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

Table 1

The characteristics of the included studies.

Subgroup

Study

Trial registration number

Country

Sample size (female/male)

Intervention

Relevant outcomes

Mean age (years)

Disease duration (years)

Disease severity

Baseline CRP (mg/L)

Baseline ESR (mm/h)

Baseline DAS28

Duration

Trial group

Control group

Trial group

Control group

Trial group

Control group

Trial group

Control group

Trial group

Control group

Trial group

Control group

Trial group

Control group

Trial group

Control group

N-acetylcysteine

Hashemi et al. 2019 [16]

IRCT2015071722965N2

Iran

23 (20/3)

19 (19/0)

N-acetylcysteine 600 mg Bid+conventional treatment (mainly methotrexate, sulfasalazine, hydroxychloroquine, prednisolone, calcium D, folic acid, nonsteroidal anti-inflammatory drugs)

Placebo+conventional treatment (mainly methotrexate, sulfasalazine, hydroxychloroquine, prednisolone, calcium D, folic acid, nonsteroidal anti-inflammatory drugs)

CRP, ESR, TNF-α, IL6, MDA, TAC, NO

Moderate: 13 patients; severe: 10 patients

Moderate: 10 patients; severe: 9 patients

—

—

12 weeks

Batooei et al. 2018 [17]

Cannot be found

Iran

27 (22/5)

24 (23/1)

N-acetylcysteine 600 mg Bid+conventional treatment (mainly methotrexate, sulfasalazine, hydroxychloroquine, calcium D, folic acid)

Placebo+conventional treatment (mainly methotrexate, sulfasalazine, hydroxychloroquine, calcium D, folic acid)

DAS28, ESR, number of tender joints, number of swollen joints, HAQ, VAS, adverse events

Moderate: 16 patients; severe: 11 patients

Moderate: 13 patients; severe: 11 patients

—

—

12 weeks

Yin et al. 2017 [18]

—

China

48 (42/6)

N-acetylcysteine 600 mg+conventional treatment (mainly sulfasalazine, methotrexate)

Conventional treatment (mainly sulfasalazine, methotrexate)

None

36-75

—

—

—

—

—

—

—

—

—

—

12 weeks

CoQ10

Abdollahzad et al. 2015 [19, 20]

IRCT201311014105N16

Iran

22 (19/3)

22 (20/2)

CoQ10 100 mg+conventional treatment (mainly methotrexate, sulfasalazine, hydroxychloroquine, prednisolone)

Placebo (wheat starch)+conventional treatment (mainly methotrexate, sulfasalazine, hydroxychloroquine, prednisolone)

DAS28, number of tender joints, number of swollen joints, TNF-α, IL6, VAS, ESR, MDA, TAC, adverse events

All patients are moderate and severe

—

—

8 weeks

Zhu et al. 2020 [30]

—

China

45 (35/10)

45 (37/8)

CoQ10 10 mg Tid+conventional treatment (mainly methotrexate, low-dose prednisone)

Placebo (wheat starch)+ conventional treatment (mainly methotrexate, low-dose prednisone)

CRP, ESR, TNF-α, IL6, MDA, TAC

5.2 (1.9, 8.6)

5.1 (2.2, 8.1)

—

—

—

—

12 weeks

Probiotic

Vaghef-Mehrabany et al. 2016 [31]

IRCT201207024105N10

Iran

22 (22/0)

24 (24/0)

Probiotic (Lactobacillus casei 01)+conventional treatment (mainly methotrexate, hydroxychloroquine, prednisolone)

Placebo+conventional treatment (mainly methotrexate, hydroxychloroquine, prednisolone)

MDA, SOD, GPx, CAT, TAC

4.75 (3.0, 9.0)

5.25 (3.75, 10.0)

All patients are inactive to moderate ()

—

—

—

—

<5.1

8 weeks

Zamani et al. 2017 [32]

IRCT201611165623N94

Iran

27 (22/5)

27 (24/3)

Synbiotic capsule (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum ( inulin)

Placebo (starch only)

CRP, DAS28, VAS, NO, TAC, GSH, MDA

All patients are moderate and severe

^#

^#

—

—

8 weeks

Pomegranate extract

Ghavipour et al. 2016 [33]

IRCT201202183236N2

Iran

30 (20/10)

30 (20/10)

Pomegranate extract (contained 40% ellagic acid) with no changes to current medication (mainly methotrexate, hydroxychloroquine, sulfasalazine, and prednisolone)

Placebo with no changes to current medication (mainly methotrexate, hydroxychloroquine, sulfasalazine, and prednisolone)

DAS28, HAQ, ESR, CRP, number of tender joints, number of swollen joints, MDA, GPx

Active RA

8 weeks

Quercetin

Javadi et al. 2017 [24, 25]

IRCT138807252394N2

Iran

20 (20/0)

20 (20/0)

Quercetin 500 mg+conventional treatment (mainly methotrexate, hydroxychloroquine, sulfasalazine, cyclosporine, prednisolone, NSAIDs)

Placebo+conventional treatment (mainly methotrexate, hydroxychloroquine, sulfasalazine, cyclosporine, prednisolone, NSAIDs)

DAS28, HAQ, ESR, CRP, TNF-α, number of tender joints, number of swollen joints, VAS, MDA, TAC

Mild to moderate disease activity

^#

^#

8 weeks

Bae et al. 2009 [34]

—

Korea

20 (19/1)

Quercetin+vitamin C (166 mg 133 mg/capsule)+conventional treatment (mainly hydroxychloroquine, sulfasalazine, methotrexate with folate, bucillamine, NSAID, low-dose steroid)

Placebo+conventional treatment (mainly hydroxychloroquine, sulfasalazine, methotrexate with folate, bucillamine, NSAID, low-dose steroid)

CRP, TNF-α, IL6

Not known

0.85 (0.28, 4.00)

1.05 (0.22, 6.44)

—

—

—

—

4 weeks

Resveratrol

Khojah et al. 2018 [35]

—

Egypt

50 (36/14)

50 (32/18)

Resveratrol 1000 mg+conventional treatment

Placebo+conventional treatment

Number of tender joints, number of swollen joints, DAS28, CRP, ESR, TNF-α, IL6

Not known

12 weeks

Garlic tablets

Moosavian et al. 2020 [26, 27]

IRCT20141108019853N6

Iran

31 (31/0)

31 (31/0)

Garlic tablets 500 mg (equivalent to 2500 mg of fresh garlic and containing 2.5 mg allicin) Bid with no changes to current medication (mainly prednisolone, methotrexate, sulfasalazine)

Placebo with no changes to current medication (mainly prednisolone, methotrexate, sulfasalazine)

HAQ, VAS, CRP, ESR, TNF-α, number of tender joints, number of swollen joints, MDA, TAC

All patients are moderate and severe

8 weeks

Conjugated linoleic acids

Aryaeian et al. 2009 [36]

—

Iran

22 (19/3)

22 (19/3)

Conjugated linoleic acid 2 g with no changes to current medication (mainly hydroxychloroquine, choloroquine and methotrexate, lower amounts of NSAIDs)

Placebo with no changes to current medication (mainly hydroxychloroquine, choloroquine and methotrexate, lower amounts of NSAIDs)

VAS, ESR, CRP, DAS28, number of tender joints, number of swollen joints

Mile: 11; moderate: 8; severe: 3

Mile: 8; moderate: 13; severe: 1

12 weeks

Conjugated linoleic acids+vitamin E

Aryaeian et al. 2009 [36]

—

Iran

22 (17/5)

Conjugated linoleic acids 2 g+vitamin E 400 mg with no changes to current medication (mainly hydroxychloroquine, choloroquine and methotrexate, lower amounts of NSAIDs)

Mile: 8; moderate: 10; severe: 4

Mile: 8; moderate: 13; severe: 1

12 weeks

Vitamin E

Aryaeian et al. 2009 [36]

—

Iran

21 (17/4)

Vitamin E 400 mg with no changes to current medication (mainly hydroxychloroquine, choloroquine and methotrexate, lower amounts of NSAIDs)

Mile: 7; moderate: 12; severe: 2

Mile: 8; moderate: 13; severe: 1

12 weeks

Edmonds et al. 1997 [37]

—

The UK

20 (16/4)

22 (15/7)

Vitamin E 600 mg Bid with no changes to current medication (mainly NSAID, methotrexate, Salazopyrin, azathioprine, D-penicillamine, Myocrisin, sulfasalazine, corticosteroids)

Placebo with no changes to current medication (mainly NSAID, methotrexate, Salazopyrin, azathioprine, D-penicillamine, Myocrisin, sulfasalazine, corticosteroids)

Adverse events

24-75

32-66

—

—

Not known

—

—

—

—

—

—

12 weeks

Wittenborg et al. 1998 [38]

—

Germany

42 (39/3)

43 (30/13)

Vitamin E 400 mg Tid with no changes to basic treatment and physical therapy; other NSAIDs are not allowed during treatment

Diclofenac-sodium 50 mg Tid with no changes to basic treatment and physical therapy; other NSAIDs are not allowed during treatment

VAS, adverse events

Not known

—

—

—

—

—

—

3 weeks

Selenium

Tarp et al. 1986 [39]

—

Denmark

20 (14/6)

20 (15/5)

Selenium 256 μg with no changes to current medication (mainly gold, 2 D-penicillamine, antimalarials, and NSAIDs)

Placebo with no changes to current medication (mainly gold, 2 D-penicillamine, antimalarials, and NSAIDs)

Number of swollen joints, ESR

Not known

—

—

—

—

24 weeks

Peretz et al. 1992 [40]

—

Belgium

8 (8/0)

7 (7/0)

Selenium 200 μg

Placebo

VAS, ESR

—

—

Not known

—

—

—

—

24 weeks

Peretz et al. 2001 [41]

—

Belgium

28 (21/7)

27 (20/7)

Selenium 200 μg with stable dose of corticosteroids and of disease-modifying drugs (such as NSAIDs and low-dose glucocorticosteroids)

Placebo with stable dose of corticosteroids and of disease-modifying drugs (such as NSAIDs and low-dose glucocorticosteroids)

Number of swollen joints, CRP, ESR, VAS

—

—

All patients are moderate

—

—

12 weeks

Heinle et al. 1997 [42]

—

Germany

38 (37/3)

32 (30/2)

Selenium 200 μg

Placebo with no changes to basic treatment and the cortisone or NSAIDs were adjusted as needed

Number of tender joints, number of swollen joints, CRP

Not known

—

—

—

—

12 weeks

Spa therapy

Karagülle et al. 2017 [43]

—

Turkey

15 (13/2)

22 (22/0)

Spa therapy+standard drug treatment (mainly methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine; glucocorticoids and NSAIDs)

Standard drug treatment (mainly methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine; glucocorticoids and NSAIDs)

VAS, HAQ, DAS28, MDA, number of tender joints, number of swollen joints, SOD, adverse events

Not known

—

—

12 weeks

Vitamins A, E, and C

Jaswal et al. 2003 [44]

—

India

20 (not known)

20 (not known)

Vitamins A, E, and C+conventional treatment

Conventional treatment

MDA, GSH

—

—

—

Not known

—

—

—

—

—

—

12 weeks

Ozone

León Fernández et al. 2016 [45]

—

Cuba

30 (28/2)

30 (27/3)

Ozone+methotrexate 12.5 mg+Ibuprophen 400 mg+folic acid 5 mg

Methotrexate 12.5 mg+Ibuprophen 400 mg+folic acid 5 mg

DAS28, HAQ, CRP, ESR, MDA, NO, GSH, SOD, CAT

All patients are moderate

3 weeks

H2-saline

Ishibashi et al. 2014 [46]

—

Japan

12 (10/2)

12 (10/2)

H2-saline 500 ml

Placebo

DAS28, CRP, TNF-α, IL6

Mean: 4.25

Mean: 4.92

Not known

—

—

4 weeks

Alpha-lipoic acid

Mirtaheri et al. 2015 [28, 29]

IRCT201205263140N5

Iran

33 (33/0)

32 (32/0)

Alpha-lipoic acid 1200 mg with no changes to current medication (mainly prednisolone, methotrexate, hydroxychloroquine, sulfasalazine, calcium and vitamin D, folic acid)

Placebo (maltodextrin) with no changes to current medication (mainly prednisolone, methotrexate, hydroxychloroquine, sulfasalazine, calcium and vitamin D, folic acid)

SOD, TAC, GPx, TNF-α, IL6, CRP

All patients are inactive to moderate ()

3 (1.1, 10.1)^#

3.5 (0.9, 9.5)^#

—

—

8 weeks

Bae et al. 2009 [34]

—

Korea

20 (19/1)

α-Lipoic acid (300 mg/capsule)+conventional treatment (mainly hydroxychloroquine, sulfasalazine, methotrexate with folate, bucillamine, NSAID, low-dose steroid)

Placebo+conventional treatment (mainly hydroxychloroquine, sulfasalazine, methotrexate with folate, bucillamine, NSAID, low-dose steroid)

CRP, TNF-α, IL6

Not known

0.84 (0.14, 4.28)

1.05 (0.22, 6.44)

—

—

—

—

4 weeks