{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:47:40Z","timestamp":1790063260593,"version":"4.0.1"},"reference-count":32,"publisher":"The Endocrine Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,5,1]]},"abstract":"<jats:p>Context: Patients with adrenal cortex autoantibodies (ACA) without overt autoimmune Addison\u2019s disease (AAD) are at risk of adrenal failure.<\/jats:p><jats:p>Design: To assess the contribution of different clinical, immunological, genetic, and functional factors in the progression to AAD, we followed up 100 ACA-positive and 63 ACA-negative patients without AAD for a maximum of 21 yr (mean 6.0 yr, median 4.8). ACA were measured by immunofluorescence and 21-OH autoantibodies (Abs) by RIA. Adrenal function was assessed by measuring basal levels of cortisol, aldosterone, ACTH, renin activity, and cortisol response to ACTH. The risk of developing AAD was calculated using survival and multivariate analyses.<\/jats:p><jats:p>Results: AAD developed in 31 ACA-positive patients and one ACA-negative patient. The cumulative risk of disease in ACA-positive patients was 48.5% [95% confidence interval (CI) 40.8\u201356.1]. The cumulative risk was higher in children than adults (100 vs. 31.9%; P &amp;lt; 0.0001), males than females (68.6 vs. 42.7%; P = 0.006), patients with subclinical rather than normal adrenal function at entry (87.4 vs. 30.1%; P &amp;lt; 0.0001), patients with hypoparathyroidism and\/or candidiasis than patients with other autoimmune or nonautoimmune diseases (100 vs. 29.7%; P &amp;lt; 0.0001), and patients with high rather than low-medium ACA titers (62.8 vs. 41.2%; P = 0.12). The presence of human leukocyte antigen (HLA)-DRB1 did not appear to contribute to the prediction of AAD. Adjusted hazard ratios by Cox model for the development of AAD were 3.37 for males (CI 1.38\u20138.24), 5.23 for hypoparathyroidism and\/or candidiasis (CI 1.53\u201317.92), 3.33 for high antibody titers (CI 1.43\u20137.78), and 6.15 for impaired adrenal function at entry (CI 2.79\u201313.57).<\/jats:p><jats:p>Conclusions: These results were used to construct a risk algorithm for estimating the probability of developing AAD from the combination of gender, age, adrenal function, antibody titer, and associated autoimmune disorders at entry. The values of estimated risk could be used to decide appropriate follow-up intervals and future immunointervention strategies.<\/jats:p>","DOI":"10.1210\/jc.2005-0860","type":"journal-article","created":{"date-parts":[[2006,3,8]],"date-time":"2006-03-08T02:33:02Z","timestamp":1141785182000},"page":"1637-1645","source":"Crossref","is-referenced-by-count":106,"title":["Estimated Risk for Developing Autoimmune Addison\u2019s Disease in Patients with Adrenal Cortex Autoantibodies"],"prefix":"10.1210","volume":"91","author":[{"given":"Graziella","family":"Coco","sequence":"first","affiliation":[{"name":"Endocrine Unit (G.C., B.P., R.Z., F.M., C.B.) I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Dal Pra","sequence":"additional","affiliation":[{"name":"the 3rd Internal Medicine Unit (F.P., C.D.P.), Department of Medical Surgical Sciences, I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Presotto","sequence":"additional","affiliation":[{"name":"the 3rd Internal Medicine Unit (F.P., C.D.P.), Department of Medical Surgical Sciences, I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Paola","family":"Albergoni","sequence":"additional","affiliation":[{"name":"Blood Bank (M.P.A.), Padua General Hospital, I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Canova","sequence":"additional","affiliation":[{"name":"Department of Medicine and Public Health (C.C.), University of Padua Medical School, I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beniamino","family":"Pedini","sequence":"additional","affiliation":[{"name":"Endocrine Unit (G.C., B.P., R.Z., F.M., C.B.) I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Zanchetta","sequence":"additional","affiliation":[{"name":"Endocrine Unit (G.C., B.P., R.Z., F.M., C.B.) I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Chen","sequence":"additional","affiliation":[{"name":"FIRS Laboratories, RSR Ltd. (S.C., J.F., B.R.S.), Cardiff CF14 5DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadwiga","family":"Furmaniak","sequence":"additional","affiliation":[{"name":"FIRS Laboratories, RSR Ltd. (S.C., J.F., B.R.S.), Cardiff CF14 5DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Rees Smith","sequence":"additional","affiliation":[{"name":"FIRS Laboratories, RSR Ltd. (S.C., J.F., B.R.S.), Cardiff CF14 5DU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Mantero","sequence":"additional","affiliation":[{"name":"Endocrine Unit (G.C., B.P., R.Z., F.M., C.B.) I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Betterle","sequence":"additional","affiliation":[{"name":"Endocrine Unit (G.C., B.P., R.Z., F.M., C.B.) I-35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071621083358000_R1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1568-9972(03)00006-5","article-title":"The epidemiology of autoimmune diseases","volume":"2","author":"Cooper","year":"2003","journal-title":"Autoimmun Rev"},{"key":"2020071621083358000_R2","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/S0140-6736(03)13492-7","article-title":"Adrenal insufficiency","volume":"361","author":"Arlt","year":"2003","journal-title":"Lancet"},{"key":"2020071621083358000_R3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1210\/edrv.23.3.0466","article-title":"Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction","volume":"23","author":"Betterle","year":"2002","journal-title":"Endocr Rev"},{"key":"2020071621083358000_R4","first-page":"1440","article-title":"Autoimmune adrenal diseases\u2014a new sensitive assay for measurement of steroid 21-hydroxylase autoantibodies","volume":"82","author":"Tanaka","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R5","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.1365-2265.1982.tb00726.x","article-title":"Development of adrenocortical failure in non-addisonian patients with antibodies to adrenal cortex","volume":"16","author":"Scherbaum","year":"1982","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071621083358000_R6","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/S0140-6736(83)92695-8","article-title":"Complement-fixing adrenal autoantibodies as a marker for predicting onset of idiopathic Addison\u2019s disease","volume":"1","author":"Betterle","year":"1983","journal-title":"Lancet"},{"key":"2020071621083358000_R7","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1210\/jcem-64-3-494","article-title":"Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure","volume":"64","author":"Ahonen","year":"1987","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R8","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1677\/joe.0.1170467","article-title":"The natural history of adrenal function in autoimmune patients with adrenal autoantibodies","volume":"117","author":"Betterle","year":"1988","journal-title":"J Endocrinol"},{"key":"2020071621083358000_R9","first-page":"1002","article-title":"Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies","volume":"76","author":"De Bellis","year":"1993","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R10","first-page":"932","article-title":"I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison\u2019s disease","volume":"82","author":"Betterle","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R11","first-page":"939","article-title":"II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison\u2019s disease","volume":"82","author":"Betterle","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1006\/clin.1996.4277","article-title":"Steroid 21-hydroxylase autoantibodies in insulin-dependent diabetes mellitus","volume":"82","author":"Peterson","year":"1997","journal-title":"Clin Immunol Immunopathol"},{"key":"2020071621083358000_R13","first-page":"3507","article-title":"Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison\u2019s disease","volume":"83","author":"Laureti","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R14","first-page":"328","article-title":"DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison\u2019s disease","volume":"84","author":"Yu","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R15","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1136\/gut.48.3.378","article-title":"Induction of autoantibodies to the adrenal cortex and pancreatic islet cells by interferon \u03b1 therapy for chronic hepatitis C","volume":"48","author":"Wesche","year":"2001","journal-title":"Gut"},{"key":"2020071621083358000_R16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1210\/jc.2004-0874","article-title":"Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison\u2019s disease in a high-risk population","volume":"90","author":"Barker","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071621083358000_R17","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1161\/01.RES.28.5_Suppl_2.II-175","article-title":"Determination of plasma renin concentration by angiotensin I immunoassay: diagnostic import of a precise measurement of subnormal renin in hyperaldosteronism","volume":"20","author":"Stockigt","year":"1971","journal-title":"Circ Res"},{"key":"2020071621083358000_R18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1399-0039.1993.tb01991.x","article-title":"DR \u201clow resolution\u201d PCR-SSP typing\u2014a correction and an update","volume":"41","author":"Olerup","year":"1993","journal-title":"Tissue Antigens"},{"key":"2020071621083358000_R19","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1111\/j.1744-313X.1994.tb00217.x","article-title":"HLA-DQB1 \u201clow resolution\u201d typing by PCR amplication with sequence-specific primers (PCR-SSP)","volume":"21","author":"Aldener-Cannava\u0300 A., Olerup","year":"1994","journal-title":"Eur J Immunogenet"},{"key":"2020071621083358000_R20","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/0021-9681(58)90126-7","article-title":"Maximum utilization of the life table in analyzing survival","volume":"8","author":"Cutler","year":"1958","journal-title":"J Chronic Dis"},{"key":"2020071621083358000_R21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/bjc.1977.1","article-title":"Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples","volume":"35","author":"Peto","year":"1977","journal-title":"Br J Cancer"},{"key":"2020071621083358000_R22","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.2517-6161.1972.tb00899.x","article-title":"Regression model and life table analysis","volume":"34","author":"Cox","year":"1972","journal-title":"J R Stat Soc B"},{"key":"2020071621083358000_R23","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1080\/00031305.1983.10483087","article-title":"A leisurely look at the bootstrap, the jackknife, and cross-validation","volume":"37","author":"Efron","year":"1983","journal-title":"Am Stat"},{"key":"2020071621083358000_R24","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/sim.4780080702","article-title":"Bootstrap investigation of the stability of a Cox regression model","volume":"8","author":"Altman","year":"1989","journal-title":"Stat Med"},{"key":"2020071621083358000_R25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1365-2265.1995.tb01894.x","article-title":"The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey","volume":"43","author":"Vanderpump","year":"1995","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071621083358000_R26","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1056\/NEJMoa012350","article-title":"Effect of insulin in relatives of patients with type 1 diabetes mellitus","volume":"346","author":"Diabetes Prevention Trial-Type 1 Diabetes Study Group","year":"2002","journal-title":"N Engl J Med"},{"key":"2020071621083358000_R27","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0140-6736(90)90013-U","article-title":"Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes","volume":"1","author":"Bonifacio","year":"1990","journal-title":"Lancet"},{"key":"2020071621083358000_R28","doi-asserted-by":"crossref","first-page":"384","DOI":"10.2337\/diabetes.53.2.384","article-title":"Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics","volume":"53","author":"Achenbach","year":"2004","journal-title":"Diabetes"},{"key":"2020071621083358000_R29","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1056\/NEJM198008073030603","article-title":"Carbimazole and the autoimmune response in Graves\u2019 disease","volume":"303","author":"McGregor","year":"1980","journal-title":"N Engl J Med"},{"key":"2020071621083358000_R30","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1056\/NEJMra042972","article-title":"Antithyroid drugs","volume":"352","author":"Cooper","year":"2005","journal-title":"N Engl J Med"},{"key":"2020071621083358000_R31","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1046\/j.1365-2036.2003.01681.x","article-title":"Type 1 diabetes mellitus in patients with chronic hepatitis C before and after interferon therapy","volume":"18","author":"Fabris","year":"2003","journal-title":"Aliment Pharmacol Ther"},{"key":"2020071621083358000_R32","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1089\/105072503322238809","article-title":"Interferon-\u03b1 and autoimmune thyroid disease","volume":"13","author":"Prummel","year":"2003","journal-title":"Thyroid"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/5\/1637\/9265394\/jcem1637.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/5\/1637\/9265394\/jcem1637.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T23:18:02Z","timestamp":1736291882000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/91\/5\/1637\/2874213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,5,1]]},"references-count":32,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2006,5,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2005-0860","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,5,1]]}}}