Genetic and geographic influence on phenotypic variation in European sarcoidosis patients.

Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.

Sarcoidosis in Iceland: a nationwide study of epidemiology, clinical picture and environmental exposure.

BACKGROUND: This nationwide study aimed to elucidate the incidence and clinical characteristics of tissue-verified sarcoidosis in Iceland. A secondary aim was to analyse sex differences and identify possible environmental factors contributing to the pathological process. MATERIALS AND METHODS: This is a descriptive study covering 36 years (January 1, 1981 through December 31, 2016). Histopathological reports and electronic hospital discharge registries were reviewed in context for granulomas and/or sarcoidosis. National data were used for comparison regarding smoking habits and occupation, adjusted for age, sex and year of diagnosis. The data were stored in FileMaker and calculations were made by extracting data from this database to the statistical software package R. RESULTS: A total of 418 patients (54% females) were diagnosed with tissue-verified sarcoidosis. The incidence rate was 4.15/100 000/year, similar among females and males. The mean age at diagnosis was higher among females (53.0±14.2 years) than males (48.2±13.8 years). Fatigue was the most frequent single symptom (49.7%), but when all respiratory symptoms were grouped, they were the most frequent symptoms (60%). No significant difference was found between smoking status and sarcoidosis. Possible hazardous exposure in the workplace was reported by 19.4% of the cases. CONCLUSION: The incidence of sarcoidosis in Iceland was higher than in an Asian population where the same inclusion criteria were applied. The clinical picture diverges partly from that in the Asian population but resembles that among other Caucasians. Fatigue and respiratory symptoms were predominant. The biphasic pattern of age at disease debut seen elsewhere among females was not evident in Iceland.

Illness severity and risk of mental morbidities among patients recovering from COVID-19: a cross-sectional study in the Icelandic population.

OBJECTIVE: To test if patients recovering from COVID-19 are at increased risk of mental morbidities and to what extent such risk is exacerbated by illness severity. DESIGN: Population-based cross-sectional study. SETTING: Iceland. PARTICIPANTS: A total of 22 861 individuals were recruited through invitations to existing nationwide cohorts and a social media campaign from 24 April to 22 July 2020, of which 373 were patients recovering from COVID-19. MAIN OUTCOME MEASURES: Symptoms of depression (Patient Health Questionnaire), anxiety (General Anxiety Disorder Scale) and posttraumatic stress disorder (PTSD; modified Primary Care PTSD Screen for DSM-5) above screening thresholds. Adjusting for multiple covariates and comorbidities, multivariable Poisson regression was used to assess the association between COVID-19 severity and mental morbidities. RESULTS: Compared with individuals without a diagnosis of COVID-19, patients recovering from COVID-19 had increased risk of depression (22.1% vs 16.2%; adjusted relative risk (aRR) 1.48, 95% CI 1.20 to 1.82) and PTSD (19.5% vs 15.6%; aRR 1.38, 95% CI 1.09 to 1.75) but not anxiety (13.1% vs 11.3%; aRR 1.24, 95% CI 0.93 to 1.64). Elevated relative risks were limited to patients recovering from COVID-19 that were 40 years or older and were particularly high among individuals with university education. Among patients recovering from COVID-19, symptoms of depression were particularly common among those in the highest, compared with the lowest tertile of influenza-like symptom burden (47.1% vs 5.8%; aRR 6.42, 95% CI 2.77 to 14.87), among patients confined to bed for 7 days or longer compared with those never confined to bed (33.3% vs 10.9%; aRR 3.67, 95% CI 1.97 to 6.86) and among patients hospitalised for COVID-19 compared with those never admitted to hospital (48.1% vs 19.9%; aRR 2.72, 95% CI 1.67 to 4.44). CONCLUSIONS: Severe disease course is associated with increased risk of depression and PTSD among patients recovering from COVID-19.

Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Regional differences in mortality, hospital discharges and primary care contacts for cardiovascular disease.

AIMS: Surveillance of geographical variations in cardiovascular health is important in order to achieve the objectives of reducing regional health disparities. We aimed to explore differences in cardiovascular disease (CVD) mortality and prevalence of CVD diagnoses made in primary and in-patient care, as well as risk factor distribution by geographic regions (urban/rural) in Iceland. METHODS: From nationwide health registers, we obtained data on CVD mortalities ( N = 7113), primary healthcare CVD contacts ( N = 58,246) and hospital CVD discharges ( N = 14,039), as well as data on CVD risk factors from a national health survey ( N = 5909; response rate 60.3%). Age-standardised annual mortality, primary healthcare contact and hospital discharge rates due to CVD were calculated per 100,000 population inside (urban) and outside (rural) the Capital Area (CA). Logistic regression was used to explore regional differences in CVD risk factors. RESULTS: We observed slightly higher total CVD mortality rates among women outside compared to inside the CA (Standardised Rate Ratio (SRR) 1.06 (95% confidence interval (CI) 1.05-1.07)), particularly due to atrial fibrillation (SRR 1.47 (95% CI 1.46-1.48)), heart failure (SRR 1.29 (95% CI 1.27-1.31)) and ischemic heart disease (SRR 1.11 (95% CI 1.10-1.12)), while reduced mortality risk for cerebrovascular disease (SRR 0.81 (95% CI 0.80-0.83)). The rates of hospital discharges and primary care contacts for these diseases, as well as prevalence of several modifiable risk factors, were generally higher outside the CA, particularly among women. CONCLUSIONS: The higher prevalence of modifiable risk factors and CVD in rural areas, especially among women, calls for refined treatment and health-promoting efforts in rural areas.

Maternal geographic residence, local health service supply and birth outcomes.

OBJECTIVE: To describe pregnancy complications, mode of delivery and neonatal outcomes by mother's residence. DESIGN: Register-based cohort study. SETTING: Geographical regions of Iceland. POPULATION: Live singleton births from 1 January 2000 to 31 December 2009 (n = 40 982) and stillbirths ≥22 weeks or weighing ≥500 g (n = 145). METHODS: Logistic regression was used to explore differences in outcomes by area of residence while controlling for potential confounders. Maternal residence was classified according to distance from Capital Area and availability of local health services. MAIN OUTCOME MEASURES: Preterm birth, low birthweight, perinatal death, gestational diabetes and hypertension. RESULTS: Of the 40 982 infants of the study population 26 255 (64.1%) were born to mothers residing in the Capital Area and 14 727 (35.9%) to mothers living outside the Capital Area. Infants outside the Capital Area were more likely to have been delivered by cesarean section (adjusted odds ratio 1.28; 95% CI 1.21-1.36). A lower prevalence of gestational diabetes (adjusted odds ratio 0.68; 95% CI 0.59-0.78), hypertension (adjusted odds ratio 0.82; 95% CI 0.71-0.94) as well as congenital malformations (adjusted odds ratio 0.55; 95% CI 0.48-0.63) was observed outside the Capital Area. We observed neither differences in mean birthweight, gestation length nor rate of preterm birth or low birthweight across Capital Area and non-Capital Area. The odds of perinatal deaths were significantly higher (adjusted odds ratio 1.87; 95% CI 1.18-2.95) outside the Capital Area in the second half of the study period. CONCLUSION: Lower prevalence of gestational diabetes and hypertension outside the Capital Area may be an indication of underreporting and/or lower diagnostic activity.

Poorer self-rated health in residential areas with limited healthcare supply.

AIMS: The aim of this study was to explore differences in self-rated health and physician-diagnosed disease across geographical regions in Iceland to better understand regional requirements for health services. METHODS: Data on self-rated health and diagnosed disease from a 2007 national health survey (n=5909; response rate 60.3%) across geographic regions were analysed. Area of residence was classified according to distance from the Capital Area (CA) and availability of local health services. We used regression models to calculate crude and multivariable adjusted odds ratios (aOR) and corresponding 95% confidence intervals (95% CI) of self-rated health and diagnosed diseases by area of residence. Models were adjusted for age, gender, education, civil status, and income. RESULTS: Residents in rural areas with no local health service supply rated their physical health worse than residents of areas with diverse supply of specialised services (aOR 1.40, 95% CI 1.21-1.61). Residents outside the CA rate both their physical (aOR 1.35, 95% CI 1.23-1.50) and mental (aOR 1.17, 95% CI 1.06-1.30) health worse than residents in the CA. In contrast, we observed a lower prevalence of several diagnosed chronic diseases, including cancers (aOR 0.78, 95% CI 0.60-0.99) and cardiovascular disease (aOR 0.77, 95% CI 0.62-0.95) outside the CA. CONCLUSIONS: These findings from a national survey of almost 6000 Icelanders indicate that self-rated health is related to regional healthcare supply. The findings have implications for national planning of health services aiming at equality both in health and access to health services.

Sarcoid arthropathy and the association with the human leukocyte antigen. The Icelandic Sarcoidosis Study.

OBJECTIVES: The aim of the present study was to evaluate whether certain HLA antigens were risk factors for developing sarcoid arthritis and whether HLA antigens appear to account for the phenotype and the resolution of the arthritis condition in an unselected nationwide cohort. METHODS: The Icelandic Sarcoidosis Study (ISS) contains all tissue-verified cases of sarcoidosis in Iceland since 1981. Of a total of 234 cases, 39 patients were identified with arthritis and of those 36 delivered a biosample for the study. The patient cohort has previously been described in detail. DNA was isolated from EDTA blood and HLA antigen typing was performed. A total of 544 Icelandic stem cell donors acted as controls. RESULTS: HLA-B8 and HLA-B14 antigens were more common among those who suffered from sarcoid arthritis (24% vs. 11%, p<0.01; 6.5% vs. 2.4%, p<0.05). DRB1*03 was also found more frequently in patients with sarcoid arthritis compared to controls (28% vs. 11%, p<0.001), while DRB1*04 was less frequently reported (5.6% vs. 17%, p<0.01). No differences were found in the HLA-A distribution between the groups. A higher proportion of patients with chronic arthritis had HLA-A11 than those with resolving joint problems (60% vs. 3.8%). CONCLUSIONS: Our nationwide study of patients with sarcoid arthritis further supports the conclusion that genetics may strongly influence the development and the clinical course of the disease. Furthermore, some HLA antigens may even be protective for the disease. Thus, classification of the major histocompatibility complex may have clinical implications.

[Research in pharmacoepidemiology in Iceland]. / Rannsóknir í lyfjafaraldsfraedi á Islandi.

Pharmacoepidemiology is a rapidly growing discipline that is useful in studies on effects and adverse effects of drugs. During past years and decades databases have been built in Iceland that are becoming powerful tools for this kind of research. The databases are, however only useful for pharmacoepidemiological research if they include personal identification and can be merged. The personal identification should be without time limits because in many cases we are interested in what happened years or decades ago. The prescriptions database was started in 2002 and has dramatically changed the possibilities for pharmacoepidemiological studies in Iceland. The main aim of this review is to give an overview of the existing databases in Iceland and to encourage research in this important field.

[Lung cancer--review]. / Lungnakrabbamein--Yfirlitsgrein.

Lung cancer is the second most common cancer in Iceland and the most frequent cause of cancer related deaths. Smoking is by far the most important cause but familial factors also contribute. The symptoms of lung cancer are often subtle and the diagnosis, in about 70% of cases, is made when metastases have occurred. Curative surgical treatment is therefore only possible in about a third of the cases whereas other patients receive chemotherapy and/or radiation therapy. In recent years some important advances have been made in the diagnostic and therapeutic approaches to lung cancer. New imaging techniques have improved diagnosis and staging practices and consequently also treatment. Recent evidence suggests that screening with low dose CT may improve survival. New approaches to chemotherapy have been shown to improve survival and well being of patients with advanced disease. Chemotherapeutic agents are now being used in conjunction with surgery to reduce the risk of tumour spread. Furthermore, advances in surgical techniques have made resections possible in cases deemed inoperable in the past. In this review we present important advances in the diagnosis and treatment of lung cancer as reflected by recent literature that should be of interest to a wide variety of specialists.

[Sarcoidosis in Iceland 1981-2003]. / Sarklíki á Islandi 1981-2003.

OBJECTIVE: To investigate the incidence of sarcoidosis in Iceland, its clinical manifestations and potential environmental influences. MATERIALS AND METHODS: All histopathological diagnoses of non-necrotizing granulomas generated in Iceland during the period 1981-2003 were reviewed with respect to a diagnosis of sarcoidosis. Further, patients were identified by searching hospital discharge diagnoses at the University Hospital in Reykjavik and the Regional Hospital in Northern Iceland. Only histologically verified cases were included. RESULTS: A total of 235 patients were found with histopathologically proven sarcoidosis. Limited to patients verified by tissue diagnosis, the annual incidence of sarcoidosis is 3,84/100.000/year. The incidence was found to be 2,8/100,000/year during the first half of the investigation period and 5,0/100,000/year during the second. This rate is lower than in other Nordic countries. There were 122 women and 113 men. The mean age at diagnosis was 50,8 years for women and 47,5 for men. The mean age at diagnosis was higher in Iceland than elsewhere. Clinically, respiratory symptoms predominated. Ocular symptoms and erythema nodosum are rare, and life-threatening cardiovascular and neurological manifestations are distinctly unusual. CONCLUSION: The low incidence is undoubtedly due to the strict inclusion criteria in the present study, i.e. only those with a tissue diagnosis were included. We have no explanation as to the higher age at diagnosis in Iceland than elsewhere. Registration of possible environmental factors and clinical evaluation may be improved.

Clinical manifestation, prevalence and prognosis of sarcoid arthropathy. A nationwide study: the Icelandic Sarcoidosis Study.

STUDY OBJECTIVE: The Icelandic Sarcoidosis Study (ISS) contains all tissue-verified cases of sarcoidosis in Iceland since 1981. The present study has extended registration and verification to the start of 2004, thus covering over 23 years and a total of 234 cases. The aim of this study was to elucidate the prevalence, clinical manifestation and long-term prognosis of sarcoid arthritis in this unselected nationwide cohort. The presence of joint or muscle symptoms was registered in 20% of these cases. METHODS: We used a questionnaire to register the lung and joint symptoms and all participants were offered a clinical evaluation with standardized interview and physical examination, including a count of the number of painful and/or inflamed joints. RESULTS: Forty-seven (20%) of the 234 individuals in the ISS reported skeletal symptoms. In thirty-nine cases (17%) it was possible to confirm a history of inflammatory joint disorder. The mean age was 45 years: women 46 years (30-66), men 43 years (28-66). In 82% of the cases one or both ankles were involved. In 22 or 56% of the cases (13 female and 9 male) reliable data on the disease course were obtained; 87% of the patients had full recovery in less than 6 months, while 13% of the patients (all female) experienced chronic arthritic disease. CONCLUSIONS: Our nationwide-based data confirmed that around a fifth of all those diagnosed with sarcoidosis will develop joint symptoms associated with their sarcoidosis, most usually in the ankle. The prognosis is favourable, but a subgroup of female patients may develop chronic polyarthritis. It is urgent to study further in detail the risk factors for a chronic arthritic condition in sarcoidosis; thus, it would be possible to offer those at risk of arthritis modifying anti-rheumatic treatment in the early phase of their disease course.