Factors Predicting Relapse of Graves’ Disease

In an effort to tease out possible factors that might predict relapse, a team of researchers from the University of Buffalo conducted a meta-analysis of studies published over nearly 4 decades, encompassing more than 4000 patients treated for hyperthyroid disease.

With Elena Christofides, MD, FACE

While nearly half of patients who take antithyroid medications for their Graves’ disease go into remission, many others will relapse. In addition to the adverse side effects that commonly result from drug treatment, patients who relapse also face increased risks associated with the side effects of further treatment, be it radioactive iodine or surgery, typical next steps in the management of Graves’ disease.

Having non-genetic markers indicative of elevated risk of relapse following discontinuation of antithyroid medications would aid clinicians in selecting the preferred treatment path for their patients.

Teasing out factors that may improve treatment choices for people with Graves' Disease.

The Possibility of Markers to Guide Treatment

In a meta-analysis of 31 studies,1 no single factor stood out as predictive of relapse. Total T4 levels, however, pivoted to become a significant predictor of relapse based on raw mean differences when univariable meta-regression analysis was used.

The team calculated that “there was a 1% increase in the risk of relapse for every 5.5 ml increase in thyroid volume, for every 4 pmol/L increase in free T4, for every 6 nmol/L increase in total T3, for every 8% rise in TBII level, for every 127% rise in TSAb, and for every 17 I/L rise in TRAb,” as reported in Clinical Thyroidology.

Using random effects confidence data on the 2322 patients who had relapsed, the authors found a slight yet statistically significant increase in risk for 2 factors: baseline orbitopathy, 1.15 (5% CI; 1.08-1.25) and smoking, 1.13 (95% CI; 1.02-1.25).

When a standard mean difference (g values) was used to evaluate the impact of potential factors, 2 different factors—pretreatment TRAb levels and goiter size—were suggestive of a higher risk.1 For patients who are both newly diagnosed with Graves’ disease and present with either of these factors, or with orbitopathy, or are regular smokers, the authors proposed that clinicians advised them to choose a treatment other than antithyroid medication.

Patients’ gender and their total T4 levels did not correlate to their risk of relapse. Applying univariable meta-regression analysis, however, rendered the previously significant variables of smoking, total T3, and TBII less significant, and thyroid volume and free T4 levels of only small significance.

Based on their findings,1 the researchers concluded that individual HLA alleles and SNPs may have predictive value in some patients, but testing is not routinely available yet.

Given the biases identified in the studies examined between 1977 and 2015, and the fact that many changes in treatment protocols occurred during that time, the authors concluded that lack of clear findings was not surprising. The research team wrote of the need for a large prospective study to better assess whether combined factors could offer a valid predictor of relapse. The authors declined a request for comment to EndocrineWeb.

Weighing Treatment Options With Patients

Although no one individual factor can be relied on to predict relapse, the authors point to the fact that certain variables do seem to confer a higher risk, according to Elena Christofides, MD, FACE, a clinical associate professor of endocrinology at Ohio University College of Medicine in Columbus, Ohio.

Until a full-scale clinical trial is mounted and results offered, clinicians might consider these soft findings when creating a treatment plan for individual patients to help guide the decision-making process.

In an interview with EndocrineWeb, Dr. Christofides offered 3 recommendations to clinicians who are concerned about relapse in patients being evaluated for the treatment of Graves’ disease:

> Consider each patient’s status
If your patient has a small thyroid gland, low levels of thyroid antibodies, and it hasn’t been that long since her Graves’ disease diagnosis, she may have a better than average chance of remission. In that case, “[you] feel more confident in suggesting medical management” with antithyroid medications, said Dr. Christofides. However, if your patient has a larger thyroid, high blood antibody levels, and a long history of Graves’ disease, you may want to have a conversation about a permanent solution, such as surgery or radioactive iodine.

> Explore your patient’s preferences
Dr. Christofides has encountered patients who have prejudices against medication, radioactive iodine, and surgery, and not always for easily discernable reasons. When a patient is strongly opposed to a particular treatment and her symptoms allow for flexibility, consider letting her wishes tip the balance, at least initially.

> Be prepared with a persuasive explanation about risks
When faced with a patient whose symptoms are strongly predictive of relapse and for whom either surgery or radioactive iodine is the clinically appropriate next step, but the patient voices strong opposition, it’s important that she be thoroughly briefed.

“The difficulty with medications is that they do carry a significant risk,” said Dr. Christofides. When the patient insists on taking antithyroid medication, the clinician should be ready to communicate the seriousness of the consequences, including liver disease, and that--given the probability of a relapse--one of the other options is highly recommended for better long-term outcomes, she said.

Continue Reading:
Duration of Graves' Disease Remission Following Anti-thyroid Drug Therapy
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