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Chronic inflammation is increasingly recognized as a risk factor for VTE, but unlike other inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis, data on the risk of VTE in patients with sarcoidosis are sparse. Do patients with sarcoidosis have a higher long-term risk of VTE (pulmonary embolism or DVT, and each of these individually) compared with the background population? Using Danish nationwide registries, patients aged ≥ 18 years with newly diagnosed sarcoidosis (two or more inpatient/outpatient visits, 1996-2020) without prior VTE were matched 1:4 by age, sex, and comorbidities with individuals from the background population. The primary outcome was VTE. We included 14,742 patients with sarcoidosis and 58,968 matched individuals (median age, 44.7 years; 57.2% male). The median follow-up was 8.8 years. Absolute 10-year risks of outcomes for patients with sarcoidosis vs the background population were the following: VTE, 2.9% vs 1.6% (P <.0001), pulmonary embolism, 1.5% vs 0.7% (P <.0001), and DVT, 1.6% vs 1.0% (P <.0001), respectively. In multivariable Cox regression, sarcoidosis was associated with an increased rate of all outcomes in the first year after diagnosis (VTE: hazard ratio [HR], 4.94; 95% CI, 3.61-6.75) and after the first year (VTE: HR, 1.65; 95% CI, 1.45-1.87) compared with the background population. These associations persisted when excluding patients with a history of cancer and censoring patients with incident cancer during follow-up. Three-month mortality was not significantly different between patients with VTE with and without sarcoidosis (adjusted HR, 0.84; 95% CI, 0.61-1.15). In this nationwide cohort study, sarcoidosis was associated with a higher long-term risk of VTE compared with a matched background population. [Display omitted] [ABSTRACT FROM AUTHOR]

This review article delves into the complexities of granuloma formation, focusing on the metabolic reprogramming within these immune structures, especially in tuberculosis and sarcoidosis. It underscores the role of the monocyte–macrophage lineage in granuloma formation and maintenance, emphasizing the adaptability of these cells to environmental cues and inflammatory stimuli. Key to the discussion is the macrophage polarization influenced by various cytokines, with a detailed exploration of the metabolic shifts towards glycolysis under hypoxic conditions and the utilization of the pentose phosphate pathway (PPP) for crucial biosynthetic processes. Significant attention is given to the metabolism of L-arginine in macrophages and its impact on immune response and granuloma function. The review also highlights the role of mechanistic target of rapamycin (mTOR) signaling in macrophage differentiation and its implications in granulomatous diseases. Discoveries such as elevated PPP activity in granuloma-associated macrophages and the protective role of NADPH against oxidative stress offer novel insights into granuloma biology. The review concludes by suggesting potential therapeutic targets within these metabolic pathways to modulate granuloma formation and function, proposing new treatment avenues for conditions characterized by chronic inflammation and granuloma formation. This work contributes significantly to the understanding of immune regulation and chronic inflammation, presenting avenues for future research and therapy in granulomatous diseases. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a chronic granulomatous disease predominantly affecting the lungs and inducing significant morbidity and elevated mortality rate. The etiology of the disease is unknown but may involve exposure to an antigenic agent and subsequent inflammatory response resulting in granuloma formation. Various environmental and occupational risk factors have been suggested by previous observations, such as moldy environments, insecticides, and bird breeding. Our study investigated the association of air pollution with diagnosis of sarcoidosis using a case-control design. Penn State Health electronic medical records from 2005 to 2018 were examined for adult patients with (cases) and without (controls) an International Classification of Disease (ICD)-9 or −10 code for sarcoidosis. Patient addresses were geocoded and 24-hr residential-level air pollution concentrations were estimated using spatio-temporal models of particulate matter <2.5 μm (PM2.5), ozone, and PM2.5 elemental carbon (EC) and moving averages calculated. In total, 877 cases and 34,510 controls were identified. Logistic regression analysis did not identify significant associations between sarcoidosis incidence and air pollution exposure estimates. However, the odds ratio (OR) for EC for exposures occurring 7–10 years prior did approach statistical significance, and ORs exhibited an increasing trend for longer averaging periods. Data suggested a latency period of more than 6 years for PM2.5 and EC for reasons that are unclear. Overall, results for PM2.5 and EC suggest that long-term exposure to traffic-related air pollution may contribute to the development of sarcoidosis and emphasize the need for additional research and, if the present findings are substantiated, for public health interventions addressing air quality as well as increasing disease surveillance in areas with a large burden of PM2.5 and EC. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionUveitis is a common ocular manifestation in individuals with sarcoidosis, a multisystem inflammatory disorder. This study aimed to explore clinical and genetic factors associated with the presence or absence of uveitis in sarcoidosis patients.Total 625 Dutch sarcoidosis patients were included. Among these, 170 underwent ophthalmic examination, and 61 were diagnosed with uveitis. Demographic and clinical data, including age, gender, race, biopsy status, chest radiography findings, TNF-α inhibitor treatment, and uveitis classification were collected retrospectively from medical records. Genetic data was available for HLA haplotypes, TNF-α G-308A, and BTNL2 G16071A polymorphisms.The majority of the patients presented with bilateral uveitis (80.3%). The proportion of women was higher in the uveitis group compared to the non-uveitis group (67.2% and 47.7%; p = 0.014). Pulmonary involvement (chest radiographic stage II-III) was significantly lower in patients with uveitis (36.1% versus 64.2%; p < 0.001). Patients with uveitis were more often treated with TNF-α inhibitors (67.2% versus 29.4%; p < 0.001) and the outcome was better compared with the non-uveitis group, 92% vs 68%, responders (p < 0.012). Uveitis patients treated with TNF-α inhibitors (either adalimumab or infliximab) were more likely to suffer from intermediate or posterior uveitis than anterior uveitis. Genetic analysis identified a significant association between the BTNL2 G16071A GG genotype and uveitis (p = 0.012).This study highlights distinctive demographic, clinical and genetic features associated with uveitis in sarcoidosis patients. Ocular sarcoidosis was more prevalent in women. Further research is warranted to explore the implications of these findings for treatment strategies and prognostic assessments. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo provide a comprehensive overview of the diagnostic and therapeutic journey of a pediatric patient with persistent sarcoid-associated panuveitis over a 10-year period, who ultimately developed bilateral macular subretinal fibrosis and visual loss.Retrospective case reportThe patient was diagnosed with sarcoidosis after undergoing a transbronchial biopsy. She was followed up because of granulomatous panuveitis, multifocal choroiditis, and papillitis bilaterally. She maintained a stable condition, and visual acuity was 0.3 RE and 0.5 LE. Immunomodulatory therapy included prednisone, methotrexate, and adalimumab. The patient was lost to follow-up for 20 months because of the COVID-19 pandemic. She was represented with active uveitis and was not responding to TNF-ɑ inhibitors (adalimumab and infliximab). Ultimately, the patient's intraocular inflammation was successfully controlled by using intravitreal steroids (Triamcinolone and Fluocinolone acetonide implant). However, the visual outcome was guarded because of bilateral subretinal fibrosis.10% of patients with sarcoidosis-associated uveitis risk blindness in one eye. The index case progressed to sight-robbing bilateral subretinal fibrosis, a rare complication of ocular sarcoidosis despite a combination of conventional and biologic anti-inflammatory therapies. There is a pressing need to develop new treatment agents for refractory non-infectious uveitis. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionUveitis and scleritis may be caused by local or systemic infection, or associated with noninfectious systemic inflammatory autoimmune disease. This study explored the all-cause mortality following an individual’s first presentation with uveitis/scleritis.A cross-sectional study was conducted on all uveitis/scleritis patients diagnosed by uveitis specialists and treated in a single tertiary referral center in New Zealand between 2006 and 2020(15y). Masquerade syndromes including intraocular lymphoma were excluded. Outcome measures: demographics, etiology of uveitis/scleritis, anatomical location and all-cause mortality.2723 subjects were identified. Median age of onset of uveitis/scleritis was 44.9 years (Range:1.5–99.5 years). 49.6% were female. Median follow-up from diagnosis of uveitis/scleritis was 8.0 years (IQR 4.1–11.6 years) with a total follow-up of 24 443.3 subject-years. The most frequent diagnosis was idiopathic disease (30.9%), HLA-B27-positive uveitis (20.0%), and sarcoidosis (4.7%). Infectious etiologies (24.1%) were most commonly from herpes zoster virus (9.3%) and toxoplasmosis (4.3%). The age-adjusted mortality rate was higher in subjects with idiopathic disease, sarcoidosis, Fuchs’ uveitis syndrome, granulomatosis with polyangiitis/ANCA-associated vasculitis, toxoplasmosis, and herpes zoster virus, when compared to HLA-B27-positive uveitis. Hazard of mortality peaked in the first seven years following diagnosis, then subsequently declined. Patients with uveitis/scleritis had a significantly higher rate of mortality compared to the general New Zealand population (IRR 1.656 p = 0.017).Infectious etiologies of uveitis/scleritis in this cohort were high when compared to other developed nations, attributable to data from a tertiary referral center treating inpatients. Potential shared inflammatory mechanisms in the eye and other organs can lead to concurrent non-ocular disease requiring systemic treatment, impacting an individual’s longevity. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Sarcoidosis, although predominantly affecting the lungs, can present with cirrhosis, posing diagnostic challenges. Elevated ACE levels and atypical liver enzyme patterns should prompt consideration of sarcoidosis in cryptogenic cirrhosis cases, necessitating comprehensive evaluation including liver biopsy and imaging for accurate diagnosis and timely management. Sarcoidosis is a systemic disease that can affect various organs, leading to a diverse range of clinical manifestations that make diagnosis challenging. Here, we present a case of sarcoidosis in a middle‐aged male who presented with cirrhosis. The cause of cirrhosis remained unknown for 4 years until the development of lymphadenopathy and ground‐glass opacities on lung imaging. A liver biopsy was performed, which revealed noncaseating granulomatous inflammation, thereby identifying sarcoidosis as the cause of cirrhosis. The patient was treated with oral steroids, which slightly improved his liver function over a short period. Given the diverse presentations of sarcoidosis, it should be considered as a possible differential diagnosis in cases of cryptogenic cirrhosis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This paper presents a rare sarcoidosis case in a child of 12 years of age presented with arthritis, bilateral parotid enlargement and ocular, but unfortunately the diagnosis has been missed due to lack of pulmonary involvement. Diagnosis of sarcoidosis is by exclusion, and sometimes, it can be challenging. This paper presents a rare sarcoidosis case in a child of 12 years of age presented with bilateral parotid enlargement. The signs of musculoskeletal and ocular involvement were present before the parotid enlargement, and the parotid swelling persisted for 3 years; but unfortunately the definite diagnosis has been missed by the previous healthcare professionals most probably due to the rarity of the situation, especially lack of pulmonary involvement. Therefore, cooperation between different healthcare specialties is important for an effective diagnosis and management. Despite its rarity, sarcoidosis should always be present in the list of differential diagnosis when encountering multisystem entities like arthritis, ocular symptoms and parotid swelling. [ABSTRACT FROM AUTHOR]

Cardiac sarcoidosis (CS) is characterized by various arrhythmic manifestations ranging from catastrophic sudden cardiac death secondary to ventricular arrhythmia, severe conduction disease, sinus node dysfunction, and atrial fibrillation. The management of CS is complex and includes not only addressing the arrhythmia but also controlling the myocardial inflammation resultant from the autoimmune reaction. Arrhythmic manifestations of CS carry significant prognostic implications and invariably affect long-term survival in these patients. In this review, we focus on management of arrhythmic manifestation of cardiac sarcoidosis as well as risk stratification for sudden cardiac death in these patients. [ABSTRACT FROM AUTHOR]

To study the rare and unusual causes of monocular elevation deficit. Five patients presenting to us with diplopia and elevation deficit were thoroughly examined and were found to have monocular elevation deficit due to rare causes. All five were found to have different underlying etiologies – iatrogenic, sphenoid wing meningioma, cysticercosis, sarcoidosis and mid brain infarct, and were managed appropriately. Monocular Elevation Deficit can occur due to a variety of causes. Having a high index of suspicion for the more serious etiologies is of utmost importance. Thorough clinical examination and imaging help clinch the diagnosis. [ABSTRACT FROM AUTHOR]

Lymphadenopathy is a common clinical finding and diagnostic challenge within general medicine and rheumatology practice. It may represent a primary manifestation of an underlying immune-mediated disease or indicate an infectious or neoplastic complication requiring differing management. Evaluating lymphadenopathy is of particular relevance in rheumatology, given that lymph node enlargement is a common finding within the clinical spectrum of several well-known rheumatologic disorders including RA, SLE and SS. In addition, lymphadenopathy represents a hallmark manifestation of rare immunological diseases such as Castleman disease and IgG4-related disease that must be considered in the differential diagnosis because effective targeted treatments can now impact the prognosis of these conditions. In this review we present an overview of the clinical significance of lymphadenopathy in common and rare rheumatologic diseases and propose a practical approach to lymphadenopathy in the rheumatology practice. Differential diagnosis of Castleman disease and therapeutic options for this condition of increasing rheumatologic interest will be discussed in detail. [ABSTRACT FROM AUTHOR]

Objectives To analyse genetic mechanisms triggering familial sarcoidosis, whole exome screening of a family of six persons with four cases of sarcoidosis and two healthy controls was performed integrating progressive and spontaneous remission cases and evaluating involved genetic alterations that could potentially determine the individual course of the disease. Methods Clinical diagnostic criteria in patients of the selected sarcoidosis family were according to American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders guidelines. Exome screening of four patients and the two intrafamilial healthy relatives was performed by paired-end (2 × 100 bp) sequencing. We then selected the gene variants considered pathogenic on the basis of a series of prediction software applications and presence only in members of the family affected by sarcoidosis, after subtracting the common variations observed in healthy subjects. Results Four persons out of six family members were affected by sarcoidosis. Fifty genes with uncommon in silico pathogenic variants could be identified that differentiated affected and healthy family members. One patient with sarcoidosis showed spontaneous remission whereas the remaining three patients required immunosuppressive treatment. Subtraction analysis revealed 18 genes that distinguished the three progressive cases from the patient with spontaneous remission. Conclusion The genetic analysis of these cases with familial sarcoidosis identified several involved genes and functional pathways that could help in understanding the basic mechanisms that determine the development of the disease and that discriminate spontaneously regressive and progressive forms. [ABSTRACT FROM AUTHOR]

Sarcoidosis results from a combination of genetic variants and environmental factors but its exact cause remains unknown. Evidence highlights a major role of monocytes as important drivers of sarcoidosis immunopathogenesis. The emerging concept of trained immunity opens new perspectives for the comprehension of sarcoidosis pathology, with a particular presumed role played by immune metabolism and epigenetics. We posit that maladaptive innate immune training may drive sarcoidosis pathogenesis. The confirmation of maladaptive innate immune training in sarcoidosis might allow the development of new candidate therapeutic strategies. The pathogenesis of sarcoidosis, an immune-mediated granulomatous disease, has long remained elusive. Recent discoveries on trained immunity might help decipher immunological mechanisms underlying the disease which in turn may inform novel putative treatment options. Sarcoidosis is a chronic immune disease of unknown origin for which we still lack an immunological framework unifying causal agents, host factors, and natural history of disease. Here, we discuss the initial triggers of disease, and how myeloid cells drive granuloma formation and contribute to immunopathogenesis. We highlight recent advances in our understanding of innate immune memory and propose the hypothesis that maladaptive innate immune training connects previous environmental exposure to granuloma maintenance and expansion. Lastly, we consider how this hypothesis may open novel therapeutic avenues, while corticosteroids remain the front-line treatment. [ABSTRACT FROM AUTHOR]

This report presents a unique case of checkrein deformities in both halluces following isolated intramuscular sarcoidosis, a rare occurrence given the infrequent musculoskeletal involvement in sarcoidosis. Typically resulting from flexor hallucis longus tendon entrapment by scar tissue post-trauma, the checkrein deformity reported in this paper presented with unusual metatarsophalangeal joint flexion and interphalangeal joint extension during ankle dorsiflexion. A 49-year-old woman with a history of intramuscular sarcoidosis presented with a great toe deformity and discomfort while wearing shoes, leading to a diagnosis of dynamic deformity, possibly attributed to tendon tethering by sarcoidosis. Surgical treatments, including abductor hallucis muscle intratendinous tenotomy, flexor hallucis longus Z-plasty lengthening, Weil osteotomy, and Kirschner wire fixation, significantly improved the functional scores and patient discomfort. This report underscores the importance of recognizing dynamic deformities and the potential for rare diseases, such as sarcoidosis, to cause such conditions, highlighting the need for careful diagnosis and tailored surgical intervention for atypical checkrein deformities. [ABSTRACT FROM AUTHOR]

Cardiovascular inflammation plays a key role in atherosclerosis and other cardiovascular complications, highlighting the importance of accurate detection methods. While traditional diagnostic tests have limitations in specificity and timing, 18-Fluoro-Deoxyglucose-Positron Emission Tomography (FDG-PET) imaging offers a non invasive approach to visualise inflammation. Radiomics, the extraction of quantitative features from medical images for analysis with machine learning algorithms, presents an opportunity to enhance the diagnostic accuracy of FDG-PET imaging in detecting cardiac inflammation. Studies investigating radiomics in various cardiovascular inflammatory conditions, including Cardiac Sarcoidosis (CS), Infective Endocarditis (IE), and active aortitis, have shown promising results in improving diagnostic performance. The review discusses the challenges and potentials of radiomics in cardiovascular imaging, emphasising the need for standardisation and validation in advancing personalised diagnosis and treatment strategies for cardiovascular inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Observational data suggest that the 19-gauge (G) needle for endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) offers a higher diagnostic yield than the 22-G needle in sarcoidosis. No randomized trial has compared the yield of the two needles. Methods: We randomized consecutive subjects with suspected sarcoidosis and enlarged thoracic lymph nodes to undergo EBUS-TBNA with either the 19-G or the 22-G needle. We compared the study groups for diagnostic sensitivity (primary outcome) assessed by the yield of granulomas in subjects finally diagnosed with sarcoidosis. We also compared the sample adequacy, difficulty performing the needle puncture assessed on a visual analog scale (VAS), the subject's cough intensity on an operator-rated VAS, and procedure-related complications (secondary outcomes). Results: We randomized 150 (mean age, 43.0 years; 55% women) subjects and diagnosed sarcoidosis in 116 subjects. The diagnostic sensitivity of the 19-G needle (45/60, 75.0%) was not higher (p = 0.52) than the 22-G needle (39/56, 69.6%). We obtained adequate aspirates in 90.0% and 85.7% of subjects in the respective groups (p = 0.48). The operators had greater difficulty puncturing lymph nodes with the 19-G needle (p = 0.03), while the operator-assessed cough intensity was similar in the groups (p = 0.41). Transient hypoxemia was the only complication encountered during EBUS-TBNA (two subjects in either group). Conclusion: We did not find the 19-G needle superior to the 22-G in diagnostic sensitivity, specimen adequacy, or safety of EBUS-TBNA in sarcoidosis. Puncturing the lymph nodes was more difficult with the 19-G needle. [ABSTRACT FROM AUTHOR]

This article presents a case study of a young woman who suffered sudden vision loss in her left eye. The article explores the various potential causes of her condition, including lymphoma, multiple sclerosis, stroke, and other eye-related conditions. Through laboratory tests and imaging studies, the doctors were able to diagnose the patient with sarcoidosis, a condition characterized by the development of non-caseating granulomas in different organs. The article highlights the importance of considering sarcoidosis as a possible cause of vision loss, even in the absence of other symptoms. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Purpose: Systematic ocular screening is recommended in sarcoidosis, because of a high rate of ocular involvement. The purpose of this study was to determine whether ocular screening is useful in sarcoidosis in a Finnish university hospital population with 0.5 M inhabitants. Methods: Patient charts of patients with sarcoidosis, without a history of ocular sarcoidosis, without ocular inflammatory symptoms, and with a comprehensive eye exam from January 2014 to January 2021 at Tays Eye Centre, Tampere, Finland, were studied. Results: Five of 262 patients (2%) were diagnosed with asymptomatic uveitis. No other types of ocular sarcoidosis were found. Anterior uveitis without complications was present in three patients, unilaterally in two and bilaterally in one patient. Posterior uveitis was present in two patients, a unilateral choroidal granuloma requiring treatment in one and bilateral punched‐out chorioretinal lesions in the other patient. Conclusions: With this low rate of ocular involvement requiring treatment in sarcoidosis, systematic screening for asymptomatic ocular sarcoidosis does not seem useful in a Finnish population. In Tays Eye Centre, systematic screening of ocular sarcoidosis was discontinued in 2021. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To describe the radiological features of patients with headache as a presenting symptom of neurosarcoidosis.Neurologic complications occur in approximately 5%–10% of patients with sarcoidosis, and approximately 50% of these patients have neurologic deficits at the time sarcoidosis is first diagnosed. A wide spectrum of central and peripheral nervous system clinical manifestations may be observed, including cranial nerve palsies, sensory and/or motor deficits, and headache. Magnetic resonance imaging (MRI) results in patients with neurosarcoidosis may include abnormal contrast enhancement, structural masses, and demyelinating lesions.This single‐center retrospective cohort study assessed patients who were diagnosed with neurosarcoidosis in an urban tertiary care center between 1995 and 2016. We included patients who had MRI results at the time of diagnosis. Patients were divided into two groups based on the presence or absence of headache as a presenting symptom. The MRI result of meningeal contrast enhancement was reviewed.Of the 110 patients analyzed, 30 (27.3%) had an initial presenting symptom of headache while 80 (72.7%) did not. Patients with headache had a higher proportion of meningeal contrast enhancement on MRI (66.7% [20/30] vs. 25.0% [20/80]; p < 0.001) and leptomeningeal involvement (53.3% [16/30] vs. 7.5% [6/80], p < 0.001) compared to patients with no headache. However, those with headache had a lower proportion of spinal cord localization (13.8% [4/29] vs. 34.2% [26/76], p = 0.038) and intraparenchymal central nervous system involvement (16.7% [5/30] vs. 51.3% [41/80], p = 0.001) compared to patients with no headache.Patients with neurosarcoidosis who presented with headache as an initial symptom had a higher proportion of meningeal contrast enhancement seen by MRI than patients who presented with other neurological symptoms. This suggests a clinico‐radiologic link between headache and meningeal disruption in patients with neurosarcoidosis. [ABSTRACT FROM AUTHOR]

Background: Metastatic Crohn's disease is a rare disorder characterized by various granulomatous skin lesions that occur independently of gastrointestinal tract involvement. However, currently there is no standardized care or specific treatment. Therapeutic approaches include immunosuppressive agents, such as corticosteroids, azathioprine, and monoclonal antibodies targeting inflammatory cytokines like tumor necrosis factor (TNF). Case presentation: We present a case of a 29-year-old western European woman with significant blind ending abdominal subcutaneous fistulas and abscesses, who sought evaluation in the dermatology department. Histological examination revealed multiple epithelioid cell granulomas. There was no evidence of infectious or rheumatologic diseases such as sarcoidosis. The tentative diagnosis was metastatic Crohn's disease, which was not related to an intestinal manifestation of the disease. The patient responded to infliximab but had to discontinue it due to an allergic reaction. Subsequent adalimumab treatment failed to induce clinical remission; thus, therapy was switched to ustekinumab, resulting in a positive response. Written informed consent for publication of their clinical details and clinical images was obtained from the patient. For our study more than 1600 publications were screened for cases of metastatic Crohn's disease on PubMed database. 59 case reports with 171 patients were included in the analysis and evaluated for localization, diagnostic and therapeutic approaches, and complications and were summarized in this review. Conclusion: The successful ustekinumab treatment of a patient with metastatic Crohn's disease underscores the potential of this minimally investigated therapeutic option, highlighting the need for future treatment guidelines given the increasing prevalence of such cases. [ABSTRACT FROM AUTHOR]

Cardiac sarcoidosis is an infiltrative cardiomyopathy that results from granulomatous inflammation of the myocardium and may present with high-grade conduction disease, ventricular arrhythmias, and right or left ventricular dysfunction. Over the past several decades, the prevalence of cardiac sarcoidosis has increased. Definitive histological confirmation is often not possible, so clinicians frequently face uncertainty about the accuracy of diagnosis. Hence, the likelihood of cardiac sarcoidosis should be thought of as a continuum (definite, highly probable, probable, possible, low probability, unlikely) rather than in a binary fashion. Treatment should be initiated in individuals with clinical manifestations and active inflammation in a tiered approach, with corticosteroids as first-line treatment. The lack of randomized clinical trials in cardiac sarcoidosis has led to treatment decisions based on cohort studies and consensus opinions, with substantial variation observed across centers. This scientific statement is intended to guide clinical practice and to facilitate management conformity by providing a framework for the diagnosis and management of cardiac sarcoidosis. [ABSTRACT FROM AUTHOR]

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

Background: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4+ T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment. Therefore, we aimed to correlate frequencies and phenotypes of circulating T cells at baseline with the pulmonary function response at 3 and 12 months during prednisone treatment in patients with pulmonary sarcoidosis. Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect. Results: Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p < 0.0001) between baseline and 3 months. Good response to prednisone (defined as absolute FVC increase of ≥ 10% predicted) was observed in 12 patients. CD4+ memory T cells and regulatory T cells from patients with sarcoidosis displayed an aberrant phenotype at baseline, compared to HCs. Good responders at 3 months had significantly increased baseline proportions of PD-1+CD4+ memory T cells and PD-1+ regulatory T cells, compared to poor responders and HCs. Moreover, decreased fractions of CD25+ cells and increased fractions of PD-1+ cells within the CD4+ memory T cell population correlated with ≥ 10% FVC increase at 12 months. During treatment, the aberrantly activated phenotype of memory and regulatory T cells reversed. Conclusions: Increased proportions of circulating PD-1+CD4+ memory T cells and PD-1+ regulatory T cells and decreased proportions of CD25+CD4+ memory T cells associate with good FVC response to prednisone in pulmonary sarcoidosis, representing promising new blood biomarkers for prednisone efficacy. Trial registration: NL44805.078.13 [ABSTRACT FROM AUTHOR]

Introduction: Due to the increasing prevalence of immune‐mediated diseases such as psoriasis, lichen planus, rheumatoid arthritis and inflammatory bowel disease, dermatologists have turned to new biologic drugs known as DMARDs (disease‐modifying anti‐rheumatic drugs) in recent years. Areas Covered: In this study, we evaluate the immune‐mediated dermatological side effects of DMARDS by reviewing and analyzing previous peer‐reviewed research on the effects of TNF‐α inhibitors in the treatment of skin diseases, as well as adverse effects of these drugs and some of the main causes of these effects. Expert Opinion: DMARDs are very effective in improving control of the above diseases. TNF‐α inhibitors are an important group of DMARDs that are widely used. The paradoxical adverse events (PAEs) associated with the use of TNF‐α inhibitors are divided into three categories: true paradoxical, borderline paradoxical, and non‐paradoxical. True PAEs include conditions for which TNF‐α inhibitors are approved for treatment. Borderline PAEs are considered to occur with this class of drugs for which there is no definite approval but for which there is sufficient evidence. Although these events are rare, early recognition of the accused drug and appropriate decision‐making may prevent progression of complications and irreversible side effects. [ABSTRACT FROM AUTHOR]

Objectives Effective steroid-sparing therapies for the treatment of sarcoidosis are lacking; IL-6 antagonists may reduce sarcoidosis disease activity. This study assessed the safety and efficacy of the IL-6 receptor antagonist, sarilumab, in subjects with glucocorticoid-dependent sarcoidosis. Methods This phase II, double-blind, placebo-controlled, randomized withdrawal trial enrolled 15 subjects with biopsy-proven sarcoidosis at Stanford University from November 2019 to September 2022. In period 1, subjects were treated with open-label s.c. sarilumab 200 mg every 2 weeks for 16 weeks, with predefined tapering of prednisone. Subjects who completed period 1 without a sarcoidosis flare entered period 2 and were randomized to continue sarilumab or to receive matching placebo for 12 weeks. The end points included flare-free survival, as well as changes in pulmonary function tests, chest imaging, patient-reported outcomes, and laboratory values. Results Fifteen subjects were enrolled in the study (median age 57 years, 80% male, 73.3% White), and 10 subjects successfully completed period 1. During period 1, 4 of the 15 subjects (26.7%) discontinued due to worsening of their sarcoidosis, and CT chest imaging worsened in 5 of the 15 subjects (35.7%). During period 2, 0 of 2 subjects in the sarilumab group and 1 of 8 subjects (12.5%) in the placebo group had a flare. Treatment with sarilumab 200 mg was generally well tolerated in subjects with sarcoidosis. Conclusion In this double-blind, placebo-controlled, randomized withdrawal trial, a meaningful signal of improvement in subjects with sarcoidosis treated with sarilumab was not observed. Given the small numbers in this study, no definitive conclusions can be drawn. Trial Registration ClinicalTrials.gov, http://clinicaltrials.gov , NCT04008069. [ABSTRACT FROM AUTHOR]

Lymphoproliferation is defined by lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytic organ and tissue infiltration. The most common etiologies of lymphoproliferation are represented by infectious diseases and lymphoid malignancies. However, it is increasingly recognized that lymphoproliferative features can be the presenting sign of rare conditions, including inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Among IEI, lymphoproliferation is frequently observed in autoimmune lymphoproliferative syndrome (ALPS) and related disorders, common variable immunodeficiency (CVID), activated phosphoinositide 3-kinase δ syndrome, and Epstein-Barr virus (EBV)-related disorders. Gaucher disease and Niemann-Pick disease are the most common IEMs that can present with isolated lymphoproliferative features. Notably, other rare conditions, such as sarcoidosis, Castleman disease, systemic autoimmune diseases, and autoinflammatory disorders, should be considered in the differential diagnosis of patients with persistent lymphoproliferation when infectious and malignant diseases have been reasonably ruled out. The clinical features of lymphoproliferative diseases, as well as the associated clinical findings and data deriving from imaging and first-level laboratory investigations, could significantly help in providing the correct diagnostic suspicion for the underlying etiology. This paper reviews the most relevant diseases associated with lymphoproliferation, including infectious diseases, hematological malignancies, IEI, and IEM. Moreover, some practical indications to orient the initial diagnostic process are provided, and two diagnostic algorithms are proposed for the first-level assessment and the approach to persistent lymphoproliferation, respectively. [ABSTRACT FROM AUTHOR]

Patients with sarcoidosis who develop severe clinical phenotypes of pulmonary fibrosis or multiorgan disease experience debilitating symptoms, with fatigue being a common chief complaint. Studies that have investigated this patient-related outcome measure (PROM) have used the Fatigue Assessment Scale (FAS), a self-reported questionnaire that reflects mental and physical domains. Despite extensive work, its cause is unknown and treatment options remain limited. Previously, we showed that the plasma of patients with sarcoidosis with extrapulmonary disease endorsing fatigue was enriched for mitochondrial DNA (mtDNA), a ligand for the innate immune receptor toll-like receptor 9 (TLR9). Through our cross-disciplinary platform, we investigated a relationship between sarcoidosis-induced fatigue and circulating mtDNA. Is there a psychobiologic mechanism that connects sarcoidosis-induced fatigue and mtDNA-mediated TLR9 activation? Using a local cohort of patients at Yale (discovery cohort) and the National Institutes of Health-sponsored Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study (validation cohort), we scored the FAS and quantified in the plasma, mtDNA concentrations, TLR9 activation, and cytokine levels. Although FAS scores were independent of corticosteroid use and Scadding stage, we observed a robust association between FAS scores, which included mental and physical domains, and multiorgan sarcoidosis. Subsequently, we identified a significant correlation between plasma mtDNA concentrations and all domains of fatigue. Additionally, we found that TLR9 activation is associated with all aspects of the FAS and partially mediates this PROM through mtDNA. Last, we found that TLR9-associated soluble mediators in the plasma are independent of all facets of fatigue. Through our cross-disciplinary translational platform, we identified a previously unrecognized psychobiologic connection between sarcoidosis-induced fatigue and circulating mtDNA concentrations. Mechanistic work that investigates the contribution of mtDNA-mediated innate immune activation in this PROM and clinical studies with prospective cohorts has the potential to catalyze novel therapeutic strategies for this patient population and those with similar conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

Mycobacterium avium‐intracellulare (MAC) infection may have different skin manifestations, including cutaneous granulomas. Granulomatous skin reactions have distinct morphologic and histopathologic appearances. We present the case of an adolescent male with cutaneous MAC, misdiagnosed as sarcoidosis after initial biopsy results, demonstrated preservation of reticulin fibers and absence of organisms within granulomas. Sarcoidal granulomas often stain positive for reticulin fibers, which could be used to distinguish them from the infectious kind. This case should alert clinicians to the fact that the presence or quantity of intact reticular fibers may not be a reliable tool to differentiate between a sarcoidal and an infectious granuloma. Our case also highlights the diagnostic challenge of cutaneous MAC infection. [ABSTRACT FROM AUTHOR]

Background Sarcoidosis is a rare, multisystem, inflammatory condition associated with the formation of granulomas. Diagnosis can be challenging because of non-specific symptoms complicating epidemiological investigations of its aetiology. Despite research efforts, a review of the current state of the evidence is needed. Aims To assess the evidence for an association between occupational exposures and the development of sarcoidosis. To determine if workers in any occupation are at a greater risk of developing sarcoidosis. Methods This rapid review follows the methodology suggested by the World Health Organization. Two electronic databases were systematically searched until April 2022. The methodological quality of the studies was critically appraised, and a best-evidence approach was used to synthesize the results. Results Titles and abstracts of 2916 articles were screened, with 67 full-text articles reviewed for eligibility. Among the 13 studies eligible for this review, none were of high quality (i.e. low risk of bias). Six studies exploring the association between sarcoidosis and a range of occupations and exposures, and one previous systematic review were of low quality reporting inconsistent findings. Six studies examined the risk of sarcoidosis associated with occupational silica exposure, two of which were of acceptable quality. Overall, the study methodologies and results were inadequate to support causal relationships. Conclusions There is limited evidence of acceptable methodological quality to assess the risk of sarcoidosis associated with occupational exposures. There is a growing body of research examining occupational exposure to silica and sarcoidosis. Additional high-quality confirmatory research is needed. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a patient who presented with symptoms of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) preceded by macrophage activation syndrome (MAS). The patient was found to have a homozygous hypomorphic mutation in the PRF1 gene associated with familial hemophagocytic lymphohistiocytosis (fHLH). The study suggests that CLIPPERS features may be seen in patients with fHLH gene mutations and highlights the importance of screening for fHLH in patients with CLIPPERS, especially those with atypical CNS findings or systemic signs of HLH. The use of anti-TNF-alpha therapy may be considered as a steroid-sparing treatment option for these patients. [Extracted from the article]

Background: Sarcoidosis is a multisystem inflammatory disorder characterized by non-caseating granulomas with predominantly lung manifestations that can cause restrictive or, less commonly, obstructive lung disease. Rarely is pneumothorax a manifestation of sarcoidosis; it has been reported as an early finding in sarcoidosis, but it is typically attributed to ruptured bullae, cysts, or pleural granulomas. Case Presentation: We present a unique case of spontaneous pneumothorax attributed to biopsy-proven sarcoid disease in a patient with no prior history of pulmonary complications. The patient’s rapid development of novel pulmonary sequelae necessitates treatment of sarcoidosis early in the disease course. Conclusion: We recommend a treatment plan of appropriate chest tube placement in the affected lung(s) and prompt steroid therapy for patients with sarcoidosis presenting with a pneumothorax. We also review the literature for the etiology, pathophysiology, and presentation of pneumothorax in sarcoidosis, treatment of this sequela, and pulmonary function test findings in these patients. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to outline the demographic data, clinical spectrum, and treatment approach of sarcoidosis in a large group of patients and sought to figure out the variations of early-onset (EOS) and late-onset paediatric sarcoidosis (LOS). Methods: The study followed a retrospective-descriptive design, with the analysis of medical records of cases diagnosed as paediatric sarcoidosis. Results: Fifty-two patients were included in the study. The median age at disease onset and follow-up duration were 83 (28.2–119) and 24 (6–48) months, respectively. Ten (19.2%) cases had EOS (before 5th birthday) and 42 (80.7%) cases had LOS. The most common clinical findings at the time of the disease onset were ocular symptoms (40.4%) followed by joint manifestation (25%), dermatological symptoms (13.5%), and features related to multi-organ involvement (11.5%). Anterior uveitis was the most common (55%) one among ocular manifestations. Patients with EOS displayed joint, eye, and dermatological findings more commonly than patients with LOS. The recurrence rate of disease in patients with EOS (5.7%) and LOS (21.1%) were not statistically different (P = .7). Conclusions: Patients with EOS and LOS may present with variable clinical features and studies addressing paediatric sarcoidosis cases in collaboration between disciplines will enhance the awareness of this rare disease among physicians and assist early diagnosis with lesser complications. [ABSTRACT FROM AUTHOR]

This document is a letter published in the Archives of Dermatological Research that discusses a cross-sectional analysis of the All of Us database to understand hypertrophic scars (HTS) in underrepresented groups. The study found that HTS patients were more likely to be Black, Asian, and female, while patients over 65, without health insurance, with lower education, and low income had lower odds of HTS. Patients with HTS also had a higher odds of various comorbidities. The letter includes two tables that provide information on the prevalence of certain characteristics and comorbidities in individuals with HTS compared to those without HTS. The study highlights the importance of early identification of at-risk populations and the need for improved accessibility and affordability of HTS diagnosis and treatment. [Extracted from the article]

Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the VKORC1 C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: n = 23), those with hypercalcemia without nephrolithiasis (Group II: n = 38), and those without nephrolithiasis or hypercalcemia (Group III: n = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no VKORC1 polymorphisms (OR = 7.73; 95% CI 1.79–33.4; p = 0.001). The presence of a VKORC1 C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying VKORC1 C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings. [ABSTRACT FROM AUTHOR]

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

Background: Sarcoidosis is a chronic inflammatory granulomatous disease of unknown cause. Delays in diagnosis can result in disease progression and poorer outcomes for patients. Our aim was to review the current literature to determine the overall diagnostic delay of sarcoidosis, factors associated with diagnostic delay, and the experiences of people with sarcoidosis of diagnostic delay. Methods: Three databases (PubMed/Medline, Scopus, and ProQuest) and grey literature sources were searched. Random effects inverse variance meta-analysis was used to pool mean diagnostic delay in all types of sarcoidosis subgroup analysis. Diagnostic delay was defined as the time from reported onset of symptoms to diagnosis of sarcoidosis. Results: We identified 374 titles, of which 29 studies were included in the review, with an overall sample of 1531 (694 females, 837 males). The overall mean diagnostic delay in all types of sarcoidosis was 7.93 months (95% CI 1.21 to 14.64 months). Meta-aggregation of factors related to diagnostic delay in the included studies identified three categories: (1) the complex and rare features of sarcoidosis, (2) healthcare factors and (3) patient-centred factors. Meta-aggregation of outcomes reported in case studies revealed that the three most frequent outcomes associated with diagnostic delay were: (1) incorrect diagnosis, (2) incorrect treatment and (3) development of complications/disease progression. There was no significant difference in diagnostic delay between countries with gatekeeper health systems (where consumers are referred from a primary care clinician to specialist care) and countries with non-gatekeeper systems. No qualitative studies examining people's experiences of diagnostic delay were identified. Conclusion: The mean diagnostic delay for sarcoidosis is almost 8 months, which has objective consequences for patient management. On the other hand, there is a paucity of evidence about the experience of diagnostic delay in sarcoidosis and factors related to this. Gaining an understanding of people's experiences while seeking a diagnosis of sarcoidosis is vital to gain insight into factors that may contribute to delays, and subsequently inform strategies, tools and training activities aimed at increasing clinician and public awareness about this rare condition. Trial registration: PROSPERO Registration number: CRD42022307236. [ABSTRACT FROM AUTHOR]

A 70-year-old female patient was admitted for close examination and treatment of hypercalcemia (corrected serum calcium levels: 3.04 mmol/L) and renal dysfunction (serum creatinine levels: 254.59 µmol/L). The patient had a history of sarcoidosis, diagnosed based on epithelioid cell granulomas in subcutaneous nodule biopsies, uveitis, and bilateral hilar lymphadenopathy, which had spontaneously remitted 10 years before admission. Because the patient was diagnosed with hypercalcemia associated with recurrent sarcoidosis, prednisone (20 mg/day) was initiated, and its dose was tapered following the decrease in serum calcium and creatinine levels. However, the levels of these parameters increased again when the prednisone dose was reduced to ≤ 4 mg/day. We were concerned about glucocorticoid-induced osteoporosis in the patient but hesitated to use first-line bisphosphonates because of renal dysfunction. Therefore, denosumab was initiated to reduce the risk of hypercalcemia, renal dysfunction, and glucocorticoid-induced osteoporosis. Serum creatinine and corrected serum calcium levels subsequently decreased. The prednisone dose could be reduced following repeated denosumab administration. Thus, denosumab can be a multifaceted, beneficial option for sarcoidosis-induced hypercalcemia, as it alleviates renal dysfunction indirectly by normalizing serum calcium levels, facilitates reduction of the glucocorticoid dose, and ameliorates glucocorticoid-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Sarcoidosis-associated pulmonary hypertension (SAPH) is a very severe complication of the disease, largely impacting its morbidity and being one of its strongest predictors of mortality. With the recent modifications of the hemodynamic definition of pulmonary hypertension (mean arterial pulmonary pressure >20 instead of <25 mmHg,) its prevalence is presently not precisely known, but it affects from 3 to 20% of sarcoid patients; mostly, although not exclusively, those with an advanced, fibrotic pulmonary disease. Its gold-standard diagnostic tool remains right heart catheterization (RHC). The decision to perform it relies on an expert decision after a non-invasive work-up, in which echocardiography remains the screening tool of choice. The mechanisms underlying SAPH, very often entangled, are crucial to define, as appropriate and personalized therapeutic strategies will aim at targeting the most significant ones. There are no recommendations so far as to the indications and modalities of the medical treatment of SAPH, which is based upon the opinion of a multidisciplinary team of sarcoidosis, pulmonary hypertension and sometimes lung transplant experts. [ABSTRACT FROM AUTHOR]

Atrioventricular block may be idiopathic or a secondary manifestation of an underlying systemic disease. Cardiac sarcoidosis is a significant underlying cause of high-grade atrioventricular block, posing diagnostic challenges and significant clinical implications. This study aimed to assess the prevalence and clinical characteristics of cardiac sarcoidosis among younger patients presenting with unexplained high-grade atrioventricular block. We evaluated patients aged between 18 and 65 years presenting with unexplained high-grade atrioventricular block, who were systematically referred for cardiac magnetic resonance imaging, positron emission tomography-computed tomography, or both, prior to pacemaker implantation. Subjects with suspected cardiac sarcoidosis based on imaging findings were further referred for tissue biopsy. Cardiac sarcoidosis diagnosis was confirmed based on biopsy results. Overall, 30 patients with high-grade atrioventricular block were included in the analysis. The median age was 56.5 years (interquartile range 53-61.75, years). In 37%, cardiac magnetic resonance imaging, positron emission tomography-computed tomography, or both, were suggestive of cardiac sarcoidosis, and in 33% cardiac sarcoidosis was confirmed by tissue biopsy. Compared with idiopathic high-grade atrioventricular block patients, all cardiac sarcoidosis patients were males (100% vs 60%, P =.029), were more likely to present with heart failure symptoms (50% vs 10%, P =.047), had thicker inter-ventricular septum on echocardiography (12.2 ± 2.7 mm vs 9.45 ± 1.6 mm, P =.002), and were more likely to present with right ventricular dysfunction (33% vs 10%, P =.047). Cardiac sarcoidosis was confirmed in one-third of patients ≤ 65 years, who presented with unexplained high-grade atrioventricular block. Cardiac sarcoidosis should be highly suspected in such patients, particularly in males who present with heart failure symptoms or exhibit thicker inter-ventricular septum and right ventricular dysfunction on echocardiography. [ABSTRACT FROM AUTHOR]

Different patterns of fibrosis on high-resolution CT scans (HRCT) have been associated with reduced survival in some interstitial lung diseases. Nothing is known about HRCT scan patterns and survival in sarcoidosis. Will a detailed description of the extent and pattern of HRCT scan fibrosis in patients with stage IV pulmonary sarcoidosis impact pulmonary function and survival? Two hundred forty patients with stage IV sarcoidosis at two large tertiary institutions were studied. The earliest HRCT scan with fibrosis was reviewed for extent of fibrosis (< 10%, 10%-20%, and > 20%) and presence of bronchiectasis, upper lobe fibrocystic changes, basal subpleural honeycombing, ground-glass opacities (GGOs), large bullae, and mycetomas. Presence of sarcoidosis-associated pulmonary hypertension (SAPH) and pulmonary function testing performed within 1 year of HRCT were recorded. Patients were followed up until last clinic visit, death, or lung transplantation. The mean age was 58.4 years. Seventy-four percent were Black, 63% were female, and mean follow-up was 7.4 years. Death or LT occurred in 53 patients (22%). Thirty-one percent had > 20% fibrosis, 25% had 10%-20% fibrosis, and 44% had < 10% fibrosis. The most common HRCT abnormalities were bronchiectasis (76%), upper lobe fibrocystic changes (36%), and GGOs (28%). Twelve percent had basal subpleural honeycombing, and 32% had SAPH. Patients with > 20% fibrosis had more severe pulmonary impairment, were more likely to have SAPH (53%), and had worse survival (44% mortality; P <.001). Upper lobe fibrocystic changes, basal subpleural honeycombing, and large bullae were associated with worse pulmonary function and worse survival. Patients with basal subpleural honeycombing had the worst pulmonary function and survival (55% mortality; P <.001). GGOs were associated with worse pulmonary function but not worse survival, and mycetomas were associated with worse survival but not worse pulmonary function. A Cox proportional hazards model indicated that basal subpleural honeycombing (hazard ratio, 7.95), diffusion capacity for carbon monoxide < 40% (HR, 5.67) and White race (hazard ratio, 2.61) were independent predictors of reduced survival. HRCT scan features of fibrotic pulmonary sarcoidosis had an impact on pulmonary function and survival. Presence of >20% fibrosis and basal subpleural honeycombing are predictive of worse pulmonary function and worse survival in patients with stage IV pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]

Key content: Sarcoidosis is an uncommon multi‐system disorder characterised by the presence of non‐caseating granulomas. It has a peak incidence between the ages of 20–40 years old.The pathogenesis of sarcoidosis is uncertain; however, it is known to be associated with an exaggerated T helper 1 (TH1) immune response leading to systemic inflammation and granuloma formation.Suppression in TH1 responses in pregnancy leads to disease remission in the majority of pregnancies. Nevertheless, the potential for decompensation in a subgroup remains, and consideration should be given to the pre‐pregnancy state.Sarcoidosis is associated with increased risk of maternal‐fetal morbidity, including growth restriction and pre‐eclampsia. Clinical management should focus on medication optimisation and mitigation of this increased risk. Learning objectives: To understand the clinical features, pathogenesis and diagnosis of sarcoidosis.To understand the effect of pregnancy on sarcoidosis.To understand the effect of sarcoidosis on pregnancy and the related obstetric outcomes.To understand the management of sarcoidosis in pregnancy. Ethical issues: There can be difficulties in appropriate management of medical disorders, such as sarcoidosis, with a limited obstetric evidence base.There are challenges in decision‐making regarding continuation of pregnancy in severe disease with an uncertain evidence base. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multisystem disease, which is diagnosed on a compatible clinical presentation, non-necrotizing granulomatous inflammation in one or more tissue samples, and exclusion of alternative causes of granulomatous disease. Considering its heterogeneity, numerous aspects of the disease remain to be elucidated. In this context, the identification and integration of biomarkers may hold significance in clinical practice, aiding in appropriate selection of patients for targeted clinical trials. This work aims to discuss and analyze how validated biomarkers are currently integrated in disease category definitions. Future studies are mandatory to unravel the diverse contributions of genetics, socioeconomic status, environmental exposures, and other sociodemographic variables to disease severity and phenotypic presentation. Furthermore, the implementation of transcriptomics, multidisciplinary approaches, and consideration of patients' perspectives, reporting innovative insights, could be pivotal for a better understanding of disease pathogenesis and the optimization of clinical assistance. [ABSTRACT FROM AUTHOR]

In sarcoidosis, granulomas develop in multiple organs including the liver and lungs. Although mechanistic target of rapamycin complex 1 (mTORC1) activation in macrophages drives granuloma development in sarcoidosis by enhancing macrophage proliferation, little is known about the macrophage subsets that proliferate and mature into granuloma macrophages. Here, we show that aberrantly increased monocytopoiesis gives rise to granulomas in a sarcoidosis model, in which Tsc2, a negative regulator of mTORC1, is conditionally deleted in CSF1R-expressing macrophages (Tsc2 csf1rΔ mice). In Tsc2 csf1rΔ mice, common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), common monocyte progenitors / monocyte progenitors (cMoPs / MPs), inducible monocyte progenitors (iMoPs), and Ly6Cint CX3CR1low CD14− immature monocytes (iMOs), but not monocyte-dendritic cell progenitors (MDPs) and common dendritic cell progenitors (CDPs), accumulated and proliferated in the spleen. Consistent with this, monocytes, neutrophils, and neutrophil-like monocytes increased in the spleens of Tsc2 csf1rΔ mice, whereas dendritic cells did not. The adoptive transfer of splenic iMOs into wild-type mice gave rise to granulomas in the liver and lungs. In these target organs, iMOs matured into Ly6Chi classical monocytes/macrophages (cMOs). Giant macrophages (gMAs) also accumulated in the liver and lungs, which were similar to granuloma macrophages in expression of cell surface markers such as MerTK and SLAMF7. Furthermore, the gMA-specific genes were expressed in human macrophages from sarcoidosis skin lesions. These results suggest that mTORC1 drives granuloma development by promoting the proliferation of monocyte/neutrophil progenitors and iMOs predominantly in the spleen, and that proliferating iMOs mature into cMOs and then gMAs to give rise to granuloma after migration into the liver and lungs in sarcoidosis. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a leading cause of non‐infectious uveitis that commonly affects middle‐aged individuals and has a female preponderance. The disease demonstrates age, sex and ethnic differences in clinical manifestations. A diagnosis of sarcoidosis is made based on a compatible clinical presentation, supporting investigations and histologic evidence of non‐caseating granulomas, although biopsy is not always possible. Multimodal imaging with widefield fundus photography, optical coherence tomography and angiography can help in the diagnosis of sarcoid uveitis and in the monitoring of treatment response. Corticosteroid remains the mainstay of treatment; chronic inflammation requires steroid‐sparing immunosuppression. Features on multimodal imaging such as vascular leakage may provide prognostic indicators of outcome. Female gender, prolonged and severe uveitis, and posterior involving uveitis are associated with poorer visual outcomes. [ABSTRACT FROM AUTHOR]

Background: Nonexcisional tissue biopsies facilitate pre‐operative confirmation of equine sarcoid yet fear of lesion deterioration currently limits its use in the diagnostic workup. Objectives: To evaluate the effect of a single punch biopsy on tumour growth dynamics [thickness, area, circumference, viral load (VL) and Visual Analog Scale (VAS)]. Animals: Six client‐owned horses with 11 sarcoids of various classification. Materials and Methods: Growth dynamics were recorded on a weekly basis, 12 weeks pre‐ and 24 weeks post‐biopsy. The effect of a single punch biopsy on growth dynamics was estimated by linear mixed‐effect models. Spearman's rank correlation coefficient (SRCC) was calculated to investigate correlations with the number of weeks before and after the intervention. Results: While statistically significant post‐biopsy changes were recorded for all parameters except VL, no parameter was consistently increased after the biopsy intervention. In two of 11 sarcoids, the VL correlation pattern revealed significant strong correlations: sarcoid 6 (pre: r = −0.66, p < 0.05; post: r = 0.81, p < 0.001), increased VL; and sarcoid 8 (pre: r = 0.85, p < 0.001; post: r = 0.17, p > 0.05), no further increase after biopsy. Conclusions and Clinical Importance: Our results indicate that post‐biopsy lesion deterioration is not a general concept that applies to all sarcoids, and both deterioration or improvement are possible outcomes over a 24‐week period. Further clinical studies with a larger sample size are needed before a definitive conclusion can be made. [ABSTRACT FROM AUTHOR]

We report the visual and clinical outcomes of a middle-aged woman who presented with exudative retinal detachment (ERD) secondary to a vasoproliferative tumor (VPT) in an eye with sarcoidosis-associated intermediate uveitis. A 55-year-old woman previously diagnosed with sarcoidosis presented with decreased vision in the left eye (LE). Visual acuity in the LE was counting fingers. She had active vitritis, and a peripheral retinal vascular mass was noted in the superotemporal periphery. The mass was associated with ERD involving the posterior pole. The patient was managed with systemic and intravitreal steroids, and cyclosporine was subsequently added as a steroid-sparing agent. Because of recurrence of ERD, the patient underwent pars plana vitrectomy, and cryotherapy and laser photocoagulation were applied to the VPT. Two months postoperatively, visual acuity in the LE improved to 6/10. There was marked regression of the VPT and total resolution of the ERD. In conclusion, we report a favorable visual and clinical outcome in a patient with VPT-associated ERD who responded to a combination of medical therapy and surgical intervention. VPT may lead to different remote complications, so timely diagnosis of these tumors and proper management of their complications is warranted. [ABSTRACT FROM AUTHOR]

Atypical chemokine receptor 4 (ACKR4), also known as CCX‐CKR, is a member of the chemokine receptor family that lacks typical G protein signaling activity. Instead, ACKR4 functions as a scavenger receptor that can bind and internalize a wide range of chemokines, influencing their availability and activity in the body. ACKR4 is involved in various physiological processes, such as immune cell trafficking and the development of thymus, spleen, and lymph nodes. Moreover, ACKR4 has been implicated in several pathological conditions, including cancer, heart and lung diseases. In cancer, ACKR4 plays a complex role, acting as a tumor suppressor or promoter depending on the type of cancer and the stage of the disease. For instance, ACKR4 may inhibit the growth and metastasis of breast cancer, but it may also promote the progression of hepatocellular carcinoma and gastric cancer. In inflammatory situations, ACKR4 has been found to modulate the recruitment and activation of immune cells, contributing to the pathogenesis of diseases such as myocardial infraction and pulmonary sarcoidosis. The study of ACKR4 is still ongoing, and further research is needed to fully understand its role in different physiological and pathological contexts. Nonetheless, ACKR4 represents a promising target for the development of novel therapeutic strategies for various diseases. Significance Statement: The exploration of Atypical Chemokine Receptor 4 (ACKR4/CCX‐CKR) represents a pivotal and timely endeavor in contemporary research, as it delves comprehensively into both the physiological and pathological landscapes. Investigating the multifaceted roles of ACKR4 across these contexts not only enhances our understanding of its fundamental biological functions but also sheds light on its potential implications in various diseases. This research contributes significantly to the current knowledge in cell biochemistry and function, offering insights that could pave the way for novel therapeutic interventions and diagnostic strategies. The comprehensive examination of ACKR4 aligns with the evolving landscape of molecular and cellular research, positioning it as a crucial player in unraveling the intricacies of cellular signaling and function, thereby advancing the frontiers of scientific knowledge in the field. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multisystem disorder of unknown etiology. The leading hypothesis involves an antigen-triggered dysregulated T-cell-driven immunologic response leading to non-necrotic granulomas. In cardiac sarcoidosis (CS), the inflammatory response can lead to fibrosis, culminating in clinical manifestations such as atrioventricular block and ventricular arrhythmias. Cardiac manifestations frequently present as first and isolated signs or may appear in conjunction with extracardiac manifestations. The incidence of sudden cardiac death (SCD) is high. Diagnosis remains a challenge. For a definite diagnosis, endomyocardial biopsy (EMB) is suggested. In clinical practice, compatible findings in advanced imaging using cardiovascular magnetic resonance (CMR) and/or positron emission tomography (PET) in combination with extracardiac histological proof is considered sufficient. Management revolves around the control of myocardial inflammation by employing immunosuppression. However, data regarding efficacy are merely based on observational evidence. Prevention of SCD is of particular importance and several guidelines provide recommendations regarding device therapy. In patients with manifest CS, outcome data indicate a 5-year survival of around 90% and a 10-year survival in the range of 80%. Data for patients with silent CS are conflicting; some studies suggest an overall benign course of disease while others reported contrasting observations. Future research challenges involve better understanding of the immunologic pathogenesis of the disease for a targeted therapy, improving imaging to aid early diagnosis, assessing the need for screening of asymptomatic patients and randomized trials. [ABSTRACT FROM AUTHOR]