TRAb Levels May Predict Fluctuating Graves’ Disease in Relapsing-Remitting MS

Endocrine system disease, endocrinology
Endocrine system disease, endocrinology
The researchers sought to determine the clinical and biochemical features of alemtuzumab-induced autoimmune thyroid events and look their risk factors with a focus on fluctuating Graves’ disease.

Thyroid‐stimulating hormone receptor antibody (TRAb) levels in patients with relapsing-remitting multiple sclerosis (RRMS) who are diagnosed with alemtuzumab‐induced Graves’ disease (GD) may be a biomarker for predicting a fluctuating disease phenotype, according to a study published in Clinical Endocrinology.

Alemtuzumab, an immunomodulary monoclonal antibody that targets CD52, a glycoprotein encoded by the CD52 gene in humans, has proven to be effective in the treatment of RRMS. Standard treatment involves a cycle of 12 mg/day IV for 5 consecutive days, followed by a second cycle of the same dose for 3 consecutive days after a year. Despite its effectiveness, alemtuzumab-induced autoimmune thyroid events (AIATEs) are common adverse events for this patient population.

The objective of the current study was to determine the clinical and biochemical features of these AIATEs and what risk factors contribute to their occurrence, specifically fluctuating GD, an autoimmune disorder that causes hyperthyroidism.

Researchers analyzed the clinical and biochemical characteristics of AIATEs in patients with RRMS, as well as the risk factors for the onset of AIATEs, including fluctuating GD (F‐GD), in this longitudinal, retrospective study.

A total of 57 patients with RRMS who were treated at a tertiary referral center in Italy from 2014 to 2020 were included. Patients had a mean age of 33±9 years at their first cycle of treatment, and 74% were female. Alemtuzumab 12 mg/day was administered for 5 consecutive days, and then for 3 days about 1 year later.

During a mean follow‐up of 32±17 months after the first treatment cycle, 39% of patients (n=22) developed an AIATE. The mean onset time was 17±11 months after the first cycle, and 10±7 months after the last cycle. GD was the most common AIATE (64%, n=14), followed by Hashimoto thyroiditis with hypothyroidism (23%, n=5), TRAb-positive hypothyroidism (9%, n=2), and silent thyroiditis (4%, n=1).

Among the patients with GD, 8 (57%) had a fluctuating course. At the end of the follow‐up, 18% of AIATEs (n=4) had regressed, and all were GD cases.

Univariate analysis showed that baseline positivity for anti‐thyroperoxidase (TPO) correlated significantly with AIATE risk (P=.02), but not for TRAb. In a comparison of absolute titers of anti‐thyroglobulin and anti‐TPO antibodies, higher levels of anti‐thyroglobulin (P=.001) and anti‐TPO (P=.01) antibodies both correlated with a higher risk of AIATEs.

In the multivariate analysis, only pretreatment anti‐TPO antibody positivity independently predicted the onset of AIATEs (odds ratio: 5.0556; 95% CI, 1.1105 to 23.0150).

Receiver operating characteristic (ROC) curve analysis, using a cutoff of 7.3 IU/L for TRAb levels at the onset of thyrotoxicosis, demonstrated that the risk of a patient’s GD evolving into F‐GD could be predicted with a sensitivity of 71.4%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 94.8% (P=.0001, area under the curve 0.893).

The researchers noted that their TRAb cutoff value should be interpreted with caution, as it was based on analysis of 8 patients. Other limitations included the study’s retrospective design, and the investigators measured TRAb titers by quantifying the presence of immunoglobulins binding to thyroid‐stimulating hormone receptor rather than analyzing their biological activity directly.

“To our knowledge, this is the first study to examine the value of routinely assaying TRAb titers at the onset of alemtuzumab‐induced GD as a novel way to predict the onset of a F‐GD phenotype, and thus orient clinical decision‐making and patients’ follow‐up,” the researchers concluded.


Manso J, Zhu YH, Margoni M, et al. Alemtuzumab‐induced autoimmune thyroid events in patients with relapsing‐remitting multiple sclerosis: a real‐life and monocentric experience at a tertiary‐level centre. Clin Endocrinol (Oxf). Published online November 1, 2021. doi: 10.1111/cen.14616