Study of predicting remission in Graves’ disease

Abstract

Background Graves’ disease (GD) is an autoimmune condition characterised by the presence of thyroid receptor auto-antibodies (TRAbs) that stimulate the thyroid gland to produce excessive thyroid hormones (hyperthyroidism). Only around half of adults will achieve remission of their GD after a course of antithyroid drugs (ATD), and there is no reliable method to accurately predict which patients will relapse their GD. The aim of the prospective observational study described in this thesis was to explore biomarkers of outcome in GD in a cohort at the time of ATD withdrawal. Method 65 patients with GD who had their ATD stopped after completing at least a 12–18 month course were followed up for 12 months, at which time they were categorised as having relapsed or remitted. Clinical, biochemical, and immunological studies were investigated at baseline and 6-10 weeks later. These factors and CD19+ B cell gene expression were assessed for their ability to predict outcome of GD. Results 16/65 (25%) relapsed their GD within 12 months after ATD withdrawal. TRAb and sTACI (soluble transmembrane activator and calcium modulator and cyclophilin ligand interactor) both proved to be good baseline biomarkers of GD relapse (OR 3.3; 95% CI 1.5-9.9 (TRAb), OR 2.3; 95% CI 1.3-4.6 (sTACI)). Investigation of the functional and biological characteristics of differentially expressed genes revealed an environment of inflammation and oxidative stress which may precipitate GD relapse. A 5-variable predictive model that included TRAb, sTACI and 3 genetic markers was developed that provided good predictive value for differentiating relapse and remission patients (ROCAUC = 0.99; 95% CI 0.96-1.0). Conclusions This study provides insight into potential humoral immunopathological pathways of GD relapse and reveals genetic and immunological B-cell biomarkers of outcome. Validation of these biomarkers in predicting relapse and translation to clinical practice would help guide timing of ATD withdrawal and assist in the formation of personalised therapeutic strategies.