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Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison’s disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

ObjectiveAutoimmune Addison's disease (AAD) entails a chronic adrenal insufficiency and is associated with an increased risk of severe infections. It is, however, unknown how patients with AAD were affected by the coronavirus disease 2019 (COVID-19) pandemic of 2020-2021. This study was aimed at investigating the incidence of COVID-19 in patients with AAD in Sweden, the self-adjustment of medications during the disease, impact on social aspects, and treatment during hospitalization. Additionally, we investigated if there were any possible risk factors for infection and hospitalization.Design and methodsQuestionnaires were sent out from April to October 2021 to 813 adult patients with AAD in the Swedish Addison Registry. The questionnaires included 55 questions inquiring about COVID-19 sickness, hospital care, medications, and comorbidities, focusing on the pre-vaccine phase.ResultsAmong the 615 included patients with AAD, COVID-19 was reported in 17% of which 8.5% required hospital care. Glucocorticoid treatment in hospitalized patients varied. For outpatients, 85% increased their glucocorticoid dosage during sickness. Older age (P = .002) and hypertension (P = .014) were associated with an increased risk of hospital care, while younger age (P < .001) and less worry about infection (P = .030) were correlated with a higher risk of COVID-19.ConclusionsIn the largest study to date examining AAD during the COVID-19 pandemic, we observed that although one-fifth of the cohort contracted COVID-19, few patients required hospital care. A majority of the patients applied general recommended sick rules despite reporting limited communication with healthcare during the pandemic.

Purpose Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources Systematic literature search in four databases. Study Selection Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P Conclusions Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

Long-term disturbances in cortisol levels might affect brain structure in individuals with autoimmune Addison’s disease (AAD). This study investigated gray and white matter brain structure in a cohort of young adults with AAD. T1- and diffusion-weighted images were acquired for 52 individuals with AAD and 70 healthy controls, aged 19–43 years, using magnetic resonance imaging. Groups were compared on cortical thickness, surface area, cortical gray matter volume, subcortical volume (FreeSurfer), and white matter microstructure (FSL tract-based spatial statistics). Individuals with AAD had 4.3% smaller total brain volume. Correcting for head size, we did not find any regional structural differences, apart from reduced volume of the right superior parietal cortex in males with AAD. Within the patient group, a higher glucocorticoid (GC) replacement dose was associated with smaller total brain volume and smaller volume of the left lingual gyrus, left rostral anterior cingulate cortex, and right supramarginal gyrus. With the exception of smaller total brain volume and potential sensitivity of the parietal cortex to GC disturbances in men, brain structure seems relatively unaffected in young adults with AAD. However, the association between GC replacement dose and reduced brain volume may be reason for concern and requires follow-up study.

In the past decade, immunotherapy with checkpoint inhibitors has revolutionized the field of oncology. Checkpoint inhibitors have been approved for several types of cancer and thousands of patients in Sweden now receive oncological immunotherapy annually. Immune-related side effects are common and can occur in almost any organ. These side effects are different from those that occur with traditional oncological treatments. The side effects are usually mild, but can be serious and even lethal. In a short time, health care providers have had to readjust to be able to handle these side effects. Early and correct diagnosis of immune-related side effects, proper management and a multidisciplinary approach is crucial. Here, we give an overview of the presentation, diagnosis and treatment of immune-related side effects, with emphasis on endocrine, rheumatologic and skin toxicity.

Objective Type 1 diabetes and Hashimoto’s thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors. Design This study is a twin cohort study. Methods National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto’s thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models. Results Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5–15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2–15.1) and 1.7 (95% CI: 0.7–4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto’s thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto’s thyroiditis. Conclusions Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto’s thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets.

Objectives: Sub-optimal replacement of glucocorticoids (GC) in autoimmune Addisons disease (AAD) may affect cognitive functioning. The present study therefore sought to investigate cognitive performance and self-reported problems with executive functions in a cohort of young adult patients with AAD. Design and methods: 67 patients with AAD (39 females), mean age 32 yrs. (range 19-41), and 80 control participants (43 females), mean age 29 yrs. (range 19-43), completed neuropsychological tests estimating verbal and non-verbal intellectual ability, learning, memory and executive functioning, in addition to self-report scales assessing problems with executive functions, fatigue and symptoms of anxiety and depression. Results: Patients performed within the average range on all cognitive tests compared to population norms. However, female AAD patients reported more problems than controls with both hot (emotion regulation) and cold (cognitive regulation) executive functions in daily life. Moreover, experienced problems with executive functions in both male and female patients were associated with increased mental fatigue and lower GC replacement doses. Conclusions: Despite average performance in neuropsychological tests by both sexes, young adult female patients with AAD experience problems with executive functions in daily life. Coping with mental fatigue and optimization of pharmacotherapy may be important factors to be addressed in order to provide timely support for patients. Future research is needed to further determine other risk factors for experiencing executive function impairments in AAD. Funding Agencies|Marianne and Marcus Wallenberg Foundation; Knut and Alice Wallenberg Foundation; International Fund raising for Congenital Adrenal Hyperplasia (IFCAH)/European Society for Pediatric Endocrinology (ESPE); Stockholm County Council (ALF-SLL); Swedish Research Council [DNR 2021-02440, DNR 2016-02849]; Region Stockholm [DNR RS 20191140]; Foundation of Johan Gronberg; Stiftelsen Frimurare Barnhuset i Stockholm; Samariten; Jerringfonden; Sallskapet Barnavard; Wera Ekstroms stiftelse for Pediatrikforskning; Foundation for Research and Education in Pediatric Endocrinology; Novo Nordisk Foundation; Torsten and Ragnar Soderbergs Foundations; Foundation of Lisa

Objective Rathkes cleft cysts are benign, embryological remnants in the pituitary gland. The majority of them are small and asymptomatic but a few may become large, and cause mass effects, pituitary hormone deficiencies and visual impairment. Recommendations for the follow-up of Rathkes cleft cysts vary since data on the natural history are sparse. Patients and Design Data at diagnosis and at 1, 5 and 10 years for patients with a Rathkes cleft cyst (434 at diagnosis, 317 females) were retrieved from the Swedish Pituitary Registry. Cysts = 10 mm that were not operated (n = 174) decreased in size over the years (p < .01). Pituitary hormone deficiencies and visual impairments were more frequent (18% and 5.7%, respectively) but were stable over time. Transphenoidal surgery was performed in 56 patients of whom 51 underwent surgery before the 1-year follow-up. The mean cyst diameter at diagnosis was 18 mm (range: 930 mm), 36% had pituitary hormone deficiency, 45% had visual field defects and 20% had impaired visual acuity. One year after surgery 60% had no cyst remnants, 50% had a pituitary deficiency, 26% had visual field defects and 12% had impaired visual acuity. No major changes were observed after 5 years. Twelve of the operated patients had a follow-up at 10 years, in eight the cyst remnants or recurrences increased in size over time (p < .05). Conclusions Rathkes cleft cysts with a size less than 10 mm rarely grow and our results indicate that radiological follow-up can be restricted to 5 years. In contrast, progression of postoperative remnants or recurrent cysts is more likely and require long-term follow-up.

Background Studies on the incidence of Cushing’s disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden. Methods Patients registered with a diagnostic code for Cushing’s syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data. Results Of 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4–1.8) cases per million. 1987–1995, 1996–2004, and 2005–2013, the mean annual incidence was 1.5 (1.1–1.8), 1.4 (1.0–1.7) and 2.0 (1.7–2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P

Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable.To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD.A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality.Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome.Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health.

Context Little is known of cardiovascular disease (CVD) in autoimmune Addison disease (AAD). Inadequate glucocorticoid replacement might potentially increase CVD risk. Objective To examine CVD in AAD in subgroups of ischemic heart disease (IHD) and cerebrovascular disease (CeVD) and investigate the effects of glucocorticoid and mineralocorticoid dosing. Design, Setting, and Patients In this cohort-control study, we used Swedish health registries from 1964 to 2013 to identify 1500 subjects with AAD and 13,758 matched controls. Incident CVD was analyzed from 2006 to 2013. Adjusted hazard ratios (aHRs) were calculated using Cox proportional hazard models. Glucocorticoid and mineralocorticoid doses were stratified to examine dose-related risks. Results During 8807 person-years (PY), 94 events of first CVD (10.7/1000 PY) in patients with AAD occurred compared with 563 events during 80,163 PY (7.0/1000 PY) in controls. IHD was significantly more common in women (aHR, 2.15; 95% CI, 1.49 to 3.10) but not men (aHR, 1.16; 95% CI, 0.75 to 1.78) with AAD compared with controls. No increase in CeVD risk was detected (aHR, 0.88; 95% CI, 0.56 to 1.37, women; aHR, 0.88; 95% CI 0.53 to 1.50, men). CVD was associated with greater glucocorticoid and mineralocorticoid replacement doses in women but not men. Conclusion The risk of IHD but not CeVD is increased in AAD, especially in women. The risk of CVD independently correlated with greater glucocorticoid and mineralocorticoid replacement doses in women. Our data suggest that close monitoring and early treatment of risk factors for CVD, among women in particular, might be warranted., CVD risk in patients with Addison disease is primarily the result of coronary events in women. The glucocorticoid and mineralocorticoid doses correlated with the risk of CVD.

Context Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are known to coaggregate in families, but the magnitude and nature of a shared etiology is unknown. Objectives To estimate the shared genetic influence on overt HT and GD and to examine if the heritability differs between men and women. Design, setting, and patients We used national health registries to identify cases of HT and GD in a cohort of 110 814 Swedish twins. By comparing intra-class and cross-twin cross-trait correlations in dizygotic and monozygotic twins, we calculated heritability and the proportions thereof shared between the diseases. Univariate estimates of heritability were calculated by sex. Results The heritability for HT and GD was 65% (95% CI, 61-70) and 63% (95% CI, 55-72), respectively. The genetic correlation was 0.35 (95% CI, 0.20-0.50) and shared genetic effects accounted for 8% of the variance for both HT and GD. Univariate heritability was significantly higher in men than in women for HT (90% vs 60%, P Conclusions From a genetic perspective, HT and GD appear to be only modestly related diseases. Hence, the term “autoimmune thyroid disease,” used to cluster these disorders, may have limited validity in a genetic context. Moreover, the mechanisms contributing to HT are partly different for the sexes, with genetic components more important in men.

Background No reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal. Objective To explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD. Methods Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. Results Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and levels of ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. Conclusions We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

Autoimmune Addison’s disease is the predominant cause of primary adrenal failure, and is highly heritable. The genetic background has remained poorly understood due to the low prevalence and complex inheritance of the disease. We performed a genome-wide association study, which identified nine independent risk loci (P < 5 × 10–8). In addition to novel and previous risk loci involved in lymphocyte functionality, we further associated autoimmune Addison’s disease with two independent protein-coding alterations in the gene Autoimmune Regulator (AIRE). The most striking is the amino-acid substitution p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10–25), which introduces an additional cysteine residue in the zinc-finger motif of the PHD2 domain of AIRE. This unbiased elucidation of the genetic contribution to development of autoimmune Addison’s disease points to the importance of central immunological tolerance, and explains 35–41 percent of heritability.

Context Whether multisystem morbidity in Cushing’s disease (CD) remains elevated during long-term remission is still undetermined. Objective To investigate comorbidities in patients with CD. Design, Setting, and Patients A retrospective, nationwide study of patients with CD identified in the Swedish National Patient Register between 1987 and 2013. Individual medical records were reviewed to verify diagnosis and remission status. Main Outcomes Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by using the Swedish general population as reference. Comorbidities were investigated during three different time periods: (i) during the 3 years before diagnosis, (ii) from diagnosis to 1 year after remission, and (iii) during long-term remission. Results We included 502 patients with confirmed CD, of whom 419 were in remission for a median of 10 (interquartile range 4 to 21) years. SIRs (95% CI) for myocardial infarction (4.4; 1.2 to 11.4), fractures (4.9; 2.7 to 8.3), and deep vein thrombosis (13.8; 3.8 to 35.3) were increased during the 3-year period before diagnosis. From diagnosis until 1 year after remission, SIRs (95% CI were increased for thromboembolism (18.3; 7.9 to 36.0), stroke (4.9; 1.3 to 12.5), and sepsis (13.6; 3.7 to 34.8). SIRs for thromboembolism (4.9; 2.6 to 8.4), stroke (3.1; 1.8 to 4.9), and sepsis (6.0; 3.1 to 10.6) remained increased during long-term remission. Conclusion Patients with CD have an increased incidence of stroke, thromboembolism, and sepsis even after remission, emphasizing the importance of early identification and management of risk factors for these comorbidities during long-term follow-up.

Context Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Design Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P Conclusion In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.

Context Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. Objective Multicenter survey on current clinical approaches in managing AI during pregnancy. Design Retrospective anonymized data collection from 19 international centers from 2013 to 2019. Setting and Patients 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). Results Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. Conclusions This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Objective Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases. Design Prospective twin cohort study. Methods We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto’s thyroiditis, atrophic gastritis, celiac disease, Graves’ disease, type 1 diabetes, vitiligo and Addison’s disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data. Results Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2–9.2) than in dizygotic twins (median HR: 2.4, range: 1.1–10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23–0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49–0.71) for Graves’ disease to 0.97 (95% CI: 0.91–1.00) for Addison’s disease. Conclusions Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.

People with rare diseases are a minority group that faces risks for healthcare and work inequities because knowledge and resources on how to systematically support health or working life are limited. Integrating voices of persons living with rare diseases are an important aspect in inclusive and relevant healthcare practices. This study sought to actively involve persons with autoimmune Addison's disease (AAD), a rare condition, in exploring challenges and possibilities situated in everyday life. Photovoice methods were utilized to incorporate experiences through photographic documentation and group discussions with five persons over seven weeks. Data generated from group sessions were visually analyzed or transcribed and analyzed with thematic analysis. Five themes emerged: Individual and fine tuning in everyday life; It is not how it was; The power of knowledge and support; Becoming the expert in an uncertain context; and, Finding balance and paving new ways. The findings showed that everyday life with AAD was more complex than earlier portrayed; entailing several barriers and negotiations. In order to meet the needs of persons with AAD, more extensive and relevant information, support and self-management education is needed. Moreover, a complementary focus on everyday life to promote their health and wellbeing is also important.

Objective: Deciding the optimal doses of glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD) is impeded by the lack of reliable biomarkers. This frequently results in over-treatment, with alarming and persistent side-effects, or under-replacement, which could be fatal. There is a need to think new in the quest for robust biomarkers to optimize GC replacement in AAD at an individual level. Aim: We aimed to identify genes that are consistently up- or down-regulated in patients with AAD in response to different GC replacement doses. This information can be used to establish novel biomarkers to guide GC treatment in AAD. Methods: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. To verify the results, we performed real-time PCR to compare gene expression levels of three of the highly differentially expressed genes (FKBP5, MMP9, and DSIPI) to compare gene expression levels before and two, four, and six hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. Results: Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. Conclusions: We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

Background: Patients with Cushing´s disease (CD) in remission have increased mortality compared to the general population. To date, large cohort studies, performed to assess long-term comorbidities in patients with CD, are lacking. Objective: To study the incidence of cardiovascular disease, sepsis, fractures and cancer in an unselected nationwide cohort of patients with CD. Methods: Patients with CD, diagnosed between 1987 and 2013, were identified in the Swedish National Patient Registry. Medical records were systematically reviewed to verify the diagnosis and remission status. Standardized incidence ratios (SIRs) for comorbidities after CD was diagnosed, with 95% confidence intervals (CI), were calculated by using the Swedish general population as the reference. Patients: A total of 502 patients had confirmed diagnosis of CD. Of these, 419 (83%) patients [325 (78%) women] were in remission at the last follow-up, and thereby eligible for the analysis. The mean±SD age at diagnosis was 41±15 years and median (interquartile range) time in remission was 10 years (4-21). Out of 419 patients in remission, 315 (75%) had been treated with pituitary surgery, 116 (28%) with radiotherapy and 102 (25%) with bilateral adrenalectomy. Results: SIR in patients in remission was 2.6 (1.9-3.4) for stroke, 1.8 (1.1-2.6) for myocardial infarction, 4.4 (2.5-7.1) for pulmonary embolism and 3.4 (1.8-6.0) for deep vein thrombosis. The risk for sepsis was markedly elevated with a SIR of 5.8 (3.8-8.4). SIR for all fractures was 1.7 (1.3-2.1), 2.6 (1.4-4.6) for wrist fracture and 1.6 (0.9-2.6) for hip fracture. The overall incidence of cancer was not increased [SIR 1.2 (0.9-1.5)] in comparison with the background population. Conclusions This large nationwide study shows that patients with CD in remission have an increased risk for cardiovascular disease, thromboembolism, fractures and severe infections. The excess morbidity in these patients illustrate the importance of early identification and management of risk factors for these comorbidities during long-term follow-up.

With few exceptions, autoimmune diseases (AIDs) are genetically complex disorders. Familial aggregation of AIDs is common, and it is therefore not surprising that many genetic risk markers in autoimmunity are pleiotropic 1. Despite this, etiologic overlap across AIDs has not yet been explored in an unbiased fashion. We therefore used the Swedish Twin Registry to study heritability and overlap between seven AIDs known to cluster. Using data on 116,320 twins of known zygosity, we identified 1,957 subjects with a diagnosis of Hashimoto’s thyroiditis, 762 with atrophic gastritis, 723 with celiac disease, 645 with Grave’s disease, 420 with type-1 diabetes, 192 with vitiligo and 31 with autoimmune Addison’s disease. Heritability for individual disorders ranged from 0.97 for Addison´s disease to 0.47 for pernicious anemia using AE-models (additive genetic and unique environmental effects). Probandwise concordance rates ranged from 0.71 in monozygotic twins (MZ) with Addison’s disease to 0 in dizygotic twins (DZ) with Addison’s disease and vitiligo. Rates were higher in MZ than in DZ pairs for all seven diseases. Probandwise pseudo-concordance was defined as the proportion of co-twins with a different AID among twins with index AID. Total probandwise concordance was defined as the proportion of co-twins with (any of the studied) AIDs among twins with index AID. The ratio of probandwise pseudo-concordance to total probandwise concordance was used as a measure of autoimmune clustering. This ratio was highest for Addison’s disease (MZ 0.54, DZ 1.0) and vitiligo (MZ 0.46, DZ 1.0), lower for Hashimoto’s thyroiditis (MZ 0.29, DZ 0.29) and lowest for Celiac disease (MZ 0.12, DZ 0.31). In the context of the seven AIDs explored here, probandwise concordance rates for individual diseases underestimate the burden of autoimmunity. This effect is considerable for disorders with significant etiological overlap, such as Addison’s disease and vitiligo, but marginal in celiac disease, which has little etiological overlap. The genetic influence on disease occurrence for individual disorders is high, with heritability estimates ranging from 0.97 to 0.47. 1. Cotsapas C, Voight BF, Rossin E, et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet 2011;7(8):e1002254. doi: 10.1371/journal.pgen.1002254

Autoimmune Addisons disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population. Funding Agencies|Swedish Research Council; Torsten and Ragnar Soderberg Foundations; European Union Seventh Framework Programme [201167]; Stockholm County Council; Karolinska Institutet; Swedish Society for Medical Research; Swedish Society of Medicine; NovoNordisk Foundation; Tore Nilsons Foundation for Medical Research; Swedish Research Council Formas; Knut and Alice Wallenberg Foundation; Marianne and Marcus Wallenberg Foundation; Swedish Reumatism Foundation; King Gustaf Vs 80-year Foundation; Ake Wiberg Foundation

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1. Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE. Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure. Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

The overal laim of this study was to generate knowledge about everyday life among people living with rare Addison’s disease (AD). Understanding experiences in contexts of everyday life are importan ...

Objective Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients. Design Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years. Methods Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians. Conclusions Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

BACKGROUND: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce. OBJECTIVE: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD. MATERIAL AND METHODS: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values. RESULTS: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L(-1) [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L(-1) [2-442]) than in those without (81 nmol L(-1) [1-668], P < 0.001). CONCLUSION: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIREs selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance. Funding Agencies|Swedish Research Council; Formas Research Council; Torsten Soderberg Foundation; Ragnar Soderberg Foundation; Novonordisk Foundation; Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addisons disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addisons disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addisons disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addisons disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addisons disease, we have identified BACH2 as a major risk locus in Addisons disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment. Funding Agencies|Swedish Research Council; Torsten Foundation; Ragnar Soderberg Foundation; European Union [201167]; Stockholm County Council; Karolinska Institutet; Swedish Society for Medical Research; Swedish Society of Medicine; NovoNordisk Foundation; Tore Nilsons Foundation for Medical Research; Swedish Research Council Formas; Knut and Alice Wallenberg Foundation; Marianne and Marcus Wallenberg Foundation; Swedish Reumatism Foundation; King Gustaf Vs 80-year Foundation; Ake Wiberg Foundation; AstraZeneca Science for Life Laboratory Research Collaboration grant (DIS-SECT)

BackgroundLymphocytic hypophysitis is an organ-specific autoimmune disease of the pituitary gland. A specific and sensitive serological test currently does not exist to aid in the diagnosis.ObjectiveTo identify target autoantigens in lymphocytic hypophysitis and develop a diagnostic assay for these proteins.Design/methodsA pituitary cDNA expression library was immunoscreened using sera from four patients with lymphocytic hypophysitis. Relevant cDNA clones from screening, along with previously identified autoantigens pituitary gland-specific factor 1a and 2 (PGSF1a and PGSF2) and neuron-specific enolase (NSE) were tested in anin vitrotranscription and translation immunoprecipitation assay. The corticotroph-specific transcription factor, TPIT, was investigated separately as a candidate autoantigen.ResultsSignificantly positive autoantibody reactivity against TPIT was found in 9/86 hypophysitis patients vs 1/90 controls (P=0.018). The reactivity against TPIT was not specific for lymphocytic hypophysitis with autoantibodies detectable in the sera from patients with other autoimmune endocrine diseases. Autoantibodies were also detected against chromodomain-helicase-DNA binding protein 8, presynaptic cytomatrix protein (piccolo), Ca2+-dependent secretion activator, PGSF2 and NSE in serum samples from patients with lymphocytic hypophysitis, but at a frequency that did not differ from healthy controls. Importantly, 8/86 patients with lymphocytic hypophysitis had autoantibodies against any two autoantigens in comparison with 0/90 controls (P=0.0093).ConclusionsTPIT, a corticotroph-specific transcription factor, was identified as a target autoantigen in 10.5% of patients with lymphocytic hypophysitis. Further autoantigens related to vesicle processing were also identified as potential autoantigens with different immunoreactivity patterns in patients and controls.

In this article, we review published studies covering epidemiology, natural course and mortality in primary adrenal insufficiency (PAI) or Addison’s disease. Autoimmune PAI is a rare disease with a prevalence of 100–220 per million inhabitants. It occurs as part of an autoimmune polyendocrine syndrome in more than half of the cases. The patients experience impaired quality of life, reduced parity and increased risk of preterm delivery. Following a conventional glucocorticoid replacement regimen leads to a reduction in bone mineral density and an increase in the prevalence of fractures. Registry studies indicate increased mortality, especially evident in patients diagnosed with PAI at a young age and in patients with the rare disease autoimmune polyendocrine syndrome type-1. Most notably, unnecessary deaths still occur because of adrenal crises. All these data imply the need to improve the therapy and care of patients with PAI.

Objectives: The results of studies of bone mineral density (BMD) in Addison's disease (AD) are inconsistent. There are no published data on hip fracture risk in patients with AD. In this study we compare hip fracture risk in adults with and without AD. Design: A population-based cohort study. Methods: Through the Swedish National Patient Register and the Total Population Register, we identified 3,219 patients without prior hip fracture who were diagnosed with AD at the age of ≥30 years during the period 1964-2006, and 31,557 age- and sex-matched controls. Time to hip fracture was measured. Results: We observed 221 hip fractures (6.9%) in patients with AD and 846 (2.7%) in the controls. Patients with AD had a higher risk of hip fracture (hazard ratio (HR) = 1.8; 95% confidence interval (CI), 1.6-2.1; p < 0.001). This risk increase was independent of sex and age at or calendar period of diagnosis. Risk estimates did not change with adjustment for type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis or coeliac disease. Women diagnosed with AD ≤50 years old had the highest risk of hip fracture (HR = 2.7; 95% CI, 1.6-4.5). We found a positive association between hip fracture and undiagnosed AD (odds ratio (OR) = 2.4; 95% CI, 2.1- 3.0) with the highest risk estimates in the last year before AD diagnosis (OR = 2.8; 95% CI, 1.8-4.2). Conclusion: Both clinically undiagnosed and diagnosed AD were associated with hip fractures, with the highest relative risk seen in women diagnosed with AD ≤50 years of age.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator ( AIRE ) gene. High titer autoantibodies (Aabs) toward intracellular enzymes are a hallmark for APS1 and serve as diagnostic markers and predictors for disease manifestations. In this study, we aimed to identify pituitary autoantigens in patients with APS1. A pituitary cDNA expression library was screened with APS1 sera and a tudor domain containing protein 6 (TDRD6) cDNA clone was isolated. Positive immunoreactivity against in vitro translated TDRD6 fragments was shown in 42/86 (49%) APS1 patients but not in patients with other autoimmune diseases or in healthy controls. By using immunohistochemistry, sera from 3/6 APS1 patients with growth hormone (GH) deficiency showed immunostaining of a small number of guinea pig anterior pituitary cells, and 40–50% of these cells were GH-positive. No such immunostaining was seen with sera from healthy controls. The APS1 Aab-positive, GH-negative cells may represent a novel subpopulation of anterior pituitary cells. In addition, 4/6 patient sera showed staining of a fiber-plexus in the pituitary intermediate lobe recognizing enzymes of monoamine and GABA synthesis. Thus, we have identified TDRD6 as a major autoantigen in APS1 patients and shown that several sera from GH-deficient patients stain specific cell populations and nerves in the pituitary gland.

Context: Conventional glucocorticoid replacement therapy fails to mimic the physiological cortisol rhythm, which may have implications for morbidity and mortality in patients with Addison’s disease. Objective: The objective of the study was to compare the effects of continuous sc hydrocortisone infusion (CSHI) with conventional oral hydrocortisone (OHC) replacement therapy. Design, Patients, and Interventions: This was a prospective crossover, randomized, multicenter clinical trial comparing 3 months of treatment with thrice-daily OHC vs CSHI. From Norway and Sweden, 33 patients were enrolled from registries and clinics. All patients were assessed at baseline and after 8 and 12 weeks in each treatment arm. Main Outcome Measures: The morning ACTH level was the primary outcome measure. Secondary outcome measures were effects on metabolism, health-related quality of life (HRQoL), sleep, and safety. Results: CSHI yielded normalization of morning ACTH and cortisol levels, and 24-hour salivary cortisol curves resembled the normal circadian variation. Urinary concentrations of glucocorticoid metabolites displayed a normal pattern with CSHI but were clearly altered with OHC. Several HRQoLindices in the vitality domain improved over time with CSHI.Nobenefit was found for either treatments for any subjective (Pittsburgh Sleep Quality Index questionnaire) or objective (actigraphy) sleep parameters. Conclusion: CSHI safely brought ACTH and cortisol toward normal circadian levels without adversely affecting glucocorticoid metabolism in the way that OHC did. Positive effects on HRQoL were noted with CSHI, indicating that physiological glucocorticoid replacement therapy may be beneficial and that CSHI might become a treatment option for patients poorly controlled on conventional therapy. publishedVersion

CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality. OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors. DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls. MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p

Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.

Context: Patients with Addison’s disease (AD) self-report impairment in specific dimensions on well-being questionnaires. An AD-specific quality-of-life questionnaire (AddiQoL) was developed to aid evaluation of patients. Objective: We aimed to translate and determine construct validity, reliability, and concurrent validity of the AddiQoL questionnaire. Methods: After translation, the final versions were tested in AD patients from Norway (n = 107), Sweden (n = 101), Italy (n = 165), Germany (n = 200), and Poland (n = 50). Construct validity was examined by exploratory factor analysis and Rasch analysis, aiming at unidimensionality and fit to the Rasch model. Reliability was determined by Cronbach’s coefficient- and Person separation index. Longitudinal reliability was tested by differential item functioning in stable patient subgroups. Concurrent validity was examined in Norwegian (n = 101) and Swedish (n = 107) patients. Results: Exploratory factor analysis and Rasch analysis identified six items with poor psychometric properties. The 30 remaining items fitted the Rasch model and proved unidimensional, supported by appropriate item and person fit residuals and a nonsignificant X² probability. Crohnbach’s α-coefficient 0.93 and Person separation index 0.86 indicate high reliability. Longitudinal reliability was excellent. Correlation with Short Form-36 and Psychological General Well-Being Index scores was high. A shorter subscale comprising eight items also proved valid and reliable. Testing of AddiQoL-30 in this large patient cohort showed significantly worse scores with increasing age and inwomencompared withmenbutnodifference between patients with isolatedADand those with concomitant diseases. Conclusion: The validation process resulted in a revised 30-item AddiQoL questionnaire and an eight-item AddiQoL short version with good psychometric properties and high reliability. publishedVersion

Objectives: The results of studies of bone mineral density (BMD) in Addison's disease (AD) are inconsistent. There are no published data on hip fracture risk in patients with AD. In this study we compare hip fracture risk in adults with and without AD. Design: A population-based cohort study. Methods: Through the Swedish National Patient Register and the Total Population Register, we identified 3,219 patients without prior hip fracture who were diagnosed with AD at the age of ≥30 years during the period 1964-2006, and 31,557 age- and sex-matched controls. Time to hip fracture was measured. Results: We observed 221 hip fractures (6.9%) in patients with AD and 846 (2.7%) in the controls. Patients with AD had a higher risk of hip fracture (hazard ratio (HR) = 1.8; 95% confidence interval (CI), 1.6-2.1; p < 0.001). This risk increase was independent of sex and age at or calendar period of diagnosis. Risk estimates did not change with adjustment for type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis or coeliac disease. Women diagnosed with AD ≤50 years old had the highest risk of hip fracture (HR = 2.7; 95% CI, 1.6-4.5). We found a positive association between hip fracture and undiagnosed AD (odds ratio (OR) = 2.4; 95% CI, 2.1- 3.0) with the highest risk estimates in the last year before AD diagnosis (OR = 2.8; 95% CI, 1.8-4.2). Conclusion: Both clinically undiagnosed and diagnosed AD were associated with hip fractures, with the highest relative risk seen in women diagnosed with AD ≤50 years of age.

Autoimmune Addison's disease (AAD) tends to affect young and middle-aged women. It is not known whether the existence of undiagnosed or diagnosed AAD influences the outcome of pregnancy.The aim of the study was to compare the number of children and pregnancy outcomes in individuals with AAD and controls.We conducted a population-based historical cohort study in Sweden.Through the Swedish National Patient Register and the Total Population Register, we identified 1,188 women with AAD and 11,879 age-matched controls who delivered infants between 1973 and 2006.We measured parity and pregnancy outcome.Adjusted odds ratios (ORs) for infants born to mothers with deliveries 3 yr or less before the diagnosis of AAD were 2.40 [95% confidence interval (CI), 1.27-4.53] for preterm birth (≤37 wk), 3.50 (95% CI, 1.83-6.67) for low birth weight (2500 g), and 1.74 (95% CI, 1.02-2.96) for cesarean section. Compared to controls, women who gave birth after their AAD diagnosis were at increased risk of both cesarean delivery (adjusted OR, 2.35; 95% CI, 1.68-3.27) and preterm delivery (adjusted OR, 2.61; 95% CI, 1.69-4.05). Stratifying by isolated AAD and concomitant type 1 diabetes and/or autoimmune thyroid disease in the mother did not essentially influence these risks. There were no differences in risks of congenital malformations or infant death. Women with AAD had a reduced overall parity compared to controls (P0.001).Clinically undiagnosed and diagnosed AAD both entail increased risks of unfavorable pregnancy outcomes. AAD also influences the number of childbirths.