**Author details**

Osteoclasts are multinucleated cells formed by the fusion of mononuclear progenitors of the monocyte and macrophage family. These cells populate the synovial membranes of RA patients and are concentrated in bones [102, 103]. Macrophage derived osteoclastogenesis requires the presence of macrophage colony-stimulating factor. It results from the interaction of the RANK and the RANK ligand (RANKL) [102]. RANKL expression is regulated by pro-

The principal cause of bone erosion is the pannus, which is found at the interface with cartilage and bone. Angiogenesis is an important process in the formation and maintenance of pannus [104]. Vascular endothelial growth factor (VEGF), is an important angiogenic mediator which promotes the migration and proliferation of endothelial cells, as well as inducing vascular permeability and mediating inflammation [105]. Increased levels of VEGF correlate with disease activity in RA patients [106]. IL-6 in the presence of sIL-6R increased VEGF levels in cultured synovial fibroblasts from RA patients and anti-IL-6R antibody significantly

Blocking antibodies were used with other agents as a combinational therapeutics for the treatment of RA. A humanized anti-IL-6R monoclonal antibody, tocilizumab (TCZ), used in a first clinical trial was conducted in patients with established RA [108]. A total of 45 patients were randomized to receive a single intravenous infusion of TCZ of 0.1, 1, 5, 10 mg/kg or placebo. Patients in the 5 and 10 mg/kg arms showed rapidly improvement in disease activity. CRP normalized after treatment in the 5 and 10 mg/kg treated patients confirming IL-6 as the dominant cytokine in generating the acute-phase response in patients with RA. Another, double-blind, placebo-controlled trial in 164 RA patients was conducted and demonstrates that the clinical response was maintained with repeated dosing of TCZ monotherapy [109]. A European study CHARISMA, examined the combinational effect of TCZ with methotrexate (MTX). In the study of 359 RA patients with partial response to MTX, it was found that TCZ was efficacious as monotherapy or in combination with MTX although the latter appeared to enhance the benefit of TCZ [110]. There were many other clinical trials and studies that ensures the use of TCZ alone or in combinational therapies such as MTX results in sustained improvement in physical function and reduced radiographic joint

RA is a complex disease that develops through a series of events often referred to as disease continuum. It is an autoimmune and inflammatory disease that can be further aggravated with the increased production and secretion of autoantibodies (RF ACPA, anti-cartilage type II antibodies) and the secretion of proinflammatory cytokines (TNF, IL-1, IL-6). With a better knowledge and understanding of the crosstalk between the molecules involved in RA disease pathogenesis, it would be easier to identify better markers for RA disease as well as design and administer specific and efficient therapeutics that can control RA pathogenesis

and deliver long term and permanent remission of the disease.

inflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-17 [103].

reduced VEGF concentration [107].

108 Autoantibodies and Cytokines

damage in RA [111–117].

**4. Conclusion**

Mohd Wajid Ali Khan1 \* and Wahid Ali Khan2

\*Address all correspondence to: wajidkhan11@gmail.com

1 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Ha'il, Kingdom of Saudi Arabia

2 Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia
