Abstract
Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for the treatment of active relapsing-remitting multiple sclerosis (MS). Alemtuzumab induces a rapid and prolonged depletion of lymphocytes from the circulation, which results in a profound immuno-suppression status followed by an immune reconstitution phase. Secondary to reconstitution autoimmune diseases represent the most common side effect of Alemtuzumab treatment. Among them, Graves’ disease (GD) is the most frequent one with an estimated prevalence ranging from 16.7 to 41.0% of MS patients receiving Alemtuzumab. Thyrotropin (TSH) receptor (R)-reactive B cells are typically observed in GD and eventually present this autoantigen to T-cells, which, in turn, secrete several pro-inflammatory cytokines and chemokines. Given that reconstitution autoimmunity is more frequently characterized by autoantibody-mediated diseases rather than by destructive Th1-mediated disorders, it is not surprising that GD is the most commonly reported side effect of Alemtuzumab treatment in patients with MS. On the other hand, immune reconstitution GD was not observed in a large series of patients with rheumatoid arthritis treated with Alemtuzumab. This negative finding supports the view that patients with MS are intrinsically more at risk for developing Alemtuzumab-related thyroid dysfunctions and in particular of GD. From a clinical point of view, Alemtuzumab-induced GD is characterized by a surprisingly high rate of remission, both spontaneous and after antithyroid drugs, as well as by a spontaneous shift to hypothyroidism, which is supposed to result from a change from stimulating to blocking TSH-receptor antibodies. These immune and clinical peculiarities support the concept that antithyroid drugs should be the first-line treatment in Alemtuzumab-induced Graves’ hyperthyroidism.
Highlights
Reviewed by: Motoyasu Saji, The Ohio State University Columbus, United States Amanda Katherine Huber, University of Michigan, United States
Alemtuzumab induces a rapid and prolonged depletion of lymphocytes from the circulation, which results in a profound immuno-suppression status followed by an immune reconstitution phase
Immune reconstitution Graves’ disease (GD) was not observed in a large series of patients with rheumatoid arthritis treated with Alemtuzumab
Summary
Alemtuzumab is a humanized monoclonal antibody that has been approved for the treatment of active relapsing-remitting (RR) multiple sclerosis (MS) [1, 2]. Changes in lymphocyte subsets result in an increased number of T regulatory (Treg) cells and of memory T and B lymphocytes; an increased production of anti-inflammatory cytokines occurs [5] These events produce a profound rebalance of the immune system [6, 7]. The above described immunomodulating actions of Alem tuzumab are responsible for its favorable effects in patients with RRMS [13], and explain the high prevalence of Alemtuzumab-induced autoimmunity. The latter event received great concern and clinical trials aimed at evaluating potential preventive measures were designed (CAM-THY) [8, 14, 15]
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