Outcomes of Patients With Graves Disease 25 Years After Initiating Antithyroid Drug Therapy

Abstract

Context: Graves disease (GD) is a leading cause of hyperthyroidism. Detailed investigations and predictors of long-term outcomes are missing.

Objective: This work aimed to investigate the outcomes in GD 25 years after initiating antithyroid drug treatment, including disease course, clinical and biochemical predictors of relapse, and quality of life.

Methods: A retrospective follow-up was conducted of GD patients that participated in a randomized trial from 1997 to 2001. Demographic and clinical data were obtained from medical records and questionnaires. Biobank samples were analyzed for inflammatory biomarkers and compared with age- and sex-matched healthy individuals.

Results: We included 83% (182/218) of the patients from the original study. At the end of follow-up, normal thyroid function was achieved in 34%. The remaining had either active disease (1%), spontaneous hypothyroidism (13%), or had undergone ablative treatment with radioiodine (40%) or thyroidectomy (13%). Age younger than or equal to 40 years, thyroid eye disease (TED), smoking, and elevated levels of interleukin 6 and tumor necrosis factor receptor superfamily member 9 (TNFRS9) increased the risk of relapsing disease (odds ratio 3.22; 2.26; 2.21; 1.99; 2.36). At the end of treatment, CD40 was lower in patients who maintained normal thyroid function (P = .04). At the end of follow-up, 47% had one or more autoimmune diseases, including vitamin B12 deficiency (26%) and rheumatoid arthritis (5%). GD patients who developed hypothyroidism had reduced quality of life.

Conclusion: Careful lifelong monitoring is indicated to detect recurrence, hypothyroidism, and other autoimmune diseases. Long-term ATD treatment emerges as a beneficial first-line treatment option, especially in patients with young age at onset or presence of TED.

Keywords: Graves disease; autoimmunity; hypothyroidism; long-term follow up; quality of life; thyroid eye disease.

Figure 1.

Flowchart of the study population. Showing outcome in the original study 2 years after discontinuation of antithyroid drugs (ATD) therapy and received treatment as of 2022. Twenty-two patients did not complete the treatment or follow-up time in the original study due to pregnancy, side effects of ATD, development of spontaneous hypothyroidism, change in residence, wish for ablative treatment, or high disease activity with indication for extended treatment duration with ATD or ablative treatment during the study period.

Figure 2.

A, Volcano plot comparing healthy individuals and patients with Graves disease (GD) at baseline. Sixty-one out of 92 biomarkers show statistically significant difference between the 2 groups. B, Principal component analysis (PCA) scores with all included samples, showing healthy controls in light blue and samples from GD patients at baseline (dark blue), 3 months (red), and 12 months (green). The separate effect of all the normalized protein expression (NPX) biomarkers are compressed into single variables called principal components (PCs). The loading plot for the group analysis is shown in the supplementary material (Supplementary Fig. S2). C and D, Longitudinal changes in inflammation during treatment in all patients and between treatment groups. Score plots showing the development of inflammation profiles in all patients C, over time and D, grouped by antithyroid drug regimen from multivariate repeated-measures analysis of variance simultaneous component analyses. The separate effects over time of all the NPX biomarkers are compressed into PCs. PC1 explains most of the variation in biomarker development over time (88%). A high PC1 score (on the y-axis) indicates higher concentrations of biomarkers with positive loadings and lower concentrations of biomarkers with negative loadings. Vertical bars represent error bars from bootstrapping.

Figure 3.

Box plot for value of TNFRSF9 at baseline, after 3 months of antithyroid drug (ATD) treatment and at end of therapy (12 months) compared with healthy controls (top), and CD40 at the end of treatment (12 months) in patients (n = 9) that had preserved thyroid function compared to patients that had persisting or relapsing disease that led to ablative treatment/hypothyroidism before the end of follow-up (n = 18). One patient with missing data and one patient with hypothyroidism of unknown cause were excluded from the analysis. The results are reported as relative quantification between samples by a unit named normalized protein expression (NPX). As NPX values are in log2 scale, a difference in one NPX equals a doubling in protein concentration.

Figure 4.

Mean Thyroid-Related Patient-Reported Outcome (ThyPRO) questionnaire scale scores in Graves disease (GD) patients treated with radioiodine (RAI) or surgery, compared to GD patients with spontaneous hypothyroidism, antithyroid drug (ATD)-treated GD patients, and the general population. Scale score ranges from 0 to 100, with higher score indicating more symptoms or effect. Items in 4 scales (impaired social life, impaired daily life, impaired sex life, and cosmetic complaints) are asked with attribution to thyroid disease and cannot be answered by respondents from the general population.