Endocrine Abstracts (2017) 50 P399 | DOI: 10.1530/endoabs.50.P399

Autoantibodies to the thyrotropin receptor in Alemtuzumab-induced thyroid autoimmunity: determination of their biological activity, and possible role as predictive marker of disease

Ilaria Muller1, Mark Willis2, Sarah Healy2, Taha Nasser2, Lei Zhang1, Mohd Shazli Draman1, Peter Taylor1, Neil Robertson2, Marian Ludgate1 & Colin Dayan1

1Thyroid Research Group, Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, UK; 2Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Background: Alemtuzumab (ALTZ) is a humanised monoclonal anti-CD52 antibody used as effective treatment for relapsing/remitting multiple sclerosis (MS), causing panlymphopenia with subsequent lymphocyte repopulation. Unfortunately, around 40% of patients develop secondary humoral autoimmunity, mainly affecting the thyroid gland. Anti-thyrotropin-receptor (TSHR) autoantibodies (TRAb) can stimulate (TSAb), block (TBAb) or not affect (‘neutral’) TSHR function, with TSAb causing hyperthyroid Graves’ disease (GD), and TBAb hypothyroidism. Low-affinity neutral TRAb could pre-exist in MS patients, then undergo somatic hypermutation to become high-affinity TSAb/TBAb post-ALTZ, causing thyroid dysfunction.

Methods: Sera from MS patients, 11 developing post-ALTZ thyroid autoimmunity (TA; 10 GD, 1 hypothyroidism) and 14 not developing it (NO-TA), were obtained from the Welsh Neuroscience Research Tissue Bank (Cardiff, UK), and evaluated at different time-points: (1) pre-ALTZ, (2) post-ALTZ before the disease onset (TA) or latest time post-ALTZ (NO-TA), (3) post-ALTZ during/after thyroid dysfunction onset (TA only). Flow cytometry (FC) detected any TSHR-binding TRAb. Luciferase bioassays (LB) detected both TRAb presence and bioactivity (neutral/TSAb/TBAb), also deduced from the corresponding thyroid function. TRAb positivity (TRAb+) was defined as FC and/or LB assays positivity.

Results: Among overall TRAb+ cases (all time-points considered), TBAb were 2/7 (28.6%) in GD, 1/1 (100%) in hypothyroidism, and 3/4 (75%) in NO-TA.

Conclusions: (A) Patients with positive TRAb prior to ALTZ had an increased tendency to develop post-treatment TA. Thus baseline TRAb could provide a predictive marker of future development of thyroid dysfunction. (B) TRAb+ patients were euthyroid at time-points 1–2, suggesting the presence of low-affinity antibodies unable to affect thyroid function. (C) Post-ALTZ TBAb subtype is common, and could be responsible for post-ALTZ hypothyroidism, and cases of post-ALTZ Graves’ disease with fluctuating thyroid function.

Time- pointsTRAb+Fisher Exact T-test
13/11 (27.3%)0/14 (0%)P=0.07
1+25/11 (45.5%)4/14 (28.6%)P=0.43
38/11 (72.7%)NANA
NA=Not Applicable.