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Introduction: Early detection of cardiac sarcoidosis (CS) is crucial due to its association with severe complications such as ventricular arrhythmias, heart failure, and sudden cardiac death. Advanced imaging techniques like cardiac magnetic resonance imaging (CMR) and 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) are effective in detecting CS but not easily accessible. The optimal method for selecting patients for advanced screening remains uncertain., Methods: In this retrospective cohort study, all extracardiac sarcoidosis patients screened for CS were reviewed. CS was defined as a multidisciplinary team (MDT) consensus diagnosis. Univariate and multivariate binary logistic regressions were used to identify factors associated with CS, assessing their diagnostic performance, and integrating them into a diagnostic model., Results: Out of 354 patients (average age 51.5 years, 52.5% male), 18.4% were diagnosed with CS. In our cohort, male gender, a QRS duration > 120 ms, and nsVT on Holter monitoring were identified as significant markers associated with CS. Combining age, gender, AV-block or QRS > 120ms on ECG, and nsVT on Holter monitoring provided the highest diagnostic accuracy (AUC of 0.82). Cardiac biomarkers NT-proBNP and troponin T did not improve the diagnostic performance., Conclusion: In our cohort, male gender, a QRS duration > 120 ms, and nsVT on Holter monitoring were identified as significant markers associated with the presence of cardiac sarcoidosis. These clinical markers may aid in selecting sarcoidosis patients for screening with advanced cardiac imaging, potentially leading to earlier detection and management of the disease., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2024. The Author(s).)

At present, no biomarker exists which is truly specific for sarcoidosis and the ones available have modest sensitivity and specificity. The clinical context should dictate the choice of biomarker(s) used to address different clinical questions such as diagnosis, monitoring disease activity or monitoring response to treatment. In the future, in addition to known serum biomarkers, it seems fruitful to further explore a possible role of imaging, exhaled air and even biopsy-related biomarkers in sarcoidosis to guide clinical management., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: No guidelines are available on the preferred method for analyzing corneal confocal microscopy (CCM) data. Manual, semiautomatic, and automatic analyzes are all currently in use. The purpose of the present study was threefold. First, we aimed to investigate the different methods for CCM analysis in patients with and without small fiber neuropathy (SFN). Second, to determine the correlation of different methods for measuring corneal nerve fiber length (CNFL) and nerve fiber area (NFA). Finally, we investigated the added value of automatic NFA analysis., Methods: We included 20 healthy controls and 80 patients with sarcoidosis, 31 with established SFN and 49 without SFN. The CNFL was measured using CCMetrics, ACCMetrics, and NeuronJ. NFA was measured with NFA FIJI and ACCMetrics NFA., Results: CNFL and NFA could not distinguish sarcoidosis with and without SFN or healthy controls. CCMetrics, NeuronJ, and ACCMetrics CNFL highly correlated. Also, NFA FIJI and ACCMetrics NFA highly correlated. Reproducing a nonlinear formula between CNFL and NFA confirmed the quadratic relation between NFA FIJI and ACCMetrics CNFL. CCMetrics and NeuronJ instead showed a square root relationship and seem to be less comparable owing to differences between automatic and manual techniques., Conclusions: ACCMetrics can be used for fully automatic analysis of CCM images to optimize efficiency. However, CNFL and NFA do not seem to have a discriminatory value for SFN in sarcoidosis. Further research is needed to determine the added value and normative values of NFA in CCM analysis., Translational Relevance: Our study improves the knowledge about CCM software and pathophysiology of SFN.

Introduction: Methotrexate (MTX), a folate antagonist, is often used as second-line treatment in patients with sarcoidosis. Effectiveness of MTX has large inter-patient variability and at present therapeutic drug monitoring (TDM) of MTX is not possible. Upon administration, MTX is actively transported into cells and metabolized to its active forms by adding glutamate residues forming MTXPG (n=1-5) resulting in enhanced cellular retention. In this study we address the question whether different MTXPG (n) concentrations in red blood cells (RBC) of patients with sarcoidosis after 3 months of MTX therapy correlate with response to treatment., Methods: We retrospectively included patients with sarcoidosis that had started on MTX therapy and from whom blood samples and FDG-PET/CT were available 3 and 6-12 months after MTX initiation, respectively. FDG-uptake was measured by SUVmax in the heart, lungs and thoracic lymph nodes. Changes in SUVmax was used to determine anti-inflammatory response after 6-12 months of MTX therapy. MTXPG (n) concentrations were measured from whole blood RBC using an LC-MS/MS method. Pearson correlation coefficients were calculated to evaluate the relationship between changes in the SUVmax and MTXPG (n) concentrations., Results: We included 42 sarcoidosis patients treated with MTX (15 mg/week); 31 with cardiac sarcoidosis and 11 with pulmonary sarcoidosis. In MTXPG 3 and MTXPG 4 a significant negative relation between the absolute changes in SUVmax and MTXPG (n) was found r = - 0.312 (n = 42, p = 0.047) for MTXPG 3 and r = - 0.336 (n = 42, p = 0.031 for MTXPG 4 ). The other MTXPG (n) did not correlate to changes in SUVmax., Conclusion: These results suggest a relation between MTXPG (n) concentrations and the anti-inflammatory effect in patients with sarcoidosis. Further prospective validation is warranted, but if measuring MTXPG concentrations could predict treatment effect of MTX this would be a step in the direction of personalized medicine., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The unknown etiology of sarcoidosis, along with the variability in organ involvement and disease course, complicates the effective treatment of this disease. Based on recent studies, the cellular inflammatory pathways involved in granuloma formation are of interest regarding possible new treatment options, such as the mechanistic (formerly mammalian) target of rapamycin complex 1 (mTORC1) pathway, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway. The aim of this study was to explore the potential coexpression of these three inflammatory pathways in patients with sarcoidosis and see whether possible differences were related to disease outcome. The tissue of 60 patients with sarcoidosis was used to determine the activity of these three signaling pathways using immunohistochemistry. The activation of NLRP3 was present in 85% of all patients, and the activation of mTORC1 and JAK/STAT was present in 49% and 50% of patients, respectively. Furthermore, the presence of NLRP3 activation at diagnosis was associated with a chronic disease course of sarcoidosis. Our finding of different new conceptual inflammatory tissue phenotypes in sarcoidosis could possibly guide future treatment studies using the available inhibitors of either NLRP3, JAK-STAT, and mTORC1 inhibitors in a more personalized medicine approach.

Background: Side effects limit the long-term use of glucocorticoids in cardiac sarcoidosis (CS), and methotrexate has gained attention as steroid sparing agent although the supporting evidence is poor. This study compared prednisone monotherapy, methotrexate monotherapy or a combination of both, in the reduction of myocardial Fluorine-18 fluorodeoxyglucose (FDG) uptake and clinical stabilization of CS patients., Methods and Results: In this retrospective cohort study, 61 newly diagnosed and treatment naïve CS patients commenced treatment with prednisone (N = 21), methotrexate (N = 30) or prednisone and methotrexate (N = 10) between January 2010 and December 2017. Primary outcome was metabolic response on FDG PET/CT and secondary outcomes were treatment patterns, major adverse cardiovascular events, left ventricular ejection fraction, biomarkers and side effects. At a median treatment duration of 6.2 [5.7-7.2] months, 71.4% of patients were FDG PET/CT responders, and the overall myocardial maximum standardized uptake value decreased from 6.9 [5.0-10.1] to 3.4 [2.1-4.7] (P < 0.001), with no significant differences between treatment groups. During 24 months of follow-up, 7 patients (33.3%; prednisone), 6 patients (20.0%; methotrexate) and 1 patient (10.0%; combination group) experienced at least one major adverse cardiovascular event (P = 0.292). Left ventricular ejection fraction was preserved in all treatment groups., Conclusions: Significant suppression of cardiac FDG uptake occurred in CS patients after 6 months of prednisone, methotrexate or combination therapy. There were no significant differences in clinical outcomes during follow-up. These results warrant further investigation of methotrexate treatment in CS patients., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Background: Cardiac sarcoidosis (CS) is associated with an increased risk for sudden cardiac death. An implantable cardiac defibrillator (ICD) is recommended in a subgroup of CS patients. However, the recommendations for primary prevention differ between guidelines. The purpose of the study was to evaluate the efficacy and safety of ICDs in CS and to identify predictors of appropriate therapy., Methods: A retrospective cohort study was performed in CS patients with an ICD implantation between 2010 and 2019. Primary outcome was appropriate ICD therapy. Independent predictors were calculated using Cox proportional hazard analysis., Results: 105 patients were included. An ICD was implanted for primary prevention in 79%. During a median follow-up of 2.8 years, 34 patients (32.4%) received appropriate ICD therapy of whom 24 (22.9%) received an appropriate shock. Three patients (2.9%) received an inappropriate shock due to atrial fibrillation. Independent predictors of appropriate therapy included prior ventricular arrhythmias (hazard ratio [HR]: 10.5 [95% confidence interval (CI): 5.0-21.9]) and right ventricular late gadolinium enhancement (LGE) (HR: 3.6 [95% CI: 1.7-7.6]). Within the primary prevention group, right ventricular LGE (HR: 5.7 [95% CI: 1.6-20.7]) was the only independent predictor of appropriate therapy. Left ventricular ejection fraction did not differ between patients with and without appropriate therapy (44.4% vs. 45.6%, p = .70)., Conclusion: In CS patients with an ICD, a high rate of appropriate therapy was observed and a low rate of inappropriate shocks. Prior ventricular arrhythmias and right ventricular LGE were independent predictors of appropriate therapy., (© 2022 Wiley Periodicals LLC.)

Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of interest for sarcoidosis disease pathogenesis. However, sarcoidosis is a heterogeneous disease and contradictory findings for ANXA11 have been reported for disease phenotypes. We performed a case-control association study to investigate if ANXA11 associates with benign (Löfgren's syndrome (LS)) or chronic sarcoidosis and performed a meta-analysis on previously reported findings. A total of 262 sarcoidosis patients, of which 149 had LS and 113 chronic sarcoidosis, and 363 controls were genotyped for rs1049550. Meta-analysis included allele findings for rs1049550 from 6 additional studies. We found a significantly lower T allele frequency in sarcoidosis patients than in healthy controls (0.30 vs. 0.41, respectively, odds ratio (OR) 0.61, 95% confidence interval (CI) 0.48-0.77, p = 3 × 10 -5 ). In LS the T allele frequency of 0.33, and in chronic sarcoidosis the T allele frequency of 0.26 were significantly lower than in healthy controls (OR 0.69, 95% CI 0.52-0.92, p = 0.01 and OR 0.51, 95% CI 0.36-0.70, p = 4 × 10 -5 , respectively). Meta-analysis including previously published European, African American and Asian cohorts confirmed the association of rs1049550 with sarcoidosis and resulted in a pooled OR of 0.70 (CI 0.66-0.75, p = 3.58 × 10 -29 ). Presence of the T allele of rs1049550 in ANXA11 is protective for sarcoidosis, including benign and chronic phenotypes of the disease.

Introduction: The impact of common measures to assess sarcoidosis have not been compared longitudinally to outcomes that are meaningful to patients. We prospectively examined the relationship of baseline measurements of sarcoidosis status to outcomes of interest to patients longitudinally over 6 months., Methods: Sarcoidosis patients cared for at 6 US medical centers were "phenotyped" at baseline with measurements of pulmonary function, organ involvement, health related quality of life (HRQoL) instruments, and their anti-sarcoidosis treatment history. These patients were followed for 6 months by monitoring outcomes of interest to patients (OIPs) including steps walked, calories expended, sleep, HRQoL measures, workdays missed and health care utilization. For each baseline phenotypic measurement, patients were dichotomized into two groups above and below a specified cutoff value. The area under the OIP versus time curve was compared between these two groups., Results: The cutoff values for many baseline phenotypic measures distinguished the patients into groups with significantly different 6-month OIPs. The chosen cutoff for the patient global estimate of health status distinguished the most OIPs (13/15). The 6-min walk distance cutoff was associated with more OIPs than spirometric measures. All of the HRQOL measure cutoffs were associated with many OIPs, although most of them were other HRQOL measures., Interpretation: Cutoffs for most of the phenotypic measures used to assess sarcoidosis distinguished groups of sarcoidosis patients with differing OIPs over the subsequent 6 months. The patients' global assessment of their disease was the most accurate of these measures., Clinical Trial Registration Number: NCT04342403., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Risk stratification for sudden cardiac death (SCD) in cardiac sarcoidosis (CS) is challenging in patients without overt cardiac symptoms., Objective: The purpose of this study was to determine the incidence of ventricular arrhythmias (VAs) and mortality after long-term monitoring with a cardiovascular implantable electronic device (CIED) in CS patients identified after systematic screening of patients with extracardiac sarcoidosis (ECS)., Methods: A retrospective study was performed in 547 predominantly Caucasian patients with ECS screened for cardiac involvement. If CS was diagnosed, risk stratification (high vs low risk) for SCD was performed by a multidisciplinary team. The primary endpoint was defined as sustained VA, appropriate implantable cardioverter-defibrillator (ICD) therapy, or cardiac death., Results: In total, 105 patients were included (mean follow-up 33 ± 16 months). An ICD was implanted in 17 high-risk patients (16.2%), whereas 80 low-risk patients (76.1%) received an implantable loop recorder (ILR). Eight low-risk patients (7.6%) did not receive a device. The primary endpoint occurred in 4.8% (n = 5), with an overall annualized event rate of 1.7%. The annualized event rate was 9.8% in high-risk patients and 0.4% in low-risk patients. Nine low-risk patients received an ICD during follow-up, in 7 patients as a result of the ILR recordings. None of these patients required ICD therapy., Conclusion: In CS patients without overt cardiac symptoms at initial presentation the annualized overall event rate was 1.7%; 10% in high-risk patients, but only 0.4% in low-risk patients. In low-risk patients long-term arrhythmia monitoring with an ILR enabled early detection of clinically important arrhythmias without showing impact on prognosis., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Previous studies mainly described a role for organic agents as possible triggers for sarcoidosis. In this review, we address recent studies suggesting a possible role for inorganic elements, such as metals or silica in sarcoidosis pathogenesis., Recent Findings: Several epidemiological papers suggest that inorganic agents, either by environmental exposures or occupational activities, could trigger sarcoidosis. Association between inorganics and sarcoidosis is also described in several recently published case reports and studies demonstrating immunological sensitization to inorganic agents in sarcoidosis patients.Studies comparing chronic beryllium disease (CBD) and sarcoidosis suggest that although antigenic triggers may differ, underlying processes may be comparable.Besides the fact that a growing number of studies show a possible role for inorganic triggers, it is also suggested that inorganic triggered sarcoidosis may result in a more severe phenotype, including pulmonary fibrosis., Summary: We can use the knowledge already gained on CBD pathogenesis to conduct further research into role of inorganics, such as metals and silica as antigens in sarcoidosis. Given the importance of a lymphocyte proliferation test (LPT) in diagnosing CBD, it seems obvious to also implement this test in the diagnostic work-up of sarcoidosis to identify patients with an inorganic antigenic trigger of their disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and Löfgren's syndrome. Löfgren's syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren's syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with Löfgren's syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1α (MIP-1α) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in Löfgren's syndrome than in healthy controls ( p = 0.0015, confidence interval (CI) 1.22-2.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype ( p = 0.026). A significantly ( p = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 α, compared with patients with the AA genotype. The rs1799987 G allele in CCR5 gene is associated with susceptibility to Löfgren's syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response.

Background: Immunosuppressive therapy in active cardiac sarcoidosis (CS) might prevent potential life-threatening complications. Infliximab (IFX) is a tumor necrosis factor alpha monoclonal antibody proven to be effective in refractory extracardiac sarcoidosis. It is sparsely used in CS, because of its association with worsening heart failure in prior studies. The goal of this study is to assess the effectiveness and safety of IFX in CS., Methods and Results: A retrospective, single center cohort study was performed in sarcoidosis patients treated with IFX based on a cardiac indication between January 2016 and March 2019. Patients received IFX intravenously at a dose of 5 mg/kg at week 0, 2, and subsequently every 4 weeks. After every six months, treatment response was evaluated within the multidisciplinary team using FDG-PET/CT, transthoracic echocardiography, biomarkers and device interrogation reports. Responder analysis definitions were based on; dosage of immunosuppressive drugs, improvement in functional class, left ventricular ejection fraction (LVEF) and SUVmax. Twenty-two patients were included (mean age 51.0 SD10.0 years, male 68.2%) with a mean follow-up of 18.9 months (6 to 44 months) of whom 18 (82%) were classified as responders. Median SUVmax on FDG-PET/CT decreased from SUVmax 5.2 [3.7-8.4] to 2.3 [1.4-2.3], p = 0.015. The target-to-background ratio decreased from 3.2 [2.1-5.1] to 1.0 [0.7-2.4], p = 0.002. The median left ventricular (LV) ejection fraction increased from 45.0% [34.0-60.0] to 55.0% [41.0-60.0], p = 0.02. The majority of patients (73%) experienced no side effects and no patients had worsening of heart failure., Conclusion: In this pilot study, patients with refractory CS treated with infliximab, on top of standard of care, had a reduction in inflammation on FDG-PET/CT and an improvement in LV function, without serious adverse events., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.

The effect of switching from originator infliximab to biosimilar infliximab in patients with sarcoidosis is unknown. The objective of this study is to investigate the effect of switching from Remicade ® or Inflectra ® to Flixabi ® in patients with severe refractory sarcoidosis. This single center retrospective cohort study was performed at St Antonius Hospital Nieuwegein, The Netherlands. All patients diagnosed with severe refractory sarcoidosis receiving Remicade ® or Inflectra ® switched to Flixabi ® . The primary outcome was infliximab discontinuation within 6 months of switching. Secondary endpoints included adverse events and loss of clinical, functional, or inflammatory response. Out of 86 patients who switched to Flixabi ® , 79 patients had complete data. None of the 79 patients discontinued infliximab during the first 6 months after switching. Five patients reported an adverse event related to Flixabi ® treatment. We found no change from baseline in FVC, FEV1, DLCOc, 6MWT, and infliximab trough levels 26 weeks after switching. An improvement in physical functioning of 7.3 ± 13.4 points ( p = 0.002) with RAND/SF36 and in biomarker sIL-2R (-475.58 ± 1452.39; p = 0.005) was observed. Switching from originator infliximab Remicade ® or biosimilar infliximab Inflectra ® to biosimilar infliximab Flixabi ® did not result in treatment discontinuation or loss of clinical/functional/inflammatory remission.

Currently prednisone is the first-line pharmacological treatment option for pulmonary sarcoidosis. Methotrexate is used as second-line therapy and seems to have fewer side-effects. No prospective comparative studies of first-line treatment with methotrexate exist. In this study, we evaluated patient reported presence and bothersomeness of side-effects of prednisone and methotrexate in a sarcoidosis population to guide the design of a larger prospective study. During a yearly patient information meeting 67 patients completed a questionnaire on medication use; 11 patients never used prednisone or methotrexate and were excluded from further analysis. Of the remaining 56 patients, 89% used prednisone and 70% methotrexate (present or former). Significantly more side-effects were reported for prednisone than for methotrexate, 78% versus 49% ( p = 0.006). In conclusion, methotrexate seems to have fewer and less bothersome side-effects than prednisone. These findings need to be confirmed in a prospective study.

Organic and inorganic antigens were studied simultaneously in the same cohort of sarcoidosis patients to investigate whether correlations between clinical characteristics and immunological sensitization could reveal new phenotypes. Sensitization to antigens of mycobacteria, Propionibacterium acnes catalase and vimentin was investigated in 201 sarcoidosis and 51 obstructive sleep apnoea patients, serving as control group. Sensitization to aluminium, beryllium, silica and zirconium was also studied in 105 of the sarcoidosis patients and in 24 of the controls. A significantly higher percentage of sarcoidosis patients (27·6%) than controls (4·2%) had an immunological response to metals or silica (P = 0·014). A higher percentage of these sarcoidosis patients showed fibrosis on chest X-ray 5 years after the diagnosis (69·2 versus 30·3%, P = 0·016). No significant differences in mycobacterial or vimentin enzyme-linked immunospot (ELISPOT) assay results were observed between sarcoidosis and control patients. A significantly lower percentage of sarcoidosis patients (3·5%) than control patients (15·7%) had a positive ELISPOT for P. acnes catalase (P = 0·003). However, sarcoidosis patients sensitized to P. acnes catalase were more likely to have skin involvement, while sarcoidosis patients sensitized to mycobacterial antigens were more likely to have cardiac involvement. Our study suggests a more prominent role for inorganic triggers in sarcoidosis pathogenesis than previously thought. Immunological sensitization to inorganic antigens was associated with development of fibrotic sarcoidosis. No association was found between sensitization to bacterial antigens or vimentin and sarcoidosis in Dutch patients. However, our data suggest that trigger-related phenotypes can exist in the heterogeneous population of sarcoidosis patients., (© 2020 British Society for Immunology.)

Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and over the years, many biomarkers have been proposed to facilitate diagnosis, prognosis, and treatment decisions. Unfortunately, the ideal biomarker for sarcoidosis has not yet been discovered. The most commonly used biomarkers are serum and bronchoalveolar lavage biomarkers, but these lack the necessary specificity and sensitivity. In sarcoidosis, therefore, a combination of these biomarkers is often used to establish a proper diagnosis or detect possible progression. Other potential biomarkers include imaging tools and cell signaling pathways. Fluor-18-deoxyglucose positron emission tomography and high-resolution computed tomography have been proven to be more sensitive for the diagnosis and prognosis of both pulmonary and cardiac sarcoidosis than the serum biomarkers ACE and sIL-2R. There is an upcoming role for exploration of signaling pathways in sarcoidosis pathogenesis. The JAK/STAT and mTOR pathways in particular have been investigated because of their role in granuloma formation. The activation of these signaling pathways also proved to be a specific biomarker for the prognosis of sarcoidosis. Furthermore, both imaging and cell signaling biomarkers also enable patients who might benefit from a particular type of treatment to be distinguished from those who will not. In conclusion, the diagnostic and prognostic path of sarcoidosis involves many different types of existing and new biomarker. Research addressing biomarkers and disease pathology is ongoing in order to find the ideal sensitive and specific biomarker for this disease., (Copyright © 2020 Kraaijvanger, Janssen Bonás, Vorselaars and Veltkamp.)

Background: Differentiating between interstitial lung diseases (ILD) is challenging. Serum soluble interleukin 2 receptor (sIL-2R) is used as a diagnostic marker in sarcoidosis, but its diagnostic value has not yet been studied in other ILDs like Idiopathic Pulmonary Fibrosis (IPF) or Hypersensitivity Pneumonitis (HP). Also, the prognostic value of sIL-2R in sarcoidosis remains unknown., Methods: This retrospective cohort study included 121 patients with sarcoidosis, 35 with cHP, 62 with IPF (idiopathic pulmonary fibrosis) and 70 healthy controls. Serum sIL-2R levels were determined at diagnosis. Follow-up data were available for patients with chronic sarcoidosis (n = 64) and patients with non-chronic sarcoidosis (n = 29)., Results: Patients with sarcoidosis had higher sIL-2R levels (median 5418 pg/mL) than patients with cHP (median 4015 pg/mL, P = 0.002) and IPF (median 4192 pg/mL, P = 0.034). No differences were found between patients with cHP and IPF. Logistic regression revealed that sIL-2R at diagnosis is a significant predictor of the development of chronic sarcoidosis (OR = 2.1, P = 0.032)., Conclusion: High levels of sIL-2R are suggestive of sarcoidosis, although a broad overlap exists in sIL-2R levels across sarcoidosis, cHP, and IPF. High levels of sIL-2R might serve as a prognostic biomarker for chronicity.

Background: Involvement of metals or silica in the pathogenesis of sarcoidosis has been suggested by several case reports and specific epidemiological studies. However, the combination of occupational exposure and an immunological reaction has not been studied before in a group of sarcoidosis patients and non-sarcoidosis controls., Methods: In 256 sarcoidosis patients and 73 control patients with obstructive sleep apnea, exposure to metal and silica was assessed using a questionnaire consisting of a complete occupational history subsequently linked to job-exposure matrices. Next, immunoreactivity to aluminium, beryllium, zirconium and silica was determined in 33 sarcoidosis and 19 control patients using a lymphocyte proliferation test., Results: In sarcoidosis, 83 out 256 patients (32.4%) had occupational exposure to metals or silica, compared to 24.7% in the control group (p = 0.21). A significantly higher percentage of the sarcoidosis patients tested showed immunoreactivity to metals or silica compared to the control group (21.2 and 0% respectively, p = 0.039)., Conclusions: Immunoreactivity to silica and metals was only found in sarcoidosis patients, supporting the hypothesis that these antigens may be involved in the pathogenesis of a distinct subgroup of sarcoidosis patients. This indicates that when searching for causative agents in sarcoidosis patients, besides beryllium, also zirconium, aluminium and silica deserve clinical investigation.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Chest imaging has a central role in the diagnosis and monitoring of sarcoidosis. For staging of pulmonary disease on chest radiograph, Scadding stages are still widely used. High-resolution CT (HRCT), however, is more accurate in visualizing the various manifestations of pulmonary sarcoidosis as well its complications. A generally accepted HRCT scoring system is lacking. Fluorodeoxyglucose F 18 positron emission tomography can visualize disease activity better than conventional makers in a significant proportion of patients. In patients with extensive changes on HRCT but no parenchymal fluorodeoxyglucose F 18 uptake, prudence with regard to initiation or intensification of immunosuppressive treatment is warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Propionibacterium acnes has been repeatedly suggested as a candidate causative agent of sarcoidosis. It is the only microorganism that has been isolated from sarcoid lesions by bacterial culture so far and this has been described in Japanese patients only. We report two non-Japanese patients in whom mediastinoscopy was performed in order to obtain lymph node tissue for histopathology, which was suggestive for sarcoidosis. Bacterial culture of these uncontaminated mediastinal lymph nodes revealed P. acnes in both patients. As shown in these two cases, P. acnes can be isolated from sterile biopsied sarcoid lymph nodes of non-Japanese patients and supports the belief that there is an etiologic link between P. acnes sarcoidosis. Further elucidation could provide an opening to novel strategies using antibiotics for treating sarcoidosis.

Sarcoidosis is an inflammatory disease of unknown etiology. Various microorganisms have been proposed as etiologic agent suggesting a role for pattern-recognition receptors such as Toll-like receptors (TLRs) in disease pathogenesis, with a special interest in TLR-2. TLR-10, TLR-1, and TLR-6 act as co-receptors for TLR-2 and the genes encoding these receptors are located in a gene cluster on chromosome 4. The aim of our study was to assess differences in genetic variation in the TLR10-TLR1-TLR6 gene cluster between patients and controls. A total of eight single nucleotide polymorphisms were genotyped in 447 healthy controls and 533 patients, divided in 425 with sarcoidosis and 108 with Löfgren's syndrome. Comparison of the total patient cohort with controls showed that the allele frequencies of rs1109695, rs7658893 (TLR-10), and rs5743604 as well as rs5743594 (TLR-1) differed significantly. Haplotype analysis showed that the most common haplotype found was significantly decreased in patients with chronic sarcoidosis. Furthermore, a less common haplotype was found to be significantly increased in patients with Löfgren's syndrome as well as sarcoidosis patients with self-remitting disease, indicating that it could act as a disease modifying haplotype. In conclusion, our study suggests that absence of the common haplotype in the TLR10-TLR1-TLR6 gene cluster increases the risk of developing chronic disease in patients already affected by sarcoidosis. Based on their role as co-receptors for TLR-2, this study supports the growing evidence that aberrant TLR-2 function is important in sarcoidosis disease pathogenesis., (© 2011 John Wiley & Sons A/S.)

Sarcoidosis is a systemic disorder characterized by the formation of non-caseating granulomas in variable organs. Toll-like receptor (TLR)-9 is important in the innate immune response against both Mycobacterium tuberculosis and Propionibacterium acnes, candidate causative agents in sarcoidosis. The aim of our study was to investigate possible genetic and functional differences in TLR-9 between patients and controls. TLR-9 single nucleotide polymorphisms were genotyped in 533 patients and divided into a study cohort and validation cohort and 185 healthy controls. Furthermore, part of the promotor as well as the entire coding region of the TLR-9 gene were sequenced in 20 patients in order to detect new mutations. No genetic differences were found between patients and controls. In order to test TLR-9 function, peripheral blood mononuclear cells (PBMCs) of 12 healthy controls and 12 sarcoidosis patients were stimulated with a TLR-9 agonist and the induction of interleukin (IL)-6, interferon (IFN)-γ and IL-23 was measured. Sarcoidosis patients produce significantly less IFN-γ upon stimulation with different stimuli. Regarding IL-23 production, a significant difference between patients and controls was found only after stimulation with the TLR-9 agonist. In conclusion, we did not find genetic differences in the TLR-9 gene between sarcoidosis patients and controls. Sarcoidosis patients produce less IFN-γ regardless of the stimulating agent, probably reflecting the anergic state often seen in their peripheral blood T lymphocytes. The differences in TLR-9-induced IL-23 production could indicate that functional defects in the TLR-9 pathway of sarcoidosis patients play a role in disease susceptibility or evolution., (© 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.)

The intracellular pathogens Propionibacterium acnes and Mycobacterium tuberculosis have been leading suspects as the cause of sarcoidosis, a systemic disorder characterized by the formation of non-caseating granulomas. Toll-like receptor (TLR) 2 is important in the innate immune response against both pathogens, and is therefore of interest in sarcoidosis research. In the present study, three single nucleotide polymorphisms and one dinucleotide repeat polymorphism in the TLR-2 gene were genotyped in 419 sarcoidosis patients, divided into a study cohort and a validation cohort, and 196 healthy controls. In the study cohort we found a significant increase in prevalence of the AA-genotype at promotor location -16934 in patients with chronic disease compared to patients with acute/self-remitting sarcoidosis (34.5% versus 15.9%, respectively, P = 0.006, P(c) = 0.019). These results could not be confirmed in our validation cohort, implicating a possible role for TLR-2 genetics in only a small percentage of sarcoidosis patients. Furthermore, linkage was found between the promotor polymorphism -16934 A/T and the number of GT repeats in intron 1 (P < 0.0001). After in vitro stimulation of peripheral blood mononuclear cells (PMBCs) with different TLR-2 agonists, a correlation between induction of TNF-alpha (P = 0.008), interleukin (IL)-12 (P = 0.008) as well as IL-6 (P = 0.02), and the number of GT repeats was observed. In conclusion, the data show that polymorphisms in TLR-2 might be important in a small group of sarcoidosis patients and that their functional consequences explain partly some of the variance in cytokine pattern observed in different clinical phenotypes of this disease.