A new risk score — combining orbital ultrasound and visual function tests — significantly predicted which patients with Graves disease would go on to develop clinically overt orbitopathy, with medium-high scores linked to a higher risk. But the test didn’t work as well in determining who was at low risk.

This kind of targeted, simple, noninvasive evaluation at the time of Graves disease diagnosis could identify a subgroup of patients at a significantly higher risk of developing overt orbitopathy, Giulia Lanzolla, MD, PhD, Department of Medical Sciences and Public Health, Endocrinology Unit, University of Cagliari and University Hospital of Cagliari, Cagliari, Italy, told Medscape Medical News.

“These patients likely warrant closer ocular follow-up,” noted Lanzolla. “Antithyroid drugs or thyroidectomy would probably be preferable to radioactive iodine” in this subgroup, “or, if radioiodine is necessary, corticosteroid prophylaxis should be considered even in the absence of traditional risk factors,” she added.

The results of the single-center study were published in The Journal of Clinical Endocrinology & Metabolism earlier this year.

Detecting ‘Silent’ Ocular Alterations

Orbitopathy involves swelling and bulging of the eye, often accompanied by light sensitivity, irritation, and double vision. An estimated 25%-40% of people with Graves disease develop the condition over time, the study authors noted.

The Functional and Morphological risk score (FUMO) was developed by Lanzolla and her colleagues at the University of Cagliari to help predict the likelihood of orbitopathy, in part by detecting “silent” ocular alterations via ultrasound in patients with Graves disease.

“Ultrasound identifies thickening of the extraocular rectus muscles and changes in echogenicity that aren’t yet clinically apparent before signs like proptosis, restricted motility, or overt diplopia appear,” Lanzolla explained.

The protocol used by the researchers classified normal muscles as < 4 mm, thickened as 4-6 mm, and very thickened as > 6 mm.

“These morphological changes can precede clinical signs by months, likely reflecting inflammation and tissue remodeling already underway in the orbit,” Lanzolla said.

Predictive Value of FUMO Scores

The researchers tested the FUMO model at the University of Cagliari from 2018 to 2024 on 160 patients with Graves disease but not clinical orbitopathy. Four patients in the study were lost by the follow-up period, for a total of 156 patients in the final analysis.

Five patients (3%) had the highest FUMO scores (between 5-6 and 7-8), and all of them were later diagnosed with moderate-to-severe orbitopathy.

Thirty-one patients (20%) had intermediate FUMO scores (3-4), 29 of whom were later diagnosed with orbitopathy; there were 16 mild cases and 13 moderate-to-severe cases.

A total of 107 patients (69%) had FUMO scores between 1 and 2. Of these, 65 patients were later diagnosed with orbitopathy: 58 were mild cases and seven were moderate-to-severe cases. 

Thirteen patients (8%) had the lowest FUMO score (0); only one was later diagnosed with a mild case of orbitopathy.

Overall, the FUMO score had a high positive predictive value of 0.96 but a low negative predictive value of 0.34.

That’s the reverse of the results seen with another model, known as PREDIGO, for which results were published in 2018. That model is based on clinical activity score, thyroid-stimulating hormone-binding inhibitory immunoglobulins, duration of hyperthyroid symptoms, and smoking status. PREDIGO was reported to have a positive predictive value of 0.28 and a negative predictive value of 0.91.

“In parallel, it would be valuable to test a unified model integrating the ocular parameters of FUMO with the serological/clinical parameters of PREDIGO,” Lanzolla said, thus combining the complementary strengths of the two approaches.

At this point, the PREDIGO screening approach hasn’t entered routine practice and isn’t explicitly recommended by current guidelines, she added. “I personally use it in my clinical practice, but I think it probably still remains more of a research/stratification tool in specialized centers than a standardized screening test.”

An important next step for the FUMO score would be external validation in multicenter, geographically diverse cohorts, Lanzolla said. The single-center study she and her co-authors conducted was done in Sardinia, which has a higher autoimmune disease prevalence than average, she noted.

Practical ‘Challenges’ for Clinical Practice

In an interview, Marius N. Stan, MD, endocrinologist and the director of the Thyroid Eye Disease Clinic at the Mayo Clinic in Rochester, Minnesota, said better tools to predict the risk for Graves orbitopathy would be helpful.

But the FUMO approach seems unlikely to be something widely adopted in practice, said Stan, who is also an author of the American Thyroid Association and the European Thyroid Association 2022 consensus statement on management of thyroid eye disease.

“I think the efforts are to be applauded,” he said of the work done by Lanzolla and her co-authors. “But from a practical perspective, I see the challenge.”

In the study, participants underwent fairly extensive ophthalmological exams, a resource that would be hard to secure for many patients, Stan said. “It is hard sometimes to get a clinical exam of patients with already existing thyroid eye disease.”

This approach might have potential in academic practice, “but I see it struggling to become part of a clinical practice,” he said.

The study was supported by funds from the University of Cagliari (Fondi di Ateneo 2016-2024).

The authors reported no relevant financial disclosures. Full disclosure information for the authors is available in the original study publication.