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 | 53.91 ± 13.90 | 50.68 ± 11.15 | 10.52 ± 7.19 | 10.05 ± 7.56 | Moderate: 13 patients; severe: 10 patients | Moderate: 10 patients; severe: 9 patients | 8.57 ± 0.99 | 7.89 ± 1.11 | 26.91 ± 4.29 | 26.26 ± 6.77 | — | — | 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 | 53.2 ± 12.5 | 51.6 ± 11.3 | 10 ± 7.0 | 9.8 ± 8.2 | Moderate: 16 patients; severe: 11 patients | Moderate: 13 patients; severe: 11 patients | 31.4 ± 19.6 | 29.2 ± 19.3 | — | — | 5.1 ± 1.2 | 5.3 ± 1.1 | 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 | 48.77 ± 11.58 | 50.41 ± 11.28 | 6.91 ± 5.87 | 6.94 ± 6.50 | All patients are moderate and severe | — | — | 39.64 ± 25.53 | 40.27 ± 25.75 | 5.01 ± 1.21 | 4.88 ± 0.96 | 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 | 48.15 ± 11.68 | 47.36 ± 12.11 | 5.2 (1.9, 8.6)∗ | 5.1 (2.2, 8.1)∗ | — | — | 56.15 ± 20.13 | 57.42 ± 18.46 | 42.21 ± 16.11 | 41.26 ± 15.26 | — | — | 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 | 41.14 ± 12.65 | 44.29 ± 9.77 | 4.75 (3.0, 9.0)∗ | 5.25 (3.75, 10.0)∗ | All patients are inactive to moderate (DAS28 < 5.1) | — | — | — | — | <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 (2 × 109 colony‐forming units/g each) + 800 mg inulin) | Placebo (starch only) | CRP, DAS28, VAS, NO, TAC, GSH, MDA | 49.3 ± 11.0 | 49.5 ± 12.9 | 7.7 ± 6.1 | 7.5 ± 6.4 | All patients are moderate and severe | 6.03 ± 4.84# | 5.64 ± 5.14# | — | — | 4.2 ± 0.7 | 3.5 ± 0.8 | 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 | 48.4 ± 11.4 | 49.1 ± 12.2 | 10.9 ± 5.8 | 12.3 ± 5.8 | Active RA | 29.0 ± 15.6 | 30.6 ± 19.6 | 8.0 ± 4.2 | 6.6 ± 4.5 | 4.9 ± 0.8 | 4.7 ± 1.1 | 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 | 46.55 ± 9.94 | 48.00 ± 8.39 | 5.17 ± 3.83 | 4.87 ± 3.03 | Mild to moderate disease activity | 2.89 ± 2.95# | 3.28 ± 2.32# | 19.00 ± 8.62 | 21.10 ± 12.38 | 3.22 ± 0.93 | 3.13 ± 1.1 | 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 | 52.1 ± 10.3 | 10.2 ± 5.9 | 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 | 46.5 ± 12.3 | 44.2 ± 16.4 | 9.4 ± 5.8 | 9.8 ± 5.5 | Not known | 2.7 ± 0.7 | 2.9 ± 0.8 | 39.4 ± 11.5 | 43.8 ± 14.8 | 4.62 ± 0.99 | 4.91 ± 0.92 | 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 | 51.06 ± 13.8 | 51.39 ± 10.38 | 6.58 ± 7.75 | 6.61 ± 8.11 | All patients are moderate and severe | 13.44 ± 13.76 | 13.57 ± 14.04 | 23.63 ± 13.82 | 20.10 ± 11.74 | 4.61 ± 0.92 | 4.52 ± 0.78 | 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 | 46.23 ± 13.07 | 47.95 ± 11.14 | 9.95 ± 8.41 | 8.88 ± 8.65 | Mile: 11; moderate: 8; severe: 3 | Mile: 8; moderate: 13; severe: 1 | 7.19 ± 10.13 | 6.44 ± 7.90 | 26.81 ± 15.50 | 28.36 ± 21.55 | 4.63 ± 1.26 | 4.35 ± 0.95 | 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) | 43.77 ± 12.75 | 47.95 ± 11.14 | 7.64 ± 6.19 | 8.88 ± 8.65 | Mile: 8; moderate: 10; severe: 4 | Mile: 8; moderate: 13; severe: 1 | 5.24 ± 6.44 | 6.44 ± 7.90 | 28.45 ± 17.26 | 28.36 ± 21.55 | 4.59 ± 1.11 | 4.35 ± 0.95 | 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) | 49.33 ± 11.89 | 47.95 ± 11.14 | 7.24 ± 5.82 | 8.88 ± 8.65 | Mile: 7; moderate: 12; severe: 2 | Mile: 8; moderate: 13; severe: 1 | 9.06 ± 14.33 | 6.44 ± 7.90 | 40.43 ± 26.22 | 28.36 ± 21.55 | 4.52 ± 1.08 | 4.35 ± 0.95 | 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 | 61 ± 9 | 58 ± 9 | 10 ± 9 | 11 ± 11 | 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 | 54.3 ± 12.4 | 54.6 ± 12.7 | 16.4 ± 10.1 | 10.5 ± 8.0 | Not known | — | — | 47 ± 35 | 39 ± 26 | — | — | 24 weeks | |
| Peretz et al. 1992 [40] | — | Belgium | 8 (8/0) | 7 (7/0) | Selenium 200 μg | Placebo | VAS, ESR | 61 ± 11 | — | — | Not known | — | — | 23 ± 15 | 30 ± 17 | — | — | 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 | 61 ± 13 | 60 ± 13 | — | — | All patients are moderate | 28 ± 17 | 28 ± 17 | 34 ± 16 | 29 ± 12 | — | — | 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 | 58.2 ± 12.78 | 57.2 ± 13.27 | 12.69 ± 8.3 | 12.03 ± 7.8 | Not known | 23.4 ± 18 | 17.1 ± 28 | — | — | — | — | 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 | 53.3 ± 11.1 | 52.3 ± 12.3 | 12.3 ± 12.9 | 13.4 ± 12.0 | Not known | — | — | 38.5 ± 18.0 | 38.5 ± 18.0 | 6.5 ± 0.9 | 5.9 ± 1.6 | 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 | 57 ± 7 | 53 ± 7 | 11 ± 3 | 7 ± 2 | All patients are moderate | 16 ± 4 | 21 ± 7 | 36 ± 6 | 40 ± 6 | 6.4 ± 0.2 | 5.6 ± 0.3 | 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 | 62.4 ± 18.4 | 68.2 ± 12.6 | Mean: 4.25 | Mean: 4.92 | Not known | 14.7 ± 17 | 13 ± 20 | — | — | 5.10 ± 0.96 | 5.18 ± 1.16 | 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 | 36.09 ± 8.77 | 38.28 ± 8.63 | 7.26 ± 4.9 | 6.78 ± 4.72 | All patients are inactive to moderate (DAS28 < 5.1) | 3 (1.1, 10.1)∗# | 3.5 (0.9, 9.5)∗# | — | — | 2.1 ± 0.76 | 2.14 ± 0.72 | 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 | 52.1 ± 10.3 | 10.2 ± 5.9 | Not known | 0.84 (0.14, 4.28)∗ | 1.05 (0.22, 6.44)∗ | — | — | — | — | 4 weeks | |||||