Smoking Worsens Treatment Response to Teprotumumab in Thyroid Eye Disease

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Smokers with TED showed less improvement in diplopia, proptosis, and overall clinical activity score compared to non-smokers.

Smoking is a modifiable risk factor which signifies a worse response to thyroid eye disease (TED) treatment with teprotumumab, according to new findings.1

In a retrospective cohort study, an investigative team from the University of Kansas hypothesized that the efficacy of teprotumumab would be reduced in patients with TED who smoke compared to patients with TED who do not smoke. Confirming their hypothesis, the data indicated smokers with TED showed less improvement in diplopia, proptosis, and overall clinical activity score (CAS).

“Aligned with our hypothesis, smokers demonstrated poorer response to teprotumumab treatment with regards to reduction of proptosis,” wrote the investigative team, led by Jason A. Sokol, MD.1

A common manifestation of Graves’ hyperthyroidism, TED can be classified as type 1 disease which affects orbital fat without diplopia, or type 2 disease which is defined as diplopia within 20 degrees of fixation with restrictive myopathy. Risk factors for TED include both genetic predisposition and environmental influences, with smoking as a consistent risk factor linked to the development and worsening of TED, according to Sokol and colleagues

A monoclonal antibody directed against insulin-like growth factor 1 receptors (IGF-1R), teprotumumab has shown significant improvements in proptosis, CAS, diplopia, and quality of life compared to placebo in the treatment of TED. However, the effectiveness of teprotumumab treatment in smokers with TED remains unknown, according to investigators. Thus, the investigative team performed a single-center, retrospective review of patients with TED treated with teprotumumab, who had started or completed therapy at the time of data collection.

A total of 34 patients with TED who were scheduled to begin teprotumumab were reviewed and 16 patients who began or completed treatment during the study period were included in the initial comparisons. Ultimately, 15 patients were included in the statistical analysis, in which 6 patients (40%) were current or former smokers. All smokers in the study had type 2 TED and all non-smokers had type 1 disease, but there was no significant difference between smokers and non-smokers in baseline variables, including sex, thyroid stimulating hormone, thyroxine, triiodothyronine, and number of infusions completed.

The primary outcome assessed was change in CAS and the mean reduction in CAS was 3.7±2in smokers, compared to 4.9±2.2 in non-smokers. Visual acuity (VA) outcomes showed no significant difference between groups, with all smokers having VA of 20/25 or better after teprotumumab treatment.

In the analysis, data showed proptosis was reduced by 1.2±1.2 in the right eye and by 1.75±0.5 in the left eye in smokers versus by 4±1.4 in the right eye and 4.2±1.8 in the left eye in non-smokers. Investigators noted this reduction was statistically significant.

Meanwhile, changes in diplopia were not significant between the groups, but the data indicated it was more likely to be present initially in smokers compared to non-smokers. Of the initial 16 patients, 6 of 7 (85.7%) smokers had diplopia prior to treatment, compared to 6 of 9 (66.6%) non-smokers. Treatment led to resolution of diplopia in one smoker and one non-smoker, while one smoker without diplopia prior to treatment developed diplopia after treatment.

Investigators noted the lack of stratification based on status as current smoker or ever smoker may have altered the results, as smoking may have a dose–dependent effect on teprotumumab outcomes. As a result, Sokol and colleagues suggest the need for more extensive research in order to assess the long-term impact of smoking on teprotumumab efficacy.

“Despite these limitations, smoking cessation resources and counseling are crucial for those diagnosed with TED to prevent further disease progression and to prevent development of TED in those with thyroid dysfunction,” they wrote.1


  1. O'Dell JM, Mussatto CC, Chu RL, Al-Sabbagh MQ, Timoney PJ, Sokol JA. Effects of Smoking on Outcomes of Thyroid Eye Disease Treated with Teprotumumab: A Retrospective Cohort Study. Kans J Med. 2023;16:62-64. Published 2023 Mar 15. doi:10.17161/kjm.vol16.18940