**3.3. Interleukin-6**

between these two groups is considered as an important therapeutic goal. This chapter provide an important role of TNF-α in the pathogenesis of RA, leading to the first clinical trials of a biological therapeutic in this disease. Other than TNF-α we address other cytokines such as IL-1, IL-6 and IL-23 that might play a role in the disease, together with selected cytokines that

TNF-α is a proinflammaotory cytokine and played a key role in RA with its potential to degrade cartilage [76] and bone [77] *in vitro*. It has been shown in an experiment that dissociated RA synovial mononuclear cell cultures that TNF-α as well as other proinflammatory cytokines (IL-1, IL-6, GM-CSF, and IL-8) [78–81] were produced in a five-day culture [82, 83]. When the activity of TNF-α was blocked in these cultures, the spontaneous production of both IL-1 protein and IL1B mRNA was remarkably decreased and IL-1 bioactivity was neutralized [82]. This is the evidence that the secretion of all these cytokines is a network and controlled

Soluble TNF receptors are found in high concentrations in the synovial fluid and serum of patient with RA [84]. RA patients are found to have high levels of TNF-α in the synovial fluid. This plays an important role in inflammation and joint destruction, both of which are hallmarks of RA. Anti-TNF-α therapy induces a shift in the cytokine equilibrium producing more anti-inflammatory cytokines. Studies have demonstrated dramatic improvement in synovial inflammation in RA patients after treatment with neutralizing anti-TNF-α Abs or soluble TNF receptors. They also suggest decreased joint destruction after treatment with IL-1Ra [85].

In a first clinical trial of a TNF-α blocking agent for the treatment of 20 active RA patients were initiated. Infliximab (Remicade), a chimeric antibody specific for human TNF-α was used. Signs and symptoms of the RA disease were substantially reduced with the treatment with infliximab together with decreased levels of CRP in the serum [86]. Other multicentric placebo-controlled trials were also confirmed the therapeutic efficacy of infliximab when coadministrated with methotrexate. This led eventually to FDA approval of the drug for the treatment of RA [87, 88]. After two-year of clinical trial, it was observed that there was a retardation or arrest of both joint space narrowing and bone erosion due to infliximab and methotrexate therapy [89]. There were two other drugs etanercept (Enbrel) and adalimumab

(Humira) which are functioned as TNF-α blockers were used in the treatment of RA.

be a potential therapeutics for the treatment of RA.

**3.2. Interleukin-1**

TNF-α is now considered as controlling a wide variety of effector functions relevant to the pathogenesis of RA, including endothelial cell activation and chemokines production which causes accumulation of leukocytes [90]; osteoclast and chondrocyte activation, promoting articular destruction. These all are RA disease pathogenesis spectrum which explains the broad role of TNF-α blockade in patients. Further, improved therapies targeting TNF-α would

Each member of the IL-1 family binds with high affinity to specific receptors. Binding of IL-1α or IL-1β to type I IL-1 receptors (IL-1RI), can is enhanced by an accessory protein, IL-1R-AcP,

bind a receptor containing the common γ-chain (γc) [75].

**3.1. TNF-α**

106 Autoantibodies and Cytokines

by hierarchy of their expressions.

IL-6 is an essential and multifunctional proinflammatory cytokine of the immune system and could be a key mediator for the development of many chronic inflammatory or autoimmune diseases including RA [95, 96].

It is well established that increased levels of autoantibodies are the characteristics of autoimmune RA and hence decreased levels of antibody producing B cells are might have a therapeutic efficacy demonstrates the impact of B-cell activity on synovial inflammation and joint damage. IL-6 stimulates B cells to differentiate into plasma cells to produce immunoglobulins [97]. IL-6 induces B-cell differentiation [98] and it has been established that B-cells induced antibody production [99].

Neutrophils can be directly activated by IL-6 through membrane-bound receptor IL-6R, which in turn help inflammation and joint destruction through the secretion of proteolytic enzymes and reactive oxygen intermediates [100]. An *in vitro* study with fibroblasts from patients with RA showed the role of IL-6 in actively encourage the recruitment of neutrophil by activated fibroblasts. Although untreated fibroblasts were able to recruit neutrophils, it was found that the recruitment was inhibited in the presence of anti-IL-6 antibody [101].

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

**Author details**

Mohd Wajid Ali Khan1

Kingdom of Saudi Arabia

2018;**29**:1-11

**42**(2):150-158

**References**

\* and Wahid Ali Khan2

1 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences,

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

Autoantibodies and Cytokines in Pathogenesis of Rheumatoid Arthritis

http://dx.doi.org/10.5772/intechopen.82265

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

University of Hail, Ha'il, Kingdom of Saudi Arabia

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 reduced VEGF concentration [107].

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 damage in RA [111–117].
