The Efficacy of Antioxidative Stress Therapy on Oxidative Stress Levels in Rheumatoid Arthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Objective To explore the efficacy of antioxidative stress therapy on oxidative stress levels in rheumatoid arthritis (RA) by a systematic review and meta-analysis of randomized controlled trials. Methods Chinese and English databases such as PubMed, Embase, China National Knowledge Infrastructure (CNKI), and China Biomedical Literature were searched, mainly searching for clinical randomized controlled trials of antioxidant therapy for rheumatoid arthritis. The search time is from the establishment of the database to July 2021. Two researchers independently carried out literature search, screening, and data extraction. The bias risk tool provided by the Cochrane Collaboration was used to evaluate the bias risk of all the included literature, and the RevMan 5.3 software was used for meta-analysis. Results A total of 24 RCTs (28 records) and 1277 participants were included. The time span of randomized controlled trials (RCTs) is from 1986 to 2020. These RCTs involve 14 types of antioxidants or antioxidant therapies, and these therapies have varying degrees of improvement on oxidative stress in RA patients. The summary results showed that the MDA in the experiment group is lower (SMD -0.82, 95% CI -1.35 to -0.28, P = 0.003). The difference of TAC, SOD, NO, GPx, CAT, and GSH between two groups was of no statistical significance (TAC (SMD 0.27, 95% CI -0.21 to 0.75, P = 0.27), SOD (SMD 0.12, 95% CI -0.16 to 0.40, P = 0.41), NO (SMD -2.03, 95% CI -4.22 to 0.16, P = 0.07), GPx (SMD 0.24, 95% CI -0.07 to 0.54, P = 0.13), CAT (SMD 2.95, 95% CI -2.6 to 8.51, P = 0.30), and GSH (SMD 2.46, 95% CI -0.06 to 4.98, P = 0.06)). For adverse events, the summary results showed that the difference was of no statistical significance (RR 1.16, 95% CI 0.79 to 1.71, P = 0.45). In addition, antioxidant therapy has also shown improvement in clinical efficacy indexes (number of tender joints, number of swollen joints, DAS28, VAS, and HAQ) and inflammation indexes (ESR, CRP, TNF-α, and IL6) for RA patients. Conclusion The existing evidence shows potential benefits, mainly in reducing MDA and increasing TAC and GSH in some subgroups. However, more large samples and higher quality RCTs are needed to provide high-quality evidence, so as to provide more clinical reference information for the antioxidant treatment of RA.


Introduction
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of unknown etiology [1]. In the United States, RA affects more than 1.3 million adults, accounting for 0.6%-1% of the population [1,2]. Epidemiological research shows that the prevalence of rheumatoid arthritis in China is 0.2%~0.36%, which has increased from 5.8 million cases in 2015 to 5.9 million cases in 2019, and the 3-year disability rate has reached 70%; it has become a serious public health problem [3,4]. The clinical manifestation of RA is mainly a chronic inflammatory (nonsuppurative inflammation) disease of peripheral multiple joints. It may be accompanied by extra-articular systemic damage (causing subcutaneous nodules, pericarditis, myocarditis, pulmonary fibrosis, pleurisy, splenomegaly, renal amyloidosis, peripheral neuritis, arteritis, etc.) [5]. The pathological features of RA are mainly manifested as synovitis of the joints (which can later spread to articular cartilage, bone tissue, joint ligaments, and tendons), followed by extensive inflammation of connective tissues such as serosa, heart, lung, and eyes [5,6]. When the disease involves cartilage and bone, joint deformities may occur, that is, synovial inflammation, exudation, cell proliferation, granuloma formation, cartilage and bone tissue destruction, and finally joint stiffness and dysfunction [6]. The cartilage destruction of joints is related to the abnormal expression of cytokines, and the imbalance between protective cytokines and destructive cytokines is the basis of RA pathology [7]. In addition, inflammatory chemokines and immune-inflammatory cells jointly promote the exacerbation of the pathological process of RA [8].
Current research shows that in addition to inflammation [9], oxidative stress products also play an important role in the pathogenesis and pathological progress of RA [10]. Oxidative stress can produce too many free radicals, which will cause the oxidation of many molecules in the body. Excessive free radicals in the body of RA patients increase the level of the oxidation marker malondialdehyde (MDA), and the antioxidant enzyme superoxide dismutase (SOD) system is disturbed, which leads to the weakening of the body's antioxidant capacity and aggravating bone destruction [11][12][13][14]. In addition, oxidative stress is closely related to the energy metabolism of synovial tissue in RA patients [15]. Therefore, research on oxidative stress, SOD antioxidation, and regulation relationship in patients with RA can reveal the pathological mechanism of RA and find new anti-RA drugs. At present, many randomized controlled trials (RCTs) of antioxidants [16][17][18][19][20] in the treatment of RA patients have been published. However, the results and interventions of these RCTs are diverse, and the quality of the evidence provided varies, which cannot provide clinical doctors with evidence to formulate treatment measures against oxidative stress. Therefore, it is urgent to conduct a comprehensive and indepth systematic review and meta-analysis of these RCTs for the treatment of RA against oxidative stress. Therefore, this study will conduct a comprehensive systematic review and meta-analysis of RCTs for the treatment of RA against oxidative stress for the first time, in order to provide clinicians with high-quality evidence and promote the clinical practice of antioxidant treatment of RA in the future and to further improve the adjuvant therapy for RA patients.

Why Is This Systematic Review Important?
Oxidative stress plays a central role in the pathogenesis of RA. At present, evidence of clinical randomized controlled trials surrounding oxidative stress interventions has been reported one after another. However, the results and interventions of these RCTs are diverse, and the quality of the evidence provided is not uniform, and the levels are not uniform, which cannot provide clinical doctors and patients with evidence and treatment measures for the pathological mechanism of oxidative stress. Therefore, it is urgent to conduct a comprehensive and in-depth systematic review and meta-analysis of these RCTs for antioxidative stress treatment, in order to provide clinicians with high-quality evidence in the future, promote the clinical practice of RA treatment, and further improve the adjuvant treatment measures of RA.

Materials and Methods
3.1. Protocol. This systematic review and meta-analysis was conducted strictly in accordance with the protocol registered in PROSPERO (CRD42021256587) and PRISMA guidelines (see Supplementary Materials (available here)) [21].  Table S1 as an example.

3.3.2.
Intervention. The treatment of the experimental group is antioxidative stress therapy with no limitations to forms, preparations, and so on; the therapy could be combined with conventional therapy or the therapy in the control group. The treatment of the control group was conventional therapy or placebo or other nonantioxidative stress therapies.

Exclusion Criteria.
Exclusion criteria include non-RCT, review, cohort study, and patients with other rheumatism (such as systemic lupus erythematosus and Sjogren's syndrome).
3.4. Literature Screening and Risk of Bias Assessment. The two researchers jointly formulate a literature search strategy, independently collect literature, read literature titles and abstracts, and conduct preliminary screening. Then, the two researchers read the full text of the selected literature and finally determined the literature that met the inclusion criteria. The Cochrane Risk Bias Assessment Form is used to systematically evaluate the quality of the included literature. If opinions are inconsistent, they are resolved through discussion. The content of the risk assessment of bias includes [22] (1) random allocation method, (2) allocation plan hiding, (3) blind method, (4) completeness of result data, (5) selective reporting of research results, and (6) other sources of bias.
3.5. Data Extraction. The two researchers independently extracted data from the included literature, filled in the data extraction form, and cross-checked. The extracted content includes general information of the literature (such as author, sample size, patient's age, intervention time, and frequency) and related efficacy evaluation indicators [23].
3.6. Statistical Analysis. The Review Manager 5.3 software was used for statistical analysis. Subgroup analysis was carried out according to the intervention measures of RCTs. A heterogeneity test was performed on the included literature. If I 2 > 50% and P < 0:1, it is considered that there is a large heterogeneity, and the source of the heterogeneity is analyzed. If I 2 < 50% and P > 0:1, the heterogeneity is considered low (i.e., RCTs are homogeneous). The random effect model was used for analysis. For continuous variables, if the indicator units or measurement methods were different, or the value differs by more than 10 times, standardized mean difference (SMD) and 95% confidence interval (CI) would be used as the effect size indicator; for indicators with the same unit, weighted mean difference (WMD) and 95% confidence interval (CI) were used as the effect size indicator. For dichotomous variables, the risk ratio (RR) and 95% CI were used as the effect size indicator [23]. The publication bias was detected by STATA 15 with the Egger method (continuous variable) for outcomes with more than 5 RCTs. P > 0:1 is considered to have no publication bias.

4.1.
Results of the Search. The total records identified through database searching and other sources were 1984. According to the search strategy, a total of 29 articles were obtained through preliminary search. By eliminating duplicate documents and carefully reading the title and abstract, a total of 1955 articles were excluded. After carefully reading the full text and comparing the selection criteria, 28 records were screened out and finally included ( Figure 1).  [16,17,26,27,[31][32][33] describe the implementation process of the blind method and were rated as low risk of bias. Four RCTs [18,24,25,44,46] did not describe the implementation process of blinding, and the indicators of this study are biochemical indicators (such as MDA); they are assessed as low risk of bias. Twelve (12) RCTs [20,28,29,34,[36][37][38][39][40][41][42][43]45] claimed to use blinding but did not describe the implementation process of blinding 3 Oxidative Medicine and Cellular Longevity and included subjective indicators (such as DAS28 and VAS), so they were assessed as unclear risk of bias. Two RCTs [30,35] did not utilize blinding, and the indicators of this study are subjective indicators (such as VAS and DAS28); they are assessed as high risk of bias. Six RCTs [16,17,28,29,31,33,34] have missing data, and the number of missing is unbalanced, but no appropriate statistical treatment method is specified, and the risk of bias is estimated to be unclear.

Other Potential Bias.
Other sources of bias were not observed in 24 RCTs; therefore, the risks of other bias of the RCTs were low.

Outcomes
(1) Oxidative Stress Index and Adverse Events. A total of 11 RCTs reported MDA; the summary results showed that the MDA in the experiment group is lower (SMD -0.82, 95% CI -1.35 to -0.27, P = 0:003; random effect model) ( Figure 4). Eight RCTs reported TAC; the summary results showed that the difference was of no statistical significance (SMD 0.27, 95% CI -0.21 to 0.75, P = 0:27; random effect model) ( Figure 5). Four RCTs reported SOD; the summary results showed that the difference was of no statistical significance (SMD 0.12, 95% CI -0.16 to 0.40, P = 0:41; random effect model) ( Figure 6). Three RCTs reported NO; the summary results showed that the difference was of no statistical significance (SMD -2.03, 95% CI -4.22 to 0.16, P = 0:07; random effect model) ( Figure 7). Three RCTs reported GPx; the summary results showed that the difference was of no statistical significance (SMD 0.24, 95% CI -0.07 to 0.54, P = 0:13; random effect model) ( Figure 8). Two RCTs reported CAT; the summary results showed that the difference was of no statistical significance (SMD 2.95, 95% CI -2.6 to 8.51, P = 0:30; random effect model) ( Figure 9). Three RCTs reported GSH; the summary results showed that the difference was of no statistical significance (SMD 2.46, 95% CI -0.06 to 4.98, P = 0:06; random effect model) ( Figure 10   Oxidative Medicine and Cellular Longevity   showed that no obvious adverse events were seen in the two groups. The summary results showed that the difference was of no statistical significance (RR 1.16, 95% CI 0.79 to 1.71, P = 0:45; random effect model).
(2) Clinical Efficacy Indexes. Nine RCTs reported the number of swollen joints; the summary results showed that the number of swollen joints in the experiment group is lower (WMD -1.15, 95% CI -1.82 to -0.47, P = 0:0008; random effect model) ( Figure 12). Seven RCTs reported the number of tender joints; the summary results showed that the number of tender joints in the experiments group is lower (WMD -2.50, 95% CI -3.12 to -1.89, P < 0:00001; random effect model) ( Figure 13). Eleven RCTs reported the DAS28; the summary results showed that the DAS28 in the experiment group is lower (WMD -1.02, 95% CI -1.37 to -0.68, P < 0:00001; random effect model) ( Figure 14). Nine RCTs reported the VAS; the summary results showed that the VAS in the experiment group is lower (SMD -0.66, 95% CI -1.02 to -0.31, P = 0:0003; random effect model) ( Figure 15). Nine RCTs reported the HAQ; the summary results showed that the HAQ in the experiment group is lower (SMD -0.74, 95% CI -0.97 to -0.50, P < 0:00001; random effect model) ( Figure 16).
4.5.6. Resveratrol. Only one RCT utilized resveratrol to treat RA, and it reported number of tender joints, number of swollen joints, DAS28, CRP, ESR, TNF-α, and IL6. The RCT evaluated 100 patients with RA. The control group used traditional RA therapy, while the test group was treated with 1 g resveratrol on the basis of traditional therapy. The treatment lasted 3 months. The study showed that the number of swollen and tender joints and the DAS28 in the resveratrol group were significantly reduced (P < 0:05) (Figures 12-14), and CRP, ESR, TNF-α, and IL6 were also reduced (P < 0:05) (Figures 17-20).

Garlic Tablets.
Only one RCT utilized garlic tablets to treat RA. Moosavian et al. 2020 assessed the HAQ, VAS, CRP, ESR, TNF-α, number of tender joints, number of swollen joints, MDA, and TAC. The summary results showed that the MDA in the experiment groups was lower (SMD -0.62, 95% CI -1.13 to -0.11, P = 0:008) (Figure 4), while the TAC in the experiment groups was higher (SMD 2.01, 95% CI 1.39 to 2.63, P < 0:00001) ( Figure 5). It also showed that the difference of number of tender and swollen joints, ESR, and CRP between two groups was of no statistical significance (P > 0:05) (Figures 12, 13, 17, and 18), while the HAQ, VAS, and TNF-α in the experimental group were lower (P < 0:05) (Figures 15, 16, and 19).     (Figures 11 and 15).  uses vitamin E alone and in combination with conjugated linoleic acids to intervene in RA patients. It showed that when conjugated linoleic acids were used alone, number of tender joints, number of swollen joints, and DAS28 were improved (P < 0:05) (Figures 12-14), but VAS, ESR, and CRP were not significantly improved

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Oxidative Medicine and Cellular Longevity (P > 0:05) (Figures 15, 17, and 18). When conjugated linoleic acids were combined with vitamin E, number of swollen joints, VAS, and DAS28 were improved (P < 0:05) (Figures 13-15), but number of tender joints, ESR, and CRP were not significantly improved (P > 0:05) (Figures 13, 17, and 18).  (Figure 15). Heinle et al. 1997 also showed that the difference of number of tender joints between two groups was of no statistical significance (P > 0:05) (Figure 13).    . It also showed the number of swollen joints (P < 0:05) (Figure 12), while the difference of number of tender joints, DAS28, VAS, and HAQ between two groups was of no statistical significance (P > 0:05) (Figures 13-16).    (Figures 4, 7, 14, 16, and 17), while the GSH and CAT in the experiment group were higher (GSH (SMD 4.44, 95% CI 3.48 to 5.41, P < 0:00001); CAT (SMD 5.81, 95% CI 4.62 to 7.00, P < 0:00001)) (Figures 9 and 10). The difference of SOD and CRP was of no statistical significance (SOD (SMD 0.44, 95% CI -0.08 to 0.95, P = 0:10); CRP (WMD -8.00, 95% CI -16.08 to 0.08, P = 0:05)) ( Figures 6 and 18 Figure 13: Number of tender joints. 16 Oxidative Medicine and Cellular Longevity the clinical symptoms of RA patients (decreased DAS28) (P < 0:05) (Figure 14), while it has no obvious improvement effect on CRP (P > 0:05) ( Figure 18). The indicators of TNFα and IL6 could not be extracted, but the author reported that there was no significant change between the two compared with the placebo group ðP > 0:05).      (Figures 23(a) and 23(b)), while that in TNF-α may not have publication bias (P = 0:351) (Figure 23(b)).       Meanwhile, the addition of vitamin E to conventional therapy will not increase the occurrence of adverse events. (9) Selenium: current research has not shown that selenium has a therapeutic effect on RA. What is interesting is that for VAS, RCT showed different results. Because the data is expressed in different ways, it cannot be combined, so it is impossible to draw a certain conclusion. (10) Spa therapy: it has no significant improvement on MDA and SOD, and it may reduce number of swollen joints. Meanwhile, spa therapy may not increase adverse events. (11) Vitamins A, E, and C combination: this combination may decrease MDA and increase GSH. (12) Ozone: it may reduce MDA and NO levels and increase CAT and GSH levels in RA patients. Meanwhile, it may also reduce inflammation and relieve the condition (reduce DAS28, HAQ, and ESR). (13) H 2 -saline: The H 2 -saline may improve the clinical symptoms of RA patients (decreased DAS28). (14) Alpha-lipoic acid: current research has not shown that alpha-lipoic acid has a therapeutic effect on RA.

Discussion
In short, most antioxidants or antioxidant therapies can reduce MDA levels in RA patients, and a small number of therapies can increase GSH or TAC levels. And several anti-oxidants or antioxidant therapies may relieve pain and improve the quality of life of patients and the patient's condition. However, pomegranate extract may cause an increase in MDA. However, since there is only one RCT in most subgroups, the interpretation of the results still requires caution.

Possible
Mechanism of Antioxidant Treatment of RA. In 1986, Koster et al. found that compared with healthy controls, the serum sulfhydryl concentration of RA patients was lower [47]. Considering that the sulfhydryl group may act as a scavenger of peroxides, this discovery had already indicated that the oxidative stress in RA patients was excessive. Subsequently, the characteristics of oxidative stress in the pathogenesis of RA have been reported successively [14,[48][49][50][51]. Oxidative stress is a state where the body's oxidation and antioxidant effects are out of balance and tend to be oxidized. Oxidative stress can cause inflammatory infiltration of neutrophils and promote the massive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) free radicals [13,52] Figure 19: TNF-α. 22 Oxidative Medicine and Cellular Longevity [54,55], hypochlorous acid (HClO) [56], and hydroxyl radical ( ⋅ OH) [57]. RNS mainly includes nitrogen monoxide (NO) [58][59][60][61] and peroxynitroso (ONOO-) [62,63]. In addition, a variety of highly active molecules including oxidative stress will be produced under pathological conditions [56,63,64]. In addition to increasing the number of ROS/RNS under oxidative stress, antioxidants will also remove ROS/RNS substances or compounds, thereby inhibiting the oxidative stress process in cells [65]. Current research shows that there are mainly two different types of antioxidants, namely, enzymatic system and nonenzymatic system. The first type is mainly composed of SOD [65][66][67], CAT [68], GPx [69], glutathione reductase (GR) [70], and thioredoxin reductase [71]. ⋅ O 2 -and H 2 O 2 are the most ROS produced during oxidative stress [52,69]. The former is cleared by SOD [65], and the latter is cleared by CAT [68], GPx [69], and perredoxin (PRX) [72]. The nonenzymatic antioxidant system is mainly composed of vitamins (A, C, and E), beta carotene, antioxidants, and minerals such as copper, ferritin, zinc, manganese, and selenium [52,73]. Current basic research shows that oxidative stress plays a key role in the initiation and maintenance of systemic inflammation in RA [32,45,74,75]. Under the pathological conditions of RA, ROS and RNS are produced by neutrophils, monocytes, and macrophages in joint tissues [76]. They can damage different types of cell structures in joints, including DNA, carbohydrates, proteins, and lipids [14,17,43,74], leading to an imbalance of oxidative stress in joint tissues. Among them, the most common oxidation promoting factor (ROS/RNS) in RA joints is composed of ⋅ O 2 -, H 2 O 2 , ⋅ OH, NO ⋅ , ONOO-, HOCl, and LOO ⋅ [32,45,74,75]. In addition, in the occurrence and progression of RA joint damage, the oxidative stress imbalance and the inflammatory biological network are interconnected in multiple directions, which eventually leads to RA (synovitis) and forms a vicious circle. For example, ROS increases in RA patients [10] (mainly H 2 O 2 ), which in turn activates the NF-κB pathway [77]. NF-κB signal transduction immunity promotes more IL-1 and TNF-α. Activated macrophages and T cells in the synovium may induce the production of ROS through the release of TNF and IL-1. This way further amplifies the inflammation of synovitis, forming a positive feedback, and worsening the process of RA synovitis [78,79]. It is specifically manifested in the disease progression of RA patients. Compared with inactive RA patients, RA patients with active disease show higher ROS levels, more severe inflammatory factor levels, and lower antioxidant potential. Moreover, compared with healthy controls, these active RA patients have worse antioxidant capacity [74]. It is manifested by a higher degree of lipid peroxidation found in the synovial fluid and blood samples of these patients with possible RA [80,81].

Oxidative Medicine and Cellular Longevity
In addition, the increase in intra-articular pressure caused by chronic long-term inflammation in the joints of RA patients may lead to chronic hypoxia, which in turn increases the production of ROS in the joints of RA individuals [82]. The oxidation of type II collagen in the joints of patients with RA [10] and the increased production of matrix metalloproteinases [33] will cause oxidative damage to the matrix (extracellular environment) of the joints [10]. These oxidative stress factors can also induce stromal cells and joint cells (chondrocytes) to undergo programmed cell death caused by endoplasmic reticulum oxidative stress, which in turn leads to early joint damage in RA [10]. Further studies have also shown that oxidative stress can also cause other complications in RA patients. For example, high levels of inflammation and oxidative stress in RA patients can cause endothelial dysfunction and cause vascular damage to the circulatory system [83,84]. Controlling the oxidative stress imbalance and inflammation in the preclinical and chronic stages of RA can avoid complications in the circulatory system of RA patients [84]. Aiming at the mechanism of oxidative stress in the clinical diagnosis and treatment of RA patients, oxidative stress biomarkers have been used as relevant markers and protocols to assess the disease activity and prognosis of RA patients [50,82]. For example, Quiñonez-Flores et al. [50] found that lipid peroxidation (through MDA level) can be used to detect disease activity in RA patients (disease activity score DAS28), which expands the potential applicability of oxidative biomarkers in the diagnosis and prognosis of RA patients.

Characteristic Analysis of Included Studies. A total of 24
RCTs were included in this study, with a time span from 1986 to 2020. These 24 RCTs used a total of 14 different therapies; they were N-acetylcysteine, CoQ10, probiotic, pomegranate extract, quercetin, resveratrol, garlic tablets, vitamin E and conjugated linoleic acids, selenium, spa therapy, vitamins A, E, and C, ozone, H 2 -saline, and alpha-lipoic acid. Hashemi et al. 2019 [16], Batooei et al. 2018 [17], included patients were mainly women. This is consistent with the facts: the incidence of RA is higher in women than in men, and women are 2 to 3 times that of men, and it occurs more frequently in 30-50 years of age [85][86][87]. Therefore, the results of this study mainly show the effect of antioxidant therapy in women with RA. Although it also shows potential effects for men, more samples are needed to further

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Oxidative Medicine and Cellular Longevity give better evidence. Most RCTs reported disease duration, baseline CRP, baseline ESR, and baseline DAS28, while a small number of RCTs did not report these baseline data. Baseline data suggest that the disease duration of most patients is more than 5 years, and most RCTs select moderate to severe patients in the active phase for the study.
In general, the quality of RCTs is medium to high. However, since most RCTs are not blinded, and a small number of studies have not conducted allocation concealment and description of random sequence generation methods, the interpretation of the results still needs to be cautious.

Strengths and Limitations of This Research and
Inspiration for Future Research. The strengths of this research is that it is the first meta-analysis involving the improvement of oxidative stress in RA patients with 25 Oxidative Medicine and Cellular Longevity antioxidants and antioxidant therapies. The RCTs collected in this study span 34 years (1986-2020) involving 1277 participants, and a comprehensive systematic review and metaanalysis of previous related studies have been extensively conducted. The quality of RCT is generally high. In addition, the RCTs included this time involve multiple countries and ethnic groups, including Belgium, China, Cuba, Denmark, Egypt, the UK, Germany, India, Iran, Japan, Korea, and Turkey, which makes the results more applicable.
The limitations of this research is that most subgroups have only one RCT (such as the N-acetylcysteine, pomegranate extract, quercetin, garlic tablets, spa therapy, vitamins A, E, and C combination, and ozone subgroup in MDA; all subgroups of SOD, NO, GPx, CAT, and GSH). This affects the credibility of the results, because only one RCT cannot represent all the population. Meanwhile, there are many RCTs that do not involve indicators of oxidative stress, such as Yin et al. 2017 [18] [42], and Ishibashi et al. 2014 [46]. Therefore, more research on the effects of these therapies on oxidative stress indicators in RA patients is needed. Meanwhile, the intervention duration of these RCTs is different, which may affect the effect of drug intervention in RA. In addition, although most RCTs are considered to be of high quality, blinding methods (such as Yin et al. 2017 [18], Abdollahzad et al. 2015 [19,20] [45], and Ishibashi et al. 2014 [46]) are not used. The main reason they were rated as low risk of bias was that the main outcome indicators were objective indicators (serum MDA, etc.). However, we still need to be vigilant, because the failure to implement blinding may affect other outcome indicators that are not focused on in this study. Therefore, in the future, more well-designed, randomized controlled double-blind clinical trials are needed to verify or modify the outcome indicators.
In MDA outcomes, there was a result contrary to most results: the MDA in the pomegranate extract group was higher than that of the control group. This is a very interesting result, because it suggests that pomegranate extract may

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Oxidative Medicine and Cellular Longevity have a reverse effect. However, since there is only one RCT, the result is unstable. Therefore, we look forward to more pomegranate extract-related RCTs in the future. In addition, although current RCTs show that antioxidants or antioxidant therapies do not increase the incidence of adverse events, most RCTs do not report safety outcomes. Therefore, it is expected that future RCTs will report more on the incidence of corresponding adverse events to determine the safety of those therapy.

Conclusion
Oxidative stress plays an important role in the pathophysiology of RA. This study showed through systematic reviews and meta-analysis that although there are currently fewer RCTs for antioxidant therapy, the existing evidence shows potential benefits, mainly in reducing MDA and increasing TAC and GSH. Meanwhile, it was also found that the combination of antioxidant therapy and conventional therapy is the main choice for reducing RA disease and preventing cardiovascular complications in the future. However, considering the small number of patients recruited, the study design varies greatly between different RCT studies, and the characteristics of RA participants included in different RCT studies are not the same; it is difficult to immediately extrapolate these results to general RA patients. In the future, more large samples and higher quality RCTs are needed to provide high-quality evidence, so as to provide more clinical reference information for the antioxidant treatment of RA.

Data Availability
All data generated or analyzed during this study are included in this published article.

Conflicts of Interest
We declare no competing interests.