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withdrawn[5].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.