History and familial aggregation of immune-mediated diseases in sarcoidosis: a register-based case-control-family study.

BACKGROUND: An autoimmune component in the etiology of sarcoidosis has long been debated, but population-based data on the clustering of immune-mediated diseases (IMD) and sarcoidosis in individuals and families suggestive of shared etiology is limited. RESEARCH QUESTION: Is there a higher risk of sarcoidosis having a history of IMDs and do IMDs cluster in sarcoidosis families? STUDY DESIGN AND METHODS: We conducted a case-control-family study (2001-2020). Sarcoidosis cases (n=14,146) were identified in the Swedish National Patient Register using a previously validated definition (≥2 International Classification of Diseases (ICD) coded inpatient/outpatient visits). At diagnosis, cases were matched to up to 10 general population controls (n=118,478) on birthyear, sex, and residential location. Cases, controls, and their first-degree relatives (FDR; Multi-Generation Register) were ascertained for IMDs by means of ICD codes in the Patient Register (1968-2020). Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of sarcoidosis associated with a history of IMDs in cases/controls and in FDRs. RESULTS: Sarcoidosis cases exhibited a higher prevalence of IMDs compared to controls (7.7% vs. 4.7%), especially of connective tissue diseases, cytopenia, and celiac disease. Familial aggregation was observed across IMDs; the strongest association was with celiac disease (OR 2.09 [95% CI 1.22, 3.58]), followed by cytopenia (OR 1.88 [95% 0.97, 3.65], thyroiditis (OR 1.72 [95% CI 1.14, 2.60]), skin psoriasis (OR 1.70 [95% CI 1.34, 2.15]), inflammatory bowel disease (OR 1.53 [95% CI 1.14, 2.03]), immune-mediated arthritis (OR 1.49 [95% CI 1.20, 1.85]), and connective tissue disease (OR 1.39 [95% CI 1.00, 1.93]). INTERPRETATION: IMDs confer a higher risk of sarcoidosis and they aggregate in sarcoidosis families signaling a shared etiology between IMDs and sarcoidosis. Our findings warrant further evaluation of shared genetic mechanisms.

Corrigendum: Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

[This corrects the article DOI: 10.3389/fmed.2023.1132799.].

Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case-control study in Sweden.

Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case-control study (2007-2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13-1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23-1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11-1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96-1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.

Lymphopenia and high Ki-67 expression in peripheral blood CD4+ and CD8+ T cells associate with progressive sarcoidosis.

BACKGROUND: Early identification of patients at risk for progressive sarcoidosis may improve intervention. High bronchoalveolar lavage fluid (BALF) lymphocytes and peripheral blood (PB) lymphopenia are associated with worse prognosis. The mechanisms behind are not disentangled, and to date, it is not possible to predict disease course with certainty. OBJECTIVES: Insight into the frequency of T regulatory cells (Tregs), proliferating CD4+ and CD8+ T cells in BALF and PB in clinically well-characterised patients, may provide clues to mechanisms behind differences in disease course. METHODS: Nineteen treatment-naïve patients with newly diagnosed sarcoidosis were assessed with BAL and PB samples at diagnosis. From the majority, repeated PB samples were collected over a year after diagnosis. The patients were followed for a median of 3 years and clinical parameters were used to classify patients into resolving, chronic progressive and chronic stable disease. Lymphocyte counts, frequency of Tregs defined as forkhead box protein 3+ (FoxP3+) CD4+T cells, and proliferating CD4+ and CD8+ T cells assessed with Ki-67 were analysed. RESULTS: Eleven patients disclosed a chronic stable, and eight a progressive disease course, no one resolved during the study period. In PB, lower number of lymphocytes associated with chronic progressive disease, an increased frequency of Ki-67+CD4+ and CD8+ T cells, and a tendency towards higher percentage of FoxP3+CD4+ T cells compared with chronic stable patients. CONCLUSION: A reduction of PB lymphocytes despite increased proliferation of CD4+and CD8+ T cells was observed in patients with chronic active compared with chronic stable sarcoidosis, indicating an increased PB lymphocyte turn-over in patients with deteriorating disease. Measurement of PB Tregs, Ki-67+CD4+ and Ki-67+CD8+ T cells may help in predicting sarcoidosis disease course.

Clinical Outcomes and Predictors of Long-Term Survival in Patients With and Without Previously Known Extracardiac Sarcoidosis Using Machine Learning: A Swedish Multicenter Study.

Background Cardiac involvement can be an initial manifestation in sarcoidosis. However, little is known about the association between various clinical phenotypes of cardiac sarcoidosis (CS) and outcomes. We aimed to analyze the relation of different clinical manifestations with outcomes of CS and to investigate the relative importance of clinical features influencing overall survival. Methods and Results A retrospective cohort of 141 patients with CS enrolled at 2 Swedish university hospitals was studied. Presentation, imaging studies, and outcomes of de novo CS and previously known extracardiac sarcoidosis were compared. Survival free of primary composite outcome (ventricular arrhythmias, heart transplantation, or death) was assessed. Machine learning algorithm was used to study the relative importance of clinical features in predicting outcome. Sixty-two patients with de novo CS and 79 with previously known extracardiac sarcoidosis were included. De novo CS showed more advanced New York Heart Association class (P=0.02), higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (P<0.001), and troponins (P<0.001), as well as a higher prevalence of right ventricular dysfunction (P<0.001). During a median (interquartile range) follow-up of 61 (44-77) months, event-free survival was shorter in patients with de novo CS (P<0.001). The top 5 features predicting worse event-free survival in order of importance were as follows: impaired tricuspid annular plane systolic excursion, de novo CS, reduced right ventricular ejection fraction, absence of ß-blockers, and lower left ventricular ejection fraction. Conclusions Patients with de novo CS displayed more severe disease and worse outcomes compared with patients with previously known extracardiac sarcoidosis. Using machine learning, right ventricular dysfunction and de novo CS stand out as strong overall predictors of impaired survival.

Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

Background: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS). Methods: A meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex. Results: We identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified. Conclusion: Our findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.

Peripheral blood lymphopenia in sarcoidosis associates with HLA-DRB1 alleles but not with lung immune cells and organ involvement.

Different human leukocyte antigen (HLA) alleles associate with disease phenotypes in sarcoidosis. Peripheral blood (PB) lymphopenia is reported as more common in sarcoidosis patients with worse prognosis. The mechanisms behind are unrecognized but a PB depletion due to lymphocytes migrating to lung and/or extra pulmonary organs has been suggested. Insights into associations between HLA alleles, lung immune cells, clinical phenotype including extra pulmonary manifestations (EPM), and PB lymphopenia may provide mechanistic clues and enable adequate intervention in this patient group. In this situdy,141 treatment naïve, newly diagnosed patients were retrospectively identified in a Swedish cohort of sarcoidosis patients. Data on HLA-DRB1 alleles, lung immune cells from bronchoalveolar lavage fluid (BALF), PB lymphocytes and clinical parameters including treatment and disease course (chronic vs. resolving) were collected. The patients were followed for 2 years. PB lymphopenia associated with male sex, development of non-resolving disease, a need for first- and second-line systemic immunosuppressant treatment and HLA- DRB1*07. No correlation between BALF and PB lymphocytes, and no difference in EPM was detected between patients with and without PB lymphopenia. In conclusion, PB lymphopenia is associated with a more severe disease phenotype and carriage of the HLA-DRB1*07 allele. The results do not lend support to the hypothesis about sarcoidosis PB lymphopenia being due to a migration of PB lymphocytes to other organs. Rather, they provide a basis for future studies on the connection between HLA-DRB1*07 and PB lymphopenia mechanisms.

Sarcoidosis: Epidemiology and clinical insights.

Sarcoidosis is characterized by noncaseating granulomas which form in almost any part of the body, primarily in the lungs and/or thoracic lymph nodes. Environmental exposures in genetically susceptible individuals are believed to cause sarcoidosis. There is variation in incidence and prevalence by region and race. Males and females are almost equally affected, although disease peaks at a later age in females than in males. The heterogeneity of presentation and disease course can make diagnosis and treatment challenging. Diagnosis is suggestive in a patient if one or more of the following is present: radiologic signs of sarcoidosis, evidence of systemic involvement, histologically confirmed noncaseating granulomas, sarcoidosis signs in bronchoalveolar lavage fluid (BALF), and low probability or exclusion of other causes of granulomatous inflammation. No sensitive or specific biomarkers for diagnosis and prognosis exist, but there are several that can be used to support clinical decisions, such as serum angiotensin-converting enzyme levels, human leukocyte antigen types, and CD4 Vα2.3+ T cells in BALF. Corticosteroids remain the mainstay of treatment for symptomatic patients with severely affected or declining organ function. Sarcoidosis is associated with a range of adverse long-term outcomes and complications, and with great variation in prognosis between populations. New data and technologies have moved sarcoidosis research forward, increasing our understanding of the disease. However, there is still much left to be discovered. The pervading challenge is how to account for patient variability. Future studies should focus on how to optimize current tools and develop new approaches so that treatment and follow-up can be targeted to individuals with more precision.

Functional link between sarcoidosis-associated gene variants and quantitative levels of bronchoalveolar lavage fluid cell types.

Background: Sarcoidosis is an inflammatory disease that affects multiple organs. Cell analysis from bronchoalveolar lavage fluid (BALF) is a valuable tool in the diagnostic workup and differential diagnosis of sarcoidosis. Besides the expansion of lymphocyte expression-specific receptor segments (Vα2.3 and Vß22) in some patients with certain HLA types, the relation between sarcoidosis susceptibility and BAL cell populations' quantitative levels is not well-understood. Methods: Quantitative levels defined by cell concentrations of BAL cells and CD4+/CD8+ ratio were evaluated together with genetic variants associated with sarcoidosis in 692 patients with extensive clinical data. Genetic variants associated with clinical phenotypes, Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS), were examined separately. An association test via linear regression using an additive model adjusted for sex, age, and correlated cell type was applied. To infer the biological function of genetic associations, enrichment analysis of expression quantitative trait (eQTLs) across publicly available eQTL databases was conducted. Results: Multiple genetic variants associated with sarcoidosis were significantly associated with quantitative levels of BAL cells. Specifically, LS genetic variants, mainly from the HLA locus, were associated with quantitative levels of BAL macrophages, lymphocytes, CD3+ cells, CD4+ cells, CD8+ cells, CD4+/CD8+ ratio, neutrophils, basophils, and eosinophils. Non-LS genetic variants were associated with quantitative levels of BAL macrophages, CD8+ cells, basophils, and eosinophils. eQTL enrichment revealed an influence of sarcoidosis-associated SNPs and regulation of gene expression in the lung, blood, and immune cells. Conclusion: Genetic variants associated with sarcoidosis are likely to modulate quantitative levels of BAL cell types and may regulate gene expression in immune cell populations. Thus, the role of sarcoidosis-associated gene-variants may be to influence cellular phenotypes underlying the disease immunopathology.

Phenotypic and HLA-DRB1 allele characterization of Swedish cardiac sarcoidosis patients.

BACKGROUND: Early detection and initiation of treatment in cardiac sarcoidosis (CS) is believed to be crucial to reduce morbidity and mortality. The diagnosis of CS is challenging, especially in isolated CS (ICS). Certain human leukocyte antigen (HLA-DRB1) alleles associate with different phenotypes of sarcoidosis. Phenotypic and genotypic characterization of patients with CS may improve our ability to identify patients being at risk for developing CS. METHODS: 87 patients with CS, identified at two Swedish university hospitals were included. Phenotypic characteristics were extracted from the medical records and the patients were HLA-DRB1 typed. RESULTS: Median age at diagnosis was 55 years, 37% were women. HLA-DRB1 distribution was similar to a general sarcoidosis population. A majority of patients (51/87) had CS as the first sarcoidosis presentation. They were younger (p = 0.04), more often presenting with ventricular tachycardia (VT) or atrioventricular block (AVB) grade II or III (p < 0.001), had lower left ventricular ejection fraction (LVEF) (p = 0.002), lower serum angiotensin converting enzyme (s-ACE) (p = 0.025), and fewer extra cardiac manifestations (ECM) (p = 0.02) than those presenting with CS later. CONCLUSIONS: Of Swedish CS patients, 59% presented with cardiac involvement as first manifestation. They had more severe cardiac symptoms than patients presenting with CS later. This phenotype disclosed less ECM and lower s-ACE thus diagnosis can be missed or delayed. We did not observe significant differences in HLA-DRB1 allele frequency between patients with CS compared to sarcoidosis in general. Awareness of CS as a primary manifestation can enable early detection and adequate intervention.

Reproductive and hormonal risk factors for sarcoidosis: a nested case-control study.

BACKGROUND: Sarcoidosis incidence peaks in females around the fifth decade of life, which coincides with menopause, suggesting hormonal factors play a role in disease development. We investigated whether longer exposure to reproductive and hormonal factors is associated with reduced sarcoidosis risk. METHODS: We conducted a matched case-control study nested within the Mammography Screening Project. Incident sarcoidosis cases were identified via medical records and matched to controls on birth and questionnaire date (1:4). Information on hormonal factors was obtained through questionnaires prior to sarcoidosis diagnosis. Multilevel modelling was used to estimate adjusted odds ratios with 95% credible intervals (OR; 95% CI). RESULTS: In total, 32 sarcoidosis cases and 124 controls were included. Higher sarcoidosis odds were associated with older age at menarche (OR 1.19: 95% CI 0.92-1.55), natural menopause versus non-natural (OR 1.53: 95% CI 0.80-2.93), later age at first pregnancy (OR 1.11: 95% CI 0.76-1.63) and ever hormone replacement therapy (HRT) use (OR 1.40: 95% CI 0.76-2.59). Lower odds were associated with older age at menopause (OR 0.90: 95% CI 0.52-1.55), longer duration of oral contraceptive use (OR 0.70: 95% CI 0.45-1.07), longer duration of HRT use (OR 0.61: 95% CI 0.22-1.70), ever local estrogen therapy (LET) use (OR 0.83: 95% CI 0.34-2.04) and longer duration of LET use (OR 0.78: 95% CI 0.21-2.81). However, the CIs could not rule out null associations. CONCLUSION: Given the inconsistency and modest magnitude in our estimates, and that the 95% credible intervals included one, it still remains unclear whether longer estrogen exposure is associated with reduced sarcoidosis risk.

Risk and predictors of heart failure in sarcoidosis in a population-based cohort study from Sweden.

OBJECTIVES: Previous studies showed a strong association between sarcoidosis and heart failure (HF) but did not consider risk stratification or risk factors to identify useful aetiological insights. We estimated overall and stratified HRs and identified risk factors for HF in sarcoidosis. METHODS: Sarcoidosis cases were identified from the Swedish National Patient Register (NPR; ≥2 International Classification of Diseases-coded visits, 2003-2013) and matched to general population comparators. They were followed for HF in the NPR. Treated were cases who were dispensed ≥1 immunosuppressant ±3 months from the first sarcoidosis visit (2006-2013). Using Cox models, we estimated HRs adjusted for demographics and comorbidity and identified independent risk factors of HF together with their attributable fractions (AFs). RESULTS: During follow-up, 204 of 8574 sarcoidosis cases and 721 of 84 192 comparators were diagnosed with HF (rate 2.2 vs 0.7/1000 person-years, respectively). The HR associated with sarcoidosis was 2.43 (95% CI 2.06 to 2.86) and did not vary by age, sex or treatment status. It was higher during the first 2 years after diagnosis (HR 3.7 vs 1.9) and in individuals without a history of ischaemic heart disease (IHD; HR 2.7 vs 1.7). Diabetes, atrial fibrillation and other arrhythmias were the strongest independent clinical predictors of HF (HR 2.5 each, 2-year AF 20%, 16% and 12%, respectively). CONCLUSIONS: Although low, the HF rate was more than twofold increased in sarcoidosis compared with the general population, particularly right after diagnosis. IHD history cannot solely explain these risks, whereas ventricular arrhythmias indicating cardiac sarcoidosis appear to be a strong predictor of HF in sarcoidosis.

Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes.

Sarcoidosis is a systemic inflammatory disease mainly affecting the lungs. The hallmark of sarcoidosis are granulomas that are surrounded by activated T cells, likely targeting the disease-inducing antigen. IFNγ-producing Th1 and Th17.1 T cells are elevated in sarcoidosis and associate with disease progression. Monocytes and dendritic cells (DCs) are antigen-presenting cells (APCs) and required for T cell activation. Several subsets of monocytes and DCs with different functions were identified in sarcoidosis. However, to what extent different monocyte and DC subsets can support activation and skewing of T cells in sarcoidosis is still unclear. In this study, we performed a transcriptional and functional side-by-side comparison of sorted monocytes and DCs from matched blood and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients. Transcriptomic analysis of all subsets showed upregulation of genes related to T cell activation and antigen presentation in DCs compared with monocytes. Allogeneic T cell proliferation was higher after coculture with monocytes and DCs from blood compared with BAL and DCs induced more T cell proliferation compared with monocytes. After coculture, proliferating T cells showed high expression of the transcription factor Tbet and IFNγ production. We also identified Tbet and RORγt coexpressing T cells that mainly produced IFNγ. Our data show that DCs rather than monocytes from sarcoidosis patients have the ability to activate and polarize T cells towards Th1 and Th17.1 cells. This study provides a useful in vitro tool to better understand the contribution of monocytes and DCs to T cell activation and immunopathology in sarcoidosis.

Differences in disease presentation between men and women with sarcoidosis: A cohort study.

BACKGROUND: Sarcoidosis is an elusive disease due to its heterogeneity. It is well recognized that the clinical picture is dependent on ethnicity, organ involvement and age. However, data on the role of sex is inconsistent. We aimed to study the gender-related differences in disease presentation in Swedish patients with sarcoidosis. SUBJECTS AND METHODS: Clinical data was collected between 1996 and 2020, yielding a register with 1429 cases with sarcoidosis in a pulmonary clinic. The diagnosis was met according to WASOG criteria. Data on age, radiologic stage at the time of disease onset, and potential extra-pulmonary manifestations, was retrieved. Differences between men and women were analyzed with Fisher's Exact Test and t-test where appropriate. RESULTS: In the register there were 61% men and they were approximately three years younger than the women at the time of diagnosis. Men presented with a more advanced radiographic stage on chest imaging compared to women, radiographic stage II (46% vs 36%, p < 0.001), while women compared to men more often had stage 0-I disease on pulmonary x-rays (6% vs 2%, p < 0.001 for stage 0 and 46% vs 38%, p < 0.01 for stage I). Women had more cutaneous involvement (13% vs 8%, p < 0.01) and more often involvement of salivary glands (3% vs 1%, p < 0.05). CONCLUSIONS: In this cohort with sarcoidosis patients, there was a predominance of men. They presented with more severe disease at a younger age, while women more often were found to have involvement of the skin and salivary glands.

Risk of acute myocardial infarction in sarcoidosis: A population-based cohort study from Sweden.

Due to conflicting findings in previous studies, it remains unclear whether individuals with sarcoidosis are at a higher relative risk of acute myocardial infarction. In this cohort study, individuals with sarcoidosis and matched general population comparators were followed for acute myocardial infarction in Swedish nationwide registers. A small (20%) risk increase associated with sarcoidosis was identified, which did not markedly vary by age at diagnosis, sex, treatment status around diagnosis, and time since diagnosis. The highest relative risk (1.4) was observed in individuals who received immunosuppressant treatment around the time of sarcoidosis diagnosis. Future studies should examine the clinical characteristics of acute myocardial infarction in these patients and investigate whether early diagnostic or preventive interventions might be beneficial for these patients.

Effects of infliximab on lung and circulating natural killer cells, CD56+ T cells and B cells in sarcoidosis.

BACKGROUND: Tumour necrosis factor α (TNF-α) is pivotal in sarcoid granuloma formation, and inhibitors of TNF-α offer an attractive third-line treatment option in sarcoidosis. The sarcoid inflammation is characterised by an exaggerated T helper 1 response, and evidence indicates a contribution of dysregulated and/or deficient NK (natural killer) cells, CD56+ T cells and B cells. OBJECTIVES: Insight into how TNF-α inhibitors influence these cells may provide more information on inflammatory mechanisms in sarcoidosis and improve understanding of such treatment. We therefore evaluated treatment effects of the TNF-α inhibitor infliximab on lung and peripheral blood (PB) NK, CD56+ T cells and B cells. METHODS: Fifteen patients were assessed with PB samples, spirometry and CT scan, and 11 of them also underwent bronchoalveolar lavage (BAL) close to start of infliximab treatment. These investigations were repeated after 6 months of treatment. RESULTS: Twelve out of 15 patients disclosed a clinical improvement at follow-up. Median percentage of BAL fluid (BALF) CD56+ T cells increased while a decrease was seen in PB (p<0.05 and 0.005, respectively). No significant changes were observed for NK cells. There was a trend towards increased median percentage of PB B cells (p=0.07), and a negative correlation was observed between PB and BALF B cells after treatment (p<0.05). CONCLUSION: In conclusion, 6 months of infliximab treatment in patients with sarcoidosis, of whom the majority benefited from the treatment, influenced immune cells in the lung and circulation differently, highlighting the importance of investigating several compartments concomitantly when evaluating treatment effects on the inflammatory activity.

Bronchoalveolar lavage fluid cell subsets associate with the disease course in Löfgren's and non-Löfgren's sarcoidosis patients.

BACKGROUND: Sarcoidosis is a multisystem granulomatous inflammatory disorder, that predominantly involves the lungs. Patients with Löfgren's syndrome (LS) are characterized by acute onset and usually have the HLA-DRB1*03 (DR3positive) allele and a good prognosis. Non-LS patients are usually DR3negative and are more likely to develop chronic disease. The study aimed to identify bronchoalveolar lavage fluid (BALF) cells that could associate with disease severity (reduced pulmonary function tests (PFTs), advanced chest radiographs, need for treatment) and/or chronicity (duration >2 years) in newly diagnosed LS and non-LS patients, respectively. METHODS: We retrospectively included data from 955 non-LS patients, 477 LS patients, and 295 healthy controls (HC) in this study. Intra-group comparison of patients with resolving versus chronic disease was performed in LS and non-LS, respectively. Non-LS patients were divided into two subgroups according to the binary BALF cell concentrations for intra-group comparison (i.e. higher or lower than the 95th percentile of the BALF cells references in healthy individuals). RESULTS: LS patients with a non-resolving disease course had higher BALF lymphocytes, neutrophils, and eosinophils than LS with a favourable outcome. In non-LS subjects increased BALF of the same cells and in addition also of basophils and mast cells were more likely associated with more severe disease course. CONCLUSION: Increased BALF cells display prognostic significance in sarcoidosis. Certain BALF profiles should promote the clinician to monitor these patients more closely as they may associate non-resolving disease, in turn, resulting in future irreversible functional impairment.

HLA-DRB1 alleles associate with hypercalcemia in sarcoidosis.

BACKGROUND: The mechanisms behind and which patients are at risk of developing sarcoidosis associated hypercalcemia (SAHC) have not been addressed. Different human leukocyte antigen (HLA) alleles associate with disease phenotypes in sarcoidosis. Insights into associations between HLA alleles, clinical phenotype and calcium levels may provide clues to mechanisms behind SAHC and help monitoring patients at risk for SAHC. AIMS AND OBJECTIVES: To identify any HLA-association with SAHC, and to phenotypically characterize this patient group. METHODS: 66 patients with SAHC (s-Ca2+>1.33 mmol/L) and 150 normocalcemic patients as controls were identified in a cohort of sarcoidosis patients. Data on HLA-DRB1 alleles, sex, angiotensin-converting enzyme (ACE), creatinine, extrapulmonary manifestations (EPM), age at sarcoidosis diagnosis, and how long after diagnosis SAHC emerged, were retrieved. RESULTS: HLA-DRB1*04 was more common in patients with SAHC and the proportion of patients with HLA-DRB1*04 increased the more pronounced hypercalcemia. In patients with s-Ca2+>1.4 mmol/L, 20 out of 30 carried the HLA-DRB1*04 allele (67%, p < 0.01). Patients with SAHC more often disclosed renal insufficiency, elevated ACE, EPM, and a non-resolving disease than controls. The mean duration between sarcoidosis diagnosis and detection of SAHC was 1.39 years. CONCLUSIONS: SAHC is associated with a more severe disease phenotype, particularly patients carrying the HLA-DRB1*04 allele are at higher risk for SAHC. HLA-assessment in the clinic can be a way to identify these patients. The results provide a basis for future studies on the connection between HLA-DRB1*04 and SAHC mechanisms.

Type 2 diabetes risk in sarcoidosis patients untreated and treated with corticosteroids.

BACKGROUND: The rate of type 2 diabetes mellitus (T2D) is increased in sarcoidosis patients but it is unknown if corticosteroid treatment plays a role. We investigated whether the T2D risk is higher in untreated and corticosteroid-treated sarcoidosis patients compared with the general population. METHODS: In this cohort study, individuals with two or more International Statistical Classification of Diseases and Related Health Problems (ICD) codes for sarcoidosis were identified from the Swedish National Patient Register (NPR) (n=5754). Corticosteroid dispensations within 3 months before or after the first sarcoidosis diagnosis were identified from the Swedish Prescribed Drug Register (PDR). General population comparators without sarcoidosis were matched to cases 10:1 on age, sex and region of residence (n=61 297). Incident T2D was identified using ICD codes (NPR) and antidiabetic drug dispensations (PDR). Follow-up was from the second sarcoidosis diagnosis/matching date until T2D, emigration, death or study end (December 2013). Cox regression models adjusted for age, sex, education, country of birth, healthcare regions and family history of diabetes were used to estimate hazard ratios (HRs). We used flexible parametric models to examine the T2D risk over time. RESULTS: 40% of sarcoidosis patients were treated with corticosteroid at diagnosis. The T2D rate was 7.7 per 1000 person-years in untreated sarcoidosis, 12.7 per 1000 person-years in corticosteroid-treated sarcoidosis and 5.5 per 1000 person-years in comparators. The HR for T2D was 1.4 (95% CI 1.2-1.8) associated with untreated sarcoidosis and 2.3 (95% CI 2.0-3.0) associated with corticosteroid-treated sarcoidosis. The T2D risk was highest for corticosteroid-treated sarcoidosis in the first 2 years after diagnosis. CONCLUSIONS: Sarcoidosis is associated with an increased risk of T2D especially in older, male, corticosteroid-treated patients at diagnosis. Screening for T2D for these patients is advisable.

Positive Predictive Value of Sarcoidosis Identified in an Administrative Healthcare Registry: A Validation Study.

BACKGROUND: International classification of disease (ICD) codes used to study sarcoidosis has previously been validated in only 1 study. We aimed to determine the accuracy of ICD codes to identify true sarcoidosis diagnoses in Sweden. METHODS: We identified adults with at least 2 ICD codes for sarcoidosis (ICD-10 D86) at Karolinska University Hospital 2010-2013 from the National Patient Register. Of these, we randomly sampled 100 patients for validation. We collected clinical data and categorized the diagnosis of sarcoidosis as definite, probable, or unlikely. We estimated the positive predictive value for definite and probable sarcoidosis-identified with at least 2 ICD codes-with 95% confidence intervals. RESULTS: We deemed 77% of the cases to be definite and 17% to be probable. The positive predictive value was 0.94 (95% confidence intervals = 0.87 to 0.98). CONCLUSIONS: Using at least 2 visits listing an ICD-10 code for sarcoidosis accurately identified patients with sarcoidosis from administrative health data in Sweden.