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Purpose of Review: To summarize data from recent reports about risks and outcomes of the infections most often reported in patients with sarcoidosis., Recent Findings: Rates of fungal infections and other severe infections are higher in patients with sarcoidosis compared to controls. Immunosuppression further increases the risk for an infection requiring hospitalization. In contrast, outcomes of coronavirus disease 2019 (COVID-19) are not worse unless lung impairment or other comorbidities are present., Summary: Tuberculosis, fungal infections, and other severe infections requiring hospital admission are, fortunately, relatively rare in patients with sarcoidosis who live in nonendemic regions. However, ongoing vigilance is required when the course of sarcoidosis is atypical or inexplicably progressive, as costs are high when these infections are missed. In contrast, COVID-19 and other respiratory viral illnesses are common, including among patients with sarcoidosis. When organ impairment is minimal, an underlying diagnosis of sarcoidosis does not appear to increase the risk of severe COVID-19, but patients may have higher risks due to comorbidities, which are important factors to address in routine sarcoidosis care. The burden from respiratory viral events, including impacts on quality of life and life functionality including work capacity, is unknown and is important to measure., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although sex- and race-based patterns have been described in the extracardiac organ involvement of sarcoidosis, cardiac sarcoidosis (CS)-specific studies are lacking., Methods: We studied CS presentation, treatment and outcomes based on sex and race in a tertiary-center cohort. Multivariable adjusted Cox proportional hazards and survival analyses were performed for primary composite outcomes (left ventricular assist device, heart transplantation, all-cause death) and for secondary outcomes (ventricular arrhythmia and all-cause death., Results: We identified 252 patients with CS (108 female, 109 Black). At presentation with CS, females vs males (P = 0.001) and Black vs White individuals (P = 0.001) more commonly had symptomatic heart failure (HF), with HF most common in Black females (ANOVA P < 0.001). Treatment differences included more corticosteroid use (90% vs 79%; P = 0.020), higher 1-year prednisone dosage (13 vs 10 mg; P = 0.003) and less frequent early steroid-sparing agent use in males (29% vs 40%; P = 0.05). Black participants more frequently received a steroid-sparing agent (75% vs 60%; P = 0.023). Composite outcome-free survival did not differ by sex or race. Male sex had an adjusted hazard ratio of 2.34 (95% CI 1.13, 4.80; P = 0.021) for ventricular arrhythmia., Conclusion: CS course may differ by sex and race and may contribute to distinct clinical CS phenotypes., Competing Interests: Disclosures The authors have no relevant disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Historically, sarcoidosis was described as a restrictive lung disease, but several alternative phenotypes of pulmonary function have been observed. Pulmonary function phenotypes in sarcoidosis may represent different clinical and/or molecular phenotypes. Objectives: To characterize the prevalence of different pulmonary function phenotypes in a large and diverse sarcoidosis cohort from a tertiary care referral center. Methods: We identified individuals seen between 2005-2015 with a confirmed diagnosis of sarcoidosis. Data were collected from the first pulmonary function test (PFT) performed at our institution which included spirometry and diffusing capacity of the lung for carbon monoxide (Dl CO ). Demographics and clinical data were collected. Chi-squared analyses and multiple linear regressions were done to assess statistical differences and associations. Global Lung Function Initiative equations were used to calculate percent predicted measurements for spirometry and Dl CO . Results: Of 602 individuals with sarcoidosis, 93% (562) had pulmonary involvement, 64% (385) were female, and 57% (341) were Black. Of those with pulmonary involvement, 56% had abnormal pulmonary function. Lung function impairment phenotypes included: 47% restriction, 22% obstruction, 15% isolated reduction in Dl CO , and 16% combined obstructive restrictive phenotype. Restriction was the most common PFT phenotype among Black individuals (41%), while no lung impairment was most common among White individuals (66%) ( P  < 0.001). Males more frequently had obstruction (19%) compared with females (9%) P  = 0.001, and females had more restriction (30%) compared with males (21%) P  = 0.031. Conclusions: Among individuals with sarcoidosis and pulmonary function impairment, less than half demonstrated a restrictive phenotype. There were significant differences in pulmonary function phenotypes by race and sex.

Cardiac sarcoidosis (CS) is an important cause of cardiomyopathy. The trajectory of left ventricular ejection fraction (LVEF) in patients with CS undergoing treatment remains unclear. Patients with CS who were treated with corticosteroids and who underwent transthoracic echocardiography were studied. Baseline characteristics, treatment, echocardiographic data (including baseline to follow-up change in LVEF), and outcomes were retrospectively evaluated. Among 100 patients, 55 had baseline reduced LVEF (<50%), and 45 had preserved LVEF (≥50%). At follow-up, 82% of patients demonstrated stable or improved LVEF. Change in LVEF was significantly higher in the baseline reduced than in the preserved LVEF group (5% [interquartile range 0 to 15] vs 0% [interquartile range -10% to 5%], p = 0.001). There was no difference in corticosteroid exposure or use of heart failure guideline-directed medical therapy between patients who did experience improvement in LVEF and those who did not experience improvement in LVEF. On multivariable analysis, baseline reduced LVEF (Odds ratio 54.89, 95% confidence interval 3.84 to 785.09, p = 0.003) and complete heart block (Odds ratio 28.88, 95% confidence interval 2.17 to 383.74, p = 0.011) at presentation were significantly associated with reduced LVEF after treatment. In conclusion, most patients with CS treated with corticosteroids maintain or improve LV systolic function. Cardiac characteristics at presentation impact prognosis in CS, despite treatment., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Sarcoidosis is a systemic disease characterized by granulomatous inflammation. Cardiac involvement is associated with increased morbidity. However, differences in clinical characteristics and outcomes based on initial sarcoidosis organ manifestation in patients with cardiac sarcoidosis (CS) have not been described., Methods: A retrospective cohort of 252 patients with CS at an urban, quaternary medical center was studied. Presentation, treatment and outcomes of de novo CS and prior ECS groups were compared. Survival free of primary composite outcome (left ventricular assist device implantation, orthotopic heart transplantation (OHT), or death) was assessed., Results: There were 124 de novo CS patients and 128 with prior ECS at time of CS diagnosis. De novo CS patients were younger at CS diagnosis (p = 0.020). De novo CS patients had a more advanced cardiac presentation: lower left ventricular ejection fraction (LVEF) (p < 0.001), more frequent sustained ventricular arrhythmias (VA) (p = 0.001), and complete heart block (p = 0.001). During follow-up, new VA (p < 0.001), ventricular tachycardia ablation (p < 0.001), and OHT (p = 0.003) were more common in the de novo CS group. Outcome free survival was significantly shorter for de novo CS patients (p = 0.005), with increased hazard of primary composite outcome (p = 0.034) and development of new VA (p = 0.027) when compared to ECS patients. Overall mortality was similar between groups., Conclusion: Patients presenting with CS as their first recognized organ manifestation of sarcoidosis have an increased risk of adverse cardiac outcomes as compared to those with a prior history of ECS. Improved awareness and diagnosis of CS is warranted for earlier recognition., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.)

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia, and/or heart failure. The diagnosis of cardiac sarcoidosis (CS) can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes, such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of CS. The mainstay of therapy for CS is immunosuppression; however, no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in CS call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits., Methods: RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well-characterised patients with pulmonary sarcoidosis enrolled in the multicentre Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted gene co-expression network analysis and nonparametric statistics were used to analyse genome-wide BAL transcriptome. Validation of results was performed using a microarray expression dataset of an independent sarcoidosis cohort (Freiburg, Germany; n=50)., Results: Our supervised analysis found associations between distinct transcriptional programmes and major pulmonary phenotypic manifestations of sarcoidosis including T-helper type 1 (Th1) and Th17 pathways associated with hilar lymphadenopathy, transforming growth factor-β1 (TGFB1) and mechanistic target of rapamycin (MTOR) signalling with parenchymal involvement, and interleukin (IL)-7 and IL-2 with airway involvement. Our unsupervised analysis revealed gene modules that uncovered four potential sarcoidosis endotypes including hilar lymphadenopathy with increased acute T-cell immune response; extraocular organ involvement with PI3K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan involvement, with increased IL-1 and IL-18 immune and inflammatory responses. We validated the occurrence of these endotypes using gene expression, pulmonary function tests and cell differentials from Freiburg., Conclusion: Taken together, our results identify BAL gene expression programmes that characterise major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes., Competing Interests: Conflict of interest: M. Vukmirovic has nothing to disclose. Conflict of interest: X. Yan has nothing to disclose. Conflict of interest: K.F. Gibson has nothing to disclose. Conflict of interest: M. Gulati reports grants from NIH, during the conduct of the study; personal fees for advisory board work and other (PI/publication committee) from Boehringer Ingelheim, other (lectures) from France Foundation, other (PI/centre director) from Pulmonary Fibrosis Foundation, grants from NIH and Sarcoidosis Research Foundation, outside the submitted work. Conflict of interest: J.C. Schupp has nothing to disclose. Conflict of interest: G. DeIuliis has nothing to disclose. Conflict of interest: T.S. Adams has nothing to disclose. Conflict of interest: B. Hu has nothing to disclose. Conflict of interest: A. Mihaljinec has nothing to disclose. Conflict of interest: T.N. Woolard has nothing to disclose. Conflict of interest: H. Lynn has nothing to disclose. Conflict of interest: N. Emeagwali has nothing to disclose. Conflict of interest: E.L Herzog reports grants from NIH, Sanofi, Bristol Myers and Promedior, personal fees for consultancy from Boehringer Ingelheim and Pfizer, outside the submitted work. Conflict of interest: E.S. Chen has nothing to disclose. Conflict of interest: A. Morris reports grants from NIH, during the conduct of the study. Conflict of interest: J.K. Leader has nothing to disclose. Conflict of interest: Y. Zhang has nothing to disclose. Conflict of interest: J.G.N. Garcia has nothing to disclose. Conflict of interest: L.A. Maier grants from NIH (1U01 HL112695-01, U01 HL112707-03) and NIH/NCRR (UL1TRR002535), during the conduct of the study; grants from National Institutes of Health (1R01 HL127461-01A1, R01HL136681-01A1, 1R01 HL140357-01A1, R01HL136681-01A1), FSR, University of Cinncinati under a Mallinckrodt foundation, MNK14344100, ATYR1923-C-002, outside the submitted work; and is a member of the FSR scientific advisory board, for which no compensation is received. Conflict of interest: R.G. Collman reports grants from National Institutes of Health, during the conduct of the study. Conflict of interest: W.P. Drake has nothing to disclose. Conflict of interest: M.J. Becich reports grants from NCATS, NCI, PCORI, NHLBI and CDC NIOSH, other (startup) from SpIntellx, during the conduct of the study; other (startup) from SpIntellx, outside the submitted work; and has patents SpIntellx (multiple) pending. Conflict of interest: H. Hochheiser has nothing to disclose. Conflict of interest: S.R. Wisniewski has nothing to disclose. Conflict of interest: P.V. Benos has nothing to disclose. Conflict of interest: D.R. Moller reports grants from NHLBI (1U01HL112708), during the conduct of the study; personal fees for consultancy from Merck, aTYR and Roivant, personal fees for advisory board work from SarcoMed, personal fees for consultancy/witness from Legal Expert, other (royalties) from Hodder Education and Taylor & Francis Group, outside the submitted work; has patents number 9,683,999 B2 issued, and number 9,977,029 B2 issued; is Chairman and Chief Technical Officer of Sarcoidosis Diagnostic Testing, LLC (a company whose goal is to develop a diagnostic blood test for sarcoidosis) and has received funding including past salary support under the NHLBI STTR programme, grant R41 HL129728 more than 3 years ago; and is a former member of the Scientific Advisory Board of the Foundation for Sarcoidosis Research. Conflict of interest: A. Prasse reports personal fees for lectures and consultancy and non-financial support for meeting attendance from Boehringer Ingelheim and Roche, personal fees for lectures from Novartis and AstraZeneca, personal fees for consultancy from Amgen, Pliant and Nitto Denko, outside the submitted work. Conflict of interest: L.L. Koth has nothing to disclose. Conflict of interest: N. Kaminski reports personal fees for consultancy and/or advisory board work from Biogen Idec, Boehringer Ingelheim, Third Rock, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, RohBar and Pliant, non-financial support from Miragen, equity with Pliant, a grant from Veracyte; all outside the submitted work; and has a patent New Therapies in Pulmonary Fibrosis and on Peripheral Blood Gene Expression that have been licensed to Biotech., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Cardiac sarcoidosis (CS) is a major cause of morbidity and mortality in patients with systemic sarcoidosis. Steroid-sparing agents are increasingly used, despite a lack of randomized trials or published guidelines to direct treatment., Methods and Results: This retrospective study included 77 patients with CS treated with prednisone monotherapy (n = 32) or a combination with mycophenolate mofetil (n = 45) between 2003 and 2018. Baseline characteristics and clinical outcomes were evaluated. The mean patient age was 53 ± 11 years at CS diagnosis, 66.2% were male, and 35.1% were Black. The total exposure to maximum prednisone dose (initial prednisone dose × days at dose) was lower in the combination therapy group (1440 mg [interquartile range (IQR), 1200-2760 mg] vs 2710 mg [IQR, 1200-5080 mg]; P = .06). On 18 F-fluorodeoxyglucose positron emission tomography scans, both groups demonstrated a significant decrease in the cardiac maximum standardized uptake value after treatment: a median decrease of 3.9 (IQR 2.7-9.0, P = .002) and 2.9 (IQR 0-5.0, P = .001) for prednisone monotherapy and combination therapy, respectively. Most patients experienced improvement or complete resolution in qualitative cardiac 18 F-fluorodeoxyglucose uptake (92.3% and 70.4% for the prednisone and combination therapy groups, respectively). Mycophenolate mofetil was well tolerated., Conclusions: Mycophenolate mofetil in combination with prednisone for the treatment of CS may minimize corticosteroid exposure and decrease cardiac inflammation without significant adverse effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Sarcoidosis is a multiorgan granulomatous disorder thought to be triggered and influenced by gene-environment interactions. Sarcoidosis affects 45-300/100 000 individuals in the USA and has an increasing mortality rate. The greatest gap in knowledge about sarcoidosis pathobiology is a lack of understanding about the underlying immunological mechanisms driving progressive pulmonary disease. The objective of this study is to define the lung-specific and blood-specific longitudinal changes in the adaptive immune response and their relationship to progressive and non-progressive pulmonary outcomes in patients with recently diagnosed sarcoidosis., Methods and Analysis: The BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints study is a US-based, NIH-sponsored longitudinal blood and bronchoscopy study. Enrolment will occur over four centres with a target sample size of 80 eligible participants within 18 months of tissue diagnosis. Participants will undergo six study visits over 18 months. In addition to serial measurement of lung function, symptom surveys and chest X-rays, participants will undergo collection of blood and two bronchoscopies with bronchoalveolar lavage separated by 6 months. Freshly processed samples will be stained and flow-sorted for isolation of CD4 +T helper (Th1, Th17.0 and Th17.1) and T regulatory cell immune populations, followed by next-generation RNA sequencing. We will construct bioinformatic tools using this gene expression to define sarcoidosis endotypes that associate with progressive and non-progressive pulmonary disease outcomes and validate the tools using an independent cohort., Ethics and Dissemination: The study protocol has been approved by the Institutional Review Boards at National Jewish Hospital (IRB# HS-3118), University of Iowa (IRB# 201801750), Johns Hopkins University (IRB# 00149513) and University of California, San Francisco (IRB# 17-23432). All participants will be required to provide written informed consent. Findings will be disseminated via journal publications, scientific conferences, patient advocacy group online content and social media platforms., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Improvement of quality of life (QoL) in patients with sarcoidosis is an important goal of management. The King's Sarcoidosis Questionnaire (KSQ) and Patient Global Assessment (PGA) are instruments that have been used in sarcoidosis. Objectives: We defined the minimal clinically important difference (MCID) as the within-patient clinically meaningful change threshold and determined the MCID of KSQ general health (KSQ GH), KSQ lung, and PGA using both anchor and distribution methods. The discriminatory properties of these MCIDs relative to other QoL instruments were then determined. Methods: Patients with sarcoidosis recruited from six centers in the United States were prospectively studied. Initially and at 6 months, patients completed a series of QoL questionnaires, including the St. George's Respiratory Questionnaire (SGRQ), Short Form 36 (SF-36), Fatigue Assessment Scale (FAS), Sarcoidosis Assessment Tool (SAT), KSQ, and PGA, and spirometry. For the anchor method, receiver operator characteristic curves were used to determine the MCID for improvement or worsening. The distribution method using half of the standard deviation was calculated for KSQ GH, KSQ lung, and PGA. Results: Of the 325 patients enrolled in the study, 271 completed the 6-month evaluation. At 6 months, approximately half of patients were worse and 30% were improved based on previously established MCID values for the SGRQ, SF-36, and FAS. There were no discordant cases. There were significant correlations between the KSQ GH, KSQ lung, and PGA and most parameters assessed. The best correlations were with the SGRQ, SF-36, and FAS, which have established MCID values. Using anchor analysis, we found that most of the domains of SGRQ and SF-36 were able to determine the significant MCIDs for all three variables. These MCIDs were similar to those determined by the half least square method. We propose an MCID of 8 for the KSQ GH, an MCID of 4 for the KSQ lung, and an MCID of 2 for the PGA because these values captured >90% of parameters studied. These MCID values discriminated between changes in other QoL instruments. Conclusions: The determination of MCID values for KSQ lung, KSQ GH, and PGA may prove useful for clinical practice as well as clinical trials.

Background: Cardiac sarcoidosis (CS) is an increasingly recognized cause of cardiomyopathy; however, data on immunosuppressive strategies are limited. Treatment with tumor necrosis factor (TNF) alpha inhibitors is not well described; moreover, there may be heart failure-related safety concerns., Methods: Retrospective multicenter study of patients with CS treated with TNF alpha inhibitors. Baseline characteristics, treatments, and outcomes were adjudicated., Results: Thirty-eight patients with CS (mean age 49.9 years, 42% women, 53% African American) were treated with TNF alpha inhibitor (30 infliximab, 8 adalimumab). Prednisone dose decreased from time of TNF alpha inhibitor initiation (21.7 ± 17.5 mg) to 6 months (10.4 ± 6.1 mg, P = .001) and 12 months (7.3 ± 7.3 mg, P = .002) after treatment. On pre-TNF alpha inhibitor treatment positron emission tomography with 18-flourodoxyglucose (FDG-PET), 84% of patients had cardiac FDG uptake. After treatment, there was a significant decrease in number of segments involved (3.5 ± 3.8 to 1.0 ± 2.5, P = .008) and maximum standardized uptake value (3.59 ± 3.70 to 0.57 ± 1.60, P = .0005), with 73% of patients demonstrating complete resolution or improvement of cardiac FDG uptake. The left ventricular ejection fraction remained stable (45.0 ± 16.5% to 47.0 ± 15.0%, P = .10). Four patients required inpatient heart failure treatment, and 8 had infections; 2 required treatment cessation., Conclusions: TNF alpha inhibitor treatment guided by FDG-PET imaging may minimize corticosteroid use and effectively reduce cardiac inflammation without significant adverse effect on cardiac function. However, infections were common, some of which were serious, and therefore patients require close monitoring for both infection and cardiac symptoms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine the characteristic clinical and spinal MRI phenotypes of sarcoidosis-associated myelopathy (SAM), we analyzed a large cohort of patients with this disorder., Methods: Patients diagnosed with SAM at a single center between 2000 and 2018 who met the established criteria for definite and probable neurosarcoidosis were included in a retrospective analysis to identify clinical profiles, CSF characteristics, and MRI lesion morphology., Results: Of 62 included patients, 33 (53%) were male, and 30 (48%) were African American. SAM was the first clinical presentation of sarcoidosis in 49 patients (79%). Temporal profile of symptom evolution was chronic in 81%, with sensory symptoms most frequently reported (87%). CSF studies showed pleocytosis in 79% and CSF-restricted oligoclonal bands in 23% of samples tested. Four discrete patterns of lesion morphology were identified on spine MRI: longitudinally extensive myelitis (n = 28, 45%), short tumefactive myelitis (n = 14, 23%), spinal meningitis/meningoradiculitis (n = 14, 23%), and anterior myelitis associated with areas of disc degeneration (n = 6, 10%). Postgadolinium enhancement was seen in all but 1 patient during the acute phase. The most frequent enhancement pattern was dorsal subpial enhancement (n = 40), followed by meningeal/radicular enhancement (n = 23) and ventral subpial enhancement (n = 12). In 26 cases (42%), enhancement occurred at locations with coexisting structural changes (e.g., spondylosis)., Conclusions: Recognition of the clinical features (chronically evolving myelopathy) and distinct MRI phenotypes (with enhancement in a subpial and/or meningeal pattern) seen in SAM can aid diagnosis of this disorder. Enhancement patterns suggest that SAM may have a predilection for areas of the spinal cord susceptible to mechanical stress., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients with end-stage cardiomyopathy due to cardiac sarcoidosis (CS) may be referred for mechanical circulatory support (MCS) and heart transplantation (HT). We describe outcomes of patients with CS undergoing HT, focusing on the use of MCS as a bridge to transplant (BTT)., Methods: Using the United Network for Organ Sharing Scientific Registry of Transplant Recipients, we identified all adult waitlisted patients and isolated HT recipients from 2006 to 2015. These were divided into those with and without CS and further divided into those who did or did not receive MCS as BTT. Outcomes included 1- and 5-year post-transplantation freedom from mortality and 5-year freedom from primary graft failure., Results: Over the study period, 31,528 patients were listed for HT, 148 (0.4%) of whom had CS. Among the CS patients, 34 (23%) received MCS as BTT. 18,348 patients (58%) eventually underwent HT, including 67 (0.4%) with CS, 20 (30%) of whom had received BTT MCS. Compared with non-CS diagnoses, CS patients had similar 1-year (91% vs 90%; log rank P = .88) and 5-year (83% vs 77%; log rank P = .46) freedom from mortality. Survival was also similar between CS BTT and non-CS BTT groups at 1 year (89% vs 89%; log-rank P = .92) and 5 years (72% vs 75%; log-rank P = .77)., Conclusions: Survivals after HT were similar between CS and non-CS patients out to 5 years, and were also similar between CS and non-CS BTT cohorts. Both HT and BTT MCS should be considered in patients with CS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sarcoidosis is a multisystem disease with tremendous heterogeneity in disease manifestations, severity, and clinical course that varies among different ethnic and racial groups. To better understand this disease and to improve the outcomes of patients, a National Heart, Lung, and Blood Institute workshop was convened to assess the current state of knowledge, gaps, and research needs across the clinical, genetic, environmental, and immunologic arenas. We also explored to what extent the interplay of the genetic, environmental, and immunologic factors could explain the different phenotypes and outcomes of patients with sarcoidosis, including the chronic phenotypes that have the greatest healthcare burden. The potential use of current genetic, epigenetic, and immunologic tools along with study approaches that integrate environmental exposures and precise clinical phenotyping were also explored. Finally, we made expert panel-based consensus recommendations for research approaches and priorities to improve our understanding of the effect of these factors on the health outcomes in sarcoidosis.

Objectives: This study sought to evaluate the effects of inflammatory sarcoid disease on coronary circulatory function and the response to immune-suppressive treatment., Background: Although positron emission tomography assessment of myocardial inflammation is increasingly applied to identify active cardiac sarcoidosis, its effect on coronary flow and immune-suppressive treatment remains to be characterized., Methods: Thirty-two individuals, who were referred for positron emission tomography/computed tomography, were evaluated for known or suspected cardiac sarcoidosis applying 18 F-fluorodeoxyglucose to determine inflammation and 13 N-ammonia to assess for perfusion deficits following a high-fat/low-carbohydrate diet and fasting state >12 h to suppress myocardial glucose uptake. Inflammation was quantified with standardized uptake value and regional myocardial blood flow at rest and during regadenoson-stimulated hyperemia was determined in ml/g/min. Positron emission tomography studies were repeated in 18 cases with a median follow-up of 2.5 years (interquartile range [IQR]:1.3 to 3.4 years)., Results: Twenty-five exams had normal perfusion but evidence of regional inflammation (group 1), and 21 exams presented a regional perfusion deficit associated with inflammation (group 2). Median myocardial blood flow did not differ between inflamed and noninflamed myocardium in both groups (0.86 ml/g/min [IQR: 0.66 to 1.11 ml/g/min] vs. 0.83 ml/g/min [IQR: 0.64 to 1.12 ml/g/min] and 0.74 ml/g/min [IQR: 0.60 to 0.93 ml/g/min] vs. 0.77 ml/g/min [IQR: 0.59 to 0.95 ml/g/min], respectively). As regards median hyperemic myocardial blood flows, they were significantly lower in the inflamed than in the remote regions in group 1 and 2 (2.31 ml/g/min [IQR: 1.81 to 2.95 ml/g/min] vs. 2.70 ml/g/min [IQR: 2.07 to 3.30 ml/g/min] and 1.61 ml/g/min [IQR: 1.17 to 2.18 ml/g/min] vs. 1.94 ml/g/min [IQR: 1.49 to 2.39 ml/g/min]; p < 0.001, respectively). Immune-suppression-mediated decrease in inflammation was associated with preserved myocardial flow reserve (MFR) at follow-up, whereas MFR significantly worsened in regions without changes or even increases in inflammation (median ΔMFR: 0.07 [IQR: -0.29 to 0.45] vs. -0.24 [IQR: -0.84 to 0.21]; p < 0.001). There was an inverse correlation between pronounced alterations in myocardial inflammation (Δ regional myocardial volume with standardized uptake value >4.1) and ΔMFR (r = -0.47; p = 0.048)., Conclusions: Sarcoid-mediated myocardial inflammation is associated with a regional impairment of coronary circulatory function. The association between immune-suppressive treatment-related alterations in myocardial inflammation and changes in coronary vasodilator capacity suggests direct adverse effect of inflammation on coronary circulatory function in cardiac sarcoidosis., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The immunopathogenesis of sarcoidosis is considered to involve contributions from both adaptive and innate immune responses. Although the identification of adaptive responses to candidate pathogenic antigens will elucidate mechanisms that regulate inflammation in sarcoidosis, innate mechanisms likely represent the 'missing link' to the initiation, maintenance, and resolution of noncaseating granulomatous inflammation, the hallmark feature of sarcoidosis. Furthermore, environments that expose patients to candidate pathogenic antigens for sarcoidosis also provide opportunities for engagement with innate ligands., Recent Findings: Several studies have identified enhanced responsiveness via pattern recognition receptor pathways, potentiating the local induction of cytokines relevant to granulomatous inflammation, such as through stimulation of nucleotide-binding oligomerization domain-like receptor and Toll-like receptor pathways. These pathways contribute to the inherent properties of granulomas including, in some cases, persistent localization of pathogens and antigen. Serum amyloid A has been identified to be abundant in sarcoidosis tissues, and this promiscuous host protein can serve as an innate ligand to regulate experimental granulomatous inflammation. Nascent evidence supports a potential role for alternatively activated macrophages to direct histopathological outcomes in sarcoidosis., Summary: Innate pathways deserve further investigation as potential therapeutic targets for inhibiting granuloma formation in sarcoidosis.

Since sarcoidosis was first described more than a century ago, the etiologic determinants causing this disease remain uncertain. Studies suggest that genetic, host immunologic, and environmental factors interact together to cause sarcoidosis. Immunologic characteristics of sarcoidosis include non-caseating granulomas, enhanced local expression of T helper-1 (and often Th17) cytokines and chemokines, dysfunctional regulatory T-cell responses, dysregulated Toll-like receptor signaling, and oligoclonal expansion of CD4+ T cells consistent with chronic antigenic stimulation. Multiple environmental agents have been suggested to cause sarcoidosis. Studies from several groups implicate mycobacterial or propionibacterial organisms in the etiology of sarcoidosis based on tissue analyses and immunologic responses in sarcoidosis patients. Despite these studies, there is no consensus on the nature of a microbial pathogenesis of sarcoidosis. Some groups postulate sarcoidosis is caused by an active viable replicating infection while other groups contend there is no clinical, pathologic, or microbiologic evidence for such a pathogenic mechanism. The authors posit a novel hypothesis that proposes that sarcoidosis is triggered by a hyperimmune Th1 response to pathogenic microbial and tissue antigens associated with the aberrant aggregation of serum amyloid A within granulomas, which promotes progressive chronic granulomatous inflammation in the absence of ongoing infection.

A consensus statement found in most peer-reviewed literature on sarcoidosis is that the etiology of sarcoidosis is unknown. It is timely to review whether this statement should be revised. Many infectious agents meet the basic requirements of inducing granulomatous inflammation and immunologic responses consistent with sarcoidosis including oligoclonal expansion of CD4+ T cells, polarized Th1 and possibly Th17 responses, and dysregulated regulatory T-cell function. Studies over the past decade provide increasing and complementary data to implicate a role for infectious agents in sarcoidosis etiology. These studies used different methodologies such as polymerase chain reaction and mass spectrometry to document microbial nucleic acids and proteins in sarcoidosis tissues. Multiple studies report antigen-specific immune responses to specific microbial proteins in sarcoidosis. In aggregate, these studies provide compelling evidence that mycobacteria play a major etiologic role in sarcoidosis in the United States and Europe. Studies from Japan support a role for Propionibacteria as a major etiologic agent in the country. There is controversy over how these (or other) infectious agents cause sarcoidosis. The hypothesis that chronic sarcoidosis is caused by a viable, replicating mycobacterial or other infection has no direct pathologic, microbiologic, or clinical evidence. A novel hypothesis links microbial triggers to a sarcoidosis outcome from the accumulation of aggregated proinflammatory serum amyloid A within granulomas, providing a mechanism for chronic disease in the absence of any viable tissue infection. Further studies are needed to provide more definitive evidence for these competing hypotheses before the statement that the etiology of sarcoidosis is unknown becomes obsolete., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Sarcoidosis is a granulomatous disease of unknown aetiology, mainly affecting the lungs. Recently, T-cell responses towards a specific mycobacterial protein, catalase-peroxidase (mKatG), were observed in sarcoidosis patients. Bronchoalveolar lavage (BAL) fluid and peripheral blood were obtained from a total of 23 sarcoidosis patients, of whom 13 had Löfgren's syndrome and lung accumulations of T-cell receptor AV2S3+ T-cells. Using six-colour flow cytometry in combination with intracellular cytokine staining, T-cell subsets were studied with regard to interferon (IFN)-γ, tumour necrosis factor (TNF) and interleukin-2 production, after stimulation with mKatG or Mycobacterium tuberculosis purified protein derivate (PPD). Stimulation with mKatG resulted in higher simultaneous IFN-γ and TNF production, but less single IFN-γ production, from total BAL fluid CD4+ T-cells of Löfgren's syndrome patients, when compared with non-Löfgren's patients. In contrast, PPD stimulation gave rise to largely similar cytokine responses in both patient subgroups. Furthermore, mKatG stimulated higher IFN-γ production in BAL fluid and blood AV2S3+ T-cells than AV2S3- T-cells, whereas the opposite was seen in BAL fluid with PPD stimulation. Our finding that patients with Löfgren's syndrome exhibited a more pronounced multifunctional cytokine profile (simultaneous IFN-γ and TNF production) towards the mycobacterial protein mKatG may help to explain the distinct disease presentation in this patient subgroup.

Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ~20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.

Sarcoidosis is an uncommon systemic inflammatory disorder characterized by noncaseating granulomatous inflammation that most commonly affects the lungs, intrathoracic lymph nodes, eyes and skin. One-third or more of patients with sarcoidosis have chronic, unremitting inflammation with progressive organ impairment. Findings of family and genetic studies indicate a genetic susceptibility to sarcoidosis, with genes in the MHC region having a dominant role. Immunologic hallmarks of the disease include highly polarized expression of cytokines produced by type 1 T helper cells and tumor necrosis factor (TNF) at sites of inflammation. Increasing evidence obtained within the past decade suggests the etiology of sarcoidosis predominantly involves microbial triggers, with the most convincing data implicating mycobacterial or propionibacterial organisms. Innate immune mechanisms, possibly involving misfolding and aggregation of serum amyloid A, might have a critical role in the pathobiology of sarcoidosis. Despite these advances, there are no clinically useful biomarkers that can assist the clinician in diagnosis, prognosis or assessment of treatment effects. Corticosteroids remain the cornerstone of therapy when organ function is threatened or progressively impaired. The role of immunosuppressive drugs and anti-TNF agents in the treatment of sarcoidosis remains uncertain, and there are no FDA-approved therapies. Meaningful progress in developing clinically useful tools and new therapies will depend on further advances in understanding the pathogenesis of sarcoidosis and its disease-specific pathways.

Sarcoidosis is a systemic granulomatous disease associated with local epithelioid granulomas, CD4(+) T cells, and Th1 cytokines. The tissue Ags that drive this granulomatous inflammation are uncertain. In this study, we used IFN-gamma-ELISPOT assays and flow cytometry to assess lung and blood T cell responses to the candidate pathogenic Ag, Mycobacterium tuberculosis catalase-peroxidase (mKatG) in patients with sarcoidosis from two centers. Despite differences in patient phenotypic, genetic, and prognostic characteristics, we report that T cell responses to mKatG were remarkably similar in these cohorts, with higher frequencies of mKatG-reactive, IFN-gamma-expressing T cells in the blood of sarcoidosis patients compared with nontuberculosis sensitized healthy controls, and (in a subset) in greater numbers than T cells reactive to purified protein derivative. In sarcoidosis, mKatG-reactive CD4(+) Th1 cells preferentially accumulated in the lung, indicating a compartmentalized response. Patients with or without Löfgren syndrome had similar frequencies of mKatG specific IFN-gamma-expressing blood T cells. Circulating mKatG-reactive T cells were found in chronic active sarcoidosis but not in patients with inactive disease. Together, these results demonstrate that T cell responses to mKatG in sarcoidosis fit a profile expected for a pathogenic Ag, supporting an immunotherapeutic approach to this disease.

Research over the past decade has advanced our understanding of the pathogenesis of sarcoidosis and provided new insights into potential causes of this disease. It is important to remember that any etiologic agent of sarcoidosis must be capable of causing the pathologic hallmark of systemic noncaseating granulomas and the heterogeneous clinical features of sarcoidosis. In addition, etiologic agents must be compatible with immunologic features, including polarized T-helper 1 cytokine profiles and oligoclonal T cell expansions consistent with antigen driven processes. Yet, even with studies conducted in this disease, there remains a lack of consensus on the etiology of sarcoidosis. This challenge is likely to be overcome only with additional research that incorporates clinical, genetic, immunologic, environmental, and microbiologic profiles in groups of patients, supplemented with testing of candidate pathogenic agents in experimental models that recapitulate critical features of this disease.

Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granulomas, oligoclonal CD4(+) T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab')(2) fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150-160, 80, or 60-64 kD) but only 3 of 22 (14%) control tissues (all 62-64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase-peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)(-) (P = 0.0059) and 4 of 10 (40%) PPD(+) (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase-peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.

Limited but encouraging progress has been made over the last several years in our understanding of the etiology of sarcoidosis as a result of recent investments in epidemiologic, immunologic, and molecular biologic studies. A recent US multicenter study of sarcoidosis found few environmental or occupational exposures associated with a two-fold or higher risk of development of sarcoidosis, suggesting noninfectious exposures play a small, if any, role in causing systemic sarcoidosis. In contrast, recent studies have linked infectious agents including mycobacterial and propionibacterial organisms with sarcoidosis. The association of sarcoidosis with the use of Th1-promoting biologic response modifiers is consistent with a central role for enhanced Th1 immune responses in the pathogenesis of sarcoidosis. Given evidence for a genetic predisposition to sarcoidosis, these findings suggest that the etiology of systemic sarcoidosis is linked to genetically determined enhanced Th1 immune responses to a limited number of microbial pathogens.

Sarcoidosis staging primarily has relied on the Scadding chest radiographic system, although chest CT imaging is finding increased clinical use. Whether standardized chest CT scan assessment provides additional understanding of lung function beyond Scadding stage and demographics is unknown and the focus of this study. We used National Heart, Lung, and Blood Institute study Genomics Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) cases of sarcoidosis (n = 351) with Scadding stage and chest CT scans obtained in a standardized manner. One chest radiologist scored all CT scans with a visual scoring system, with a subset read by another chest radiologist. We compared demographic features, Scadding stage and CT scan findings, and the correlation between these measures. Associations between spirometry and diffusing capacity of the lungs for carbon monoxide (D lco) results and CT scan findings and Scadding stage were determined using regression analysis (n = 318). Agreement between readers was evaluated using Cohen's κ value. CT scan features were inconsistent with Scadding stage in approximately 40% of cases. Most CT scan features assessed on visual scoring were associated negatively with lung function. Associations persisted for FEV 1 and D lco when adjusting for Scadding stage, although some CT scan feature associations with FVC became insignificant. Scadding stage was associated primarily with FEV 1 , and inclusion of CT scan features reduced significance in association between Scadding stage and lung function. Multivariable regression modeling to identify radiologic measures explaining lung function included Scadding stage for FEV 1 and FEV 1 to FVC ratio (P <. 05) and marginally for D lco (P <. 15). Combinations of CT scan measures accounted for Scadding stage for FVC. Correlations among Scadding stage and CT scan features were noted. Agreement between readers was poor to moderate for presence or absence of CT scan features and poor for degree and location of abnormality. In this study, CT scan features explained additional variability in lung function beyond Scadding stage, with some CT scan features obviating the associations between lung function and Scadding stage. Whether CT scan features, phenotypes, or endotypes could be useful for treating patients with sarcoidosis needs more study. [ABSTRACT FROM AUTHOR]

The contribution and regulation of various CD4+ T cell lineages that occur with remitting vs progressive courses in sarcoidosis are poorly understood. We developed a multiparameter flow cytometry panel to sort these CD4+ T cell lineages followed by measurement of their functional potential using RNA-sequencing analysis at six-month intervals across multiple study sites. To obtain good quality RNA for sequencing, we relied on chemokine receptor expression to identify and sort lineages. To minimize gene expression changes induced by perturbations of T cells and avoid protein denaturation caused by freeze/thaw cycles, we optimized our protocols using freshly isolated samples at each study site. To accomplish this study, we had to overcome significant standardization challenges across multiple sites. Here, we detail standardization considerations for cell processing, flow staining, data acquisition, sorting parameters, and RNA quality control analysis that were performed as part of the NIH-sponsored, multi-center study, BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints (BRITE). After several rounds of iterative optimization, we identified the following aspects as critical for successful standardization: 1) alignment of PMT voltages across sites using CS&T/rainbow bead technology; 2) a single template created in the cytometer program that was used by all sites to gate cell populations during data acquisition and cell sorting; 3) use of standardized lyophilized flow cytometry staining cocktails to reduce technical error during processing; 4) development and implementation of a standardized Manual of Procedures. After standardization of cell sorting, we were able to determine the minimum number of sorted cells necessary for next generation sequencing through analysis of RNA quality and quantity from sorted T cell populations. Overall, we found that implementing a multi-parameter cell sorting with RNA-seq analysis clinical study across multiple study sites requires iteratively tested standardized procedures to ensure comparable and high-quality results. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis, one of the most common interstitial lung diseases, has significant health disparities. Approximately 50% of individuals affected with sarcoidosis will undergo spontaneous remission, but those who do not undergo remission often require long-term or lifelong treatment to prevent disease progression. We sought to assess the association between medication adherence and clinical outcomes in sarcoidosis.Methods: Adult patients in the Johns Hopkins Sarcoidosis Clinic diagnosed with pulmonary sarcoidosis on treatment were eligible for enrollment. Questionnaires were administered to assess medication adherence, health-related quality of life (HRQoL), health-care utilization, and sociodemographic information. Clinical information was abstracted from medical charts including lung function, disease duration, comorbidities, and sarcoidosis organ involvement.Results: A total of 117 participants were enrolled (57% women; 55% black; median age, 57 years). Within the cohort, 66% of individuals reported at least one nonadherent behavior. Higher medication adherence was associated with better HRQoL (P < .05). There was no association between medication adherence and the odds of health-care utilization, FVC % predicted, FEV1 % predicted, or diffusion capacity of the lungs for carbon monoxide % predicted. Black participants reported lower medication adherence than white participants (P < .05).Conclusions: This is the first observational study of medication adherence in sarcoidosis. We found that higher medication adherence was associated with better HRQoL, with blacks more likely to report nonadherence. Medication adherence may be an important target to improve patient-reported outcomes and health disparities in sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure.Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability.Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality.Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available. [ABSTRACT FROM AUTHOR]

Thoracic sarcoidosis is the most common form of sarcoidosis, encompassing a heterogeneous group of patients with a wide range of clinical features and associated outcomes. The distinction between isolated thoracic lymphadenopathy and pulmonary involvement matters. Morbidity is often higher, and long-term outcomes are worse for the latter. Although inflammatory infiltrates in pulmonary sarcoidosis may resolve, persistent disease activity is common and can result in lung fibrosis. Given the distinct clinical features and natural history of pulmonary sarcoidosis, its pathogenesis may differ in important ways from other sarcoidosis manifestations. This review highlights recent advances in the pathogenesis of pulmonary sarcoidosis, including the nature of the sarcoidosis antigen, the role of serum amyloid A and other host factors that contribute to alterations in innate immunity, factors that shape adaptive T-cell profiles in the lung, and how these mechanisms influence the maintenance of granulomatous inflammation in sarcoidosis. We discuss questions raised by recent findings, including the role of innate immunity in the pathogenesis, the meaning of immune cell exhaustion, and mechanisms that may contribute to lung fibrosis in sarcoidosis. We conclude with a reflection on when and how immunosuppressive therapies may be helpful for pulmonary sarcoidosis, a consideration of nonpharmacologic management strategies, and a survey of potential novel therapeutic targets for this vexing disease. [ABSTRACT FROM AUTHOR]

Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ~20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granutomas, oligoclonal CD4+ T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab')2 fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150-160, 80, or 60-64 kD) but only 3 of 22 (14%) control tissues (all 62-64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase-peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)- (P = 0.0059) and 4 of 10 (40%) PPD+ (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase-peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis. [ABSTRACT FROM AUTHOR]

Introduction: Right ventricular (RV) involvement in cardiac sarcoidosis (CS) is associated with adverse outcomes. Positron emission tomography (PET) using 18-flourodeoxyglucose (FDG) can detect RV involvement but is costly, associated with ionizing radiation, and not widely available. Speckle-tracking echocardiography (STE) is sensitive in detecting early ventricular systolic dysfunction. We characterized RV systolic function using STE in 3 cohorts of patients with systemic sarcoidosis and tested the hypothesis that right ventricular free wall strain (RVFWS) is more abnormal in patients with a higher burden of FDG uptake on PET. Methods: We retrospectively reviewed imaging studies in 61 patients with systemic sarcoidosis. Patients were categorized as follows based on PET: 1. Non-cardiac sarcoid (control, Group 1, n=16); 2. Left ventricular CS (Group 2, n=33); and 3. Biventricular CS (Group 3, n=4). RVFWS was measured using 2-dimensional STE; a value of ≥ -18% was considered abnormal. Results: The l eft ventricular ejection fraction was 57%, 45%, and 28%, and left ventricular global longitudinal strain was -16.1 ± 4.7%, -12.5 ± 6.1%, -8.3 ± 6.5% in Groups 1, 2, and 3 respectively. There was no significant difference in RV fractional area change (RVFAC) between the 3 groups (28.7 ± 12.1%, 25.9 ± 11.8, and 20.8 ± 24.8, respectively; p=0.5). However, there was a significant difference in RVFWS between the 3 groups, with progressively worse RVFWS in groups with progressively higher burdens of FDG uptake on PET (Fig 1, p<0.001). Conclusions: RVFWS is more sensitive than RVFAC in detecting RV dysfunction in patients with CS. RVFWS is reduced in CS patients with either left ventricular or biventricular FDG uptake. RVFWS may be more sensitive than FDG-PET in detecting early RV involvement in patients with CS. [ABSTRACT FROM AUTHOR]