Introduction:
Multiple sclerosis (MS) is known to be the most common neurologic demyelinating disease in young adults that it is characteristically a relapsing inflammatory demyelinating disease of the white matter. MS is rather complex inflammatory disorder that involves multiple immune cell lines, including macrophages, B cells, CD4+, CD8+, and T helper cells (Th 1, 2, 9, 17, 22)[1]. Initially a large body of literature supported the role of T cells in MS evident by earlier treatments for MS like Interferon B and Glatiramer acetate that act on these cells which were effective in decreasing relapses but not for the progression of the disease[2].However, the recently approved Sphingosine Phosphate 1 receptor (SPR1) modulator drugs have shown to be effective in decreasing the progression of the disease via limiting T-cell migration to tissues, and as a consequence, decreasing the immune response[3]. SPR1 are expressed in lymphocytes T and are part of the signaling process that promotes egress of lymphocytes from lymph nodes into the circulation[4]. Additionally, targeting CD25 on T cells using daclizumab has been proven to be effective for reducing MS relapses, however, due reported cases of autoimmune encephalitis the drug has been withdrawn[5].
Interestingly, over the last decade B cells have been consistently shown to drive a large portion of MS pathology[2, 6]. B cells harbor several antigens that are expressed at certain points of B cell evolution and play distinct role in its function and differentiation. Among these antigens, B cells express CD20 at most stages of development and differentiation. Due its presence in most B cell lineage, CD20 has been an attractive target for immunotherapy against B-cell lymphoma and leukemias[6]. Targeting CD20 either leads to accumulation of CD20 aggregates resulting in complement-mediated cytotoxicity or activation of apoptosis pathways. Evidently, CD20 antagonists limit MS relapses by depleting B cells, thus modulate the immune-inflammatory process of MS[7]. Several CD20 inhibitors have been approved by the FDA till now including ocrelizumab, ofatumumab, and rituximab[7, 8].
While rituximab cardiovascular adverse events have been reported, much less is known about the cardiotoxic effects of the other CD20 inhibitors, T-cell targeting therapy or S1P inhibitors. For example, the two large clinical trials (OPERA I and II) have established ocrelizumab as an effective therapy for multiple sclerosis. While multiple adverse events have been reported in these studies, cardiovascular complications were absent[9, 10]. Therefore, we sought to investigate the newly approved CD20, CD25 and S1P targeting agents and their cardiovascular complications.