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 12, 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- points||TRAb+||Fisher Exact T-test|
|1||3/11 (27.3%)||0/14 (0%)||P=0.07|
|1+2||5/11 (45.5%)||4/14 (28.6%)||P=0.43|