Developmental drugs for sarcoidosis.

Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%-30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality. Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited. The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity. Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.

SACE and IL-2R as serum biomarkers for evaluation of multi-organ involvement and prognosis of sarcoidosis.

BACKGROUND: Serum biomarkers in the evaluation of organ involvement and prognostic monitoring of sarcoidosis have not been determined. The purpose of this study was to identify common biomarkers that could be used to assess organ involvement and monitor outcomes in sarcoidosis patients. METHODS: From Mar 2013 to Sep 2021, patients with newly diagnosed pulmonary sarcoidosis were enrolled in this study in Shanghai Pulmonary Hospital. The information from medical records was retrospectively collected including diagnosis, organ involvement, laboratory tests and follow up data. Differences of continuous variables between groups were analyzed by unpaired Student's t-test. Multivariate logistic regression model was performed to identify potential independent factors associated with multiple organ involvement. RESULTS: A total of 832 patients were included in the study. There were 339 (40.7%) patients with single organ pulmonary involvement, while 493 (59.3%) patients had two to seven organs involved. Among the routine serum tests, only the serum angiotensin converting enzyme (SACE) level was an independent factor of multiple organ involvement. Compared to those patients without involvement, SACE levels were higher in patients with extra-thoracic lymph node, skin, or spleen involvement as well as abnormal calcium metabolism. Interleukin-2 receptor (IL-2R) levels were higher in patients with extra-thoracic lymph node, spleen involvement and abnormal calcium metabolism than in those without it. The mean levels of SACE and IL-2R showed upward trends paralleling the increase on number of organs involved. In follow up, SACE and IL-2R levels were both decreased in an improved patient group, while there was no obvious difference was noticed before and after treatment in patients with persistent disease. CONCLUSION: SACE and IL-2R were useful as serum biomarkers in the initial evaluation of organ involvement as well as monitoring prognosis in sarcoidosis.

Management of Advanced Pulmonary Sarcoidosis.

The term "advanced sarcoidosis" is used for forms of sarcoidosis with a significant risk of loss of organ function or death. Advanced sarcoidosis often involves the lung and is described as "advanced pulmonary sarcoidosis" (APS), which includes advanced pulmonary fibrosis, associated complications such as bronchiectasis and infections, and pulmonary hypertension. Although APS affects a small proportion of patients with sarcoidosis, it is the leading cause of poor outcomes, including death. Here we review the major patterns of APS with a focus on the current management as well as potential approaches for improved outcomes for this most serious sarcoidosis phenotype.

Chest high-resolution computed tomography can make higher accurate stages for thoracic sarcoidosis than X-ray.

BACKGROUND: To explore if chest high-resolution computed tomography (HRCT) can make higher accurate stages for thoracic sarcoidosis stage than X-ray (CRX) only. METHODS: Clinical data from medical records of consecutive patients with a confirmed diagnosis of pulmonary sarcoidosis at Shanghai Pulmonary Hospital from January 1 2012 to December 31 2016 and consecutive patients treated at the Sarcoidosis Center of University of Cincinnati Medical Center, Ohio, USA from January 1 2010 to December 31 2015 were reviewed. The clinical records of 227 patients diagnosed with sarcoidosis (140 Chinese and 87 American) were reviewed. Their sarcoidosis stage was determined by three thoracic radiologists based on CXR and HRCT presentations, respectively. The stage determined from CXR was compared with that determined from HRCT. RESULTS: Overall, 50.2% patients showed discordant sarcoidosis stage between CXR and HRCT (52.9% in Chinese and 44.8% in American, respectively). The primary reason for inconsistent stage between CXR and HRCT was failure to detect mediastinal lymph node enlargement in the shadow of the heart in CXR (22.1%) and small nodules because of the limited resolution of CXR (56.6%). Stage determined from HRCT negatively correlated with carbon monoxide diffusing capacity (DLCO) significantly (P < .01) but stage determined from CXR did not. Pleural involvement was detected by HRCT in 58 (25.6%) patients but only in 17 patients (7.5%) by CXR. Patients with pleural involvement had significantly lower forced vital capacity and DLCO than patients without it (both P < .05). CONCLUSION: Revised staging criteria based on HRCT presentations included 5 stages with subtypes in the presence of pleural involvement were proposed. Thoracic sarcoidosis can be staged more accurately based on chest HRCT presentations than based on CXR presentations. Pleural involvement can be detected more accurately by HRCT.

ERS clinical practice guidelines on treatment of sarcoidosis.

BACKGROUND: The major reasons to treat sarcoidosis are to lower the morbidity and mortality risk or to improve quality of life (QoL). The indication for treatment varies depending on which manifestation is the cause of symptoms: lungs, heart, brain, skin or other manifestations. While glucocorticoids remain the first choice for initial treatment of symptomatic disease, prolonged use is associated with significant toxicity. Glucocorticoid-sparing alternatives are available. The presented treatment guidelines aim to provide guidance to physicians treating the very heterogenous sarcoidosis manifestations. METHODS: A European Respiratory Society Task Force committee composed of clinicians, methodologists and patients with experience in sarcoidosis developed recommendations based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The committee developed eight PICO (Patients, Intervention, Comparison, Outcomes) questions and these were used to make specific evidence-based recommendations. RESULTS: The Task Force committee delivered 12 recommendations for seven PICOs. These included treatment of pulmonary, cutaneous, cardiac and neurologic disease as well as fatigue. One PICO question regarding small-fibre neuropathy had insufficient evidence to support a recommendation. In addition to the recommendations, the committee provided information on how they use alternative treatments, when there was insufficient evidence to support a recommendation. CONCLUSIONS: There are many treatments available to treat sarcoidosis. Given the diverse nature of the disease, treatment decisions require an assessment of organ involvement, risk for significant morbidity, and impact on QoL of the disease and treatment.

Detection of early phenotype cardiac sarcoidosis by cardiovascular magnetic resonance.

PURPOSE OF REVIEW: Cardiac sarcoidosis has high prevalence in sarcoidosis patients and contributes to significant morbidity and mortality. Early detection of cardiac sarcoidosis is essential to improving patients' symptoms and cardiovascular outcomes. RECENT FINDINGS: Cardiovascular magnetic resonance imaging (CMR) is an excellent diagnostic modality for cardiac sarcoidosis. However, early phenotypes of cardiac sarcoidosis have more mild imaging phenotypes. These mild and sometimes subtle imaging phenotypes of cardiac sarcoidosis have lower diagnostic sensitivity and specificity for cardiac sarcoidosis by CMR when compared with more severe imaging phenotypes of cardiac sarcoidosis. In addition, many sarcoidosis patient cohorts frequently have heterogenous potential alternative etiologies for mild myocardial disease detected by mild late gadolinium enhancement (LGE) findings. In early phenotype cardiac sarcoidosis, analysis of the LGE pattern and location can improve the diagnostic specificity of these mild LGE findings. SUMMARY: The current review focuses on the current strengths and challenges in CMR detection of early phenotypes of cardiac sarcoidosis by the LGE technique.

Management of immunosuppressants in the era of coronavirus disease-2019.

PURPOSE OF REVIEW: Patients on chronic immunosuppressive treatments at baseline are at increased risk of opportunistic infections. These patients are at especially increased risk of morbidity and mortality during the coronavirus-19 (COVID-19) pandemic. This review will focus on patients with diseases in which immunosuppression is a vital part of the treatment regimen, including those with solid organ transplants, rheumatologic disorders, sarcoidosis, and inflammatory bowel disease (IBD). We will summarize the current knowledge of immunosuppression in these diseases and the risk of contracting COVID-19. Furthermore, we will discuss if immunosuppression increases severity of COVID-19 presentation. RECENT FINDINGS: Since the start of the COVID-19 pandemic, a large number patients receiving chronic immunosuppression have been infected with SARS-CoV-2. Moreover, our understanding of the immunology of SARS-CoV-2 is advancing at a rapid pace. Currently, a number of clinical trials are underway to investigate the role of immunosuppressive treatments in the management of this disease. SUMMARY: Currently, there is no conclusive evidence to suggest that solid organ transplant recipients on chronic immunosuppression are at increased risk of contracting COVID-19. Solid organ transplant recipients may be at increased risk for worse COVID-19 outcomes but the data are not consistent. There is evidence to suggest that patients with rheumatologic disorders or IBDs are not at increased risk of contracting COVID-19 and do not necessarily experience worse clinical outcomes. Patients with sarcoidosis are not necessarily at increased risk of COVID-19, although there is limited data available to determine if immunosuppression worsens outcomes in this population.

The Value of a Patient Global Assessment in Management of Sarcoidosis.

The patient global assessment (PGA) is a reported outcome instrument used to gauge the patient's well-being. We performed a prospective study of patients seen at the University of Cincinnati Sarcoidosis Clinic. Two groups were studied: those at first visit during the time period (initial) and those seen at least one more time by the same physician (follow-up). A total of 1006, including 677 initial, visits occurred during the six-month period. Patients in whom anti-inflammatory treatment was initiated or increased had a significantly lower PGA score (ANOVA p < 0.001, p < 0.05 for increased versus all others). There was no significant difference in initial PGA score based on race, sex, or age. The change in PGA was significantly lower for patients in whom treatment was increased (ANOVA p < 0.001, increased different from all others, p < 0.05). The PGA was significantly lower for patients in whom anti-inflammatory therapy was increased; however, there was overlap between groups.

Income and Other Contributors to Poor Outcomes in U.S. Patients with Sarcoidosis.

Rationale: Socioeconomic factors are associated with worse disease severity at presentation in sarcoidosis, but the relative importance of socioeconomic variables on morbidity and disease burden has not been fully elucidated.Objectives: To determine the association between income and sarcoidosis outcomes after controlling for socioeconomic and disease-related factors.Methods: Using the Sarcoidosis Advanced Registry for Cures database, we analyzed data from 2,318 patients with sarcoidosis in the United States to determine the effect of income and other variables on outcomes. We divided comorbidities arising after diagnosis into those likely related to steroid use and those likely related to sarcoidosis. We assessed the development of health-related, functional, and socioeconomic outcomes following the diagnosis of sarcoidosis.Measurements and Main Results: In multivariate analysis, low-income patients had significantly higher rates of new sarcoidosis-related comorbidities (<$35,000, odds ratio [OR], 2.4 [1.7-3.3]; $35,000-84,999, OR, 1.4 [1.1-1.9]; and ≥$85,000 [reference (Ref)]) and new steroid-related comorbidities (<$35,000, OR, 1.3 [0.9-2.0]; $35,000-84,999, OR, 1.5 [1.1-2.1]; and ≥$85,000 [Ref]), had lower health-related quality of life as assessed by the Sarcoidosis Health Questionnaire (P < 0.001), and experienced more impact on family finances (<$35,000, OR, 7.9 [4.9-12.7]; $35,000-84,999, OR, 2.7 [1.9-3.9]; and ≥$85,000 [Ref]). The use of supplemental oxygen, need for assistive devices, and job loss were more common in lower income patients. Development of comorbidities after diagnosis of sarcoidosis occurred in 63% of patients and were strong independent predictors of poor outcomes. In random forest modeling, income was consistently a leading predictor of outcome.Conclusions: These results suggest the burden from sarcoidosis preferentially impacts the economically disadvantaged.

Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline.

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.

Symptoms, impacts, and suitability of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT™) questionnaire in patients with sarcoidosis-associated pulmonary hypertension (SAPH): a qualitative interview study.

BACKGROUND: Sarcoidosis-associated pulmonary hypertension (SAPH) is a prevalent and serious complication of sarcoidosis. No SAPH-specific self-report instruments for assessing SAPH symptoms and their impact on patients are available to date. This study sought to determine whether the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT™) questionnaire is suitable for use in patients with SAPH. METHODS: Patients diagnosed with SAPH participated in qualitative one-on-one telephone interviews to better understand SAPH symptoms and their impacts on patients' lives and to determine the appropriateness of the PAH-SYMPACT™ for use in patients with SAPH. The interviews comprised concept elicitation, completion of the PAH-SYMPACT™, and cognitive debriefing. Interview transcripts were analyzed by content analysis. RESULTS: Eleven patients with SAPH were interviewed between August 2019 and June 2020. In the concept elicitation, all 11 participants endorsed shortness of breath and nine participants (82%) rated it as their "most bothersome or severe" symptom. Impacts endorsed by all 11 participants were difficulty walking uphill or up stairs and difficulty in performing daily activities. Cognitive debriefing indicated that the PAH-SYMPACT™ items were relevant and understandable to most participants and reflected their experiences of SAPH. Participants indicated that no key symptoms or impacts of SAPH were missing. They also reported that the PAH-SYMPACT™ instructions and response options were clear, and that it would be feasible to complete the 11 symptom items and one oxygen use item as part of their daily schedule. CONCLUSIONS: This study suggests the PAH-SYMPACT™ is suitable for assessing symptoms and their impact in patients with SAPH. However, larger longitudinal studies are needed to confirm that it is fit for use in this patient population and that it can be used to reliably detect temporal changes in patients' symptom status. Trial registration Not applicable.

Physiological predictors of survival in patients with sarcoidosis-associated pulmonary hypertension: results from an international registry.

INTRODUCTION: Sarcoidosis-associated pulmonary hypertension (SAPH) is associated with reduced survival in single-centre studies. The international Registry for SAPH (ReSAPH) with long-term follow-up was established to enrich our knowledge of this complication of sarcoidosis. This analysis aims to elucidate factors associated with reduced transplant-free survival in SAPH patients. METHODS: ReSAPH contains prospectively collected outcomes of SAPH patients since the time of registry enrolment. Information analysed includes right heart catheterisation data, pulmonary function testing, chest radiography, Scadding stage and 6-min walk distance (6MWD), among others. Cox regression models were used to identify independent predictors of transplant-free survival. RESULTS: Data from 215 patients followed for a mean±sd 2.5±1.9 years were available for analysis. In the 159 precapillary patients, the Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival was 89.2%, 71.7% and 62.0%, respectively. Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival in the incident group was 83.5%, 70.3% and 58.3%, respectively, and in the prevalent group was 94.7%, 72.2% and 66.3%, respectively. Patients with reduced diffusing capacity of the lung for carbon monoxide (D LCO) (<35% predicted) and 6MWD <300 m in the precapillary cohort had significantly worse transplant-free survival. Reduced 6MWD and preserved forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio were identified as independent risk factors for reduced transplant-free survival in the precapillary cohort. CONCLUSION: Reduced D LCO (<35% pred) and 6MWD (<300 m) at the time of registry enrolment were associated with reduced transplant-free survival in the overall precapillary cohort. Preserved FEV1/FVC ratio was identified as an independent risk factor for worsened outcomes.

Current treatment of sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a granulomatous systemic disease of unknown cause where the lung is the most frequently affected organ. Therapeutic management of the disease is challenging as clinical presentation and prognosis are very heterogeneous. In the present review, we will summarize the main advances in sarcoidosis therapy. RECENT FINDINGS: Current sarcoidosis therapies are categorized in three lines: glucocorticoids (first line), immunosuppressants (second line), and biologics (third line). Recent glucocorticoid studies have reported that efficacy could be similar with high and low doses, but with an increase in side effects with higher doses. In immunosuppressants, recent publications in mycophenolate and repository corticotropin injection (RCI) have added more information in their use and efficacy. Finally, new evidence has been published in the use of antitumor necrosis factor (anti-TNFα) agents in refractory cardiac sarcoidosis and neurosarcoidosis. SUMMARY: Sarcoidosis therapy is constantly evolving, and new drugs have been added to the recommended treatments. However, extensive clinical trials are still necessary to optimize the current recommendations.

Use of third-line therapies in advanced sarcoidosis.

OBJECTIVES: Patients with advanced sarcoidosis often require third-line therapies including infliximab, adalimumab, rituximab, and repository corticotropin injection (RCI). Over time, some patients discontinue therapy. METHODS: In a retrospective review of patients at the University of Cincinnati Sarcoidosis Clinic, we identified patients who received one or more third-line treatments. Age, race, gender, organ involvement, and initial date of therapy were collected. For patients in whom a drug was discontinued, the last date of treatment, reason for drug discontinuation, and outcome of drug withdrawal were noted. RESULTS: Of the 2109 patients identified, 317 (15%) had received one or more third-line therapies (infliximab: 258 patients; adalimumab: 52 patients; rituximab: 34 patients; RCI: 101 patients). Patients with neurologic, cutaneous, or ocular sarcoidosis involvement were more likely to have received third-line therapy. Overall, 225 (50.6%) of treatment regimens were discontinued. Rate of discontinuation was higher for infliximab (55%), adalimumab (58%), or RCI (43%) than for rituximab (29%, Chi square=11.959, p=0.0075). Compared to RCI, the hazard ratio (HR) for discontinuing therapy due to infection was increased for infliximab (HR=12.14, p=0.0134) and adalimumab (HR=9.71, p=0.0356). The hazard ratio was higher for drug discontinuation due to allergic reactions to infliximab (HR=9.40, p=0.0017) or adalimumab (HR=5.83, p=0.0273). For patients receiving at least two years of therapy, drug survival was significantly shorter for infliximab compared to other therapies (Chi square=5.4054, p=0.0201). CONCLUSIONS: While third-line therapies are often initially effective, a significant number of patients discontinued individual treatments and initiated an alternative third-line therapy.

Advanced Pulmonary Sarcoidosis.

At least 5% of sarcoidosis patients die from their disease, usually from advanced pulmonary sarcoidosis. The three major problems encountered in advanced pulmonary sarcoidosis are pulmonary fibrosis, pulmonary hypertension, and respiratory infections. Pulmonary fibrosis is the result of chronic inflammation, but other factors including abnormal wound healing may be important. Sarcoidosis-associated pulmonary hypertension (SAPH) is multifactorial including parenchymal fibrosis, vascular granulomas, and hypoxia. Respiratory infections can be cause by structural changes in the lung and impaired immunity due to sarcoidosis or therapy. Anti-inflammatory therapy alone is not effective in most forms of advanced pulmonary sarcoidosis. New techniques, including high-resolution computer tomography and 18F-fluorodeoxyglucose positron emission tomography (PET) have proved helpful in identifying the cause of advanced disease and directing specific therapy.

Management of neurosarcoidosis: a clinical challenge.

PURPOSE OF REVIEW: Sarcoidosis is a complex disease with many faces, and the clinical manifestation and course of neurosarcoidosis are particularly variable. Although neurosarcoidosis occurs in up to 10% of sarcoidosis patients, it can lead to significant morbidity and some mortality. RECENT FINDINGS: Three criteria are usually required for a diagnosis of (neuro)sarcoidosis: clinical and radiologic manifestations, noncaseating granulomas, and no evidence of alternative disease. Recent guidelines have helped to clarify criteria for diagnosing neurosarcoidosis. No firm guidelines exist on whether, when, and how treatment should be started. Treatment depends on the presentation and distribution, extensiveness, and severity of neurosarcoidosis. As regards evidence-based treatment, only a few randomized controlled trials have been done. Hence, several aspects of (neuro)sarcoidosis management are not fully addressed by the current literature. SUMMARY: Significant advances have been made in the potential and accuracy of diagnostics for neurosarcoidosis. Treatment should be approached within the context of the patient's anticipated clinical course, avoidance of adverse drug effects, and, if necessary, from the perspective of the comprehensive management of a chronic disease. A multidisciplinary approach to the management of sarcoidosis is strongly recommended.

Sarcoidosis Involving the Gastrointestinal Tract: Diagnostic and Therapeutic Management.

Involvement of the gastrointestinal (GI) tract is an infrequent extrathoracic presentation of sarcoidosis. We reviewed 305 cases of GI involvement reported in 238 patients, in whom GI sarcoidosis was the first sign of the disease in half the cases. The disease does not affect the GI tract uniformly, with a clear oral-anal gradient (80% of reported cases involved the esophagus, stomach, and duodenum). Clinicopathological mechanisms of damage may include diffuse mucosal infiltration, endoluminal exophytic lesions, involvement of the myenteric plexus, and extrinsic compressions. Ten percent of patients presented with asymptomatic or subclinical disease found on endoscopy. The diagnosis is relevant clinically because 22% of cases reviewed presented as life threatening. In addition, initial clinical/endoscopic findings may be highly suggestive of GI cancer. The therapeutic approach is heterogeneous and included wait-and-see or symptomatic approaches, glucocorticoid/immunosuppressive therapy, and surgery. Sarcoidosis of the gut is a heterogeneous, potentially life-threatening condition that requires a multidisciplinary approach and early clinical suspicion to institute personalized therapeutic management and follow-up.

Advanced sarcoidosis.

PURPOSE OF REVIEW: Advanced sarcoidosis is an important cause of morbidity and mortality in sarcoidosis. Over the past few years, several studies have been published clarifying the prevalence and severity of this condition. RECENT FINDINGS: Pulmonary involvement is the most common form of sarcoidosis. Increased morbidity and significant mortality is encountered in advanced lung disease. Although many sarcoidosis patients with pulmonary fibrosis have a normal life expectancy, at least 20% develop progression and may die from this complication. Sarcoidosis-associated pulmonary hypertension (SAPH) is an independent cause of death in advanced pulmonary sarcoidosis. Two large multicenter registries and a large single-center report provide more details regarding presentation and outcome of SAPH. Advanced neurologic disease is associated with significant morbidity, but not much mortality. Two large retrospective reviews demonstrated the effectiveness of infliximab in treating advanced neurosarcoidosis. Advanced cardiac sarcoidosis can lead to mortality. SUMMARY: Advanced sarcoidosis is associated with significant morbidity and some mortality. Up to a quarter of all sarcoidosis patients have one or more forms of advanced disease. These patients require closer monitoring and often multiples treatments.

Geoepidemiological big data approach to sarcoidosis: geographical and ethnic determinants.

In sarcoidosis, a rare multiorgan disease of unknown aetiology characterised by non-caseating epitheloid cell granulomas, three geoepidemiological factors are major aetiopathogenic factors: geolocation, ethnicity, and personal environment. Geographically, sarcoidosis is mainly reported in the Northern Hemisphere, with the highest incidence rates uniformly reported in countries located at the highest latitudes. The main geoepidemiological-driven differences across the world are of greater female involvement in Southern Europe, the Southern US and Japan, a differentiated radiological pattern (predominance of stage I in Southern Europe and Middle East/Asia and of stage II in Northern Europe, China and India, with the US and Japan having the highest frequencies of stages III/IV) and the extrathoracic phenotype: the most frequent extrathoracic organs involved are the skin in Southern Europe and Middle East/Asia, the eyes in Northern Europe, Northeast US and Japan, the liver in India and the lymph nodes in China. In addition, there are large ethnicity-driven variations in the frequency, epidemiology, clinical expression and outcome of sarcoidosis. The highest incidence rates are uniformly reported in Black/African-American people, independently of the geographical location, with rates between 2- and 10-fold higher than those reported in White people living in the same geographical area. Furthermore, ethnicity heavily influences the clinical phenotype by modifying the age at diagnosis and the rates of thoracic and extrathoracic involvements. Geoepidemiological studies enhanced by big data may yield important clues to understanding the role of these factors in the frequency and clinical phenotypes of sarcoidosis.

Endobronchial ultrasound-guided transbronchial needle aspiration in sarcoidosis: Beyond the diagnostic yield.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the commonly used technique for pathological confirmation of clinically suspected sarcoidosis, mostly owing to its consistently high success rate in the detection of granulomas. However, other possible advantages, which are less appreciated and often poorly studied, may also contribute to the wider use of EBUS-TBNA in the future. These advantages include refinement of differential diagnoses through the study of lymph node characteristics during B-mode examination; reduction of complications associated with bronchoscopy, as well as improved triage of the specimen for ancillary studies with the use of rapid on-site evaluation; optimization of the quality of the sample through the selection of a target area for biopsy with minimal vascularity and absence of calcifications by using the colour Doppler and the B-mode; and prediction of the presence of extensive lymph node fibrosis by using the strain elastography module. Yet, limitations and possible clinical drawbacks should also be acknowledged. Indeed, due to the lack of specificity of the pathology findings in EBUS-derived samples, the diagnosis of sarcoidosis is one of the exclusion and should remain essentially clinical. The external validity of EBUS-TBNA results in sarcoidosis is questionable, as they mainly derive from studies in populations with a high disease prevalence. Finally, the risk exists that the low morbidity and high diagnostic yield of EBUS-TBNA may lead to its overuse in patients with clinical/radiological findings specific enough to secure a clinical diagnosis of sarcoidosis.