Oxidative Stress Relevance in the Pathogenesis of the Rheumatoid Arthritis: A Systematic Review

Table 2

Summary of reported oxidant and antioxidant markers in RA patients compared to control group.

Author	Lipid oxidation	Protein oxidation	DNA oxidation	Urate oxidation	Enzymatic activity	Antioxidants	Free radicals/anions	Main findings
García-González et al., 2015 [27]	TBARS:	PC:	NE	NE	SOD: ; GPx:	GSH: ; GSSG:	NE	Oxidative damage was elevated in RA patients. Antioxidants enzyme activities, GSH levels, and GSH/GSSG ratio were higher in RA than in control group; however they were insufficient to prevent oxidative damage.
Thiele et al., 2015 [18]	MAA:	NE	NE	NE	NE	NE	NE	MAA adduct formation is increased in RA and colocalized with citrullinated proteins. MAA antibodies are associated with ACPA production. This suggests that MAA formation may drive tolerance loss to autoantibody formation in RA.
Datta et al., 2014 [16]	MDA: sf^❖	PC: sf^❖; AOPP: sf^❖; RSNO: sf^❖	NE	NE	NE	NE	Total ROS: sf^❖; : sf^❖	All oxidative damage markers correlated positively with DAS-28; therefore the measurement of oxidative stress could serve as a biomarker for monitoring disease severity in RA.
Nakajima et al., 2014 [17]	NE	NE	NE	NE	NE	NE	ROM:	Serum level of ROM was associated with CRP and DAS-28 suggesting that ROM may be able to be used as a disease marker to evaluate the disease activity.
Nzeusseu Toukap et al., 2014 [19]	NE	CT:	NE	NE	MPO:	NE	NE	MPO activity, MPO, and CT levels were significantly higher in synovial fluid of RA patients than OA patients. MPO activity and concentration were correlated with IL-8 and IL-18 in untreated but not in treated RA patients.
Veselinovic et al., 2014 [28]	TBARS:	NE	NE	NE	CAT: ; SOD:	GSH:	H2O2: ; : ; :	Higher levels of prooxidants in RA compared to control group. Stronger response in samples with higher diseases activity suggests that oxidative stress markers may be useful in evaluating the progression of RA.
Wang et al., 2014 [35]	NE	NE	NE	NE	MPO:	NE	NE	Serum levels of MPO higher in RA than control group. Moderate positive correlations between MPO levels and CRP, DAS-28. These results support a role for MPO in the inflammatory process of RA.
Jacobson et al., 2012 [26]	MDA:	NE	NE	NE	GPx:	Anti-Cap:	NE	There were no differences between RA cases and control group for oxidative stress and antioxidant capacity; however, GPx level was markedly elevated in RA. GPx levels were not associated with severity disease or CRP.
Kundu et al., 2012 [33]	NE	NE	NE	NE	NADPH ox: ,	NE	Total ROS: , ; : , ; OH: , ; : ,	ROS generated in both peripheral blood and synovial infiltrate correlated positively with both DAS-28 and CRP/ACPA levels; its measurement can serve as an indirect measure of the degree of inflammation in patients with RA.
Kwaśny-Krochin et al., 2012 [29]	F2-I:	NE	NE	NE	NE	NE	NE	ADMA levels are significantly higher in RA than in control group. Positive associations between plasma ADMA levels and the production of 8-isoprostanes and CRP in RA.
Mishra et al., 2012 [42]	MDA: s	NE	NE	NE	NE	NE	NE	LDL, total lipid, cholesterol, MDA, CRP, and triglycerides are elevated and HDL levels decreased in RA compared with control group.
Stamp et al., 2012 [20]	NE	PC: ; CT: sf	NE	ALLA:	MPO:	NE	NE	MPO protein concentration is elevated in RA and promotes oxidative stress through the production of hypochlorous acid. There is a significant relationship between plasma MPO concentration and DAS-28.
Staroń et al., 2012 [21]	TBARS:	NE	NE	NE	CAT: ; SOD: ; GPx:	GSH: ; -SH:	NE	There are no significant differences in CAT and GPx activities. SOD activity is lower and lipid peroxidation is increased in RA. GSH and -SH groups are significantly lower in RA.
Alver et al., 2011 [31]	MDA: ,	NE	NE	NE	CAT: ; SOD: ; GPx:	GSH:	NE	The CAII autoantibody titers were significantly higher in RA. The increased erythrocyte oxidative stress in RA may be effective in the mechanism of CA II autoantibody production.
Aryaeian et al., 2011 [34]	MDA:	NE	NE	NE	GR: ; AE:	β-C: ; VE:	NE	There is an increased oxidative stress (MDA elevated) and a low antioxidant status (vitamin E, β-carotene, and GR activity diminished) in patients with RA.
Ediz et al., 2011 [25]	MDA: , ,	NE	NE	NE	CAT: , , ; GPx: , , ; MPO: , ,	NE	NE	There was positive correlation between ACPA levels and synovial MDA and MPO in ACCP (+) group. ACPA positivity seems to be associated with increased synovial fluid oxidant activity in RA.
Hassan et al., 2011 [10]	MDA:	NE	NE	NE	GPx:	GSH:	NE	Oxidative stress was increased in RA. DAS-28 significantly correlated with MDA levels and negatively with GSH.
Karaman et al., 2011 [30]	MDA:	NE	DNA sb: ; MN:	NE	SOD: ; GPx:	NE	NE	Elevated degree of oxidative stress in RA patients associated with DNA damage.
Shah et al., 2011 [32]	MDA:	NE	NE	NE	CAT: ; SOD: ; GPx:	GSH:	NE	Elevated ROS production disturbs redox status and can modulate the expression of inflammatory chemokines leading to inflammatory processes, exacerbating inflammation, and affecting tissue damage.
Desai et al., 2010 [22]	MDA:	NE	NE	NE	SOD: ; GR:	NE	NE	There is an increased oxidative stress and a decreased antioxidant defense in patients with RA.
Rho et al., 2010 [23]	F2-I:	NE	NE	NE	NE	NE	NE	F2-isoprostanes were higher in RA and they significantly modified the protective effect of HDL cholesterol against coronary calcification.
Tetik et al., 2010 [24]	NE	PC:	NE	NE	NE	-SH:	NE	Protein carbonyls content was higher in RA as compared to controls while the plasma -SH levels in RA was significantly lower than control. CRP levels were higher in RA.

ACPA: anti-citrullinated protein antibodies, ADMA: asymmetric dimethylarginine, AE: arylesterase, ALLA: allantoin, Anti-cap: total antioxidant capacity, AOPP: advanced oxidation protein products, CAII: carbonic anhydrase II autoantibody, CAT: catalase, CRP: C-Reactive Protein, CT: 3-chlorotyrosine, DAS-28: disease activity score, DNA sb: DNA strand breaks, e: erythrocyte, F2-I: F2-isoprostane, GPx: glutathione peroxidase, GR: glutathione reductase, GSH: reduced glutathione, GSSG: oxidized glutathione, H₂O₂: hydrogen peroxide, HDL: high density lipoprotein, IL: interleukin, L: lymphocytes, LDL: low density lipoprotein, MAA: malondialdehyde-acetaldehyde, MDA: malondialdehyde, MN: micronucleus, MPO: myeloperoxidase, n-b: neutrophils isolated from blood, n-sf: neutrophils isolated from synovial fluid, NADPH ox: nicotinamide adenine dinucleotide phosphate oxidase, NE: not evaluated, : nitric oxide, : superoxide anion radical, OA: osteoarthritis, OH: hydroxyl radical, p: plasma, PC: protein carbonyls, RA: rheumatoid arthritis, ROM: reactive oxygen metabolites, ROS: reactive oxygen species, RSNO: S-nitrosothiols, s: serum, -SH: thiol group, sf: synovial fluid, st: synovial tissue, SOD: superoxide dismutase, TBARS: thiobarbituric acid reactive substances, U: urine, VE: vitamin E, wb: whole blood, and β-C: -carotene.
Significantly elevated levels, significantly diminished levels, no significantly difference, and marker measured with no comparison control group; protein concentration (no activity); significantly elevated levels of MPO protein concentration in SF compared with plasma (both derived from RA patients); marker compared with neutrophils from RA patients.