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Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy; evidence that TRAb may precede thyroid dysfunction by many years.

Muller, Ilaria, Willis, Mark, Healy, Sarah, Nasser, Taha, Loveless, Samantha, Butterworth, Sara, Zhang, Lei, Draman Yusof, Mohd, Taylor, Peter, Robertson, Neil, Dayan, Colin and Ludgate, Marian 2018. Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy; evidence that TRAb may precede thyroid dysfunction by many years. Thyroid 10.1089/thy.2018.0232

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Abstract

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 (MS) 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”: TNAb) the TSHR function, causing hyperthyroidism, hypothyroidism or euthyroidism, respectively. METHODS We conducted a longitudinal retrospective analysis of TRAb bioactivity over a period of 9 years in 45 MS patients receiving ALTZ using available stored serum; 31 developed thyroid dysfunction (TD) and 14 remained euthyroid despite being followed for a minimum of 5 years (NO-TD). The presence of TRAb was evaluated at standardized time points: A) pre-ALTZ, B) latest time available post-ALTZ and before TD onset, C) post-ALTZ during/after TD onset. Serum TRAb were detected by published in-house assays (ihTRAb): flow cytometry (FC) detecting any TSHR-binding TRAb and luciferase bioassays (LB) detecting TSAb/TBAb bioactivity. Purified IgGs were used to verify TSAb/TBAb in selected hypothyroid cases. Standard clinical automated measurements of TRAb (autTRAb), anti-thyroid peroxidase autoantibodies (TPOAb), thyroid stimulating hormone, free-thyroxine and free-triiodothyronine were also collected. RESULTS Pre-ALTZ, combined ihTRAb (positive with FC and/or LB), but not autTRAb, 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 We present evidence 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. Our 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 our ability to predict those who will develop thyroid dysfunction post ALTZ.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Mary Ann Liebert
ISSN: 1050-7256
Date of First Compliant Deposit: 15 November 2018
Date of Acceptance: 23 October 2018
Last Modified: 23 Oct 2019 02:16
URI: http://orca.cf.ac.uk/id/eprint/116795

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