before treatment, 100 % of patients with sarcoidosis showed signs of moderate endogenous inflammation, an active granulomatous process, hypoxemia, and a decrease in the body’s antioxidant defense. The sensitivity of the serum adenosine deaminase (ADA) enzyme in exacerbations of sarcoidosis was 31 %, and the specificity was 48 %. The correlation coefficient (CC) had a sensitivity of 85.0 %; specificity 78.8 %; diagnostic efficiency of 80.0 % and higher clinical value than ACE, ADA, PAL, SVR, UKO. Thus, the serum enzyme adenosine deaminase (ADA) should be included in the mandatory minimum of laboratory methods in patients with sarcoidosis.

Abstract 17979: Cardiogenic Shock - The Index Presentation of Cardiac Sarcoidosis; Challenges in Diagnosis and Management

Cardiac sarcoidosis often presents with ventricular dysrhythmias but can manifest as cardiogenic shock. We discuss a patient who presented with the latter requiring escalating support serving multiple challenges including making a definitive diagnosis &amp; its management. 59 year-old male presented in cardiogenic shock requiring inotropic assisted diuresis. Due to continued clinical decline, he underwent Impella 5.5 placement for mechanical circulatory support (MCS). Echocardiogram showed ejection fraction of 25-30% with global hypokinesis. Reviewing his prior medical records, revealed a lymph node biopsy with non-caseating granulomas 5 years ago concerning for sarcoidosis. Due to his dependence on temporary MCS, we were unable to confirm with a cardiac MRI. Knowing that FDG-PET can only elucidate the site of active sarcoidosis, it was pursued as the only viable imaging modality. His FDG-PET scan was positive for involvement of the inferior wall &amp; right atrium. He was placed on immunosuppression with mycophenolate mofetil &amp; prednisone. During his hospitalization, serial FDG-PET scans were performed showing resolution of active inflammation which allowed for weaning of immunosuppressants. Despite treating his active disease, his course was complicated by worsening renal failure requiring hemodialysis, MCS-dependent heart failure, placement of a left ventricular assist device (LVAD) and fungemia. Following treatment, he was placed on lifelong suppression with fluconazole. Given his renal failure and infection, he was not a candidate for heart transplant. His infection also precluded our ability for long-term immunosuppression. There are no guidelines or detailed pathways on managing cardiogenic shock in patients with cardiac sarcoidosis. Our case highlights the challenges faced when shock is the index presentation as it increases the risk of end organ damage which therefore requires expedited work up for destination therapy. Though LVAD is a viable option for patients with cardiac sarcoidosis, duration of immunosuppression, long term follow up for scar, risk and treatment of infection in patients that are not transplant candidates is largely unexplored. More studies are needed to help guide management of shock in this patient population.

Outpatient management of sarcoidosis in the COVID-19 pandemic

Introduction. COVID-19 infection alters the body’s immune tolerance, which can affect the course of systemic diseases caused by alterations in immune function. Patients with sarcoidosis, just like patients with systemic diseases, have impaired immune system function. They receive immunosuppressive therapy, so they are at risk of infectious diseases, including the viral ones.Aim. To investigate the course of sarcoidosis in the period 2020-2022, the incidence of COVID-19 infection in patients treated by the pulmonologist of the sarcoidosis-polyclinic office of the Krasnoyarsk Regional Clinical Hospital and to evaluate the incidence of sarcoidosis after COVID-19.Materials and methods. 301 outpatient charts of patients diagnosed with sarcoidosis were analyzed. Anamnestic data, information on vaccination against COVID-19, results of physical examination, multispiral computed tomography of thoracic organs in dynamics, data and methods of morphological verification, the volume of the received therapy for sarcoidosis were assessed.Results. There was evidence that the combination of active sarcoidosis and COVID-19 did not contribute to a severe course of viral infection and progression in the course of granulomatosis. In patients with baseline moderate or severe pulmonary function impairment due to sarcoidosis and long-term use of systemic glucocorticosteroids, no increase in the incidence of adverse COVID-19 outcomes was noted. When analyzing fatal cases, it became known that in the first case, chronic recurrent sarcoidosis and prolonged use of systemic glucocorticosteroids were the factors determining the adverse prognosis in COVID- 19 In the second case, the combination of sarcoidosis with cardiovascular disease, diabetes mellitus, and obesity were adverse outcome factors. New cases of sarcoidosis after COVID-19 have been reported, this may be explained by the interaction between SARS-CoV-2 and human immune system, imbalance of proand anti-inflammatory cytokines, disruption of interferon production. However, this statement requires further research.

Abstract P3167: Identification Of Macrophage-specific Markers On Extracellular Vesicles In A Transgenic Mouse Model And Humans

Extracellular Vesicles (EVs) are key mediators of intercellular communication. Macrophages, a prominent type of immune cells, are known to release EVs with distinct contents and functions. The ExoMap mice model provides a platform to investigate tissue-specific EV subpopulations and the complexity of EV heterogeneity. CD169 and CD68 markers are specific to macrophages and have been associated with immune diseases, including Sarcoidosis. Double Transgenic vav-cre/ExoMap mice and appropriate controls were used to assay for immune cell derived EVs. Expression of cre in the vav-expressing cells, leads to expression of humanized CD81 (hsCD81) and mNeonGreen in the immune cells and in their EVs. Size Exclusion Column and immuno-pulldown (IP) with anti-hsCD81 or anti-CD169/CD68 antibodies were used to isolate macrophage-specific EVs. 3 miRNAs (mir223, mir374c, mir412) specific to macrophages were tested using Droplet Digital PCR (ddPCR). To design our human pilot study, we chose patients with active sarcoidosis (n=10), latent sarcoidosis (n=10), healthy controls (n=10) to compare the level of expression of specific immune markers in their blood. Bone marrow cells prepared from vav-cre/ExoMap mice were found to express mNeon Green and hsCD81. IP combined with vesicle flow cytometry defined the presence of hsCD81/mNeonGreen EVs in the plasma of double transgenic mice. Expression of CD68 and CD169 was robust on the EVs isolated using IP with hsCD81 antibodies from Double Transgenic mice. These results are consistent with the immune specificity of the vav-cre expression. Using human pooled plasma, we detected expression of CD68 on the EVs isolated using IP with CD169 antibody, suggesting the presence of both markers on macrophage specific EVs. Our findings support these markers as conserved between mouse and human samples, indicating their potential as universal markers of macrophage-derived EVs. Ongoing experiments aim to comprehensively characterize individual macrophage-derived EVs using the quantitative single molecule localization microscopy (qSMLM). Together, our findings provide a valuable resource for future studies of macrophage-EV communication and could serve in the development of EV-based diagnostic and therapeutic strategies.

Calcium, Phosphate, and Vitamin D Status in Patients with Sarcoidosis-Associations with Disease Activity and Symptoms.

Sarcoidosis is a systemic granulomatous disease with a variety of presentations. One of the known symptoms are altered vitamin D metabolism and hypercalcemia. In our study, we aimed to assess associations between disease activity, inflammatory parameters, and vitamin D and calcium status. The secondary aim was to find any dependencies between calcium and vitamin D metabolism and fatigue and quality of life in patients with sarcoidosis. We enrolled 58 patients with sarcoidosis (47 classified as active disease, 11 classified as non-active) and compared them with 25 healthy volunteers. Calcium concentration was significantly higher in the study group than in healthy controls. It correlated with some inflammatory markers but not with vitamin D status. Not calcium nor vitamin D, but phosphate concentration correlated with life quality was assessed with the use of the Sarcoidosis Health Questionnaire. An association between phosphate concentration and fatigue was also noted, but it did not reach statistical significance. Calcium concentration was higher in patients with sarcoidosis, but it was not an indicator of the disease activity, while phosphate concentration was significantly lower in patients with active sarcoidosis.

Imbalanced distribution of regulatory T cells and Th17.1 cells in the peripheral blood and BALF of sarcoidosis patients: relationship to disease activity and the fibrotic radiographic phenotype.

Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.