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The treatment of rheumatoid
arthritis has been revolutionized by advances in the understanding of its
pathologic mechanisms and introduction of drugs that provide promise at
improving disease outcomes (Abdin et al., 2012). The main categories
of drugs used to treat rheumatoid arthritis are DMARDs, non-steroidal
anti-inflammatory drugs, corticosteroids and immunosuppressive drugs. However, these
agents are associated with numerous side effects. Thus, there is a strong need
to develop safe and effective drugs for the long-term use (Suke et al., 2013).

arthritis in rats is a well-established experimental model that has features
similar to the human rheumatoid arthritis.
Adjuvant arthritis is characterized by chronic proliferative and inflammatory
reactions in synovial membranes and eventually destruction of joints with a
good response to therapies effective in RA (Bauerova et al., 2010). In addition, extra-articular signs such as the
hepatic system are found to be a feature of adjuvant arthritis (Refaat et al., 2013).

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In the present study, the arthritic
parameters (hind paw diameter, arthrogram score and histopathological picture
of rat joint) were assessed.  Leflunomide monotherapy suppressed arthritis progression as evidenced
by reduction in the arthritic parameters rat joint grossly and microscopically.
These findings confirmed previous observations demonstrating the potency of
leflunomide in reducing arthritis progression (Wang et al., 2010; Gowayed et al., 2015). Additionally, the quercetin treated rats in this study showed
reduction of arthritic parameters in concordance with beneficial effect of
quercetin on joint inflammation that was previously documented (Mamani-Matsuda et al., 2006; Haleagrahara et al., 2017). Paradoxically, the
combination of leflunomide and quercetin was not more effective in suppressing
the intensity of joint inflammation in comparison to leflunomide monotherapy.

It was found previously
that, TNF-? have been elevated in adjuvant
arthritic models (Yi et al.,
2012) which plays dominant role in mediating progression of
inflammatory joint disease and its local and systemic levels correspond to
disease activity (Suke et al., 2013).
Leflunomide is known to reduce cytokine generation
through prevention of activation and gene expression of NF-?B , in
addition reduction of the cell-cell contact activation and homing of
inflammatory cells during the inflammatory reaction leading to decrease production
of TNF-? (Cutolo et al., 2003). The generation of TNF-? in serum of adjuvant arthritic rat
was also suppressed by quercetin by inhibition of degradation of IkB
which in turn contribute to inhibition of NF-?B activation and scavenging
reactive oxygen species which are involved in the promotion of inflammatory
processes via activation of NF-?B (Boots et al., 2008; Haleagrahara et al., 2017). The results of the previous mentioned studies were in
concordance with the results of our study as each drug alone showed decrease in
TNF-? level. The combined therapy was found to be highly beneficial in
decreasing elevated TNF-? serum level than either drug alone.

As lipid species such as
prostaglandins play crucial roles in the tight regulation of inflammation, thus
they are considered to have an important function in the onset and development
of arthritic diseases (Giera et al., 2012). In
animal models of inflammatory arthritis, COX-2 increases parallel with
prostaglandin production and clinical inflammation.(Penning et al., 1997). In
our study, there is reduction in serum level of COX-2 in leflunomide treated
and quercetin treated group. The Reduction of serum level of COX-2 by both
leflunomide and quercetin is mainly due to direct inhibition of COX-2 activity
and attenuation NF-?B activation as
COX-2 is considered to be one of the genes induced by activated NF-?B.
In addition, quercetin inhibit phospholipase c enzyme which release arachidonic
acid from cell membrane on which COX-2 act on to produce prostaglandins (Burger et al., 2003; Roman-Blas and Jimenez, 2006; Bellik et al., 2012; Ansari et al., 2014).
Moreover, the combination therapy expressed the highest decrease in COX-2 serum
level among the treatment groups.

key to cartilage erosion in RA is the matrix metalloproteinases. It has been
previously reported that the expression of MMP-1 correlates with the invasive
growth of RA synovial fibroblast as increasing the expression of MMP-1 results
in increasing cartilage invasion by RA synovial fibroblast (Niedermeier et
al., 2010). The
present study demonstrated that adjuvant arthritic rats have shown a
significant increase in serum level of MMP-1 compared to their control
counterpart and this result matched previous reported study (Mahmoud et al., 2005). In our study, quercetin
combination with leflunomide showed significant potentiating suppression of
MMP-1 serum level compared to other monotherapy regimens. The concomitant
inhibition of activation of NF-?B and phosphorylation of MAPK
pathways are reported to be the mechanism by which both leflunomide and quercetin
inhibit the MMP-1 in rheumatoid synovial fibroblast, since these two pathways
are involved in MMP transcription (Migita et al., 2004; Sung et al., 2012).

Both oxidative stress and
inflammation are inextricably tied processes. Chronic inflammation is
associated with elevated reactive oxygen species levels and the converse is
true (Terlecky et al., 2012). It has been discussed
that oxidative stress has an important role in etiology
of rheumatoid arthritis and pathogenesis of joint tissue injury and may lead to
connective tissue degradation and joint and periarticular deformities.(Hassan et al., 2011). Several clinical studies as well as
preclinical animal models of rheumatoid arthritis have documented an imbalance
in the body redox homeostasis to a more pro-oxidative environment and these
studies are in line with our results, suggesting that therapies that restore
the balance have a beneficial effect on the disease process (Jaswal et al., 2003; Drafi et al., 2012). Data of our study showed that
leflunomide had antioxidative activity which may be explained by its direct
effect via inhibition of ROS products through suppressing TNF-induced ROS
generation or indirect effect via prevention of polymorphonuclear cells
activation which is the main source of ROS in RA (Karaman et al., 2006; Szabó-Taylor et al., 2013). Quercetin appears also to have an antioxidant
effect on arthritic joint in our study in concordance with other study (Ansari et al., 2014). The
anti-oxidant properties are largely a function of the chemical structure of
quercetin, particularly the presence and location of the hydroxyl (–OH)
substitutions and the catechol-type B-ring thus allowing it to scavenge free
radicals more efficiently. In addition it augments glutathione and antioxidant
enzyme levels (Heijnen et al., 2002; Liu et al., 2012).
Therefore, combining quercetin with leflunomide showed substantial increase in
the antioxidant activity which is mainly revealed to the quercetin effect.

Among patients with arthritis,
hepatic involvement has been reported in cases of rheumatoid arthritis (Subramanian, 2009). Liver
abnormalities in rheumatoid arthritis are either secondary to the underlying
disease or due to the toxicity of therapies (Selmi et al., 2011). Furthermore, tissue damage is
assessed by measuring the liver transaminases in serum and histopathological
examination of the liver tissue of rats. A marked
increase in serum transaminases levels was found to be a feature of adjuvant
arthritis (Borashan et al., 2009; Comar et al., 2013) and was supported by our results. Leflunomide
therapy expressed more pronounced increase in liver transaminases compared to
untreated adjuvant arthritis in this study which
confirmed the hepatotoxic effect of leflunomide observed in other research
which revealed that this effect may be explained by causing oxidative
stress to liver (Lodhi et al., 2013; Bilasy et al., 2015a). To the best of our knowledge, this is
the first study to highlight the effect of quercetin on liver damage caused by
rheumatoid arthritis & leflunomide therapy. The
decrease in serum transaminases was observed by quercetin and combination
therapies. This beneficial effect of quercetin can occur through alleviation of liver damage by improving the
antioxidant status and ameliorating inflammatory reactions (Qader et al.,

A harmony was found in the present
work between the microscopic picture of liver tissue and the results of liver
enzymes. In quercetin-treated as well as
combination-treated rats, the normal cellular architecture of the liver was
more retained as compared to leflunomide-treated and untreated adjuvant
arthritic rats, thereby emphasizing a hepatoprotective effect for quercetin. The proposed mechanism by which leflunomide
affects the liver tissue is through activation of both neutrophils and kupffer
cells leading to release of cytotoxic mediators, such as reactive oxygen
species and proinflammatory mediators which cause the recruitment of
inflammatory cells to liver and induce liver cell injury (Jaeschke et al.,
2002). Quercetin might reduce cytotoxicity and
oxidative stress damage to liver tissue which is induced by the disease itself
and leflunomide treatment through it antioxidant and anti-inflammatory effect (Miltonprabu et
al., 2017).


It is, therefore,
possible that by combining both leflunomide and quercetin, a window of
opportunity exists in the disease process not only for suppressing the disease
action but also for limiting inflammation 

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