The natural history of autoimmune Addison’s disease from the detection of autoantibodies to development of the disease: a long-term follow-up study on 143 patients

in European Journal of Endocrinology
Correspondence should be addressed to C Betterle; Email: corrado.betterle@unipd.it
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Background

Adrenal cortex autoantibodies (ACAs) 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 to 90% in different studies.

Aim

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

Materials and methods

Twenty-nine 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 to 33 years) and were assessed using 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%) than in patients with APS-2/APS-4 (38.7%). The CR was high in both male and female 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 and 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.

 

     European Society of Endocrinology

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    (A and B) Assessment of adrenocortical function at entry into the study and at the end of follow-up in ACA/21OHAb-positive patients with APS-1 or APS-2/APS-4.

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    (A, B, C, D, E and F) Kaplan–Meier analysis of ACA/21OHAb-positive patients with the probability to survive free from overt AAD.

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    (A, B, C, D, E and F) Graphic model for estimating the probability to survive free of AAD for ACA/21OHAb-positive patients on the basis of the three independent risk factors: gender (left column for females and right column for males), coexistence of autoimmune diseases (APS-1, APS-2, APS-4) and stages of adrenal dysfunction (0, 1, 2) at the start of follow-up.

References

  • 1

    OelkersW. Adrenal insufficiency. New England Journal of Medicine 1996 335 12061212. (https://doi.org/10.1056/NEJM199610173351607)

  • 2

    BetterleCDal PraCManteroFZanchettaR. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocrine Review 2002 23 327364. (https://doi.org/10.1210/edrv.23.3.0466)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    CharmandariENicolaidesNCChrousosGP. Adrenal insufficiency. Lancet 2014 383 21522167. (https://doi.org/10.1016/S0140-6736(13)61684-0)

  • 4

    OlafssonASSigurjonsdottirHA. Increasing prevalence of Addison’s disease. Results from a Nationwide study. Endocrine Practice 2016 22 3035. (https://doi.org/10.4158/EP15754.OR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    BetterleCScarpaRGarelliSMorlinLLazzarottoFPresottoFCocoGMasieroSParoloAAlbergoniMP et al. Addison’s disease: a survey on 633 patients in Padova. European Journal of Endocrinology 2013 169 773784. (https://doi.org/10.1530/EJE-13-0528)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    EisenbarthGSGottliebPA. Autoimmune polyendocrine syndromes. New England Journal Medicine 2004 350 20682079. (https://doi.org/10.1056/NEJMra030158)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    HusebyeESAndersonMSKampeO. Autoimmune polyendocrine syndrome. New England Journal of Medicine 2018 378 11321141. (https://doi.org/10.1056/NEJMra1713301)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    PerheentupaJ. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Journal of Clinical Endocrinology and Metabolism 2006 91 28432845.

  • 9

    OrlovaEMSozaevaLSKarevaMAOftedalBEWolffASBBreivikLZakharovaEYIvanovaONKämpeODedovII et al. Expanding the phenotypic and genotypic landscape of autoimmune polyendocrine syndrome type 1. Journal of Clinical Endocrinology and Metabolism 2017 102 35463556. (https://doi.org/10.1210/jc.2017-00139)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    BlizzardRMKyleMAChandlerRWHungW. Adrenal antibodies in Addison’s disease. Lancet 1962 2 901903. (https://doi.org/10.1016/S0140-6736(62)90681-5)

  • 11

    BetterleCCocoGZanchettaR. Adrenal cortex autoantibodies in subjects with normal adrenal function. Best Practice and Research Clinical Endocrinology and Metabolism 2005 19 8589. (https://doi.org/10.1016/j.beem.2004.11.008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    WinqvistOKarlssonFAKampeO. 21-Hydroxylase, a major autoantigen in idiopathic Addison’s disease. Lancet 1992 339 15591562. (https://doi.org/10.1016/0140-6736(92)91829-W)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Baumann AntczakAWedlockNBednarekJKisoYKrishnanHFowlerSRees SmithBFurmaniakJ. Autoimmune Addison’s disease and 21-hydroxylase. Lancet 1992 340 429430. (https://doi.org/10.1016/0140-6736(92)91513-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    BetterleCVolpatoMRees SmithBFurmaniakJChenSZanchettaRGreggioNAPediniBBoscaroMPresottoF. II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison’s disease. Journal of Clinical Endocrinology and Metabolism 1997 82 939942. (https://doi.org/10.1210/jcem.82.3.3849)

    • Search Google Scholar
    • Export Citation
  • 15

    BetterleCVolpatoMRees SmithBFurmaniakJChenSGreggioNASanzariMTedescoFPediniBBoscaroM et al. I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ specific autoimmune diseases: markers of low progression to clinical Addison’s disease. Journal of Clinical Endocrinology and Metabolism 1997 82 932938. (https://doi.org/10.1210/jcem.82.3.3819)

    • Search Google Scholar
    • Export Citation
  • 16

    FalorniALauretiSNikoshkovAPicchioMLHallengrenBVandewalleCLGorusFKTortoioliCLuthmanHBrunettiP et al. 21-Hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison’s disease. Belgian Diabetes Registry. Clinical and Experimental Immunology 1997 107 341346. (https://doi.org/10.1111/j.1365-2249.1997.262-ce1153.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    YuLBrewerKWGatesSWuAWangTBabuSRGottliebPAFreedBMNobleJErlichHA et al. DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison’s disease. Journal of Clinical Endocrinology and Metabolism 1999 84 328335. (https://doi.org/10.1210/jcem.84.1.5414)

    • Search Google Scholar
    • Export Citation
  • 18

    PetersonPSalmiHHyötyHMiettinenAIlonenJReijonenHKnipMAkerblomHKKrohnK. Steroid 21-hydroxylase autoantibodies in insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. Clinical Immunology and Immunopathology 1997 82 3742. (https://doi.org/10.1006/clin.1996.4277)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    BarkerJMIdeAHostetlerCYuLMiaoDFainPREisenbarthGSGottliebPA. Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison’s disease in a high-risk population. Journal of Clinical Endocrinology and Metabolism 2005 90 128134. (https://doi.org/10.1210/jc.2004-0874)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    BakerPRNanduriPGottliebPAYuLKlingensmithGJEisenbarthGSBarkerJM. Predicting the onset of Addison’s disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies. Clinical Endocrinology 2012 76 617624. (https://doi.org/10.1111/j.1365-2265.2011.04276.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Del Pilar LarosaMChenSSteinmausNMacraeHGuoLMasieroSGarelliSDalla CostaMBossowskiAFurmaniakJ et al. A new ELISA for autoantibodies to steroid 21-hydroxylase. Clinical Chemistry and Laboratory Medicine 2018 56 933938. (https://doi.org/10.1515/cclm-2017-0456)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    BetterleCZanetteFZanchettaRPediniBTrevisanAManteroFRigonF. Complement-fixing adrenal autoantibodies as a marker for predicting onset of idiopathic Addison’s disease. Lancet 1983 1 12381241. (https://doi.org/10.1016/S0140-6736(83)92695-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    AhonenPMiettinenAPerheentupaJ. Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. Journal of Clinical Endocrinology and Metabolism 1987 64 494500. (https://doi.org/10.1210/jcem-64-3-494)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    BetterleCScaliciCPresottoFPediniBMoroLRigonFManteroF. The natural history of adrenal function in autoimmune patients with adrenal autoantibodies. Journal of Endocrinology 1988 117 467475. (https://doi.org/10.1677/joe.0.1170467)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    LauretiSDe BellisAMMuccitelliVICalcinaroFBizzaroARossiRBellastellaASanteusanioFFalorniA. Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison’s disease. Journal of Clinical Endocrinology and Metabolism 1998 83 35073511. (https://doi.org/10.1210/jcem.83.10.5149)

    • Search Google Scholar
    • Export Citation
  • 26

    CocoGDal PraCPresottoFAlbergoniMPCanovaCPediniBZanchettaRChenSFurmaniakJRees SmithB et al. Estimated risk for developing autoimmune Addison’s disease in patients with adrenal cortex autoantibodies. Journal of Clinical Endocrinology and Metabolism 2006 91 16371645. (https://doi.org/10.1210/jc.2005-0860)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    EasonRJCroxonMSPerryMCSomerfieldSD. Addison’s disease, adrenal autoantibodies and computerized adrenal tomography. New Zealand Medical Journal 1982 95 569573.

    • Search Google Scholar
    • Export Citation
  • 28

    BetterleCGarelliSPresottoFFurmaniakJ. From appearance of adrenal autoantibodies to clinical symptoms of Addison’s disease: natural history. Frontiers of Hormonal Research 2016 46 133145. (https://doi.org/10.1159/000443872)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    CervatoSMarinielloBLazzarottoFMorlinLZanchettaRRadettiGDe LucaFValenziseMGiordanoRRizzoD et al. Evaluation of these autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and in their relatives. Clinical Endocrinology 2009 70 421428. (https://doi.org/10.1111/j.1365-2265.2008.03318.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    De BellisABizzarroARossiRPaglionicoVACriscuoloTLombardiGBellastellaA. Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. Journal of Clinical Endocrinology and Metabolism 1993 76 10021007. (https://doi.org/10.1210/jcem.76.4.8473373)

    • Search Google Scholar
    • Export Citation
  • 31

    De BellisAMFalorniALauretiSPerrinoSCoronellaCForiniFBizzarroEBizzarroAAbbateGBellastellaA. Time course of 21-hydroxylase antibodies and long-term remission of subclinical autoimmune adrenalitis after corticosteroid therapy: case report. Journal of Clinical Endocrinology and Metabolism 2001 86 675678. (https://doi.org/10.1210/jcem.86.2.7212)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    MansoJPezzaniRScarpaRGalloNBetterleC. The natural history of autoimmune Addison’s disease with a non-classical presentation: a case report and review of literature. Clinical Chemistry and Laboratory Medicine 2018 56 896900. (https://doi.org/10.1515/cclm-2017-1108)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    GambelungheGFalorniAGhaderiMLauretiSTortoioliCSanteusanioFBrunettiPSanjeeviCB. Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison’s disease. Journal of Clinical Endocrinology and Metabolism 1999 84 37013707. (https://doi.org/10.1210/jcem.84.10.6069)

    • Search Google Scholar
    • Export Citation

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