Sarcoidosis is a complex, multi-system granulomatous disease characterized by immune dysregulation and chronic inflammation, primarily affecting the lungs. To identify cell specific molecular changes associated with sarcoidosis development and progression, we aimed to characterize cellular composition, gene expression patterns, and cell-cell interactions in bronchoalveolar lavage (BAL) cells from patients with pulmonary sarcoidosis and healthy controls. Single cell RNA-seq on 16 sarcoidosis cases (8 progressive and 8 non-progressive) and 14 controls were analyzed to identify differences in cell proportions by disease group using F-tests and differential gene expression (DE) using pseudobulk analysis. Enriched pathways and upstream regulators were identified using Ingenuity Pathway Analysis (IPA). Cell-to-cell communication and ligand-receptor interaction analyses were performed using CellChat. We identified significant DE of genes and pathways associated with sarcoidosis in resident macrophages (upregulation of IL1R1, PSTPIP2, TAPBP), recruited macrophages (downregulation of AKT1, ACKR3, AZU1), and proliferating macrophages (upregulation of CCL4). We also observed a limited number of DE transcripts associated with disease progression in resident and recruited macrophages. In non-macrophages cells, we observed a significant reduction in the number of B cells in sarcoidosis. Among T cell populations, we identified specific transcriptional alterations at gene and pathway levels. Most changes in upstream regulators were observed in CD4+ T cells, including activation of TNF, IFNG, and IL1B. We observed distinct differences in cell-to-cell interactions of macrophages and T cells between sarcoidosis patients and controls. While overall cell interactions were reduced in sarcoidosis, there was a relative increase in CD4+ T cell interactions, indicating a potential shift in immune dynamics. Key disruptions observed included downregulation of LGALS9-CD45 signaling. These findings underscore the complexity of immune cell involvement in pulmonary sarcoidosis and highlight potential cellular and molecular targets
Pulmonary fibrosis is a severe chronic lung disease whose prevalence has been rising in recent years, representing one of the major respiratory health challenges globally in the 21st century. The burden of this disease on the elderly population is garnering growing attention, particularly as the global population ages. The Global Burden of Disease (GBD) study has provided valuable insights; however, systematic analyses focused on this condition remain limited. To date, few studies have specifically examined interstitial lung disease and pulmonary sarcoidosis among individuals aged 55 years and older. This study aims to conduct a comprehensive analysis of burden trends from 1990 to 2021 for those aged 55 and above and to project future trends up to 2035. Our approach utilizes the estimation of four broad component measures: incidence, prevalence, death and Disability-Adjusted Life Years (DALYs), using data on ILD&PS from the Global Burden of Disease (GBD) 2021 database. Joinpoint regression models were applied to calculate the average annual percentage change (AAPC) in order to analyze temporal trends in disease burden and to identify years with significant trend shifts. Analyses were further stratified by age, sex, region, country, and Sociodemographic Index (SDI). Additionally, a Bayesian age-period-cohort (BAPC) model was used to project future disease burden trends. Between 1990 and 2021, significant increases were observed in incidence, DALYs, and death rates for ILD&PS (AAPC incidence = 1.09, 95% CI: 1.04 to 1.15; AAPC DALYs = 1.10, 95% CI: 0.97 to 1.23; AAPC death = 1.65, 95% CI: 1.47 to 1.83). In 2021, the total number of incident cases reached 284,887 (95% UI 248,300-328,800), with the highest incidence rates observed in Andean Latin America. Across age- and sex-specific analyses, global burden trends were similar, though males consistently exhibited higher
Immune-mediated cochleovestibular dysfunction has gained recognition as an important yet frequently overlooked entity in recent decades. These disorders-ranging from isolated inner-ear syndromes to cochleovestibular manifestations of systemic autoimmune diseases-exhibit humoral or cellular immune attacks on inner-ear structures, commonly accompanied by microvascular injury and inflammatory cascades. Despite increasing awareness, the precise pathophysiological mechanisms remain incompletely understood for most conditions, and diagnostic and therapeutic approaches vary considerably. This narrative review summarizes current evidence on immune-mediated cochleovestibular disorders, dividing them into two main categories (1): primary Isolated disorders (delayed endolymphatic hydrops, bilateral vestibulopathy, and Ménière's disease with established or suspected autoimmune features) (2) cochleovestibular manifestations of rheumatologic diseases (systemic lupus erythematosus, multiple sclerosis, autoimmune thyroid disease, Behçet's disease, Vogt-Koyanagi-Harada disease, psoriasis, Cogan's syndrome, Susac syndrome, Sarcoidosis, Rheumatoid arthritis, Necrotizing vasculitides with polyangiitis and Giant cell arteritis). We examine their clinical features, proposed immune and microvascular mechanisms, diagnostic evaluation, and current management strategies, with particular emphasis on immunomodulatory and immunosuppressive therapies. Systemic corticosteroids at high doses are the primary treatment for most of these disorders, though the ideal duration, tapering protocols, and indications for steroid-sparing medications differ significantly across various syndromes. Evidence supporting many adjunctive therapies is limited or conflicting, underscoring the need for higher-quality clinical trials. Early recognition and prompt immunomodulatory treatment can often reverse or stabilize symptoms in immune-mediated cochleovestibular dysfunction. This review offers a clinically oriented synthesis of current evidence, elucidating the complex immunological underpinnings and the corresponding therapeutic landscape of these disorders. By integrating otologic and rheumatologic perspectives, we aim to heighten awareness, promote earlier diagnosis, and inform more effective treatment of patients presenting with vertigo, hearing loss, or imbalance suggestive of immune-mediated inner-ear pathology.
A newsletter destaca que a sequência terapêutica na osteoporose é crítica, revelando que o uso de teriparatida após romosozumabe pode resultar em perda de força óssea estrutural. Além disso, fornece uma revisão detalhada sobre a sarcoidose extrapulmonar, enfatizando a importância da triagem cardíaca e ocular sistemática e o papel de exames avançados como PET-CT e RM cardíaca no manejo da doença.
Sarcoidosis is a multisystem chronic inflammatory disorder of unknown etiology that primarily affects the lungs and currently has no cure. Macrophages are central to granuloma formation, and βc cytokines tightly regulate their activation and function. This study investigates the role of the βc receptor in granuloma development and evaluates βc antagonism as a potential therapeutic strategy for sarcoidosis. We utilized an in vitro model of human granuloma formation using sarcoidosis patient human peripheral blood mononuclear cells (PBMCs) and an in vivo vimentin-induced pulmonary sarcoidosis model in unique humanized βc transgenic (hβcTg) mice to assess the efficacy of βc antagonism in reducing granuloma formation and evaluate the underlying mechanism of action. Anti-βc receptor antibody, CSL311, significantly reduced the formation of human granulomas from PBMCs exposed to purified protein derivative and decreased the pro-inflammatory cytokine production by the granulomas. Mechanistically, CSL311 inhibited hyperactivation of mTOR signaling and reduced lipid droplet formation in granuloma macrophages. In hβcTg mice challenged with vimentin, CSL311 effectively reduced both granuloma size and immune cell infiltration in the lung. RNA sequencing analysis of lung tissue further showed that CSL311 treatment suppressed the activation of vimentin-induced inflammatory, fibrotic, and lipid metabolic pathways. We identified that βc cytokines are critical regulators in driving inflammatory and metabolic processes that lead to granuloma formation in sarcoidosis. Precisely targeting the βc receptor effectively disrupts these pathogenic networks and offers a promising new strategy for mitigating sarcoidosis immunopathology.
IgG4-related disease (IgG4-RD) is a chronic immune-mediated disease characterised by mass-forming lesions. The smouldering tempo and often asymptomatic nature of IgG4-RD pose challenges in the monitoring of disease activity. The goal of this study is to identify novel biomarkers capable of distinguishing active disease from remission. Ninety-two inflammation-associated proteins were measured across 67 patients with IgG4-RD, 49 healthy donors (HDs), and 21 patients with sarcoidosis. Statistical analyses were adjusted for age, sex, race, and false discovery rate. Biomarkers that distinguished IgG4-RD were studied by unsupervised hierarchical clustering, receiver operator characteristic curves, and statistical analyses. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to validate findings in a cohort of 80 patients with IgG4-RD, including 28 patients with paired longitudinal samples, and 80 age, sex, and race-matched HDs. Twelve inflammation-associated proteins distinguished IgG4-RD. Although most markers correlated with one another, CCL19, CCL2, and CCL13 were the most distinguishing of IgG4-RD. Among these, only CCL19 decreased during treatment-induced remission relative to active IgG4-RD. CCL19 correlated with clinical and laboratory parameters of disease activity and severity. Quantitative ELISA validated the systemic elevation of CCL19 in patients with IgG4-RD. CCL19 performed similarly to IgG4 in dynamically declining in response to treatment and increasing with subsequent relapse. Importantly, CCL19 and IgG4 supplemented one another in distinguishing active disease from remission. CCL19 is a novel and promising biomarker for the longitudinal monitoring of disease activity in patients with IgG4-RD and may provide supplemental value to IgG4 in identifying relapsing disease.
Sarcoidosis is a heterogeneous granulomatous disease with highly variable clinical trajectories, yet no validated biomarkers exist to distinguish progressive sarcoidosis (P-sarcoidosis) from non-progressive disease (NP-sarcoidosis). This lack of tractable biomarkers limits early risk stratification and impedes therapeutic decision-making. Preliminary data from our group suggest that P-sarcoidosis and NP-sarcoidosis may be differentiated by blood-derived and peripheral blood mononuclear cell (PBMC)-derived molecular signatures, as well as ex vivo granuloma biogenesis in response to putative disease-causing antigens. This protocol describes a multi-omic study aimed at identifying mechanistically grounded, clinically translatable biomarkers that distinguish P-sarcoidosis from NP-sarcoidosis. We will perform an integrative proteomic and transcriptomic analysis across three biological compartments: ex vivo granuloma model, PBMCs and plasma. Participants with clinically adjudicated P-sarcoidosis or NP-sarcoidosis will provide blood samples for multi-omic profiling. P-sarcoidosis versus NP-sarcoidosis phenotype will be assessed based on changes in spirometry, diffusing capacity for carbon monoxide, chest radiography and need for treatment for pulmonary symptoms. Patient-reported outcomes will also be recorded. Data-driven computational approaches will be used to identify molecular pathways associated with granuloma formation and disease persistence and to develop a classifier that distinguishes P-sarcoidosis from NP-sarcoidosis. Rigorous internal validation, feature-selection procedures and statistical controls for high-dimensional data will be applied. Candidate biomarkers emerging from multi-compartment integration will be prioritised based on biological coherence, reproducibility and clinical feasibility. The study protocol has been approved by the Biomedical Research Alliance of New York, serving as a single Institutional Review Board (IRB) for the project (IRB # 23-02-503), as well as at National Jewish Health (IRB# HS-4091), University of Minnesota (STUDY00020121/SITE00002051) and The Ohio State University (IRB# 2023X0140). All participants will provide informed consent prior to enrolment. Results will be disseminated through peer-reviewed
Chronic respiratory diseases (CRDs) are a growing global health concern. Emerging evidence implicates circulating metabolites in their development and progression, but definitive causal insights into how metabolic patterns influence disease pathways remain limited. We conducted a two-sample Mendelian randomization (MR) analysis to evaluate potential causal effects of 1400 serum metabolites on 5 major CRDs: chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sarcoidosis, and pneumoconiosis. Each disease was analyzed separately; no composite CRD outcome was constructed. The inverse-variance weighted method was the primary approach, complemented by MR-Egger, weighted median, and MR-PRESSO for outlier detection and correction. Robustness was examined using sensitivity analyses, including Cochran Q for heterogeneity, MR-Egger intercept for directional pleiotropy, the MR-PRESSO global test, and leave-one-out analyses. MR analyses identified significant causal associations between multiple metabolites/metabolite ratios and the 5 CRDs, revealing distinct metabolic profiles for each disease. For COPD, we found 54 potentially causal metabolites (30 risk, 24 protective). Asthma showed 36 associations (13 risk, 20 protective). IPF had 39 (22 risk, 17 protective). Sarcoidosis exhibited the broadest signature with 69 associations (24 risk, 45 protective). Pneumoconiosis showed 53 (25 risk, 28 protective). Most signals were disease-specific; only a small subset overlapped across at least 2 diseases (e.g., four shared between COPD and sarcoidosis, two between pneumoconiosis and asthma), suggesting partially shared pathways. No metabolite displayed consistent associations across all 5 diseases. Circulating metabolites exhibit protective or detrimental causal effects on COPD, asthma, IPF, sarcoidosis, and pneumoconiosis. Effects are heterogeneous and largely disease-specific, with limited overlap across conditions, indicating predominantly distinct etiologic pathways and offering mechanistic insights that may inform risk stratification and target prioritization. Further validation using integrated multi-omics and experimental models is warranted
To characterise the key epidemiological, clinical, immunological, imaging, and pathological features of the coexistence between sarcoidosis and spondyloarthritis (SpA). All centres included in two large multicentre registries (the Sjögren Syndrome Big Data Consortium and the Sarco-GEAS-SEMI Registry) identified potential cases of coexisting SpA and sarcoidosis. Inclusion criteria were the fulfilment of the current classification criteria both for SpA (ASAS) and sarcoidosis (WASOG). We identified twenty-three patients (14 females and 9 males) with a mean age of 44 years at diagnosis of SpA and of 45 years at diagnosis of sarcoidosis. Most of the patients fulfilled the ASAS criteria for axial SpA. In 8 patients, sarcoidosis was diagnosed after SpA, in 9 patients sarcoidosis preceded SpA and in 6 patients the diagnoses were concurrent. Within these groups, the HLA*B-27 haplotype was detected in 5 (62%), 2/8 (25%) and 3 (50%) of patients respectively. A median of 2 years (range 1-19) occurred between the diagnosis of the two diseases in the first 2 groups. Lung, skin, and extra-thoracic lymph nodes were the most frequent sarcoidosis manifestations in all 3 groups. We have characterised 23 patients who fulfilled the current classification criteria for both SpA and sarcoidosis. Therefore, sarcoidosis may coexist with SpA like other systemic autoimmune diseases, and this may be explained by shared pathogenic mechanisms. Since Th17 cells are leading actors in the pathogenesis of both SpA and sarcoidosis, these cells may be the missing link connecting the two diseases.
To evaluate changes in cardiac magnetic resonance (CMR) tissue characteristics in patients with active cardiac sarcoidosis (CS) confirmed by positron emission tomography (PET)-CT undergoing immunomodulatory therapy (IMT), and to explore their potential use for inflammation monitoring. Retrospective observational cohort study. Tertiary care referral centre in Germany. From a cohort of 47 patients with CS, 24 patients with PET-confirmed active myocardial inflammation and complete baseline and follow-up CMR imaging after ≥6 months of IMT were included. Primary outcome: Changes in CMR-derived tissue characteristics (T1, T2 mapping, late gadolinium enhancement (LGE) mass). Changes in functional (ejection fraction (EF) and global longitudinal strain (GLS)) and morphological parameters (end-diastolic/systolic volume indices (EDVi/ESVi)). Patients with PET-confirmed active CS show increased global T1 and T2 compared with healthy volunteers. Over the course of IMT, significant reductions in global T2 (median (IQR): 39 (38-41) ms vs 37 (36-39) ms; p=0.002), LGE-region T2 (43 (40-46) ms vs 41 (38-42) ms; p=0.003), and relative LGE mass (23% (17-38) vs 15% (8-32); p=0.006) were observed. No significant differences were found in EF (p=0.78), GLS (p=0.49), EDVi (p=0.56), ESVi (p=0.28) or native T1 values (p=0.23). In patients with PET-confirmed active CS undergoing IMT, serial CMR demonstrated measurable changes in T2 mapping and LGE parameters, suggesting a potential role for CMR tissue characterisation in monitoring myocardial inflammation. However, due to the observational design and absence of a control group, causal treatment effects cannot be confirmed. Further prospective studies are needed to validate the utility of CMR for treatment monitoring in CS.
Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, pneumoconiosis, interstitial lung disease (ILD) and pulmonary sarcoidosis, are major global causes of mortality and morbidity. Although the COVID-19 pandemic has influenced acute respiratory health, its impact on chronic respiratory conditions remains unclear. We estimated the global, regional and national burden of chronic respiratory diseases from 1990 to 2023, including risk factors, and evaluated how these burdens have shifted during the COVID-19 pandemic using the Global Burden of Disease Study 2023. In 2023, chronic respiratory diseases accounted for 569.2 million (95% uncertainty interval (UI), 508.8-639.8) cases and 4.2 million (3.6-5.1) deaths. The age-standardized death rate declined by 25.7% globally from 1990 to 2023 despite an increase in ILD and pulmonary sarcoidosis. Mortality declined in younger males, especially for asthma, whereas older adults experienced a rise in ILD and pulmonary sarcoidosis. Smoking was the primary risk factor for COPD, whereas high body mass index and silica exposure were key risk factors for asthma and pneumoconiosis. During the pandemic, the incidence of chronic respiratory diseases increased modestly, but the decline in mortality rates became more pronounced, highlighting the need for sustained global attention and action to address their long-term burden.
Sarcoidosis is a multisystem disorder with variable presentation and disease course. Diagnosis requires the exclusion of other causes of granulomatous inflammation. Current clinical management is often fraught with diagnostic uncertainy and the lack of tools to predict pulmonary disease progression. To address these challenges, we designed a study using data from bronchoalveolar lavage (BAL) fluid and cells to develop diagnostic and prognostic tools in patients with pulmonary sarcoidosis. This multicentre study will include discovery and validation cohorts of healthy controls, interstitial lung disease controls and pulmonary sarcoidosis cases from three study sites. Sarcoidosis participants will be grouped into progressive and non-progressive pulmonary disease based on changes in pulmonary function testing, chest radiographs or treatment requirements. The discovery cohort consists of participants with existing BAL fluid, BAL cells, and clinical datasets; the validation cohort will be prospectively enrolled and participants will consent for BAL collection from either a clinical or research bronchoscopy. Untargeted proteomic profiling of BALF along with statistical modelling with variable selection techniques will generate a classifier for diagnosis and prognosis. Targeted proteomics using parallel reaction monitoring-mass spectrometry will be used for internal and external validation. Additionally, BAL cell single-cell gene-expression analysis using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) will be integrated with proteome-wide data to elucidate cell-specific pathways implicated in the development and progression of sarcoidosis. The study will be conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. The protocol has been approved by the Biomedical Research Alliance of New York Institutional Review Board (IRB), which serves as the single IRB across all study sites. The findings of this study will be presented as abstracts at scientific meetings and summarised in
Sarcoidosis is an inflammatory granulomatous disease that affects people worldwide and can involve virtually any organ but most commonly the lungs and thoracic lymph nodes. The cause of sarcoidosis remains unknown, but occupational and environmental exposures, genetic background, and ethnicity are likely contributors to disease development. Recent immunological studies, including single-cell RNA sequencing and spatial transcriptomics, have increased our understanding of disease pathogenesis. Diagnosing sarcoidosis is often challenging due to the lack of a diagnostic gold standard and the remarkable variability in clinical presentation. Accordingly, the diagnosis requires the presence of compatible clinical and radiological features along with histopathological evidence of noncaseating granulomas and exclusion of other granulomatous diseases. The differential diagnosis includes infection, drug-induced granulomatosis, inborn error of immunity, vasculitis and malignancies. Sarcoidosis often resolves spontaneously, but it is not a benign disease. Up to one-third of patients develops chronic or progressive disease, which carries an increased risk of organ failure or death. Treatment is not always required, but is clearly indicated for progressive pulmonary disease, symptomatic cardiac or central nervous system involvement, and significantly impaired quality of life. Treatment aims to decrease symptom burden and preserve organ function. Corticosteroids have been considered first-line treatment for decades, but their long-term use is associated with substantial toxicity. Recently, methotrexate was found to be equally effective as prednisone as first-line treatment in pulmonary sarcoidosis. The identification of novel pathways involved in disease pathogenesis has suggested JAK inhibitors and mTOR inhibitors as potential therapies. More efficacious and better tolerated therapies are urgently needed; however, the rarity of the disease, its heterogeneous clinical course and the lack of prognostic biomarkers make it difficult to design and implement clinical trials of novel therapies.
Pregnancy in systemic autoimmune diseases is associated with increased maternal and fetal morbidity, yet the specific impact of neurological involvement remains poorly characterized. This review synthesizes pregnancy outcomes in systemic lupus erythematosus (SLE), Sjögren's syndrome, sarcoidosis, and Behçet's disease, focusing on neurological manifestations. A narrative review (2010-2025) was conducted via PubMed/MEDLINE. Observational cohorts, registries, and systematic reviews reporting maternal, fetal, and neonatal outcomes were included. Across autoimmune conditions, pregnancy risks are significantly elevated, most pronounced in SLE. Meta-analyses in SLE reported preeclampsia rates of 2-35%, preterm birth in 14.7-50%, and fetal loss up to 21.7%. In sarcoidosis, studies showed increased risks of preeclampsia (OR 1.62) and preterm delivery (OR 1.73), while Sjögren's syndrome was associated with congenital heart block in up to 17.9% of at-risk pregnancies. Neurological manifestations are frequently documented but rarely analyzed as independent risk factors; in one study, neuropsychiatric lupus was associated with higher rates of maternal (38.1% vs 14.1%) and fetal complications, although evidence remains limited and should be interpreted with caution. Neurological involvement is a critical but under-studied dimension of pregnancy risk. Improved phenotyping, multidisciplinary care, and prospective registries are needed to optimize risk stratification and maternal-fetal management.