Thyroid Autoimmunity Following Alemtuzumab Treatment in Multiple Sclerosis Patients

Abstract

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for the treatment of highly active relapsing-remitting multiple sclerosis (MS). The principal adverse effect is the development of secondary autoimmune disorders during the immune reconstitution period after alemtuzumab, with autoimmune thyroid disease (AITD) being the most common. To define the type, timing and course of AITD after alemtuzumab treatment for MS we analyzed clinical and serologic data from 31 patients (follow-up range 8 to 58 months). Hashimoto thyroiditis (HT) with positive anti-TPO and/or anti-Tg antibodies was present at baseline in four patients. Of note, one of them 13 months after the first dose developed mild hyperthyroidism [stimulating TRAbs: 1,8U/L, normal range:<0,1] with subsequent spontaneous shift to hypothyroidism within two months. Of 26 patients without previous history of thyroid dysfunction, 17 (65,3%) developed adverse thyroid events, principally Graves’ disease (GD) with positive stimulating TRAbs (n=10, 58,8%) after a mean of 22,4 months following the first alemtuzumab course. Half of the GD cases exhibited fluctuating thyroid status, transitioning from hyperthyroidism to hypothyroidism and vice versa. Most of them were started on block and replace antithyroid drug (ATD) treatment. Three GD patients are currently under treatment with ATD in a dose-reducing regimen. Two patients developed Graves’ ophthalmopathy. One of them underwent total thyroidectomy and 27 months post-surgery TRAbs are still positive. One patient developed hypothyroidism associated with surprisingly high stimulating TRAbs (>40 U/L) as well as anti-Tg antibodies. Seven cases of HT with positive anti-TPO/anti-Tg antibodies were documented, of which one developed hypothyroidism. During follow-up, two successful pregnancies were recorded. The first, a 32-year-old woman, developed HT with hypothyroidism 12 months after the first cycle of alemtuzumab and gave birth to a healthy boy 22 months following last dose. The second, a 31-year-old woman, developed GD hyperthyroidism during the first trimester of pregnancy and was started on PTU that was stopped in the beginning of the second trimester. TRAbs titer declined and a healthy girl was delivered. Contrary to published literature, we recorded frequent occurrence of GD with fluctuating and unpredictable course requiring block and replace ATD regimen. This is suggestive of alternating stimulating and inhibitory TRAbs, while further studies are needed to understand the underlying mechanisms responsible for Th1-Th2 balance and cytokine pathways towards AITD. Pretreatment screening and careful follow-up allow for early diagnosis and treatment. Finally, concerning future pregnancies post-alemtuzumab it is important to address the risk for secondary AITD in women of childbearing age in conjunction with their treating obstetrician.