OBJECTIVE: Autoimmune 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. The aim of this study was to investigate 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 METHODS: Questionnaires 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 co-morbidities, focusing on the pre-vaccine phase.
RESULTS: Among the 615 included patients with AAD, COVID-19 was reported by 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=0.002) and hypertension (p=0.014) were associated with an increased risk of hospital care while younger age (p<0.001) and less worry about infection (p=0.030) correlated with a higher risk of COVID-19.
CONCLUSIONS : In 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.
Autoimmune Addison’s disease is the most common form of primary adrenal insufficiency in the Western world. The low prevalence of the disease has hampered large-scale unbiased genetic studies where ...the entire genome could be examined at once. By combining the two largest biobanks of DNA from patients with autoimmune Addison’s disease, we identified in Paper I nine independent risk loci with a genome-wide association study of 1223 patients and 4097 geographically matched controls. These results explained up to 41% of the heritability of the disease, which, in a twin study, has been estimated to be as high as 0.97 95% CI 0.88-0.99.In Paper II, we derived a polygenic risk score for autoimmune Addison’s disease with the same dataset from the first study. The polygenic risk score enabled an estimation of disease susceptibility at the individual level and the discrimination of other etiologies of primary adrenal insufficiency, uncovering cases previously presumed to have the autoimmune form of Addison’s disease.In Paper III, we explored the use of our polygenic risk score to efficiently triage patients who may benefit most from whole-genome sequencing to achieve the correct diagnosis and appropriate clinical management of the disease. Monogenic forms of primary adrenal insufficiency were found in 5 out of 35 cases with low polygenic risk score for autoimmune Addison’s disease, and we found an additional of three cases with suspected monogenic disease. This study highlights the potential of polygenic risk score as a tool to in the clinical evaluation of primary adrenal insufficiency.In summary, this thesis sheds light on the genetic risk factors behind the development of autoimmune Addison’s disease and their potential utility as diagnostic classifiers. Future studies are warranted to further our understanding of the biological role of the associated genetic risk factors.
Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the HLA ...region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the two genes, and therefore we asked if genetic variation of the CYP21 genes is associated with AAD.
Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P together with HLA alleles in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase, and in 1,393 healthy controls.
With 95% of individuals carrying two functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (p = 5 x 10-44) together with associations of additional nucleotide variants in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (p = 9 x 10-63), which in combination with the DRB1*04:04-DQB1*03:02 haplotype imposed the greatest risk of AAD.
We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.
Abstract
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.
To determine the prevalence of medically unexplained physical symptoms and the characteristics and use of health services in a group of patients with medically unexplained physical symptoms and a ...group of patients with other illnesses.
This was a cross-sectional, retrospective and multicenter study. We included 1,043 patients over 18 years of age from 30 primary care units of a government health institution, in 11 states of Mexico, attended by 39 family physicians. The prevalence of medically unexplained physical symptoms was determined and both groups with or without symptoms were compared with regard to drug use, laboratory and other studies, leaves of absence, and referrals in the last six months. The group with medically unexplained physical symptoms was diagnosed using the Patient Health Questionnaire and the diagnostic criteria of Reid
. Emergency or terminal illnesses were excluded. The chi square test was used with a statistical significance of p < 0.05.
Medically unexplained physical symptoms was diagnosed in 73 patients (7.0%). The majority were women (91.8%); their predominant symptom was from the gastrointestinal system in 56 (76.7%). This group had a greater use of clinical studies and referrals to other services (mean 1.1 vs. 0.5;
<0.0001 and 0.6 vs. 0.8;
< 0.01, respectively).
The prevalence of medically unexplained physical symptoms was low, but with a greater impact on some health services. This could represent an overload in medical costs.
Determinar la prevalencia de Síntomas Físicos Medicamente No Explicables y las características y uso de los servicios de salud entre el grupo de pacientes con Síntomas Físicos Medicamente No Explicables, y el grupo con otras enfermedades.
Estudio transversal, retroprospectivo y multicéntrico. Se incluyeron a 1,043 pacientes mayores de 18 años, en 30 unidades de atención primaria de una institución gubernamental en salud, en 11 estados de la República Mexicana, atendidos por 39 médicos familiares. Se estimó la prevalencia de Síntomas Físicos Medicamente No Explicables y se compararon los dos grupos con y sin estos síntomas, en cuanto al uso de medicamentos, estudios de laboratorio, de gabinete, incapacidades y referencias en los últimos seis meses. El grupo de Síntomas Físicos Medicamente No Explicables fue diagnosticado por el Patient Health Questionnaire (son los síntomas físicos más comúnmente referidos por estos pacientes en el primer nivel de atención), además de criterios diagnósticos de Reid
. Se excluyeron urgencias o con enfermedad terminal. Se utilizó prueba Chi cuadrada con
<0.05 para significancia estadística.
El 7.0% (73) se diagnosticó como Síntomas Físicos Medicamente No Explicables, la mayoría mujeres (91.8%); el síntoma predominante pertenece al sistema gastrointestinal con 76.7% (56). Este grupo demandó mayor uso de estudios de gabinete y referencias a otros servicios (media 1.1 vs. 0.5;
<0.0001 y 0.8 vs 0.6;
<0.01, respectivamente).
La prevalencia de Síntomas Físicos Medicamente No Explicables fue baja, pero con impacto significativo en el uso de algunos servicios de salud. Esto pudiera representar un mayor costo comparado con otro grupo de pacientes.
Objetivo:Determinar la prevalencia de Síntomas Físicos Medicamente No Explicables y las características y uso de los servicios de salud entre el grupo de pacientes con Síntomas Físicos Medicamente No ...Explicables, y el grupo con otras enfermedades.Métodos:Estudio transversal, retroprospectivo y multicéntrico. Se incluyeron a 1,043 pacientes mayores de 18 años, en 30 unidades de atención primaria de una institución gubernamental en salud, en 11 estados de la República Mexicana, atendidos por 39 médicos familiares. Se estimó la prevalencia de Síntomas Físicos Medicamente No Explicables y se compararon los dos grupos con y sin estos síntomas, en cuanto al uso de medicamentos, estudios de laboratorio, de gabinete, incapacidades y referencias en los últimos seis meses. El grupo de Síntomas Físicos Medicamente No Explicables fue diagnosticado por el Patient Health Questionnaire (son los síntomas físicos más comúnmente referidos por estos pacientes en el primer nivel de atención), además de criterios diagnósticos de Reid et al. Se excluyeron urgencias o con enfermedad terminal. Se utilizó prueba Chi cuadrada con p <0.05 para significancia estadística.Resultados:El 7.0% (73) se diagnosticó como Síntomas Físicos Medicamente No Explicables, la mayoría mujeres (91.8%); el síntoma predominante pertenece al sistema gastrointestinal con 76.7% (56). Este grupo demandó mayor uso de estudios de gabinete y referencias a otros servicios (media 1.1 vs. 0.5; p <0.0001 y 0.8 vs 0.6; p <0.01, respectivamente).Conclusiones:La prevalencia de Síntomas Físicos Medicamente No Explicables fue baja, pero con impacto significativo en el uso de algunos servicios de salud. Esto pudiera representar un mayor costo comparado con otro grupo de pacientes.
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