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Corrado Betterle, Riccardo Scarpa, Silvia Garelli, Luca Morlin, Francesca Lazzarotto, Fabio Presotto, Graziella Coco, Stefano Masiero, Anna Parolo, Maria Paola Albergoni, Roberta Favero, Susi Barollo, Monica Salvà, Daniela Basso, Shu Chen, Bernard Rees Smith, Jadwiga Furmaniak and Franco Mantero

Objective

Addison's disease (AD) is a rare endocrine condition.

Design

We aimed to evaluate clinical, immunologic, adrenal imaging, and genetic features in 633 Italian patients with AD followed up since 1967.

Methods

Adrenal cortex autoantibodies, presence of other autoimmune and nonautoimmune diseases, nonadrenal autoantibodies, adrenal imaging, and genetic profile for HLA-DRB1 and AIRE were analyzed.

Results

A total of 492 (77.7%) patients were found to be affected by autoimmune AD (A-AD), 57 (9%) tuberculous AD, 29 (4.6%) genetic-associated AD, 10 (1.6%) adrenal cancer, six (0.94%) post-surgical AD, four (0.6%) vascular disorder-related AD, three (0.5%) post-infectious AD, and 32 (5.1%) were defined as idiopathic. Adrenal cortex antibodies were detected in the vast majority (88–100%) of patients with recent onset A-AD, but in none of those with nonautoimmune AD. Adrenal imaging revealed normal/atrophic glands in all A-AD patients: 88% of patients with A-AD had other clinical or subclinical autoimmune diseases or were positive for nonadrenal autoantibodies.

Based on the coexistence of other autoimmune disorders, 65.6% of patients with A-AD were found to have type 2 autoimmune polyendocrine syndrome (APS2), 14.4% have APS1, and 8.5% have APS4. Class II HLA alleles DRB1*03 and DRB1*04 were increased, and DRB1*01, DRB1*07, DRB1*013 were reduced in APS2 patients when compared with controls. Of the patients with APS1, 96% were revealed to have AIRE gene mutations.

Conclusions

A-AD is the most prevalent form of adrenal insufficiency in Italy, and ∼90% of the patients are adrenal autoantibody-positive at the onset. Assessment of patients with A-AD for the presence of other autoimmune diseases should be helpful in monitoring and diagnosing APS types 1, 2, or 4 and improving patients' care.

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Lara Naletto, Annachiara Frigo, Filippo Ceccato, Chiara Sabbadin, Riccardo Scarpa, Fabio Presotto, Miriam Dalla Costa, Diego Faggian, Mario Plebani, Simona Censi, Jacopo Manso, Jadwiga Furmaniak, Shu Chen, Bernard Rees Smith, Stefano Masiero, Francesca Pigliaru, Marco Boscaro, Carla Scaroni and Corrado Betterle

Background. Adrenal cortex autoantibodies (ACA) and/or 21-hydroxylase (21OHAb) are markers of autoimmune Addison’s disease (AAD) and progression to overt AAD. The reported cumulative risk of developing AAD varies from 0-90% in different studies.

Aim To assess the predictive value of different parameters for progression towards AAD in ACA and/or 21OHAb-positive patients with autoimmune polyendocrine syndromes (APS).

Materials and Methods 29 patients with APS-1 and 114 patients with APS-2 or APS-4, were followed-up for a median of 10 years (range 6 months-33 years) and assessed by ACTH test. The risk of AAD was estimated according to age, gender, stage of adrenal dysfunction, associated diseases and antibody titer. Univariate and multivariate Cox proportional hazard models were used for statistical analysis.

Results The cumulative risk (CR) of developing AAD was higher in APS-1 patients (94.2%) compared to patients with APS-2/APS-4 (38.7%). The CR was high in both males and females with APS-1 patients, while in patients with APS-2/APS-4 it was high only in males. Stage 1 (increased plasma renin) for patients with APS-1 and Stage 2 (no response of cortisol to ACTH-test) for patients with APS-2/APS-4 were established as the points of no return in the progression to AAD. Adjusted hazard ratio analyses by multivariate Cox model for AAD showed that gender, diseases, adrenal function were independent risk factors for developing clinical AAD. The risk of developing clinical AAD appears to subside after 19 years of follow up.

Conclusions A model for estimating the probability to survive free of AAD has been developed and should be a useful tool in designing appropriate follow-up intervals and future therapeutic strategies.