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.

Hematologic and Oncologic Aspects of Sarcoidosis: Some of the Least Studied but Most Common Dilemmas.

The hematologic system is frequently involved in sarcoidosis. Lymphopenia is the most common hematologic manifestation noted, although anemia and thrombocytopenia also occur. The etiology of these common manifestations can be direct granulomatous infiltration of bone marrow, lymph nodes, or spleen or related to immunologic dysfunction. Although not life threatening, these problems can lead to cytopenias requiring close monitoring in patients receiving a variety of disease treatments. The relationship between sarcoidosis and malignancy remains complex. However, some sarcoidosis patients are at increased risk for the development of malignancies, particularly lymphomas and gastrointestinal cancers. Conversely, cancer patients can experience an increase in the likelihood for the development of breast cancer and lymphomas.

Hematological involvement in sarcoidosis: from cytopenias to lymphoma.

INTRODUCTION: We present an updated overview of the hematological involvementassociated with sarcoidosis, including a management approach forcytopenias and revisiting the association with hematologicalmalignancies. AREAS COVERED: Theetiology of cytopenias in sarcoidosis can be attributed to two majoretiopathogenic mechanisms: infiltration of hematopoietic organs suchas the spleen and bone marrow, and autoimmune-mediated cytopenias.With respect to the association with hematological malignancies, itrequires careful evaluation of patients from a chronologicalperspective. Patients must be classified into one of three pathogenicscenarios, including preexisting hematological malignancies,synchronous development of malignancy and sarcoidosis due to commonpredisposing factors, or sarcoidosis as a predisposing factor formalignancies. EXPERT OPINION: The association between sarcoidosis and hematologic involvement isbest understood as a pathogenic continuum, with cytopenias andhematologic neoplasms intertwined due to various etiopathogenicmechanisms. These mechanisms include sarcoid infiltration ofhematopoietic organs, common predisposing immunogenetics for thedevelopment of autoimmune cytopenias and malignancies, and anincreased risk of neoplasm development in patients with autoimmunecytopenias. Collaboration among the main specialties involved in theclinical management of these patients is crucial for an earlymonitoring and management.

High-Resolution CT Scan Fibrotic Patterns in Stage IV Pulmonary Sarcoidosis: Impact on Pulmonary Function and Survival.

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

High-resolution CT phenotypes in pulmonary sarcoidosis: a multinational Delphi consensus study.

One view of sarcoidosis is that the term covers many different diseases. However, no classification framework exists for the future exploration of pathogenetic pathways, genetic or trigger predilections, patterns of lung function impairment, or treatment separations, or for the development of diagnostic algorithms or relevant outcome measures. We aimed to establish agreement on high-resolution CT (HRCT) phenotypic separations in sarcoidosis to anchor future CT research through a multinational two-round Delphi consensus process. Delphi participants included members of the Fleischner Society and the World Association of Sarcoidosis and other Granulomatous Disorders, as well as members' nominees. 146 individuals (98 chest physicians, 48 thoracic radiologists) from 28 countries took part, 144 of whom completed both Delphi rounds. After rating of 35 Delphi statements on a five-point Likert scale, consensus was achieved for 22 (63%) statements. There was 97% agreement on the existence of distinct HRCT phenotypes, with seven HRCT phenotypes that were categorised by participants as non-fibrotic or likely to be fibrotic. The international consensus reached in this Delphi exercise justifies the formulation of a CT classification as a basis for the possible definition of separate diseases. Further refinement of phenotypes with rapidly achievable CT studies is now needed to underpin the development of a formal classification of sarcoidosis.

Images in Sarcoidosis: new section of our Journal.

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D. Geraint James Lecture: The sarcoidosis saga: what insights from the past will guide us in the future.

The sarcoidosis community in general and the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) in particular have led efforts to improve sarcoidosis diagnosis and care. Evidence based guidelines regarding the diagnosis and treatment have recently been published. In addition, several clinical trials examining existing and new treatments for sarcoidosis have been completed and published. In addition, WASOG has developed criteria and identified Centers of Excellence for sarcoidosis care around the world. In discussing what insights from the past will guide us in the future, this paper focuses on three specific topics: updating the diagnosis of sarcoidosis, using placebo-controlled trials to illuminate the natural course of pulmonary sarcoidosis; and exploring multidisciplinary sarcoidosis clinic care using Centers of Excellence. New approaches for diagnosis of sarcoidosis and steroid tapering are proposed based on current literature.

Diagnosis of pulmonary sarcoidosis in tuberculosis endemic area-a narrative review.

Background and Objective: Pulmonary sarcoidosis and tuberculosis (TB) are the most frequent tissue-confirmed granulomatous diseases. Due to its unknown etiology, pulmonary sarcoidosis is diagnosed by ruling out other granulomatous diseases and necessitating clinical, radiological, and pathological evidence. There are many factors that contribute to the diagnostic dilemma between these two diseases. Even though some aspects of both diseases, such as their pathological evidence and abnormal X-ray findings, are quite similar, the treatment options for each are entirely different. The standard treatment for sarcoidosis is immunosuppressive agents such as glucocorticoids, which can exacerbate TB. Consequently, the overlap between clinical and radiological features constitutes a significant challenge for many physicians in selecting the optimal treatment for each patient. Therefore, the exclusion of pulmonary TB is a mandatory step for the diagnosis of pulmonary sarcoidosis. This article reviews and summarizes basic science and clinical research on distinguishing these two disorders. Methods: A systematic search of the MEDLINE and PubMed databases focusing on studies published within the last 35 years was conducted. The last search date is February 4, 2023. The authors used the following combinations of terms: tuberculosis, sarcoidosis, diagnosis, bronchoscopy, biomarkers, and radiography. All studies were reviewed, and 69 references from 1990 to 2023 were found to be relevant. Key Content and Findings: Innovative laboratory tests are essential for distinguishing between pulmonary sarcoidosis and TB. The Xpert MTB/RIF assay diagnoses TB with 98% sensitivity and 89% specificity. Loop-mediated isothermal amplification (LAMP) and simultaneous amplification and testing method for Mycobacterium tuberculosis rRNA (SAT-TB) are also highly sensitive and specific for TB diagnosis. Several novel tests, such as the difference of immune complexes for the ESAT-6/SFP-10 antigen in vitro with dynamic light scattering (DLS), lung tissue-based molecular markers, and the blood transcriptome, are promising for differentiating TB from sarcoidosis. Conclusions: Recent advancements in laboratory investigations, non-invasive procedures, and invasive procedures play an important role in the diagnosis of sarcoidosis in TB-endemic areas. However, further study is needed to evaluate the diagnostic performance of all tests in terms of their competency in distinguishing between TB and sarcoidosis.

Pulmonary hemodynamics and transplant-free survival in sarcoidosis-associated pulmonary hypertension: Results from an international registry.

Pulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m2. However, there is no clear definition denoting severity of sarcoidosis-associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut-off values where transplant-free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant-free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan-Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut-off values where transplant-free survival was decreased. Decreased transplant-free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant-free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut-offs with decreased transplant-free survival in the SAPH population. Neither cut-off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant-free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease.

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.

Initial behaviors and attitudes towards the COVID-19 vaccine in sarcoidosis patients: results of a self-reporting questionnaire.

BACKGROUND: Individuals with self-declared sarcoidosis are at increased risk of COVID-19 related morbidity and mortality for which vaccination can be lifesaving. Despite this, vaccine hesitancy remains a large barrier to global acceptance of vaccination against COVID-19. We aimed to identify individuals with sarcoidosis who had and had not been vaccinated against COVID-19 vaccine to 1) establish a safety profile of COVID-19 vaccination in those with sarcoidosis and 2) to elucidate factors that contribute to COVID-19 vaccine hesitancy. METHODS: A questionnaire inquiring about COVID-19 vaccination status, vaccination side effects, and willingness for future vaccination was distributed from December 2020 to May 2021 to individuals with sarcoidosis living in the US and European countries. Details regarding sarcoidosis manifestations and treatment were solicited. Vaccine attitudes were classified as pro or anti-COVID-19 vaccination for subgroup analysis. RESULTS: At the time of questionnaire administration, 42% of respondents had already received a COVID-19 vaccination, most of whom either denied side effects or reported a local reaction only. Those off sarcoidosis therapy were more likely to report systemic side effects. Among subjects who had not yet received a COVID-19 vaccine, 27% of individuals reported they would not receive one once available. Reasons against vaccination were overwhelmingly related to the lack of confidence in vaccine safety and/or efficacy and less related to concerns associated with convenience or complacency. Black individuals, women, and younger adults were more likely to decline vaccination. CONCLUSIONS: Among individuals with sarcoidosis, COVID-19 vaccination is well-accepted and well-tolerated. Subjects on sarcoidosis therapy reported significantly less vaccination side effects, and thus the correlation between side effects, vaccine type, and vaccine efficacy requires further investigation. Strategies to improve vaccination should focus on improving knowledge and education regarding vaccine safety and efficacy, as well as targeting sources of misinformation, particularly in young, black, and female subpopulations.

Results From a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Repository Corticotropin Injection for the Treatment of Pulmonary Sarcoidosis.

INTRODUCTION: Long-term treatment of pulmonary sarcoidosis with glucocorticoids has been associated with toxicity and other adverse events, highlighting the need for alternative therapies. The goal of this study was to evaluate the efficacy and safety of repository corticotropin injection (RCI, Acthar® Gel) in patients with pulmonary sarcoidosis and to validate endpoints for use in future clinical trials. METHODS: In this multicenter, randomized, placebo-controlled trial, subjects received subcutaneous RCI (80 U) twice weekly or matching placebo through 24 weeks in a double-blind treatment phase, followed by an optional 24-week open-label extension. Efficacy was measured by glucocorticoid tapering, pulmonary function tests, chest imaging, patient-reported outcomes, and a novel sarcoidosis treatment score (STS). Safety was assessed by adverse events, physical examinations, vital signs, clinical laboratory abnormalities, and imaging. The study was terminated early due to low enrollment caused by the COVID-19 pandemic, thereby precluding statistical analysis. RESULTS: Fifty-five subjects were randomized to receive either RCI (n = 27) or placebo (n = 28). Mean STS at week 24 showed greater improvement with RCI (1.4) compared with placebo (0.7). At week 48, those who remained on RCI had an STS of 1.8 compared with 0.9 in those who switched from placebo to RCI. More subjects in the RCI group discontinued glucocorticoids at week 24 compared to the placebo group. Glucocorticoid discontinuation was comparable at week 48 for those who switched from placebo to RCI and those who continued RCI. Similar trends in favor of RCI over placebo were observed with the other efficacy endpoints. No new or unexpected safety signals were identified. CONCLUSIONS: RCI was safe and well tolerated, with trends in efficacy data suggesting greater improvement with RCI compared to placebo in patients receiving standard-of-care therapy for pulmonary sarcoidosis. The study also provided validation of efficacy endpoints that may be used in larger trials for pulmonary sarcoidosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03320070.

Pulmonary sarcoidosis is a disease characterized by inflammation of the lungs. Standard treatments include glucocorticoids, which may have harmful side effects. This clinical trial investigated whether repository corticotropin injection (RCI, Acthar^® Gel) was safe and effective in patients who were already taking glucocorticoids to treat pulmonary sarcoidosis. Patients were randomly assigned to be in one of two treatment groups: RCI or placebo. In the first 24 weeks of the study, 27 patients were injected with RCI twice weekly, while 28 patients were injected with an inactive substance (placebo). Forty-seven patients continued into an optional phase of the study for an additional 24 weeks in which all patients received RCI twice weekly. A sarcoidosis treatment score and assessments of lung health, general health, and fatigue were used to determine whether RCI was effective. These assessments showed greater improvements with RCI compared to placebo. Patients who switched from placebo to RCI showed similar improvements to those who remained on RCI throughout the entire study. Patients receiving RCI were able to discontinue their use of glucocorticoids more quickly than those taking placebo, thus helping them to avoid the harmful side effects of the glucocorticoids. Side effects for RCI were mostly mild or moderate, and no new or unexpected safety concerns for RCI were seen throughout the study.

Living with sarcoidosis: Virtual roundtable dialogue with patients and healthcare professionals.

BACKGROUND: Sarcoidosis is a multisystem disease, characterised by the infiltration of various organs by non-necrotising granulomas. The disease's heterogeneity complicates the study of patients' experiences. OBJECTIVE: To gather insight into life experiences, unmet needs and views on hypothetically emerging treatment options among patients living with sarcoidosis. METHODS: Multinational, virtual, interactive, moderated discussion of specific questions between people with sarcoidosis, with experienced clinicians participating. RESULTS: Nine patients with sarcoidosis from Australia, Denmark, Germany, Italy, Japan and the US, and three clinicians took part. All patients had pulmonary sarcoidosis, self-assessed as mild by five patients. The path to diagnosis was convoluted, with up to four physicians and a large number of tests involved. There was agreement that the process would be improved by earlier referral to specialists. The patients made a clear distinction between 'living with a condition' (adapting to the disease) and 'being ill'. The concept of remission was viewed sceptically as disease might develop in multiple organs. Panellists had a pragmatic attitude to therapies: side effects during a treatment course were accepted if overall symptoms improved. When considering hypothetical new therapies, improved quality of life (QoL) was the most important need; improved tolerability had lower priority. New therapies should be targeted on reducing disease progression and improving symptoms and QoL rather than corticosteroid withdrawal. CONCLUSIONS: The interactive exchange provided insights into the need for earlier specialist referrals, distrust of the concept of remission in sarcoidosis, and the need for therapies targeted on reducing disease progression and improving symptoms and QoL.

An expert overview of pulmonary fibrosis in sarcoidosis.

INTRODUCTION: Advanced pulmonary sarcoidosis refers to phenotypes of pulmonary sarcoidosis that often lead to significant loss of lung function, respiratory failure, or death. Around 20% of patients with sarcoidosis may progress to this state which is mainly driven by advanced pulmonary fibrosis. Advanced fibrosis often presents with associated complications of sarcoidosis including infections, bronchiectasis, and pulmonary hypertension. AREAS COVERED: This article will focus on the pathogenesis, natural history of disease, diagnosis, and potential treatment options of pulmonary fibrosis in sarcoidosis. In the expert opinion section, we will discuss the prognosis and management of patients with significant disease. EXPERT OPINION: While some patients with pulmonary sarcoidosis remain stable or improve with anti-inflammatory therapies, others develop pulmonary fibrosis and further complications. Although advanced pulmonary fibrosis is the leading cause of death in sarcoidosis, there are no evidence-based guidelines for the management of fibrotic sarcoidosis. Current recommendations are based on expert consensus and often include multidisciplinary discussions with experts in sarcoidosis, pulmonary hypertension, and lung transplantation to facilitate care for such complex patients. Current works evaluating treatments include the use of antifibrotic therapies for treatment in advanced pulmonary sarcoidosis.

Efzofitimod: a novel anti-inflammatory agent for sarcoidosis.

Efzofitimod is a first-in-class biologic based on a naturally occurring splice variant of histidyl-tRNA synthetase (HARS) that downregulates immune responses via selective modulation of neuropilin-2 (NRP2). Preclinical data found high expression of NRP2 in sarcoidosis granulomas. Treatment with efzofitimod reduced the granulomatous inflammation induced by P. acnes in an animal model of sarcoidosis. A dose escalating trial of efzofitimod in sarcoidosis with chronic symptomatic pulmonary disease found that treatment with efzofitimod was associated with improved quality of life with a trend towards reduced glucocorticoid use and stable to improved pulmonary function. These studies have led to a large Phase 3 trial of efzofitimod in symptomatic pulmonary sarcoidosis.

Validation of the Sarcoidosis Diagnostic Score in a Multicontinental Study.

Rationale: The Sarcoidosis Diagnostic Score (SDS) has been established to quantitate the clinical features consistent with sarcoidosis in a monocentric study. Objectives: We aimed to confirm the diagnostic value of SDS in a large, multicontinental study and to assess the utility of SDS in differentiating sarcoidosis from alternative diagnoses, including infectious and noninfectious granulomatous diseases. Methods: We included patients with biopsy-confirmed sarcoidosis at nine centers across the world. Patients without sarcoidosis seen at the same sites served as control patients. Using a modified World Association of Sarcoidosis and Other Granulomatous Disorders organ assessment instrument, we scored all patients for the presence of granuloma on biopsy, highly probable symptoms, and least probable symptoms for each area. Two sarcoidosis scores were generated: SDS Biopsy (with biopsy) and SDS Clinical (without biopsy). SDS Clinical and Biopsy were calculated for all patients. We calculated and compared the area under the curve (AUC) for SDS Clinical and Biopsy according to different diagnosis scenarios. Results: A total of 1,041 patients with sarcoidosis and 1,035 without sarcoidosis were included. The results for SDS Clinical (AUC, 0.888; 95% confidence interval [CI], 0.874-0.902) and SDS Biopsy (AUC, 0.979; 95% CI, 0.973-0.985) according to AUC were good to excellent for differentiating sarcoidosis from alternative diagnosis. SDS Clinical was less discriminatory in males (P = 0.01) and in high tuberculosis prevalence centers (P < 0.001). However, SDS Clinical (AUC, 0.684; 95% CI, 0.602-0.766) and SDS Biopsy (AUC, 0.754; 95% CI, 0.673-0.835) were not sufficiently discriminative for noninfectious granulomatous diseases, but both SDSs could differentiate sarcoidosis from infectious granulomatous diseases. Algorithms were proposed for the SDS Clinical and SDS Biopsy to assist the clinician in the diagnostic process, and cutoff values were proposed for the SDS Clinical and SDS Biopsy, allowing the diagnosis of sarcoidosis to be safely confirmed or rejected in most cases except for noninfectious granulomatous disease. Conclusions: This multicontinental study confirms that both SDS Clinical and SDS Biopsy have good to excellent performance in discriminating sarcoidosis from alternative diagnoses. Differences in the AUC were seen for high tuberculosis prevalence versus low tuberculosis prevalence centers and for males versus females. Both SDSs had good discriminatory function for infectious granulomatous disease but failed in cases of noninfectious granulomatous disease such as berylliosis.

Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a severe complication of sarcoidosis in a minority of patients. Several genetic defects are known to cause hereditary or sporadic PH, but whether variants in PH-associated genes are also involved in sarcoidosis-associated PH (SAPH) is unknown. METHODS: 40 patients with SAPH were individually matched to 40 sarcoidosis patients without PH (SA). Whole exome sequencing was performed to identify rare genetic variants in a diagnostic PH gene panel of 13 genes. Additionally, an exploratory analysis was performed to search for other genes of interest. From 572 genes biologically involved in PH pathways, genes were selected in which at least 15% of the SAPH patients and no more than 5% of patients without PH carried a rare variant. RESULTS: In the diagnostic PH gene panel, 20 different rare variants, of which 18 cause an amino-acid substitution, were detected in 23 patients: 14 SAPH patients carried a variant, as compared to 5 SA patients without PH (p = 0.018). Most variants were of yet unknown significance. The exploratory approach yielded five genes of interest. First, the NOTCH3 gene that was previously linked to PH, and furthermore PDE6B, GUCY2F, COL5A1, and MMP21. CONCLUSIONS: The increased frequency of variants in PH genes in SAPH suggests a mechanism whereby the presence of such a genetic variant in a patient may increase risk for the development of PH in the context of pulmonary sarcoidosis. Replication and studies into the functionality of the variants are required for further understanding the pathogenesis of SAPH.