Rena Pollack

Clinically significant liver enzyme elevation is a recognized adverse effect of antithyroid drugs (ATDs) and often necessitates treatment discontinuation and switching to an alternative agent. Using TriNetX, we conducted a retrospective cohort study of patients with hyperthyroidism who initiated methimazole/carbimazole (MMI) or propylthiouracil (PTU), developed significant liver enzyme elevation within 4 months, and switched to the alternate ATD within 12 months. Baseline characteristics were indexed to the initial prescription, and outcomes were assessed for 120 days following the second prescription. The cohort included 276 patients who switched from MMI to PTU and 82 patients who switched from PTU to MMI. Significant liver enzyme elevation occurred in 111/276 (40%) and 25/82 (30%) of patients, respectively. Hepatocellular-pattern elevation occurred in 48/276 (17%) and 13/82 (16%), while cholestatic-pattern elevation occurred in 91/276 (33%) and 15/82 (18%). These findings demonstrate that significant liver injury after ATD switching is frequent but not inevitable and occurs at comparable rates across switch groups, underscoring the need for close biochemical monitoring and individualized treatment decisions.

Background: Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are widely used for type 2 diabetes (T2DM) and obesity, but their potential association with thyroid cancer remains a concern. This study assessed thyroid cancer risk with long‐term GLP‐1RA use in a large real‐world cohort. Methods: We conducted a propensity score matched cohort study using electronic health records from TriNetX, including 89,646 adults with T2DM who initiated GLP‐1RA therapy between 2014 and 2020, and demonstrated continued use for at least 1 year. Active comparator controls included users of insulin, metformin, sodium‐glucose transporter‐2 inhibitors, dipeptidyl peptidase‐4 inhibitors, sulfonylureas, and thiazolidinediones. The primary outcome was the incidence of thyroid cancer. Results: During a median follow‐up of 4.5 ± 2.3 years, GLP‐1RA use was not associated with an increased risk of thyroid cancer compared with any of the other antidiabetic medications. As expected, GLP‐1RA use was associated with a greater reduction in HbA1c levels, while the negative control outcome remained unaffected. Findings remained consistent across subgroups stratified by sex, age, obesity‐status, glycaemic‐control, and GLP‐1RA type and in multiple sensitivity analyses. Conclusions: In this large real‐world cohort study, long‐term GLP‐1RA use was not associated with an increased risk of thyroid cancer. These findings provide reassurance for the safety of GLP‐1RAs and support their continued evidence‐based use in clinical practice.

Romosozumab is a potent treatment for osteoporosis, with significant effects on bone density and fracture prevention. This study evaluated the cardiovascular safety of romosozumab in a real-world cohort of postmenopausal women at high fracture risk. We retrospectively evaluated postmenopausal women who initiated treatment with romosozumab between January 1, 2020, and June 30, 2023. We examined the occurrence of a major adverse cardiovascular event (MACE) across two distinct segments during the treatment period and after its conclusion. After applying inclusion and exclusion criteria, 847 women were followed for a median of 729 days (IQR: 445-1060). The incidence rate of MACE was 24.0 (95% CI 17.7-32.5) per 1000 person-years during the study period. The change in the rate of MACE from 0-90 days and 90-365 days post-treatment initiation was 0.04 and 0.06 events per 1000 days, respectively. The difference in the rate between these intervals was not statistically significant (p = .09). After 1 yr of treatment, the slope of MACE increased to 0.10, differing significantly from the preceding 12 mo on treatment (p<.001). The incidence of MACE was higher in those with a background of previous cardiovascular disease or diabetes at all timepoints, as expected. The consistency in event rates during treatment suggests that romosozumab is not associated with an increase in MACE in postmenopausal women. This finding challenges reports suggesting an increase in cardiovascular events within the first year of romosozumab treatment.

Ami Schattner, MD, Shilo Voichanski, MD, Rena Pollack, MD, Livnat Uliel, MD; Euthyroid Graves’ Ophthalmopathy, QJM: An International Journal of Medicine, , hcad

Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.8, FDR < 0.05). Only 35 DEG were identified with αPD-L1, and we therefore focused on the αPD-1 group alone. Ingenuity Pathway Analysis revealed that of 952 DEGs with αPD-1 treatment, 362 were associated with functions of cell death and survival, with predicated activation of pathways for apoptosis and necrosis (Z = 2.89 and Z = 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z = −6.22 and Z = −6.45, respectively). Compared to previously published datasets of interleukin-1β and interferon γ-treated human thyroid cells, apoptosis pathways were similarly activated. However, unique changes related to organ inflammation and upstream regulation by cytokines were observed. Our data suggest that there are unique changes in gene expression in the thyroid associated with αPD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.

Context Obesity is a pro-inflammatory metabolic state that may play a role in the development of immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy. Objective To characterize the association between body mass index (BMI) and thyroid irAEs. Methods We performed a single center, retrospective analysis of 185 cancer patients treated with anti-PD-1/L1 from January 2014 to December 2018. Patients with normal thyroid function at baseline and available BMI were included. Main outcome measures The primary endpoint was difference in BMI in patients who developed overt thyroid dysfunction vs. remained euthyroid following anti-PD-1/L1 initiation. Additional endpoints included any (overt or subclinical) thyroid dysfunction, overt thyrotoxicosis or overt hypothyroidism, and time to development of dysfunction according to BMI. Results Any thyroid dysfunction developed in 72 (38.9%) patients and 41 (22.1%) developed overt thyroid dysfunction. Mean BMI was higher in those with overt thyroid dysfunction vs. euthyroid (27.3±6.0 vs. 24.9±4.5, p=0.03). Development of overt thyrotoxicosis vs. remaining euthyroid was associated with higher BMI (28.9±5.9 vs. 24.9±4.5; p<0.01), whereas overt hypothyroidism was not (26.7±5.5 vs. 24.9±4.5, p=0.10). Overt thyrotoxicosis developed within 57.5 (IQR 31.8-78.8) days of treatment in the low-normal BMI group, 38.0 (IQR 26.8-40.5) days in the overweight and 23.0 (IQR 21.0-28.0) days in the obese group (p=0.02). Conclusions Patients treated with PD-1/L1 inhibitors were more likely to develop thyroid irAEs, specifically overt thyrotoxicosis, with increasing BMI. Overt thyrotoxicosis occurred earlier in obese vs. leaner patients. These data highlight the complex interplay between obesity and immune response in ICI-treated patients.