Active Sarcoidosis Research Articles

Novel biomarkers for the assessment of disease activity in patients with sarcoidosis: a case-control study.

The prognosis of sarcoidosis is challenging and largely depends on the persistence of disease activity and the degree of organ dysfunction. Various biomarkers have been evaluated for diagnosis, disease activity assessment, and prognosis. This study aimed to determine if the ratios of monocytes to high-density lipoprotein cholesterol (MHR), platelets to lymphocytes (PLR), neutrophils to lymphocytes (NLR), and lymphocytes to monocytes ratio (LMR) could be used as novel sarcoidosis activity markers. In a case-control study, 54 patients with biopsy-confirmed sarcoidosis were divided into two groups; group 1: consisted of 27 patients with active sarcoidosis who were newly diagnosed and treatment-naive, and group 2: consisted of 27 patients with inactive sarcoidosis who had been on treatment for at least 6 months. All patients were subjected to a comprehensive history, physical examination, laboratory tests, chest imaging, spirometry, and screening for extrapulmonary organ involvement by means of electrocardiogram and eye examination. The mean age of the patients was 44 ± 11 years (79.6% were females & 20.4% were males). MHR, NLR, and LMR were significantly higher in patients with active sarcoidosis than in an inactive disease with a cut-off value of 8.6, a sensitivity of 81.5%, and a specificity of 70.4% (P-value < 0.001), a cut-off value of 1.95, sensitivity of 74% and specificity of 66.7% (P-value 0.007) and a cut-off value of < 4, a sensitivity of 81.5%, and a specificity of 85.2% (P-value < 0.001), respectively. In contrast, PLR was not statistically significant between active and inactive sarcoidosis patients. The lymphocytes monocytes ratio is a highly sensitive and specific biomarker that could be used to assess the disease activity in sarcoidosis patients.

Chronotype and the Big-Five personality traits as predictors of chronic fatigue among patients with sarcoidosis. A cross-sectional study.

Sarcoidosis may seriously hamper patients' quality of life despite fairly good prognosis. To assess the relationship between the Big Five personality traits, chronotype and severity of fatigue symptoms, in the context of selected clinical variables and general mental health among patients with sarcoidosis. The study group comprised 60 patients with a confirmed diagnosis of sarcoidosis. They were asked to share relevant clinical data and complete a set of questionnaires: Fatigue Asessment Scale (FAS), General Health Questionnaire (GHQ-28), the NEO Five Factor Inventory and Composite Scale of Morningness. In linear regression analysis, FAS score was predicted by female sex, active sarcoidosis status, Morning Affect and Conscientiousness. In principal component analysis, FAS score and all GHQ-28 subscale scores (somatic symptoms, anxiety/insomnia, social dysfunction and depressive symptoms) formed a single component explaining 60% of variance. The factor loading for each variable exceeded 0.6. The psychological burden appeared to rise with the severity of the fatigue, regardless the inactive/active phase of sarcoidosis. The severity of fatigue may be linked to patient's poor morning affect. The profile of psychological burden presented by the patients may be associated with their personality and clinical presentation of sarcoidosis.

Potential clinical utility of 68Ga-DOTATATE PET/CT for detection and response assessment in cardiac sarcoidosis

BackgroundSomatostatin receptor is expressed in sarcoid granulomas, and preliminary clinical studies have shown that myocardial sarcoidosis can be identified on somatostatin receptor-targeted PET. We examined the potential clinical use of 68Ga-DOTATATE PET/CT for diagnosis and response assessment in cardiac sarcoidosis compared to 18F-FDG PET/CT. MethodsEleven cardiac sarcoidosis patients with 18F-FDG PET/CT were prospectively enrolled for cardiac 68Ga-DOTATATE PET/CT. The two PET/CT studies were interpreted independently and were compared for patient-level and segment-level concordance, as well as for the degree of radiotracer uptake. Follow-up 68Ga-DOTATATE PET/CT was performed in eight patients. ResultsPatient-level concordance was 91%: ten patients had multifocal DOTATATE uptake (active cardiac sarcoidosis) and one patient showed diffuse DOTATATE uptake. Segment-level agreement was 77.1% (Kappa 0.53 ± 0.07). The SUVmax-to-blood pool ratio was lower on 68Ga-DOTATATE PET/CT (3.2 ± 0.6 vs. 4.9 ± 1.5, P = 0.006 on paired t test). Follow-up 68Ga-DOTATATE PET/CT showed one case of complete response and one case of partial response, while 18F-FDG PET/CT showed four cases of response, including three with complete response. ConclusionCompared to 18F-FDG PET/CT, 68Ga-DOTATATE PET/CT can identify active cardiac sarcoidosis with high patient-level concordance, but with moderate segment-level concordance, low signal-to-background ratio, and underestimation of treatment response.

Exploring the Utility of Cardiovascular Magnetic Resonance Radiomic Feature Extraction for Evaluation of Cardiac Sarcoidosis.

The aim of this study is to explore the utility of cardiac magnetic resonance (CMR) imaging of radiomic features to distinguish active and inactive cardiac sarcoidosis (CS). Subjects were classified into active cardiac sarcoidosis (CSactive) and inactive cardiac sarcoidosis (CSinactive) based on PET-CMR imaging. CSactive was classified as featuring patchy [18F]fluorodeoxyglucose ([18F]FDG) uptake on PET and presence of late gadolinium enhancement (LGE) on CMR, while CSinactive was classified as featuring no [18F]FDG uptake in the presence of LGE on CMR. Among those screened, thirty CSactive and thirty-one CSinactive patients met these criteria. A total of 94 radiomic features were subsequently extracted using PyRadiomics. The values of individual features were compared between CSactive and CSinactive using the Mann-Whitney U test. Subsequently, machine learning (ML) approaches were tested. ML was applied to two sub-sets of radiomic features (signatures A and B) that were selected by logistic regression and PCA, respectively. Univariate analysis of individual features showed no significant differences. Of all features, gray level co-occurrence matrix (GLCM) joint entropy had a good area under the curve (AUC) and accuracy with the smallest confidence interval, suggesting it may be a good target for further investigation. Some ML classifiers achieved reasonable discrimination between CSactive and CSinactive patients. With signature A, support vector machine and k-neighbors showed good performance with AUC (0.77 and 0.73) and accuracy (0.67 and 0.72), respectively. With signature B, decision tree demonstrated AUC and accuracy around 0.7; Conclusion: CMR radiomic analysis in CS provides promising results to distinguish patients with active and inactive disease.

Quantitative myocardial T2 mapping adds value to Japanese circulation society diagnostic criteria for active cardiac sarcoidosis.

Noninvasive identification of active myocardial inflammation in patients with cardiac sarcoidosis plays a key role in management but remains elusive. T2 mapping is a proposed solution, but the added value of quantitative myocardial T2 mapping for active cardiac sarcoidosis is unknown. Retrospective cohort analysis of 56 sequential patients with biopsy-confirmed extracardiac sarcoidosis who underwent cardiac MRI for myocardial T2 mapping. The presence or absence of active myocardial inflammation in patients with CS was defined using a modified Japanese circulation society criteria within one month of MRI. Myocardial T2 values were obtained for the 16 standard American Heart Association left ventricular segments. The best model was selected using logistic regression. Receiver operating characteristic curves and dominance analysis were used to evaluate the diagnostic performance and variable importance. Of the 56 sarcoidosis patients included, 14 met criteria for active myocardial inflammation. Mean basal T2 value was the best performing model for the diagnosis of active myocardial inflammation in CS patients (pR2 = 0.493, AUC = 0.918, 95% CI 0.835-1). Mean basal T2 value > 50.8ms was the most accurate threshold (accuracy = 0.911). Mean basal T2 value + JCS criteria was significantly more accurate than JCS criteria alone (AUC = 0.981 vs. 0.887, p = 0.017). Quantitative regional T2 values are independent predictors of active myocardial inflammation in CS and may add additional discriminatory capability to JCS criteria for active disease.

Abstract LB064: Using a genomic only approach to a radiation-age association for supplementing differentiation amongst lung diseases and cancer using PMBCs

Abstract Purpose: Ionizing radiation may serve as a reference variable to estimating biological age since it mirrors cumulative DNA damage similar to aging processes. To do this, we aim to establish a rad-age association using genomics as its foundation and clinical applicability with lung disease as an overlapping health concern. Methods: Two datasets were combined and used to empirically find the age cutoff between young and old patients: GSE42488 (Data-A1) and GSE53351 (Data-A2). With age as both a categorical and continuous variable, two other datasets that include radiation exposure are used to test the interaction between radiation and age: GSE21240 (Data-B1) and GSE23515 (Data-B2). A radiation only data was also used in conjunction to evaluate trend analysis with increasing exposure levels: GSE20173 (Data-R1). The gene lists are oriented in preranked lists for both pathway and diseases functional analysis. Finally, these genes are used to evaluate another dataset via GSE42834 (Data-D1) on the clinical relevance in differentiating lung diseases given ethnicity and sex using both pairwise t-tests and linear models including pneumonic, tuberculosis, active and non-active sarcoidosis, lung cancer, and healthy controls. Results: Using 12 well-known genes associated with aging, a threshold of 29 years old was found to be the difference between young and old patients. The two interaction tests (rad and age as continuous plus rad and age as categorical) yielded 234 unique genes such that pathway analysis flagged IL-1 signaling and PRPP biosynthesis as significant with high cell proliferation diseases and carcinomas being a common trend. From the radiation only t-tests, we see a trend of continued upregulation in gene expression as radiation levels increase in 15 of the 17 common genes. When looking at pairwise comparison of disease, ethnicity, or sex, 10 genes were statistically significant, 3 of which had a combination of pairwise significance and fold-change, while LAPTM4B (probe identifier ILMN1680196) was the only gene with significant interaction (p-value=0.004) between lung disease, ethnicity, and sex and fold change greater than two. Conclusion: The results corroborate an initial association between radiation and age given inflammation and metabolic pathways and multiple genes emphasizing mitochondrial function, oxidation, and histone modification. Being able to tie rad-age genes to lung disease supplements a geroscience approach in future work. Citation Format: Nathan A. Ruprecht, Sonalika Singhal, Kalli Schaefer, Jappreet S. Gill, Benu Bansal, Sandeep K. Singhal. Using a genomic only approach to a radiation-age association for supplementing differentiation amongst lung diseases and cancer using PMBCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB064.

Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment.

Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease. Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis. Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model. Results: XTMAB-16 dose levels of 2 and 4mg/kg, once every 2weeks (Q2W) or once every 4 weeks (Q4W) for up to 12weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1β (IL-1β) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5μg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations. Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.

DISSEMINATED ACTIVE SARCOIDOSIS WITH RV FAILURE IN LVAD PATIENT

DISSEMINATED ACTIVE SARCOIDOSIS WITH RV FAILURE IN LVAD PATIENT

Sarcoid Granulomas and Systemic Sarcoidosis Triggered by Cosmetic Tattoos.

Cosmetic tattooing of eyebrow and lips has become very popular and is expected to be paralleled by more frequent complications. We present 4 cases of granulomas in cosmetic tattoos complicated by regional or systemic manifestations of sarcoidosis including affection of the lungs in 2 cases, the activity triggered by the tattoo. Three cases of traditional decorative tattoos on extremities serve as reference. It is noteworthy that cosmetic tattoos despite small size and thereby low relative dose of pigment injected in the skin can trigger fully developed systemic sarcoidosis. It is hypothesized that iron oxide pigments popular in cosmetic tattoo inks of red or brown color may be prone to elicit sarcoid reactions and thus carry a special risk of granuloma. In decorative tattoos, carbon black is the commonest trigger. It is emphasized that the finding of granulomas in tattoos shall be followed by search of other manifestations of sarcoidosis through patient history and diagnostic examinations to exclude pulmonary, ocular, and other organ manifestations. Patients with granulomas in tattoos shall be informed that active sarcoidosis, if not already present, can become manifest later with a latency of months or years and often with abrupt debut when the triggering tattoo may be overlooked by the doctor who is unfamiliar with this less common type of sarcoidosis.

Abstract 14627: Angiotensin-Neprilysin Inhibition in Cardiac Sarcoidosis

Introduction: Sacubitril/Valsartan is an established treatment for heart failure patients with reduced ejection fraction (HFrEF). However, there is a paucity of data on its use in patients with cardiac sarcoidosis (CS). Hypothesis To establish the beneficial role of Sacubitril/Valsartan in cardiac sarcoidosis. Methods All consecutive CS patients taking Sacubitril/Valsartan were identified from our database from 2016 to 2022. They were followed up for at least 6 months with serial echocardiography. Data regarding symptoms and echocardiographic parameters were compared using Wilcoxon signed rank test. Results A total of 30 CS patients taking Sacubitril/Valsartan were identified (mean age: 56.73±11.63 years old). The diagnosis of CS was determined in all patients by a multi-disciplinary team. Patients were male predominant (73.3%). The prevalence of smoking, diabetes, hypertension and ischaemic heart disease was 20%, 10%, 10% and 3.3% respectively. Beta-blockers, mineralocorticoid receptor antagonists, prednisolone, implantable cardioverter defibrillator and cardiac resynchronisation therapy (defibrillator) were present in 93.3%, 96.7%, 53.3%, 16.7% and 56.7% patients respectively. At the time of diagnosis, 24 (80%) patients were found to have active cardiac sarcoidosis on cardiac PET. At 6-months following the commencement of Sacubitril/Valsartan, there was a significant improvement in LV ejection fraction (38.77±10.26% vs 32.87±9.30%, p&lt;0.001), LV end-systolic diameter (4.89±1.06cm vs 5.14±1.07cm, p=0.013) and New York Heart Association class (1.6±0.55 vs 2.0±0.52, p=0.001). During the median follow up of 24.9 months, the composite end-point of death and cardiac transplantation was reached in 3 (10%) patients (3 deaths and 0 cardiac transplantation). The patients experiencing at least one sustained ventricular arrhythmia (or aborted sudden cardiac death) decreased from 9 to 7 (p=0.21), the mean prednisolone dose was also comparable (11.56±4.42 vs 10.28±3.71, p=0.50) and none of the patients stopped Sacubitril/Valsartan. Conclusions Sacubitril/Valsartan in cardiac sarcoidosis patients with HFrEF is associated with at least short-term improvements in LV remodelling and functional status.

Impact of cardiac resynchronisation therapy in patients with cardiac sarcoidosis

Abstract Background Implantation of a device is usually required in cardiac sarcoidosis (CS) patients presenting with advanced conduction abnormalities or ventricular arrhythmias. A cardiac resynchronisation therapy (CRT) device is often chosen in patients with concomitant left ventricular systolic impairment. The role of CRT in CS is not well established. Purpose To describe the cohort of CS patients with CRT device in situ in our hospital focusing on the short-term effect in serial echocardiography and long-term outcomes on morbidity and mortality. Methods All consecutive CS patients with a CRT device in situ were identified in our CS database (2005–2022). A confident CS diagnosis was provided after review of all relevant clinical and imaging baseline data in our CS multi-disciplinary meeting and a consensus decision for CRT-D implantation was made based on international guidelines. All patients were followed up for at least 6 months with serial echocardiography. Serial data regarding symptoms, rhythm disturbance and echocardiographic parameters were obtained and comparisons were performed using Wilcoxon signed rank test. Results A total of 51 CS patients with CRT-D were identified (mean age: 57±10 years old). Patients were male predominant (64.7%) and Caucasian in origin (86.2%). Extra-cardiac sarcoidosis was confirmed histologically in 33 (64.7%) patients. The prevalence of smoking, diabetes, hypertension and ischaemic heart disease was 27.5%, 21.6%, 49.0% and 7.8% respectively. At the time of device implantation or during follow-up, 43 (84.3%) patients were found to have active cardiac sarcoidosis on cardiac PET. Post CRT implantation there was a significant difference in LV ejection fraction (35.9±15.0% vs 42.2±14.1%, p&amp;lt;0.001), LV end-systolic diameter (4.90±1.46 cm vs 4.62±1.32 cm, p=0.012) and LV end-diastolic diameter (5.99±1.18 cm vs 5.66±1.06 cm, p&amp;lt;0.001). No significant changes were observed in the right ventricular function (p=0.09) and severity of mitral regurgitation (p=0.40). There was one patient who experienced acute heart failure decompensation admission within six months of CRT-D implantation. The New York Heart Association (NYHA) class improved in 26 patients (51.0%), worsened in 4 (7.8%) patients and remained the same in 21 (41.2%) patients at 6 months post CRT-implantation. During the mean follow up of 47.6 months, the composite end-point of death and cardiac transplantation was reached in 9 (17.6%) patients (8 deaths and 1 cardiac transplantation). 5 patients had major complications including a large haematoma, a small atrio-septal defect, haemothorax, device associated endocarditis and lead fracture. Minor wound infections were seen in 3 patients and 4 patients received inappropriate shock or anti-tachycardia pacing. Conclusions CRT in cardiac sarcoidosis patients is associated with short-term improvement in LV remodelling and functional status but over a four year follow up, morbidity and mortality are common. Funding Acknowledgement Type of funding sources: None.

The role of PET in the management of sarcoidosis.

Purpose of reviewPET has emerged as method to determine the location and extent of disease activity in sarcoidosis. As most clinicians do not routinely utilize PET in the management of sarcoidosis, an understanding of the imaging technique is needed to comprehend the impact that PET abnormalities have on diagnosis, prognosis, and treatment.Recent findingsAlthough PET can detect inflammation because of sarcoidosis throughout the body, it is most often utilized for the diagnosis of cardiac sarcoidosis for which it may provide information about prognosis and adverse events. Whenever PET is combined with cardiac magnetic resonance (CMR), clinicians may be able to increase the diagnostic yield of imaging. Furthermore, PET abnormalities have the potential to be utilized in the reduction or augmentation of therapy based on an individual's response to treatment. Although various biomarkers are used to monitor disease activity in sarcoidosis, an established and reproducible relationship between PET and biomarkers does not exist.SummaryPET has the potential to improve the diagnosis of sarcoidosis and alter treatment decisions but prospective trials are needed to define the role of PET while also standardizing the performance and interpretation of the imaging modality.

The Relationship between Tumor Development and Sarcoidosis in Aspects of Carcinogenesis before and after the Onset of Sarcoidosis.

Background and Objectives: It is still unclear whether sarcoidosis is likely to be associated with tumors. In addition, the use of an immune checkpoint inhibitor has been reported to initiate the onset of sarcoidosis. We retrospectively analyzed tumor development before and after the diagnosis of sarcoidosis and examined the impact of having a history of tumors on the activity or the severity of sarcoidosis. Materials and Methods: We recruited 312 consecutive cases of sarcoidosis and analyzed the tumor development before and after the onset of sarcoidosis. Results: Among them, 25 cases were diagnosed with malignant tumor after diagnosis of sarcoidosis. In the analysis of the tumor-development group after diagnosis of sarcoidosis, both serum angiotensin I-converting enzyme and mediastinal lymph node size were significantly reduced at the time of malignant tumor diagnosis compared to at the onset of sarcoidosis, indicating that the decreasing activity of sarcoidosis may be partly associated with tumor development. Furthermore, we examined 34 cases having tumor history before the onset of sarcoidosis and analyzed the effect of tumor history on the severity of sarcoidosis. Cases with a malignant tumor in the past were older and had less complicated organs of sarcoidosis than cases without malignant tumors in the past. Oral corticosteroid therapy was administrated more frequently in cases without malignant tumors in the past, indicating that the history of a malignant tumor may influence the severity of sarcoidosis. Conclusion: These results indicate that tumor development may be partly associated with the activity or severity of sarcoidosis.

Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.

Increased 18F-fluorodeoxyglucose uptake in the cardiac atria: an evidence for increased atrial inflammation in patients with atrial fibrillation?

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial inflammation and fibrotic remodelling underlie the pathophysiology of atrial cardiomyopathy, which is associated with the development of atrial fibrillation (AF) and atrial flutter (AFL). 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) has been used to detect inflammatory processes. Recent studies have revealed an increased FDG-uptake in the atria of patients with AF, but also in patients with diagnosis of cardiac sarcoidosis with ventricular inflammation. Purpose This study aimed to assess the capability of PET/CT to detect and quantify the degree of atrial inflammation (FDG-uptake) in a population with dedicated cardiac FDG-PET/CT. Methods We investigated 101 patients suspected of sarcoidosis (57±12 years, 72% male) who underwent 18F-FDG PET/CT scan with dedicated cardiac specific preparation (heparin infusion, 12 hours fasting, and high-fat low-carbohydrate diet). We excluded patients with active ventricular cardiac sarcoidosis or undergoing high-dose immunosuppressive therapy (prednisolone ≥20mg/day or prednisolone combined with other immunotherapy like methotrexate). We measured the maximum standardized uptake value (SUVmax) in atrial myocardium and mean standardized uptake value (SUVmean) in blood pool and calculated the target-to-background ratio (TBR) of SUVmax in atrial myocardium to SUVmean in blood pool. All medical records, ECG data on arrhythmia type and diagnosis of systemic sarcoidosis (with absence of ventricular involvement) were used for the analysis. Sarcoidosis was diagnosed based on the criteria established in 2006 by the Japanese Ministry of Health and Welfare. The collected data were sorted according to presence of arrhythmia and systemic sarcoidosis and TBR of each group were compared. Results AF or AFL was found in 30/101 patients. Systemic sarcoidosis was found in 37/101 patients. Patients with known AF/AFL had significantly increased TBR within the atrial tissue compared to those without AF/AFL: (median: 1.26, 1st-3rd quartile: 1.20-1.33) versus (median: 1.22, 1st-3rd quartile: 1.14-1.25; p = 0.004; figure A). Arrhythmia-associated atrial inflammation was consistently observed, independently of presence of concomitant systemic sarcoidosis (figure B). Patients with both atrial arrhythmias and systemic sarcoidosis had the highest atrial inflammation level, as identified by TBR (figure B). Conclusion Development of atrial fibrillation or flutter is associated with an increased atrial FDG-uptake as metabolic marker of atrial inflammation. The level of atrial inflammation is further enhanced by additional presence of systemic sarcoidosis.

Multimodality Approach for Surveillance of Cardiac Sarcoidosis After Heart Transplantation Based on a Case Series

<h3>Purpose</h3> Cardiac sarcoidosis is an inflammatory, granulomatous disease of a progressive nature, which may clinically present as sudden death, arrhythmias, or heart failure (HF). When advanced, heart transplantation (HT) emerges as a therapeutic option. The post-transplant outcomes of this patients, regarding survival and rejections, seem to be similar to those related to other etiologies. However, the involvement of multiple organs by the disease and its reactivation potential is a concern regarding its recurrence in the transplanted heart, but its diagnosis, screening and immunosuppression strategy in this scenario are still little explored in the literature. <h3>Methods</h3> We retrospectively reviewed the clinical course of 4 patients with cardiac sarcoidosis who underwent HT between 2014 and 2021. <h3>Results</h3> We followed 4 female patients submitted to HT due to sarcoidosis. The first one transplanted in 2014, aged 32 years, and reativated sarcoidosis after 1 year, diagnosed by cardiac magnetic resonance imaging (MRI) compatible with inflammatory cardiomyopathy and died in 2017 of a non-cardiac cause. Second patient transplanted in 2020, aged 55 years, had high troponin levels also after 1 year post HT, with no evidence of rejection - subsequently, underwent cardiac PET/CT with accentuated diffuse uptake, received treatment with increased steroid dose, with an improvement in the marker after. The third, transplanted in 2021 aged 50 years, presented cardiac MRI after 1 month with a non-ischemic late mesoepicardial enhancement and PET/CT with moderate FDG uptake in the corresponding region suggestive of active cardiac sarcoidosis, using corticosteroids in increased dose for a while, showing improvement in the control PET/CT pattern. Finally, fourth patient transplanted in 2015, aged 40, with no evidence of reactivation of the disease so far, but due to sarcoidosis diagnosis previous to HT, she has always received higher doses of steroids. <h3>Conclusion</h3> There are few reports of recurrence of sarcoidosis after heart transplantation, which makes management of these cases challenging. An integrated approach that includes advanced imaging methods, routine serial endomyocardial biopsies, and serum biomarkers may be useful in monitoring this patients after HT, giving early diagnosis and treatment, which may be lifesaving given it´s potential fatal prognosis.

An Unusual Clinical Presentation of Danon Disease in a Female

<h3>Introduction</h3> Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder with multisystem clinical manifestations caused by mutations in the <i>LAMP2</i> gene. <i>LAMP2</i> mutations are identified in unselected cardiomyopathy cohorts in <0.3% of cases. We report a patient with Danon cardiomyopathy and no skeletal muscle involvement who underwent successful left ventricular assist device (LVAD) implantation. <h3>Case Report</h3> A 39-year-old patient with stage D heart failure (HF) and a LV ejection fraction of 20%, paroxysmal atrial fibrillation, Wolf-Parkinson-White (WPW) syndrome, and type 2 diabetes mellitus was admitted with decompensated HF. There was no family history of cardiomyopathy or sudden cardiac death. She was diagnosed with HF 4 years prior at that time she had concentric LV hypertrophy (interventricular septal thickness 1.4 mm) and LV end diastolic diameter of 5 cm. A cardiac PET did not identify any areas of ischemia and no FDG uptake to suggest active sarcoidosis. Left heart catheterization revealed angiographically normal coronary arteries. Genetic testing identified a heterozygous deletion in <i>LAMP2</i> (5'UTR_3'UTRdel), resulting in complete deletion of 1 allele. She was started on inotrope therapy due to low cardiac output but deteriorated due to incessant ventricular arrhythmias. She underwent HeartMate 3 (HM3) LVAD implantation as a bridge to heart transplant. The LV apical core biopsy revealed vacuolated and hypertrophic cardiomyocytes with endocardial fibrosis, consistent with Danon disease. In 6 months since surgery, she is doing well without LVAD-related complications. She was referred to genetic counseling and her now 10 years old daughter is being genetically tested. <h3>Summary</h3> This case reports an unusual clinical presentation of severe HF due to Danon disease in a female. She had primary myocardial involvement with WPW and mild learning disability but had no skeletal muscle or retinal involvement. Because of the X-linked nature of the disease, males are more severely affected, though progression to advanced HF has rarely been reported in females. This case highlights the importance of genetic testing for cardiomyopathies and subsequent genetic counseling of family members.

Urine autotaxin levels reflect the disease activity of sarcoidosis

Since the clinical outcome of patients with sarcoidosis is still unpredictable, a good prognostic biomarker is necessary. Autotaxin (ATX) and phosphatidylserine-specific phospholipase A1 (PS-PLA1) function as main enzymes to produce lysophospholipids (LPLs), and these enzymes are attracting attention as useful biomarkers for several chronic inflammatory diseases. Here, we investigated the relationships between LPLs-producing enzymes and the disease activity of sarcoidosis. In total, 157 patients with sarcoidosis (active state, 51%) were consecutively enrolled. Using plasma or urine specimens, we measured the values of LPLs-producing enzymes. Urine ATX (U-ATX) levels were significantly lower in the active state compared to those in the inactive state, while the plasma ATX (P-ATX) and PS-PLA1 levels showed no significant difference between these two states. Concerning the comparison with existing clinical biomarkers for sarcoidosis, U-ATX showed a weak negative correlation to ACE, P-ATX a weak positive correlation to both ACE and sIL-2R, and PS-PLA1 a weak positive one to sIL-2R. Notably, only the U-ATX levels inversely fluctuated depending on the status of disease activity whether OCS had been used or not. These findings suggest that U-ATX is likely to be a novel and useful molecule for assessing the disease activity of sarcoidosis.

Exploring the Utility of Radiomic Feature Extraction to Improve the Diagnostic Accuracy of Cardiac Sarcoidosis Using FDG PET.

BackgroundThis study aimed to explore the radiomic features from PET images to detect active cardiac sarcoidosis (CS).MethodsForty sarcoid patients and twenty-nine controls were scanned using FDG PET-CMR. Five feature classes were compared between the groups. From the PET images alone, two different segmentations were drawn. For segmentation A, a region of interest (ROI) was manually delineated for the patients' myocardium hot regions with standardized uptake value (SUV) higher than 2.5 and the controls' normal myocardium region. A second ROI was drawn in the entire left ventricular myocardium for both study groups, segmentation B. The conventional metrics and radiomic features were then extracted for each ROI. Mann-Whitney U-test and a logistic regression classifier were used to compare the individual features of the study groups.ResultsFor segmentation A, the SUVmin had the highest area under the curve (AUC) and greatest accuracy among the conventional metrics. However, for both segmentations, the AUC and accuracy of the TBRmax were relatively high, >0.85. Twenty-two (from segmentation A) and thirty-five (from segmentation B) of 75 radiomic features fulfilled the criteria: P-value < 0.00061 (after Bonferroni correction), AUC >0.5, and accuracy >0.7. Principal Component Analysis (PCA) was conducted, with five components leading to cumulative variance higher than 90%. Ten machine learning classifiers were then tested and trained. Most of them had AUCs and accuracies ≥0.8. For segmentation A, the AUCs and accuracies of all classifiers are >0.9, but k-neighbors and neural network classifiers were the highest (=1). For segmentation B, there are four classifiers with AUCs and accuracies ≥0.8. However, the gaussian process classifier indicated the highest AUC and accuracy (0.9 and 0.8, respectively).ConclusionsRadiomic analysis of the specific PET data was not proven to be necessary for the detection of CS. However, building an automated procedure will help to accelerate the analysis and potentially lead to more reproducible findings across different scanners and imaging centers and consequently improve standardization procedures that are important for clinical trials and development of more robust diagnostic protocols.

Muscular sarcoidosis in the eyes of 18 F-FDG PET/CT.

The aim of this study was to determine the frequency, symptoms, activity and pattern of muscle sarcoidosis, correlation with laboratory parameters, and to assess its therapy response with 18 F-FDG PET/CT. Study included 90 patients with biopsy confirmed sarcoidosis and symptoms/biochemical/imaging findings suggestive of active disease. The exclusion criteria were: presence of cancer or other diseases that resemble sarcoidosis on PET/CT (Wegener syndrome, tuberculosis, aspergillosis), and the glucose level being greater than 11 mmol/L. All patients were screened for muscle sarcoidosis with 18 F-FDG PET/CT examination. Follow-up examination was done 1 year after the baseline in order to evaluate therapy response. Disease was very rare and present in only 7/90 patients. Most of the patients had polysymptomatic disease, while muscle pain was less frequent, present only in one-third of the patients. The disease was usually present in the lower limbs, upper limbs, and skeletal striated muscles. The most common pattern of disease was nodular. Disease activity estimated with SUVmax was not in correlation with the ACE findings, creatine kinase, and aldolase levels (p > 0.05). Follow-up PET/CT revealed complete remission in one patient and partial remission in two. 18 F-FDG PET/CT can be useful in asymptomatic young patients with nodular pattern of disease, who have easily relapsing form of disease. It can help in further management of these patients and can affect prognosis of the disease, since most of the laboratory parameters in this entity are within normal limits.