The DMARDs, non-steroidal anti-inflammatory drugs, corticosteroids and immunosuppressive

The treatment of rheumatoidarthritis has been revolutionized by advances in the understanding of itspathologic mechanisms and introduction of drugs that provide promise atimproving disease outcomes (Abdin et al., 2012). The main categoriesof drugs used to treat rheumatoid arthritis are DMARDs, non-steroidalanti-inflammatory drugs, corticosteroids and immunosuppressive drugs.

However, theseagents are associated with numerous side effects. Thus, there is a strong needto develop safe and effective drugs for the long-term use (Suke et al., 2013).

Adjuvant-inducedarthritis in rats is a well-established experimental model that has featuressimilar to the human rheumatoid arthritis.Adjuvant arthritis is characterized by chronic proliferative and inflammatoryreactions in synovial membranes and eventually destruction of joints with agood response to therapies effective in RA (Bauerova et al., 2010).

In addition, extra-articular signs such as thehepatic system are found to be a feature of adjuvant arthritis (Refaat et al., 2013).In the present study, the arthriticparameters (hind paw diameter, arthrogram score and histopathological pictureof rat joint) were assessed.  Leflunomide monotherapy suppressed arthritis progression as evidencedby reduction in the arthritic parameters rat joint grossly and microscopically.These findings confirmed previous observations demonstrating the potency ofleflunomide in reducing arthritis progression (Wang et al., 2010; Gowayed et al., 2015). Additionally, the quercetin treated rats in this study showedreduction of arthritic parameters in concordance with beneficial effect ofquercetin on joint inflammation that was previously documented (Mamani-Matsuda et al.

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, 2006; Haleagrahara et al., 2017). Paradoxically, thecombination of leflunomide and quercetin was not more effective in suppressingthe intensity of joint inflammation in comparison to leflunomide monotherapy.It was found previouslythat, TNF-? have been elevated in adjuvantarthritic models (Yi et al.,2012) which plays dominant role in mediating progression ofinflammatory joint disease and its local and systemic levels correspond todisease activity (Suke et al., 2013).Leflunomide is known to reduce cytokine generationthrough prevention of activation and gene expression of NF-?B , inaddition reduction of the cell-cell contact activation and homing ofinflammatory cells during the inflammatory reaction leading to decrease productionof TNF-? (Cutolo et al., 2003).

The generation of TNF-? in serum of adjuvant arthritic ratwas also suppressed by quercetin by inhibition of degradation of IkBwhich in turn contribute to inhibition of NF-?B activation and scavengingreactive oxygen species which are involved in the promotion of inflammatoryprocesses via activation of NF-?B (Boots et al., 2008; Haleagrahara et al., 2017). The results of the previous mentioned studies were inconcordance with the results of our study as each drug alone showed decrease inTNF-? level. The combined therapy was found to be highly beneficial indecreasing elevated TNF-? serum level than either drug alone.As lipid species such asprostaglandins play crucial roles in the tight regulation of inflammation, thusthey are considered to have an important function in the onset and developmentof arthritic diseases (Giera et al., 2012). Inanimal models of inflammatory arthritis, COX-2 increases parallel withprostaglandin production and clinical inflammation.

(Penning et al., 1997). Inour study, there is reduction in serum level of COX-2 in leflunomide treatedand quercetin treated group. The Reduction of serum level of COX-2 by bothleflunomide and quercetin is mainly due to direct inhibition of COX-2 activityand attenuation NF-?B activation asCOX-2 is considered to be one of the genes induced by activated NF-?B.

In addition, quercetin inhibit phospholipase c enzyme which release arachidonicacid 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 serumlevel among the treatment groups.

 Akey to cartilage erosion in RA is the matrix metalloproteinases. It has beenpreviously reported that the expression of MMP-1 correlates with the invasivegrowth of RA synovial fibroblast as increasing the expression of MMP-1 resultsin increasing cartilage invasion by RA synovial fibroblast (Niedermeier etal., 2010). Thepresent study demonstrated that adjuvant arthritic rats have shown asignificant increase in serum level of MMP-1 compared to their controlcounterpart and this result matched previous reported study (Mahmoud et al., 2005).

In our study, quercetincombination with leflunomide showed significant potentiating suppression ofMMP-1 serum level compared to other monotherapy regimens. The concomitantinhibition of activation of NF-?B and phosphorylation of MAPKpathways are reported to be the mechanism by which both leflunomide and quercetininhibit the MMP-1 in rheumatoid synovial fibroblast, since these two pathwaysare involved in MMP transcription (Migita et al., 2004; Sung et al., 2012).

Both oxidative stress andinflammation are inextricably tied processes. Chronic inflammation isassociated with elevated reactive oxygen species levels and the converse istrue (Terlecky et al., 2012). It has been discussedthat oxidative stress has an important role in etiologyof rheumatoid arthritis and pathogenesis of joint tissue injury and may lead toconnective tissue degradation and joint and periarticular deformities.(Hassan et al., 2011). Several clinical studies as well aspreclinical animal models of rheumatoid arthritis have documented an imbalancein the body redox homeostasis to a more pro-oxidative environment and thesestudies are in line with our results, suggesting that therapies that restorethe balance have a beneficial effect on the disease process (Jaswal et al., 2003; Drafi et al.

, 2012). Data of our study showed thatleflunomide had antioxidative activity which may be explained by its directeffect via inhibition of ROS products through suppressing TNF-induced ROSgeneration or indirect effect via prevention of polymorphonuclear cellsactivation which is the main source of ROS in RA (Karaman et al., 2006; Szabó-Taylor et al., 2013). Quercetin appears also to have an antioxidanteffect on arthritic joint in our study in concordance with other study (Ansari et al.

, 2014). Theanti-oxidant properties are largely a function of the chemical structure ofquercetin, particularly the presence and location of the hydroxyl (–OH)substitutions and the catechol-type B-ring thus allowing it to scavenge freeradicals more efficiently. In addition it augments glutathione and antioxidantenzyme levels (Heijnen et al., 2002; Liu et al., 2012).

Therefore, combining quercetin with leflunomide showed substantial increase inthe 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). Liverabnormalities in rheumatoid arthritis are either secondary to the underlyingdisease or due to the toxicity of therapies (Selmi et al.

, 2011). Furthermore, tissue damage isassessed by measuring the liver transaminases in serum and histopathologicalexamination of the liver tissue of rats. A markedincrease in serum transaminases levels was found to be a feature of adjuvantarthritis (Borashan et al., 2009; Comar et al., 2013) and was supported by our results.

Leflunomidetherapy expressed more pronounced increase in liver transaminases compared tountreated adjuvant arthritis in this study whichconfirmed the hepatotoxic effect of leflunomide observed in other researchwhich revealed that this effect may be explained by causing oxidativestress to liver (Lodhi et al., 2013; Bilasy et al., 2015a).

To the best of our knowledge, this isthe first study to highlight the effect of quercetin on liver damage caused byrheumatoid arthritis & leflunomide therapy. Thedecrease in serum transaminases was observed by quercetin and combinationtherapies. This beneficial effect of quercetin can occur through alleviation of liver damage by improving theantioxidant status and ameliorating inflammatory reactions (Qader et al.

,2014).A harmony was found in the presentwork between the microscopic picture of liver tissue and the results of liverenzymes. In quercetin-treated as well ascombination-treated rats, the normal cellular architecture of the liver wasmore retained as compared to leflunomide-treated and untreated adjuvantarthritic rats, thereby emphasizing a hepatoprotective effect for quercetin. The proposed mechanism by which leflunomideaffects the liver tissue is through activation of both neutrophils and kupffercells leading to release of cytotoxic mediators, such as reactive oxygenspecies and proinflammatory mediators which cause the recruitment ofinflammatory cells to liver and induce liver cell injury (Jaeschke et al.

,2002). Quercetin might reduce cytotoxicity andoxidative stress damage to liver tissue which is induced by the disease itselfand leflunomide treatment through it antioxidant and anti-inflammatory effect (Miltonprabu etal., 2017).

1.     ConclusionIt is, therefore,possible that by combining both leflunomide and quercetin, a window ofopportunity exists in the disease process not only for suppressing the diseaseaction but also for limiting inflammation 

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