Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy; evidence that TRAb may precede thyroid dysfunction by many years
Open accessAbstract
BACKGROUND: Thyroid autoimmunity, especially Graves' disease or hypothyroidism with positive autoantibodies (TRAb) to the thyrotropin receptor (TSHR), occurs in 30-40% of patients with relapsing multiple sclerosis following treatment with alemtuzumab (ALTZ). ALTZ therapy therefore provides a unique opportunity to study the evolution of TRAb prior to clinical presentation. TRAb can stimulate (TSAb), block (TBAb), or not affect ("neutral") the TSHR function, causing hyperthyroidism, hypothyroidism, or euthyroidism, respectively. METHODS: A longitudinal retrospective analysis was conducted of TRAb bioactivity over a period of nine years in 45 multiple sclerosis patients receiving ALTZ using available stored serum. Of these 45 patients, 31 developed thyroid dysfunction (TD) and 14 remained euthyroid despite being followed for a minimum of five years (NO-TD). The presence of TRAb was evaluated at standardized time points: (i) before ALTZ, (ii) latest time available following ALTZ and before TD onset, and (iii) following ALTZ during/after TD onset. Serum TRAb were detected by published in-house assays (ihTRAb): flow cytometry detecting any TSHR-binding TRAb, and luciferase bioassays detecting TSAb/TBAb bioactivity. Purified immunoglobulin G was used to verify TSAb/TBAb in selected hypothyroid cases. Standard clinical automated measurements of TRAb, antithyroid peroxidase autoantibodies (TPOAb), thyrotropin, free thyroxine, and free triiodothyronine were also collected. RESULTS: Before ALTZ, combined ihTRAb (positive with flow cytometry and/or luciferase bioassay) but not automated TRAb were present in 5/16 (31.2%) TD versus 0/14 (0%) NO-TD (p = 0.017). Detectable ihTRAb preceded TD development in 9/28 (32.1%) and by a median of 1.2 years (range 28 days-7.3 years). Combination testing of ihTRAb and TPOAb at baseline predicted 20% of subsequent cases of hyperthyroidism and 83% of hypothyroidism. CONCLUSIONS: Evidence is presented that TRAb measured with custom-made assays can be detected prior to any change in thyroid function in up to a third of cases of ALTZ-related TD. Furthermore, the presence of ihTRAb prior to ALTZ treatment was strongly predictive of subsequent TD. The findings suggest that a period of affinity maturation of TRAb may precede clinical disease onset in some cases. Combined testing of TPOAb and ihTRAb may increase the ability to predict those who will develop TD following ALTZ.
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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 [37]
TRAb with blocking activity on TSHR (TBAb) are responsible for around 30-50% of all hypothyroid cases.
“TRAb with blocking activity on TSHR (TBAb) are responsible for around 30-50% of all hypothyroid cases [37].”
From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [37]
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- Authors
- Muller, I., Willis, M., Healy, S., Nasser, T., Loveless, S., Butterworth, S., Zhang, L., Draman, M. S., Taylor, P. N., Robertson, N., Dayan, C. M., & Ludgate, M. E.
- Affiliations
- University Hospital of Wales (GB)
- Corresponding author
- Muller, Ilaria
- ORCID
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2018-12
- Volume
- 28
- Issue
- 12
- Pages
- 1682-1693
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- OpenAlex
- W2905085044
- Cited by
- 34
- References
- 38
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 8 · 2018: 2
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Thyroid (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Medical Research Council (MR/L010305/1)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Keywords
- thyrotropin receptor autoantibodies, TRAb, alemtuzumab, thyroid dysfunction, multiple sclerosis, Graves' disease, hypothyroidism, hyperthyroidism, thyroid autoimmunity, relapsing multiple sclerosis, TSHR
- MeSH terms
- Alemtuzumab, Adult, Autoantibodies, Female, Humans, Hyperthyroidism, Hypothyroidism, Longitudinal Studies, Luciferases, Male, Middle Aged, Multiple Sclerosis, Receptors, Thyrotropin, Retrospective Studies, Thyroid Gland, Thyrotropin, Immunoglobulins, Thyroid-Stimulating
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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