The natural history of 21-hydroxylase autoantibodies in autoimmune Addison's disease

Abstract

Background: The most common cause of primary adrenal failure (Addison's disease) in the Western world is autoimmunity characterized by autoantibodies against the steroidogenic enzyme 21-hydroxylase (CYP21A2, 21OH). Detection of 21OH-autoantibodies is currently used for aetiological diagnosis, but how levels of 21OH-autoantibodies vary over time is not known.

Setting: Samples from the national Norwegian Addison's Registry and Biobank established in 1996 (n = 711). Multi-parameter modelling of the course of 21OH-autoantibody indices over time.

Results: 21OH-autoantibody positivity is remarkably stable, and >90% of the patients are still positive 30 years after diagnosis. Even though the antibody levels decline with disease duration, it is only rarely that this downturn reaches negativity. 21OH-autoantibody indices are affected by age at diagnosis, sex, type of Addison's disease (isolated vs autoimmune polyendocrine syndrome type I or II) and HLA genotype.

Conclusion: 21OH-autoantibodies are reliable and robust markers for autoimmune Addison's disease, linked to HLA risk genotype. However, a negative test in patients with long disease duration does not exclude autoimmune aetiology.

Figure 1

Flow chart describing the patients in this study.

Figure 2

Individual variables’ impact on 21OH-Abs frequency and indices (A) Percentage of isolated PAI and APS-II patients positive for antibodies against 21OH (21OH-Abs) separated in groups according to disease duration at sampling. The statistical test was done with logistic regression analysis. (B) Percentage of isolated PAI and APS-II patients positive for 21OH-Abs sampled within 1 year of diagnosis in relation to age at diagnosis. Statistical analysis was done with logistic regression analysis. (C) 21OH-Abs-indicies in males and females. Percentage positive for each sex is shown inside the corresponding box. Statistical test for indices between the groups was achieved by a parametric t-test while statistical differences between the frequencies were done by a Pearson’s chi test. (D) 21OH-Abs indices stratified by HLA-risk groups given in Table 2 and percentage positives in each group. Statistical differences were calculated by ANOVA and Tukey’s test. (E) 21OH-Abs-indices stratified into phenotypic groups and disease duration at sampling; isolated PAI (black) and APS-II (red). (F) Percent positive for 21OH-Abs stratified to disease duration at sampling; isolated PAI (black) and APS-II (red). The dashed line (A, B and F) represents the mean positivity for autoantibodies against 21OH-Abs in the whole isolated, AAD autoimmune PAI and APS-II cohort. The dashed line (C and E) represents the mean indices of 21OH-Abs. The shaded area (C–E) in the lower part of the graph represent where the test gives negative results (sets the threshold for positivity). 95% CI is shown by vertical bars.

Figure 3

Estimated individual trajectories from mixed-effects longitudinal regression model for 21OH-Abs (n = 1287 observations from 277 individuals). The lines corresponds to individual patients. Includes data from patients with at least two samples. The thick lines show the predicted trajectory for a ‘typical’ patient (all random effects set to 0), that is a 40-year-old female with APS-II.

Figure 4

Course of 21OH-Abs in the 45 patients from the verification study (n = 389 samples) assayed at inclusion in the registry and in the verification study.