Early Biochemical Response to Antithyroid Drugs in Graves’ Disease: The Role of Initial Dosing

Introduction: Optimal initial antithyroid drugs (ATD) dosing may achieve rapid improvement in thyroid hormone levels while minimizing risk of adverse events. As ATD have become the most common first line therapy for the treatment of Graves’ disease (GD), we examined trends over time in initial ATD dosing, and the association between guideline-based ATD dosing with time to normalization of FT4 and frequency of adverse events. Methods: This is a single cohort retrospective study in Mayo Clinic, Rochester, MN. We identified adults (≥18 years old) diagnosed with new onset GD between January 1, 2002-December 31, 2019 treated with at least 14 days of ATD and with available initial follow up data within 3 months prior to a dose change. Propylthiouracil (PTU) doses were converted to Methimazole (MMI) equivalents at 10:1 ratio. Guideline concordant care was defined as initial ATD dosed based on 2016 American Thyroid Association guidelines (i.e. 5-10 mg for presenting FT4 between >1.7-2.55 ng/dL, 10-20 mg for 2.56-3.40 ng/dL, and 30-40 mg for 3.41 ng/dL and above). Based on the first follow up FT4 values, patients were grouped into categories of: normal range (FT4 0.9-1.7 ng/dL) and under treated (FT4 >1.7 ng/dL). Results: 398 patients were included; mean (SD) age was 49 years (16.6), and 75% were women. Mean initial (SD) Free T4 value was 3.9 ng/dL (2.8), with patients treated with ATD at mean (SD) starting dose of 21.9 mg (13.3) MMI equivalent. Over time there was a decrease in the starting ATD dose from 30 mg MMI equivalent in 2002-2004 to 20 mg in 2017-2019, despite steady presenting FT4 values (2.7 ng/dL in 2002-2005 and 3.1 ng/dL in 2017-2019). In the subset of 340 patients with overt hyperthyroidism, 181 (53%) received guideline concordant (GC) dosing. Patients receiving GC care had a higher initial FT4 (4.9 vs. 3.6 ng/dL, p=0.002), larger goiters (40 vs. 30 g, p<0.001) and higher initial ATD mean dose (SD) 25 mg (15.7) vs. 21.3 mg (9.9), p= 0.05. However at follow up (median 32 days vs 35 days respectively), both groups had similar proportion of patients with normal FT4 values (43% vs. 42%, p=0.79); undertreated patients (45% vs. 45%, p=0.99) and frequency of adverse events (4% vs. 6%, p=0.40). Conclusion: The initial dose of ATD for the treatment of GD has decreased over the past 2 decades. Most clinicians initiate ATD at a dose concordant to guidelines. Despite this, a significant proportion of patients have persistent hyperthyroidism on initial follow up. In light of evidence of risks associated with duration of hyperthyroidism, strategies to improve optimization of initial dosing are needed. Pending further subgroup analysis by presenting FT4 severity, these preliminary results suggest and approach factoring other variables apart from guideline based initial ATD dose is needed to optimize response. Our data will be utilized to pilot an individualized, patient specific predictive model to guide initial dosing to this end.