INTRODUCTION
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease
that leads to painful joint destruction and disability [1,2].
Traditional RA therapy includes disease-modifying anti-rheumatic drugs
(DMARDs), such as first line therapy methotrexate, hydroxychloroquine,
sulfasalazine, minocycline and leflunomide [3]. In recent years,
emerging novel biologic agents targeting specific pathways proven to
contribute to inflammatory pathways have also been included:
anti-interleukine-1 (anakinra), anti-IL-6 ( tocilizumab), tumor necrosis
factor α (TNFα) blockers (infliximab, etanercept, adalimumab Enbrel),
Janus-kinase inhibitors (tofacitinib, baricitinib) and anti-CD20 (
rituximab) [4-7]. Despite the significant progress that has been
achieved with the administration of biological therapies in changing the
natural history of RA, such medications induce immune suppression, which
is nonselective to the pathogenesis of the disease, resulting in higher
rates of common and opportunistic infections. Thus, different strategies
used to overcome these issues. For example, processing of antibodies
under specific high dilution technology to produce drugs that change
conformation state of the antigen and have specific target-modification
activity [8,9], or produce domain antibodies such as nanobodies
recently approved by FDA for the first time [10]. One of another
highly promising approach is the usage of Intravenous immunoglobulins
(IVIG) as a therapy for RA.
IVIG is a blood product, predominantly IgG (>95%),
isolated from 5,000-20,000 healthy donors. The first mentioned triumph
of the use of IVIG therapy was in primary immunodeficiency diseases in
the 1950s. IVIG has a good proven beneficial and safety profile, and is
one of the first biological therapies which was introduced already in
1981 by Imbach I et al [11], for immune thrombocytopenic purpura
(ITP). To date, the Food and Drug Administration (FDA) has approved the
use of IVIG as a first line therapy in B-cell chronic lymphocytic
leukemia, primary humoral immunodeficiency, ITP, Kawasaki syndrome and
multifocal motor neuropathy [12]. Despite FDA off labeling, IVIG
therapy has been expanded for diverse autoimmune diseases such as :
specific subgroups of RA patients, juvenile chronic arthritis (JCA),
Guillain-Barré syndrome, chronic inflammatory demyelinating
polyneuropathy occurring in the context of rheumatic disease, systemic
lupus erythematosis (SLE), idiopathic inflammatory myopathies, systemic
sclerosis, anti-neutrophil cytoplasmic antibody (ANCA)-associated
vasculitides, Still’s disease and more [13-26]. The mode of action
of IVIG encompass various mechanisms, attributed to the F(ab)2 or Fc
portions of the molecule [27-31]. The Fab part of the IVIG is
related to neutralization of inflammatory cytokines, anti-idiotypic
activity, blocking of cellular receptors, antibody dependent
cellular cytotoxicity (ADCC), and anaphylatoxin scavenging. Whereas the
Fc related activities encompass regulation of FcγR, immunomodulation of
the function of dendritic cells, blocking activating receptors,
expansion of T regulatory cells and saturation of FcRn.
One of the frequent murine model used in preclinical studies to evaluate
potential anti-rheumatic agents, is the collagen induced arthritis (CIA)
model which imitate human RA. CIA-treated mice share several
pathological features with RA including generation of autoantibodies,
synovial inflammatory cell infiltration, synovial hyperplasia, cartilage
destruction, and bone erosion [32].