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].