Alemtuzumab-Related Thyroid Dysfunction in a Phase 2 Trial of Patients With Relapsing-Remitting Multiple Sclerosis
Abstract
CONTEXT: Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis. OBJECTIVE: The objective of the study was a detailed description of thyroid dysfunction in CAMMS223. DESIGN: Relapsing-remitting multiple sclerosis patients (n=334) were randomized 1:1:1 to 44 μg sc interferon-β-1a (SC IFNB-1a, Rebif) or annual courses of 12 or 24 mg iv alemtuzumab. Thyroid function tests (TSH, free T3, free T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) were assessed at screening, month 1, and quarterly thereafter; antithyroid peroxidase antibodies were assessed at screening and every 6 months. Thyroid dysfunction episodes were categorized post hoc by an endocrinologist. RESULTS: During a median follow-up of 57.3 months, 34% of alemtuzumab and 6.5% of SC IFNB-1a patients had thyroid dysfunction (P<.0001). Ten percent of alemtuzumab and 3% of SC IFNB-1a patients had more than one episode of thyroid dysfunction. With alemtuzumab, Graves' hyperthyroidism occurred in 22%, hypothyroidism in 7%, and subacute thyroiditis in 4%. Of patients with overt Graves' hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism. Of patients with overt hypothyroidism, 74% were TBII positive. The annual incidence of a first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent study year. CONCLUSIONS: Thyroid dysfunction was more common with alemtuzumab than with SC IFNB-1a. There were few serious episodes. Regular monitoring facilitated early detection. Unique features of this population included high prevalence of Graves' hyperthyroidism, multiple episodes of thyroid dysfunction in individual patients, spontaneous hypothyroidism after overt Graves' hyperthyroidism, and a high prevalence of TBII-positive overt hypothyroidism.
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Similar observations were made in Alemtuzumab use for multiple sclerosis in the 1990s: during reconstitution of autoimmunity, a significant proportion of patients developed GD, with an unusual evolution towards spontaneous euthyroidism or hypothyroidism in 40% despite TRAb positivity.
“Similar observations were made in Alemtuzumab use for multiple sclerosis in the 1990s: during the reconstitution of autoimmunity, a significant proportion of patients developed GD, with an unusual evolution towards spontaneous euthyroidism or hypothyroidism in 40% of the patients, despite TRAb positivity. [28].”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [28]
Thyroid dysfunction frequently occurs as an autoimmune complication of immune reconstitution therapy, especially in individuals with multiple sclerosis treated with alemtuzumab.
“Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers.”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
In alemtuzumab-induced TD, autoantibodies against the thyrotropin receptor (TRAb) play a major role.
“In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves' disease, followed by hypothyroidism and thyroiditis.
“In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves' disease (GD), followed by hypothyroidism and thyroiditis; Graves' orbitopathy is observed in some GD patients.”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
Around one-third of patients with no previous history of thyroid disorders will develop TD following alemtuzumab.
“Around one-third of patients with no previous history of thyroid disorders will develop TD following alemtuzumab [12-14]”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
In one study, 69% of MS patients who had positive TPOAb before receiving alemtuzumab developed TD, compared to 31% of those with negative TPOAb.
“In one study, 69% of MS patients who had positive TPOAb before receiving alemtuzumab developed TD, compared to 31% of those with negative TPOAb.”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
In the phase 2 trial of alemtuzumab as a treatment of relapsing remitting MS, TD rates were higher in patients treated with a daily dose of 12 mg versus those treated with 24 mg (39 vs. 29%, Fisher's exact test, p = 0.015).
“It is noteworthy that in the phase 2 trial of alemtuzumab as a treatment of relapsing remitting MS, TD rates were higher in patients treated with a daily dose of 12 mg versus those treated with 24 mg (39 vs. 29%, Fisher's exact test, p = 0.015) [13].”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
Small independent studies have suggested that the risk of TD is increased in subjects with established TA.
“Small independent studies have suggested that the risk of TD is increased in subjects with established TA [13, 37].”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
Thyroid dysfunction onset after alemtuzumab for MS has been described at an average of 32 months after the first treatment.
“The TD onset has been described 32 months (average) or 16-23 months (range 2-107 months) after the first and last alemtuzumab treatment for MS, respectively [12-14]”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
Thyroid dysfunction onset after alemtuzumab for MS has been described at 16-23 months (range 2-107 months) after the last treatment.
“The TD onset has been described 32 months (average) or 16-23 months (range 2-107 months) after the first and last alemtuzumab treatment for MS, respectively [12-14]”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
Not all patients who became positive for TRAb and TPOAb during post-alemtuzumab surveillance developed thyroid dysfunction.
“Although TRAb and TPOAb became positive during postalemtuzumab surveillance, not all of these patients developed TD”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
A number of patients developed thyroid dysfunction but remained antibody negative.
“Similarly, a number of patients developed TD but remained antibody negative [12, 13].”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
The significance of positive antibodies in asymptomatic, euthyroid individuals is unclear.
“so the significance of positive antibodies in such asymptomatic, euthyroid individuals is unclear [13].”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
A patient subset (30%) experienced numerous thyroid dysfunction episodes post-alemtuzumab.
“Of note, a patient subset (30%) experienced numerous TD episodes post-alemtuzumab [13];”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
The difference in reported spontaneous resolution may be related to differences in the definition of thyroid dysfunction: persistent for ≥ 3 months in Pariani et al. versus present on one occasion in Daniels et al.
“This difference may be related to differences in the definition of TD: persistent for ≥ 3 months in Pariani et al. [12] versus present on one occasion in Daniels et al. [13].”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
Some studies have reported spontaneous resolution of post-IRT Graves' disease in 20% of cases.
“similarly, some studies have reported spontaneous resolution of post-IRT GD in 20% of cases [13],”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
Around 85-100% of patients with alemtuzumab-induced Graves' disease have positive TRAb.
“Around 85-100% of patients with alemtuzumab-induced GD have positive TRAb [12, 13].”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
In the series from Daniels et al., one case developed Graves' disease after painless thyroiditis.
“In the series from Daniels et al. [13], one case developed GD after painless thyroiditis; another case developed hypothyroidism post-thyroiditis followed by another episode of painless thyroiditis.”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
In the series from Daniels et al., another case developed hypothyroidism post-thyroiditis followed by another episode of painless thyroiditis.
“In the series from Daniels et al. [13], one case developed GD after painless thyroiditis; another case developed hypothyroidism post-thyroiditis followed by another episode of painless thyroiditis.”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [13]
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- Authors
- Daniels, G. H., Vladic, A., Brinar, V., Zavalishin, I., Valente, W., Oyuela, P., Palmer, J., & Margolin, D. H.
- Affiliations
- University of Maryland, Baltimore (US)
- University Hospital Centre Zagreb (HR)
- Sanofi (United States) (US)
- Corresponding author
- Daniels, Gilbert H.
- ORCID
- Daniels, Gilbert H.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-01
- Volume
- 99
- Issue
- 1
- Pages
- 80-89
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2005475150
- Cited by
- 150
- References
- 27
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 7 · 2023: 13 · 2022: 9 · 2021: 6 · 2020: 14 · 2019: 15 · 2018: 15 · 2017: 15 · 2016: 14 · 2015: 17 · 2014: 9
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- alemtuzumab, thyroid dysfunction, relapsing-remitting multiple sclerosis, interferon beta-1a, Graves' hyperthyroidism, hypothyroidism, subacute thyroiditis, thyrotropin-binding inhibitory immunoglobulin, thyroid peroxidase antibodies, adverse drug reactions
- MeSH terms
- Interferon beta-1a, Alemtuzumab, Adult, Autoantibodies, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Thyroid Diseases, Thyroid Function Tests, Interferon-beta, Immunoglobulins, Thyroid-Stimulating, Multiple Sclerosis, Relapsing-Remitting, Young Adult, Antibodies, Monoclonal, Humanized
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