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*Corresponding author: E-mail: elmafary@gmail.com; 
 
 
 

Asian Journal of Immunology 
 
3(1): 259-268, 2020; Article no.AJI.57314 
 

 
 

 

 

Role of Inflammatory Cytokines in the  
Pathogenesis of Rheumatoid Arthritis and  

Novel Therapeutic Targets 
 

Shaayau Shehu1*, Abdulaziz Umar Kurya2, Usama Aliyu1  
and Dinesh C. Sharma2 

 
1
Department of Biochemistry, Usmanu Danfodiyo University, Sokoto, Nigeria. 

2
School of Life and Allied Health Sciences, Glocal University, Saharanpur,  

Uttar Pradesh, India. 
 

Authors’ contributions  
 

This work was carried out in collaboration among all authors. Author SS designed and supervised the 
study. Author AUK wrote the first draft of the manuscript, outline the protocol and performed the 

statistical analysis while authors UA and DCS managed the literature search and analyses of the 
study. All authors read and approved the final manuscript. 

 
Article Information 

 
Editor(s): 

(1) Dr. Jaffu Othniel Chilongola, Tumaini University, Tanzania. 
Reviewers: 

(1) S. Tripathy, Sri Vasavi Institute of Pharmaceutical Sciences, India. 
(2) Ingrid Patricia, Dávalos Rodríguez, México. 

Complete Peer review History: http://www.sdiarticle4.com/review-history/57314 
 
 
 
 

Received 06 April 2020  
Accepted 12 June 2020 
Published 29 June 2020 

 
 

ABSTRACT 
 

Cytokines are low molecular weight secreted proteins that mediate and regulate immune 
responses, inflammation and hematopoiesis; they act by autocrine, paracrine, endocrine and 
antagonistic mode of actions. cytokines have strong correlation with autoimmune disease, the most 
prominent among others is rheumatoid arthritis (RA) which targets synovial joints, and often 
accompanied by an array of extra-articular manifestations which are ultimately major predictors of 
increased morbidity and mortality, RA affect about 1% of the world population and about 0.6% of 
the American population with annual incidence estimated to about 40 per 100,000 individuals and 
mostly women. Persistent inflammation endorsed by major pro-inflammatory cytokines such as 
Interleukins (IL-1, IL-6) and tumor necrosis factors (TNF-α) and imbalance between the pro-
inflammatory and anti-inflammatory cytokines is the main pathogenesis of RA. Evidence suggests 
that interaction between antigen-presenting cells and CD4+ T helper cells is involved in the 
induction of inflammation in RA. Continuous recruitment and activation of macrophages and 

Review Article 



 
 
 
 

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260 

 

monocytes occur with the recruitment of pro-inflammatory cytokines, specifically TNF-α, IL-1 and 
IL-6 into the synovial cavity resulting to loss of cartilage and bone erosion. These activated immune 
cells stimulate angiogenesis, which explains increased vascularity found in the synovium of 
patients with RA. Novel therapeutic targets are developed to minimize the morbidity rate, the use of 
TNF-α blockade drugs such as Adalimumab, Etanercept and Infliximab is widely approved globally 
with more precise therapeutic effect on inflammation. As the IL-1 plays a critical role in joint 
damage by facilitating the degradation of cartilage which leads to RA, the use of interleukin-1 
receptor antagonist drugs such as Anakinra suppresses RA by inhibiting the release of IL-1, 
likewise, the use of anti-IL-6 receptor agent such as tocilizumab has become a major resource for 
the treatment of RA.  
 

 

Keywords: Interleukins; rheumatoid arthritis; tumor necrosis factor; therapeutics. 
 

1. INTRODUCTION 
 
The concept of cytokines was described in 1974 
after the discovery of interferon for the first time. 
Cytokines are small secreted proteins with a 
molecular weight less than 30 kDa (˂200 amino 
acids) that mediate and regulate immune 
responses, inflammation, and hematopoiesis 
they are released by varieties of cells such as 
leukocytes, produced de novo(starting from the 
beginning) in response to an immune stimulus 
and act by binding to the surface membranes of 
target cells to evoke a cascade of responsive 
reactions [1-2]. They bind to specific receptors on 
target cells, triggering signal-transduction 
pathways that ultimately alter gene expression in 
these cells to produce cytokines that are involved 
in innate, adaptive immunity, the gene products 
(proteins) participate in the cell proliferation, 
differentiation, migration, and apoptosis activities 
[3-4]. 
 
To be more precise, cytokines regulate the 
intensity and duration of the immune response by 
stimulating or inhibiting proliferation, 
differentiation, trafficking or emigration of 
lymphocytes all the while acting as a messenger 
for both arms of the immune system [5]. 
Cytokines either stimulate or suppress the 
responses of various cells involved in host 
immune mechanisms, they assist such cells to 
interact or convey the essential messages for the 
proper functioning of defense systems against 

numerous pathogens or disease conditions. 
Cytokines and their receptors exhibit very high 
affinity for each other as a result they can exert 
their biological effects even at very low 
concentrations [6]. 
 

According to the secretion of cytokines, they are 
classified in Table 1. 
 

2. MATERIALS AND METHODS 
 

This literature review titled ‘role of inflammatory 
cytokines in the pathogenesis of rheumatoid 
arthritis and novel therapeutic targets’’ was 
conducted using online database of scientific 
collections, key articles used were retrieved 
precisely from NCBI (PMC, PUBMED), Google 
Scholar, using the terms ‘Rheumatoid arthritis, 
cytokines, and therapeutics of rheumatoid 
arthritis as keywords for our search. We included 
scientific publications from December 2004 to 
November 2018. Articles focusing on clinical 
characteristics, epidemiology, pathogenesis, and 
treatments for rheumatoid arthritis were eligible 
for inclusion. 
 

2.1 Mode of Cytokines Action 
 

A particular cytokine might bind to receptors on 
the membrane of the same cell that secreted it 
and exert its biological effect, a condition which is 
referred as autocrine action [8].It can also bind to 
receptors on a target cell nearby and exert its 
biological effect which is known as paracrine

 
Table 1. Shows different classes of cytokine and their function 

 

Chemokine Function  Ref. 

Lymphokines cytokines that are secreted by T cells and regulate the immune 
response 

[7] 

Proinflammatory cytokines that amplify and perpetuate the inflammatory process [7] 
Anti-inflammatory cytokines that negatively modulate the inflammatory response [7] 
Growth factors cytokines that promote cell survival and result in structural changes in 

the airways 
[7] 

Chemokine cytokines which are chemotactic for inflammatory cells [7] 



 
 
 
 

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261 

 

action [8]. Besides, those cytokines which bind to 
target cells in distant locations and exert their 
biological effect are known to exert endocrine 
mode of action [8]. However the synergistic effect 
is seen when the combined effect of two or more 
cytokines is greater than the additive effect of 
individual cytokine [9]. 
 

Another mode of action exhibit by cytokine is 
their ability to activate multiple signaling 
pathways thereby affecting the activity of multiple 
cells which is known as pleiotropic mode of 
action [9]. Besides, redundant mode of action is 
also seen when multiple cytokines have the 
ability to exert similar function [9]. Under some 
circumstance two or more cytokines may act on 
one cell and the effect of one cytokine inhibit or 
offset the effects of another cytokine [10]. 
 

2.2 Pro-inflammatory Cytokines 
 

Pro-inflammatory cytokines or simply 
inflammatory cytokines are special types of 
signaling molecules that are excreted from 
immune cells like T helper cells and 
macrophages and certain other cells that 
promote inflammation [11]. The most prominent 
among them are interleukins (IL-1, IL-6) and 
tumor necrosis factor (TNF-α and TNF-β) which 
play an important role in mediating immune 
response, excess production of inflammatory 
cytokines contributes to inflammatory diseases 
[11]. Inflammatory cytokines are proved to be 
beneficial for their bactericidal capacity of 
phagocytes, recruit additional innate cell 
populations to sites of infection, induce dendritic 
cell maturation and direct the subsequent 
specific immune response to the invading 
microbes [12]. Three pro-inflammatory cytokines, 
interleukin-1, interleukin-6,  and tumor necrosis 
factor-α, appear to have a central role in tissue 
destruction and are secreted by a variety of cell 
types comprising monocytes, macrophages, 
dendritic cells, epithelial cells, keratinocytes and 
fibroblasts [12]. 
 

Interleukin-1 (IL-1) is one of the primary 
inflammatory cytokines that mediate many local 
and systemic features of inflammation, they are 
made mainly by monocytes and macrophages in 
response to a range of stimuli including various 
microbial products, viruses, immune complexes, 
activated T cells and combine the action of other 
cytokines such as interleukin-2 and interferon-
gamma [13]. IL-1 exist in two isoformIL-1 α and β 
both of which are prototypic pro-inflammatory 
cytokines that exert pleiotropic effects on a 
variety of cells and play key roles in acute and 

chronic inflammatory and autoimmune disorders 
[13]. IL-1α is a regulator of intracellular events 
and a local inflammatory mediator, while IL-1β is 
primarily an extracellular protein released from 
cells [13]. IL-1 also stimulates the proliferation of 
keratinocytes, fibroblasts and endothelial cells of 
the tissues, therefore IL-1 is a critical component 
in the homeostasis of tissues and its unrestricted 
production may lead to tissue damage [14]. IL-6 
is produced locally in the inflamed tissues 
following cellular activation by bacterial 
lipopolysaccharide or other cytokines such as IL-
1β or TNF- α [14]. 
 

There are two IL-1 receptors, IL-1RI and IL-1RII. 
IL-1α and IL-1β signal through IL-1RI, binding to 
IL-1RII does not lead to cell signaling and is 
therefore considered as a decoy receptor, upon 
binding of IL-1 to IL-1RI, a second receptor 
termed IL-1 receptor accessory protein (IL-
1RAcP) gets recruited at the cell membrane to 
form a high-affinity binding receptor complex 
leading to intracellular signalling [15]. A third IL-1 
family member, IL-1 receptor antagonist (IL-
1Ra), binds to IL-1 receptors and prevents the 
interaction of IL-1 with its receptors, acting as a 
natural IL-1 inhibitor.IL-1β has important 
homeostatic functions in the normal organism, 
such as regulation of feeding, sleep, and 
temperature, however, overproduction of IL-1β is 
implicated in the pathophysiological changes that 
occur during different disease states such as 
rheumatoid arthritis, neuropathic pain, 
inflammatory bowel disease, osteoarthritis, 
vascular diseases, multiple sclerosis, and 
Alzheimer's disease [15]. 
 

Tumor necrosis factor- α (TNF- α): Is a pro-
inflammatory cytokine that possesses a wide 
range of immune regulatory functions and has 
the potential to stimulate the production of 
secondary mediators, including chemokine or 
cyclooxygenase products, which amplifies the 
degree of inflammation [16]. TNF-α was cloned 
over 2 decades ago and its identification in part 
led to the discovery of a superfamily of tumor 
necrosis factor (TNFs) and their receptors [17]. 
Macrophages are major producers of TNFα and 
interestingly are also highly responsive to TNFα, 
it signals through two transmembrane receptors, 
TNFR1 and TNFR2 and regulate several critical 
cell functions including cell proliferation, survival, 
differentiation and apoptosis [17]. 
 

Aberrant TNFα production and TNFα receptor 
signaling have been associated with the 
pathogenesis of several diseases, including 
rheumatoid arthritis, Crohn's disease, 



 
 
 
 

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262 

 

atherosclerosis, psoriasis, sepsis, diabetes               
and obesity [18]. TNFα has been shown                          
to play a pivotal role in orchestrating the     
cytokine cascade in many inflammatory  
diseases and because of this role as a             
"master regulator" of inflammatory cytokine 
production, it has been proposed as a 
therapeutic target for several diseases [19]. 
Indeed, anti-TNFα drugs are now licensed for 
treating certain inflammatory diseases including 
rheumatoid arthritis and inflammatory bowel 
disease [20]. 
 
Interleukin 6 (IL-6): Is a pleiotropic inflammatory 
cytokine synthesized by a variety of cells such as 
T lymphocytes, macrophages, monocytes, and 
synovial fibroblasts [21]. IL-6 was initially 
discovered and referred as B-cell differentiation 
factor identified in tissue culture supernatants 
which induce B cells to produce immune 
globulins and involved in diverse biological 
functions, such as T lymphocytes activation, 
induction of acute-phase response, growth 
stimulation, differentiation of hematopoietic 
precursor cells and proliferation of synovial 
fibroblasts [22]. IL-6 is among the major 
cytokines which contribute to the progression of 
many chronic inflammatory diseases and a well-
established target for pharmacological 
intervention [23-24]. 

 
Mammalian IL-6 exerts its biological effects by 
binding to two cell surface receptors, IL-6Rα and 
glycoprotein 130 receptors [25-27] The assembly 
of the IL-6·IL-6Rα·gp130 on the cell surface 
forming a complex activates the JAK family of 
tyrosine kinases and the downstream STAT3 
transcription factor [28-30]. In cells that express 
IL-6Rα, IL-6-dependent activation of the signal-
transducing gp130 receptor is mediated by 
membrane-bound IL-6Rα. alternatively; IL-6 in a 
complex with soluble IL-6Rα (sIL-6Rα) can 
activate gp130 in cells [31]. 

 
2.3 Rheumatoid Arthritis 
 
Rheumatoid arthritis (RA) is an autoimmune 
disease that causes chronic inflammation of the 
joint. Autoimmune diseases are illnesses that 
occur when the immune system mistakenly 
attacks the body [32]. The immune system 
contains a complex organization of cells and 
antibodies design to protect the body against 
infections, one of the most prominent among 
autoimmune diseases is rheumatoid arthritis; 
also refer to as systemic illness or rheumatoid 
disease [33].  

The other type of Rheumatoid arthritis is juvenile 
idiopathic arthritis which manifests in individuals 
less than 16 years of age [33]. When tissue 
inflammation occurs, the disease is active    
(relapsed) and the symptoms include fatigue, 
loss of appetite, muscle and joint pain, joint 
redness, joint swelling joint tenderness 
rheumatoid nodules and finally if the symptoms 
persist it lead to loss of joint function [33]. When 
tissue inflammation subsides, the disease is 
inactive (remission), remission may occur 
spontaneously with treatment and can last for 
weeks, month and years [33].  
 

RA targets synovial joints and is often 
accompanied by an array of extra-articular 
manifestations which are ultimately major 
predictors of increased morbidity and mortality 
[34]. It was discovered that joint damage occurs 
very early in RA, and after 2 years, 
approximately 50% of patients will exhibit bone 
erosions [35]. Early management of rheumatoid 
arthritis with disease-modifying antirheumatic 
drugs (DMARDs) is well recognized in regulating 
the disease severity, until recently, treatment 
options were limited to single or combination 
therapy with a relatively restricted therapeutic 
armament [36]. These comprise of 
immunosuppressive and DMARDs such as 
azathioprine, prednisolone sulfasalazine, and 
methotrexate [37]. Many of these medications 
reduce disease activity and block the radiological 
progression of bone erosion, judging by the 
clinical experience they are regarded to be 
suitable in many patients [38].  
 

2.4 Prevalence of Rheumatoid Arthritis 
Globally and in the US 

 

RA is a common disease that affects about 1% of 
the world population and about 0.6% of the 
American population, many adults are impacted 
by the condition with prevalence of 0·8–1·0% 
and the disease continues to cause significant 
morbidity and premature mortality [39]. The 
annual incidence of RA has been estimated to 
about 40 per 100,000 individuals, this shows that 
in each 100,000 individuals 40 new cases of RA 
are been diagnosed [40]. RA often initially 
impacts many children and individuals between 
30-50 years of age, surprisingly, about three-
quarters of all the individuals with RA are women 
[41]. 
 

2.5 Pathogenesis of Rheumatoid Arthritis 
 

In the synovial joint, there is an imbalance 
between pro-inflammatory cytokines and anti-



 
 
 
 

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263 

 

inflammatory cytokines [42]. T lymphocytes play 
an essential role by the production of various 
cytokines with different properties which facilitate 
the process of inflammation at the disease state 
[42]. Interestingly, the T-helper cells which have 
two main phenotypes are characterized by two 
distinct cytokine profiles namely Th1 and Th2 
along with the third subset called Th0 which is 
found to be the precursor of the two subsets [42]. 
Th0 cytokine profile is intermediate, hence Th1 
cells significantly intercede the cell-mediated 
immune response (CMI) while the Th2 cells 
intercede the humoral immune response, and 
these crucial steps determine whether the 
acquired immune response is dominated by 
activation of macrophage, cell - mediated 
immune response, pro-inflammatory activity of 
humoral immune response and anti-inflammatory 
activity [42]. 
 

T cell-induced in the presence of TNF α, IFN-γ, 
and IL-12 develop into Th-1 type of phenotype 
whereas those induced in the presence of IL-4, 
IL-6 and IL-10develops into Th-2 phenotype [43]. 
Evidence suggests that interaction between an 
unknown exogenous or endogenous antigen via 
antigen-presenting cells and CD4+ T helper cells 
are involved in the induction of inflammation in 
RA [43]. Continuous recruitment and activation of 
macrophages and monocytes occur with the 
recruitment of pro-inflammatory cytokines, 
specifically TNF-α and IL-1 and IL-6 into the 
synovial cavity, the release of these cytokines 

mediates tissue destruction by activation of 
chondrocytes and fibroblasts which release 
collagenases and metalloproteinase with 
resultant cartilage loss and bone erosion [44]. 
These activated macrophages, monocytes, 
lymphocytes and fibroblasts, as well as their 
product, also stimulate angiogenesis, which 
explains increased vascularity found in the 
synovium of patients with RA [44]. 

 
3. THERAPEUTIC TARGET  
 
TNF-α blockade: TNF-αis a potent cytokine that 
promotes inflammation by stimulating fibroblasts 
to express intercellular adhesion molecules that 
play a substantial role in inflammation, immune 
response and intracellular signalling event [46]. 
Interaction of these adhesion molecules with 
their respective ligands on the surface of 
leukocytes results in increased transport of 
leukocytes to inflammatory sites, including the 
joints in patients with rheumatoid arthritis [45].  

 
TNF-αindirectly down-regulates inflammation by 
stimulating the release of the corticotrophin-
releasing hormone, this hormone stimulates the 
adrenal cortex to release cortisol, which inhibits 
inflammation [46]. As an inflammatory cytokine, 
TNF-αhas an important role in rheumatoid 
synovitis as studied in the culture of synovial 
cells from patients with rheumatoid arthritis, by 
blocking the TNF-αwith antibodies significantly

 

 
 

Fig. 1. RA is characterized by proliferative synovium (pannus) and an excessive immune 
response of T-cells. Pannus comprises T-cells, synovial fibroblasts, and macrophages that 

produce inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin-1 (IL-1), IL-
6, and IL-17. These inflammatory cytokines activate osteoclasts, leading to bone destruction 

[45] 



 
 
 
 

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264 

 

reduced the production of interleukin-1, 
interleukin-6, interleukin-8, and granulocyte–
monocyte colony-stimulating factor [47]. Thus, 
the blockade of TNF-αhas a more precise effect 
on inflammation than the blockade of other 
cytokines present in high concentrations in the 
synovial membrane, such as interleukin-1 [48].  
 

The result of studies in the animal model shows 
the importance of TNF-αin rheumatoid arthritis, in 
transgenic mice that expressed a deregulated 
human TNF-αgene, there is the spontaneous 
development of polyarthritis which is another 
form of arthritis that affects many joints, and 
however first aid treatment of these animals with 
a monoclonal antibody against TNF-αprevents 
the development of RA [49]. 
 

Interleukin-1 receptor antagonist: The IL-1 
receptor antagonist (IL-1RA) is an endogenous 
ligand that binds the interleukin-1 receptor (IL-
1R) without recruiting the interleukin-1 receptor 
accessory protein (IL1-RAcP) to hinder the 
activation of the receptor, IL-1RA has a higher 
affinity for the IL-1R than IL-1α or IL-1β and 
serves to regulate the signaling of IL-1 by 
preventing the binding of other active cytokines 
[51].  
 

Deficiency of IL-1RA results in a reduction of 
regulatory function and can lead to severe 
inflammation and auto inflammatory disorders 
such as arthritis, vasculitis, and skin lesions in 
humans [52]. IL-1 binds to two types of cell-
surface receptors, type I receptors are found on 
many cells in trace amount, they have a 
cytoplasmic tail and are capable of intracellular 
signaling, while type II receptors are expressed 
primarily on neutrophils, monocytes and B cells, 
they are decoy receptors which bind circulating 
IL-1 without delivering any intracellular signal 
[53]. 
 

Soluble forms of both types of IL-1R compete 
with cell surface receptors thereby decreasing IL-
1 mediated activation of cells [54]. IL-1RA, binds 
the type I receptor with high affinity without 

triggering a signal, therefore providing another 
mechanism for inhibiting the IL-1 activity [55]. IL-
1 plays a critical role in joint damage by 
facilitating the degradation of cartilage which 
leads to rheumatoid arthritis, whereas the 
injection of antibodies against IL-1 suppresses 
collagen-induced arthritis in mice and decreases 
the damage to the cartilage [56]. 
 

Anti-interleukin 6 receptor: Interleukin-6 (IL-6) 
is a major pro-inflammatory cytokine with 
pleiotropic functions, IL-6 plays a key role in 
immune activation and inflammation in RA, thus, 
inhibition of IL-6 is a good strategy in controlling 
RA [57]. IL-6 has diverse and protein effects on 
many cell types, involved in both homeostatic 
and inflammatory pathways, however anti-IL-6 
receptor agent tocilizumab (TCZ) has become a 
major resource for the treatment of RA [58]. 
 

In patients with RA, TCZ has a dramatic effect on 
B lineage cells, with decreases in levels of 
circulating switched and unswitched memory B 
cells and with overall decreases in measured 
levels of antibody gene hypermutation in blood B 
cells [59]. A humanized IL-6R antibody, 
tocilizumab (TCZ), was developed by a research 
team from Chugai Pharmaceutical Company and 
Osaka University in Japan [59]. After several 
randomized clinical trials (RCTs), an intravenous 
formulation of TCZ (TCZ-IV) was approved for 
RA treatment in Japan in 2008, in Europe in 
2009, and in the USA in 2010 [58].  
 

Recently, a subcutaneous formulation of TCZ 
(TCZ-SC) was developed in consideration of 
patients’ preferences after a non-inferiority trial of 
TCZSC and TCZ-IV, TCZ-SC was approved in 
Japan and the USA in 2013 and Europe in 2014 
[60]. TCZ displays a good efficacy in patients 
with RA, including disease-modifying anti-
rheumatic drug (DMARD) naïve patients and 
patients with an inadequate response to 
conventional synthetic DMARDs (csDMARDs), 
methotrexate (MTX), or TNF inhibitors (TNFi) 
[60]. 

 

Table 2. Showing TNF-α blockers as the first therapeutic agents approved for the treatment of 
rheumatoid arthritis; TNF-α blockade has become a central strategy of targeted anti-

inflammatory therapy in the disease 
 

Agent Class Target Structure Ref. 

Adalimumab Cytokine inhibitor TNF-α Human monoclonal Antibody [50] 
Certolizumab 
 

Cytokine inhibitor TNF-α  egylated humani ed  Fab  fragment of an 
anti–TNF-α monoclonal antibody 

[50] 

Etanercept Cytokine inhibitor TNF-α TNF-α receptor–Fc fusion [50] 
Golimumab Cytokine inhibitor TNF-α Human monoclonal Antibody [50] 
Infliximab Cytokine inhibitor TNF-α Chimeric monoclonal Antibody [50] 



 
 
 
 

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Table 3. This therapeutic agent is considered one of the cytokine blockades in rheumatoid 
arthritis; it has profound effects on systemic features, acute phase response and synovitis 

 

Agent Class Target Structure Ref 

Anakinra Cytokine inhibitor Interleukin-1 Interleukin-1 receptor antagonist [57] 
 

Table 4. This therapeutic agent is considered to be one of the cytokine blockades in 
rheumatoid arthritis; it has profound effects on systemic features, acute phase response and 

synovitis 
. 

Agent Class Target Structure Ref 

Tocilizumab Cytokine inhibitor Interleukin-6 receptor Human monoclonal antibodies  [63] 

The overall efficacy including clinical responses 
and the radiographic damage progression of TCZ 
was comparable to that of other biological 
DMARDs such as TNFi [61]. IL-6 was found to 
affects psychosomatic functioning, sleep-related 
symptoms, and fatigue, while on the other hand, 
TCZ improves sleep quality and fatigue [62]. 
 

4. CONCLUSION 
 

This review has summarized the critical role 
played by the cytokines in the pathogenesis of 
RA. Persistent recruitment and activation of 
macrophages and monocytes occur with the 
recruitment of pro-inflammatory cytokines, 
specifically TNF-α and IL-1 and IL-6 into the 
synovial cavity which leads to tissue destruction 
by activation of chondrocytes and fibroblasts 
thereby releasing collagenases and 
metalloproteinase with resultant cartilage loss 
and bone erosion. However, due to the increase 
morbidity and premature mortality of RA in the 
world population, many therapeutic strategies are 
adopted to overcome the disease. The novel 
therapeutic approaches to RA that are aimed at 
restoring this cytokines imbalance include the 
use of monoclonal antibodies to TNF-α as 
mentioned in (Table 2) which mainly inhibit the 
proinflammatory cytokine activity, IL-1R-
antagonist such as Anakinra which suppresses 
collagen-induced arthritis thereby decreasing the 
damage to cartilage and the use of Tocilizumab 
which displays a good efficacy in patients with 
RA, including disease-modifying anti-rheumatic 
drug naïve patients and patients with an 
inadequate response to conventional synthetic 
DMARDs. 
 

CONSENT 
 

It is not applicable. 
 

ETHICAL APPROVAL 
 

It is not applicable. 

COMPETING INTERESTS 
 

Authors have declared that no competing 
interests exist. 
 

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