Background Autoimmune diseases (ADs) often co-occur within individuals and families, indicating shared genetic risk factors. However, the composition of genetic overlap across autoimmunity is largely unknown. Methods This nationwide study included 6,336,615 individuals born in Sweden between 1932 and 1983, comprising 3,839,400 full-sibling pairs. Based on national heath-registers, 22 ADs were identified from 1969-2013. Aggregation and co-aggregation of ADs among siblings was used to estimate pairwise genetic correlations of ADs under a liability-threshold model. Network analysis and principal component analysis was used to characterize the structure of shared genetic risk across ADs. Results A total of 707,995 individuals (11.2%) were diagnosed with at least one AD. The studied ADs formed a network of significant genetic correlations (mean rg = 0.24, range 0.08-0.84) with clusters of more closely related ADs (rg ≥ 0.3). We found no evidence of a significant universal factor predisposing to autoimmunity. Conclusions This study demonstrates that ADs share substantial cluster-specific genetic overlap that largely aligns with affected tissue types, leading to distinct groupings of connective tissue diseases, gastrointestinal disorders, and endocrinopathies, whereas diseases of the nervous system show limited genetic cohesion. This suggests that shared biological mechanisms may drive coaggregation within disease groups. Clinically, these insights highlight the importance of monitoring patients and their relatives for related autoimmune disorders. Funding The Swedish Society of Medicine, Region Värmland's County Research Council, The Swedish Research Council, the Knut and Alice Wallenberg Foundation, The Regional Agreement on medical training and Clinical research (ALF) between Stockholm County Council and Karolinska Institutet.

Objective: Self-management and patient education are cornerstones in managing adrenal insufficiency (AI) to prevent adrenal crisis (AC). Glucocorticoid (GC) education group meetings are increasingly being incorporated into regular healthcare. However, few studies have evaluated its effectiveness. Design: This is a multicentre pre–post intervention study conducted at four university hospitals in Sweden between 2015 and 2019. Methods: A total of 254 patients with AI along with 138 relatives were included. Participants attended a GC education group meeting led by an endocrinologist. Detailed guidance was provided on when and how to adjust GC doses to prevent AC together with instructions and supervised practice of hydrocortisone injections. Questionnaires on self-management were completed by both patients and relatives before the session and again 6 months later. In addition, patients also completed two HRQoL instruments. Results: Patients with AI felt relatively safe and informed about their GC treatment at baseline. However, many lacked adequate knowledge on dose adjustments, including high-risk situations for AC. At follow up, 194 patients (76.4%) and 94 relatives (68.1%) completed the questionnaires. Both patients and relatives showed significant improvements in perceived safety and management of high-risk scenarios for AC. However, some knowledge gaps persisted. The education effort did not result in significant changes in HRQoL. Conclusion: Structured GC education group meetings enhance the knowledge of patients and their relatives to manage AI safely. We consider this a valuable component of AI care. Significance: We highlight the value of repeating sick-day rules and using group education to improve self-management in patients with AI and their relatives.

Context: The effect of autoimmune Addison's disease (AAD) on work ability and income over time remains unclear. Objective: This work aimed to evaluate differences and temporal trends in income and lost workdays among patients with AAD before and after diagnosis, vs matched general population comparators. This nationwide, register-based cohort study was conducted in Sweden. We linked the Swedish Addison Register with national health registers to identify 716 working-age individuals (aged 20-62 years) with incident AAD 2003 to 2019 and 3271 general-population comparators matched by sex, age, county, calendar year, and education level. Annual work loss, taxable earnings, and disposable income were examined over a 10-year period around diagnosis using linear (work loss) and quantile (earnings, income) regression. Results: Patients with AAD had significantly more work loss than comparators from 1 year before to 3 years after diagnosis, with the largest difference the year after diagnosis (mean difference: 30.5 days; 95% CI, 22.9-38.0 days). Median taxable earnings were lower in patients with AAD 1 year before (median difference: $-1107; 95% CI, $-2042 to $-173; P = .02) and 1 year after diagnosis ($-1105; 95% CI, $-2166 to $-43; P = .04). Disposable income was also reduced 1 year after diagnosis (median difference: $-1084; 95% CI, $-1813 to $-354; P = .004). Conclusion: In AAD, increased work loss and reduced earnings and income were concentrated around diagnosis, peaking in the year after. Reassuringly, both absence from work and income normalized within 4 years following diagnosis.

To investigate adenoma progression, pituitary function, visual impairment, and need for later surgery in elderly patients with conservatively managed nonfunctioning pituitary macroadenomas (macro-NFPAs). Patients ≥ 65 years in the Swedish Pituitary Registry diagnosed 1991–2023 with macro-NFPA and a decision for conservative management were included (n = 673, 38

Primary aldosteronism affects 5 to 20% of the hypertensive population and is associated with increased cardiovascular and metabolic risk compared with primary hypertension. Alterations in the dynamics of aldosterone secretion are key, but these are not well captured by current diagnostic pathways, and the disease is often missed. In this proof-of-concept study, we used ambulatory microdialysis sampling to continuously monitor tissue corticosteroid dynamics in primary aldosteronism over 24 hours. In a cohort of 60 patients, we found pulsatile nocturnal hypersecretion of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxocortisol with a preserved daily rhythm. This was most prominent in unilateral disease, with normalization after adrenalectomy. Our findings confirm that a key pathophysiological feature of primary aldosteronism is disruption of corticosteroid rhythms rather than persistent elevation of hormones. We show that ambulatory dynamic hormone profiling is a viable technique that offers substantially more information than current diagnostic approaches relying on single-time point hormone measurements. In the future, this offers the opportunity to investigate more subtle dynamic phenotypes and potentially earlier detection of disease.

BACKGROUND:Women with autoimmune diseases have an increased risk of premature ovarian insufficiency (POI), leading to early menopause and infertility. We hypothesized that B-cell depletion with rituximab could reverse autoimmune activity, enhance ovarian responsiveness to gonadotropins, and transiently restore fertility in autoimmune POI. METHODS:In this proof-of-concept study, we enrolled women between the ages of 18 and 35 years with autoimmune POI. Each participant underwent controlled ovarian hyperstimulation before and 4 to 6 months after treatment with rituximab (two 1-g infusions, administered 2 weeks apart). Participants were followed for 12 months after rituximab infusion. The primary outcomes of interest were the number of antral follicles and the size of the largest follicle in response to ovarian stimulation. In the case of successful oocyte retrieval, oocytes were cryopreserved or fertilized. For safety, embryo transfer was deferred until at least 12 months after rituximab administration. RESULTS:We enrolled 12 women, with a mean (standard deviation) age of 30.8 (2.8) years. Two women withdrew consent prior to initiating the study. Prior to rituximab, none of the participants responded to ovarian hyperstimulation with follicular development. Following rituximab, after undergoing another ovarian hyperstimulation, follicular development occurred in six women that led to oocyte retrieval (responders). In three of these cases, oocytes were fertilized and embryos preserved; all three women subsequently delivered healthy children. One serious adverse event occurred during the trial, related to ovarian hyperstimulation. CONCLUSIONS:In this small proof-of-concept study with no control group, of 10 women with premature ovarian insufficiency who received rituximab followed by ovarian stimulation, six underwent oocyte retrieval. A randomized controlled trial is needed to further evaluate this treatment strategy. (Funded by the Swedish Research Council and others; EudraCT number, 2017-004532-10; ClinicalTrials.gov number, NCT05586737.).

Does rituximab, a B cell specific monoclonal drug, improve ovarian response to gonadotropin stimulation and restore fertility in women with autoimmune premature ovarian insufficiency (POI)? This proof-of concept study has for the first time shown successful results by immunomodulatory therapy in improving fertility in women with autoimmune POI. Autoimmune disorders are associated with increased risk of POI, leading to early menopause and infertility. The etiology of autoimmune POI remains unknown, but measurable levels of anti-Müllerian hormone indicate that some follicles may be intact. We hypothesized that rituximab, a medication of B cell-specific monoclonal antibodies, can improve the ovarian response to gonadotropin stimulation and restore fertility in women with autoimmune POI. This is an open label pilot study. The procedure comprised controlled ovarian hyperstimulation according to a standard high dose protocol with daily subcutaneous injections of follitropin alpha, prior to, and 4-6 months after two infusions of 1-gram rituximab 2 weeks apart, and a follow-up period of 12 months. Primary outcome was the number of antral follicles and/or the size of the largest follicle in response to ovarian stimulation after rituximab. Ten women, aged 18-35 years, BMI 19-30 kg/m2, with autoimmune POI (S- FSH 40 IE/L), of which seven had Addison’s disease, were included. If positive response to ovarian stimulation was obtained, GnRH antagonist was given to prevent premature ovulation and choriogonadotropin alpha to induce ovulation. When possible, oocytes were retrieved for cryopreservation or after fertilization. Due to safety reasons, embryo transfer was possible at the earliest one year after the last infusion of rituximab. None of the ten patients responded to ovarian stimulation prior to rituximab treatment. After rituximab therapy, 8 out of 10 women reported spontaneous menstrual bleedings, 6 out of 10 patients responded with follicular development and in 5 women, mature eggs were harvested for preservation. In 3 of those, eggs were fertilized for embryo preservation. Three women became pregnant and so far, there have been two successful deliveries. All responders had Addison’s disease, whereas those with no response had Myasthenia gravis or Hashimoto thyroiditis. We observed no serious drug reactions or other complications. The results are based on an open label pilot study. Future randomized clinical trials are needed to confirm the results. The only fertility treatment that can be offered today to women with POI is egg donation. POI also has negative health consequences including increased risk of cardiovascular disease, fractures, and cognitive impairment. Rituximab has the potential to improve fertility and probably also negative health effects in women with autoimmune POI. Yes

OBJECTIVE:Autoimmune Addison's disease (AAD) is associated with reduced health-related quality of life and possibly reduced employability. The aim of this study was to assess differences in income and work loss between patients with AAD and matched comparators. DESIGN:Nationwide, cross-sectional register-based study. METHODS:By linking the Swedish Addison Register and national health registers, we identified working age (18-64 years) individuals with AAD and general population comparators (matched 1:5 by sex, age, and county of residence). We assessed differences in taxable earnings and disposable income through quantile regression and differences in work loss through linear regression during 2019. RESULTS:We identified 1140 cases with AAD and 5700 comparators (mean age 46.1 years, 48.4% men). Type 1 diabetes was prevalent in 15.7% and 1.1%, respectively. Work loss was higher in AAD; adjusted mean difference 14.4 days; 95% CI, 8.6-20. The adjusted median differences in taxable earnings and disposable income were non-significant overall at -617 (95% CI; -2317 to 1083) and -405 (95% CI; -1417 to 607) €. However, significantly lower taxable earnings and disposable income were found among patients with short education: -5303 (95% CI; -9603 to -992) and -3754 (95% CI; -6486 to -1022) €, or concomitant type 1 diabetes: -5808 (95% CI; -9937 to -1690) and -3349 (95% CI; -6203 to -506) €. CONCLUSION:Patients with AAD had more work loss, yet overall similar taxable earnings and disposable incomes versus comparators. Patients with AAD with shorter education or type 1 diabetes were most socioeconomically vulnerable.

OBJECTIVE:Standard glucocorticoid (GC) replacement therapy in autoimmune Addison's disease (AAD) fails to replicate natural cortisol rhythms. Despite adherence, patients report persistent fatigue, reduced vitality, and impaired wellbeing, ultimately lowering health-related quality of life (HRQoL). Cortisol is essential for sleep regulation, yet the impact of cortisol imbalance on sleep and HRQoL in AAD remains poorly understood. This study investigates self-reported sleep impairments and their associations with fatigue and HRQoL in young adults with AAD. PATIENTS AND METHODS:Sixty-four patients with AAD and 128 healthy controls completed validated questionnaires assessing sleep (Karolinska Sleep Questionnaire), fatigue (Multidimensional Fatigue Inventory), and HRQoL (Short Form-36). RESULTS:Patients reported significantly more non-restorative sleep (p = 0.015) than controls. While overall rates of clinically relevant sleep impairments were similar, patients more frequently experienced awakening difficulties (p = 0.011) and struggling to stay awake (p = 0.036). Patients also reported poorer physical health (p < 0.001) and greater general fatigue (p = 0.007), with female patients experiencing more mental fatigue (p = 0.013). Poor sleep and fatigue were associated with reduced HRQoL across the cohort, with patients showing a more pronounced decline in physical health in relation to these factors. Mental health scores remained similar between groups. CONCLUSION:Non-restorative sleep emerged as a distinct feature of AAD. While the prevalence and severity of sleep impairments were similar to controls, the association with poorer physical health was stronger in patients. Mental health remained similar despite sleep disturbances. These findings highlight the importance of addressing even modest sleep disturbances, which may worsen fatigue and reduce physical wellbeing in AAD.

BACKGROUND:The risk of major osteoporotic fractures (MOFs) and osteoporosis in patients with autoimmune Addison's disease (AAD) is unclear. OBJECTIVE:To investigate the risk of MOF in patients with AAD and the possible correlation with adrenal hormone replacement doses. METHODS:Swedish national health registers were used to identify 1869 subjects with AAD and 16,844 matched controls. The primary outcome was MOF, and the secondary outcome was treatment with osteoporosis medications. Marginal Cox models were used to compare time-to-event outcomes. The study period spanned from 1 July 2005 until 31 December 2020. Individuals at risk were followed from inclusion until censored or the end of the study period. RESULTS:A total of 77 patients with AAD (7.1/1000 person-years [PY]), and 387 matched controls (3.9/1000 PY) were diagnosed with MOF. The risk of MOF was higher in patients with AAD compared to matched controls, with an adjusted hazard ratio (aHR) of 1.82 (95% confidence interval [CI], 1.41-2.35) and increased in both male and female patients, with aHR of 2.51 (95% CI, 1.56-4.02) and 1.65 (95% CI, 1.22-2.24), respectively. Patients with AAD had an increased risk of treatment with osteoporosis medications: aHR 3.25 (95% CI, 2.71-3.99), compared to controls. No significant differences in MOF rates were observed between patients treated with intermediate or high doses of glucocorticoids compared to low doses (p = 0.967 and p = 0.580, respectively). Similarly, stratification by mineralocorticoid dose (<0.10 vs. ≥0.10 mg/day) showed no significant association regarding MOF (p = 0.915). CONCLUSIONS:The risk of MOF is increased in patients with AAD without any apparent correlation to adrenal hormone replacement doses.

Objective:Prolactin (PRL) promotes cell proliferation, and PRL receptor expression is elevated in various cancer types. However, only a few studies have examined cancer risk in patients with hyperprolactinemia (HPL). The aim of this study was to investigate cancer risk in a nationwide cohort of patients with a diagnosis of HPL, with special emphasis on breast cancer. Design:In this Swedish population-based cohort study, we used nationwide registries to identify 3,837 patients (2,955 (77%) women) with HPL, treated with dopamine agonists (DA), diagnosed between 2006 and 2019, along with 38,370 controls matched by age, sex, calendar year and county of residence at first HPL diagnosis. Methods:Cancer outcomes (overall and specific types), as registered in the Swedish Cancer Register, were analyzed using Cox regression, internally stratified by the matching variables and additionally adjusted for diabetes mellitus, obesity, smoking, alcohol overconsumption, hormone replacement therapy and educational level to estimate adjusted hazard ratios (aHRs). Results:During a median follow-up time of 6.1 years (interquartile range (IQR) 3.4-9.6), 168 (4.6%) new cases of cancer were identified in patients with HPL and 1,608 (4.4%) in the control group (aHR 1.05 (95% CI: 0.89-1.23)). Twenty-eight (0.7%) patients (all women) in the HPL group and 267 (0.7%) in the control group developed breast cancer (aHR 1.02 (95% CI: 0.68-1.51)). Similarly, there was no increased risk of any other site-specific cancer. Conclusions:In this nationwide cohort study of patients with DA-treated HPL, no increased risk of overall cancer, breast cancer or other site-specific malignancies was observed.

OBJECTIVE:The effect of autoimmune Addison's disease (AAD) on mental health is not well known. The aim of this study was to examine the use of psychotropic drugs around diagnosis and after long-term follow-up in Swedish individuals with AAD. DESIGN AND METHODS:In this population-based cohort study, national health and population registers and the Swedish Addison Registry were used to identify individuals diagnosed with AAD between July 2006 and December 2019 and matched population controls. The Swedish Prescribed Drug Register was used to retrieve information on annual dispensations (yes/no) of anti-psychotics [Anatomical Therapeutic Chemical (ATC) N05A], anxiolytics (ATC N05B), hypnotics/sedatives (ATC N05C), and anti-depressants (ATC N06A), from 3 years before to 3 years after diagnosis. A cross-sectional analysis of the year 2019 was also performed. RESULTS:A total of 963 persons with AAD and 9366 matched controls were identified. Use of hypnotics/sedatives, anxiolytics, and anti-depressants was significantly higher in patients with AAD the year preceding diagnosis [ORs 1.72 (1.40-2.11), 1.38 (1.07-1.78), and 1.29 (1.05-1.59), respectively]. After diagnosis, use of hypnotics/sedatives remained significantly higher [ORs 1.42 (1.13-1.78) to 1.78 (1.45-2.19)]. We found no difference in dispensation of other psychotropic drugs after diagnosis. In the cross-sectional analysis of 2019, the increased dispensation of hypnotics/sedatives remained elevated [odds ratio (OR) 1.31 (1.01-1.70)]. CONCLUSIONS:Prescription patterns suggest that early symptoms of AAD are associated with or mistaken for mental health disorders. Furthermore, insomnia is common in patients with AAD.

Context:Substantial diagnostic delay in acromegaly contributes to increased morbidity and mortality. Screening attempts in high-risk groups have yielded few positive cases, underscoring the need for simple and precise prescreening methods. Objective:Machine-learning analysis of facial images shows promise for acromegaly detection but requires validation in larger, well-characterized cohorts using robust machine-learning frameworks as performed in this study. Methods:Facial images from different angles were collected via smartphone from 155 acromegaly patients (79% biochemically controlled) and 153 matched controls at all Swedish university hospitals. Six machine-learning models were trained to distinguish acromegaly from control images, including 3 deep neural networks pretrained on diverse image datasets (ImageNet models: ResNet50, InceptionV2, and DenseNet121) and 1 network pretrained specifically on facial images (FaRL). Model performance was compared to assessment by 12 experienced endocrinologists. Results:The diagnostic accuracy of the FaRL-based model was superior to all ImageNet models and matched the accuracy of human experts (area under the receiver operating characteristic curve 0.89 for both) with similar specificity (0.87 vs 0.93) but higher sensitivity (0.82 vs 0.66). Classification agreement between the best machine-learning model (FaRL) and human experts was 86% for true negatives and 60% for true positives. Machine-learning models and human experts both showed greater sensitivity in identifying acromegaly in male patients. Conclusion:A deep learning model pretrained on facial features (FaRL) can detect acromegaly from standard photographs with accuracy comparable to that of expert endocrinologists. This supports the feasibility of face analysis as a screening tool for acromegaly.

Cortisol is released upon activation of the hypothalamic-pituitary-adrenal axis, varies across the day, possesses an underlying diurnal rhythm and is responsive to stressors. The endogenous circadian peak of cortisol occurs in the morning, and increases in cortisol observed post-awakening have been named the cortisol awakening response (CAR) based on the belief that the act of waking up stimulates cortisol secretion. However, objective evidence that awakening induces cortisol secretion is limited. We used a mixed effects model with a linear spline fitted to the data to examine tissue-free cortisol measurements obtained from 201 healthy volunteers by automated ambulatory microdialysis before and after awakening in their home environments. We also examined rate of change of cortisol depending on sleep duration and relative timing. We found no evidence for a change in the rate of cortisol increase in the hour after waking when compared with the hour prior to waking. We instead observed substantial interindividual variability in the absolute concentration and rate of change of cortisol levels, and differences in dynamics that may be attributable to duration and relative timing of sleep. Based on these results, we strongly suggest caution is needed when interpreting cortisol measurements solely obtained in the hour after waking.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Autoimmune Addison’s disease (AAD) is treated with daily oral hormone replacements for cortisol and aldosterone. The current treatment is sub-optimal, and frequently results in supra- and infra-physiological cortisol levels that might negatively affect the brain and cognitive functioning. It is currently unclear if the brains of these patients need to be better protected. The present study investigates brain function during working memory in young adults with AAD compared to healthy controls. All participants (56 AAD (33 females), 62 controls (39 females), 19-43 years), underwent MRI brain scanning while performing a visuo-spatial and verbal working memory task. No main group differences in accuracy, reaction time or brain activity during the tasks were found. These findings suggest that patients perform equal to controls, and achieve similar levels of brain activity during working memory. However, variations in the patient population may have confounded this outcome. Controlled studies on larger cohorts are therefore needed to confirm these findings and test if having AAD affects the brain on the long term.

Patients with adrenal insufficiency (AI) have excess morbidity and mortality related to infectious disorders. Whether patients with AI have increased morbidity and mortality from COVID-19 is unknown. In this linked Swedish national register-based cohort study, patients with primary and secondary AI diagnosis were identified and followed from 1 January 2020 to 28 February 2021. They were compared with a control cohort from the general population matched 10:1 for age and sex. The following COVID-19 outcomes were studied: incidence of COVID-19 infection, rates of hospitalization, intensive care admission and death. Hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for socioeconomic factors and comorbidities were estimated using Cox regression analysis. We identified 5430 patients with AI and 54,300 matched controls: There were 47.6% women, mean age was 57.1 (standard deviation 18.1) years, and the frequency of COVID-19 infection was similar, but the frequency of hospitalization (2.1% vs. 0.8%), intensive care (0.3% vs. 0.1%) and death (0.8% vs. 0.2%) for COVID-19 was higher in AI patients than matched controls. After adjustment for socioeconomic factors and comorbidities, the HR (95% CI) was increased for hospitalization (1.96, 1.59–2.43), intensive care admission (2.76, 1.49–5.09) and death (2.29, 1.60–3.28). Patients with AI have a similar incidence of COVID-19 infection to a matched control population, but a more than twofold increased risk of developing a severe infection or a fatal outcome. They should therefore be prioritized for vaccination, antiviral therapy and other appropriate treatment to mitigate hospitalization and death.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)