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Review
. 2023 Apr 28;9(5):e15839.
doi: 10.1016/j.heliyon.2023.e15839. eCollection 2023 May.

Efficacy and safety of tofacitinib combined with methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis

Yan Gao  1 , Yi-Ni Gao  1 , Mei-Jiao Wang  1 , Yi Zhang  1 , Feng-Qi Zhang  1 , Zhi-Xing He  1 , Wu Chen  1 , Hai-Chang Li  1 , Zhi-Jun Xie  1 , Cheng-Ping Wen  1
Affiliations
Review

Efficacy and safety of tofacitinib combined with methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis

Yan Gao et al. Heliyon. .

Abstract

Objective: To evaluate the efficacy and safety of tofacitinib in combination with methotrexate (MTX) versus MTX monotherapy in patients with active rheumatoid arthritis (RA).

Methods: Trials were identified from four electronic databases: PubMed, Web of science, Cochrane Library and EMBASE from inception to April 2022. Two independent reviewers evaluated each database to scan the title, abstract and keywords of each record retrieved. Full articles were further assessed when the information suggested that the study was a randomized clinical trial (RCT) comparing tofacitinib combined with MTX vs. MTX monotherapy in patients with active RA. Data were extracted from the literature, and the methodological quality of the included literature were evaluated and screened by two reviewers independently. The results were analyzed using RevMan5.3 software. The full text of the studies and extracted data were reviewed independently according to PRISMA guidelines. The outcome indicators were ACR 20, ACR 50, ACR 70, Disease activity score 28 (DAS28), erythrocyte sedimentation Rate (ESR) and adverse events (AEs).

Results: Of 1152 studies yielded by the search, 4 were retained, totaling 1782 patients (1345 treated with tofacitinib combined with MTX vs 437 received MTX. In the trial of insufficient response to MTX treatment, tofacitinib combined with MTX had significant advantages compared with MTX monotherapy. Numerically higher ACR20, ACR50 and ACR70 response rates were observed in the tofacitinib combined with MTX groups versus MTX monotherapy. ACR20 (odds ratio (OR), 3.62; 95% CI, 2.84-4.61; P < 0.001), ACR50 (OR, 5.17; 95% CI, 3.62-7.38; P < 0.001), and ACR70 (OR, 8.44; 95% CI, 4.34-16.41; P < 0.001), DAS28 (ESR) < 2.6 (OR, 4.71, 95% CI, 2.06-10.77; P < 0.001). The probability of adverse events of tofacitinib combined with MTX was lower than that of MTX monotherapy (OR, 1.42; 95% CI, 1.08-1.88; P = 0.01). The number of cases discontinued due to lack of efficacy or adverse events was similar in both groups (OR, 0.93; 95% CI, 0.52-1.68). The probability of abnormal liver enzymes in the treatment of tofacitinib combined with MTX was significantly lower than that of MTX monotherapy (OR, 1.86; 95% CI, 1.35-2.56). However, there was no significant difference between the two groups in severe adverse reactions, neutropenia, anemia and cardiovascular disease.

Conclusions: In terms of ACR20/50/70 and DAS28 (ESR), tofacitinib combined with MTX demonstrated superiority to MTX monotherapy in the treatment of patients with refractory RA. Considering the hepatoprotective and observably therapeutic efficacy, tofacitinib combined with MTX could be effective in treating refractory RA. However, in terms of hepatoprotective, it requires further large-scale and high-quality clinical trials to confirm.

Keywords: Meta-analysis; Methotrexate; Randomized controlled trial; Rheumatoid arthritis; Systematic review; Tofacitinib.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of study selection. RA = Rheumatoid arthritis; RCT = randomized controlled trial.
Fig. 2
Fig. 2
Risk-of-bias summary.
Fig. 3
Fig. 3
Pooled effects of Efficacy and safety of MTX combined with tofacitinib vs. MTX monotherapy for RA. Forest plots comparing tofacitinib plus MTX and MTX monotherapy for RA. (A) ACR20; (B) ACR50; (C) ACR70; （D）DAS28; MTX, methotrexate; ACR20, American college of Rheumatology 20; ACR50, American college of Rheumatology 50; ACR70, American college of Rheumatology 70; DAS28, Disease Activity Score.
Fig. 4
Fig. 4
Pooled effects of total AEs of MTX combined with tofacitinib vs. MTX monotherapy for RA. Forest plots comparing MTX and MTX plus tofacitinib treatment. Abbreviations: AEs, adverse events; MTX, methotrexate; RA, rheumatoid arthritis.
Fig. 5
Fig. 5
The sensitivity analysis of DAS28 Abbreviations: DAS28, Disease Activity Score.
Fig. 6
Fig. 6
Subgroup analysis of DAS28 based on different doses of tofacitinib. Forest plots comparing tofacitinib plus MTX and MTX monotherapy for RA. Abbreviations: MTX, methotrexate; DAS28, Disease Activity Score; RA, rheumatoid arthritis.
Fig. 7
Fig. 7
Subgroup analysis of AEs based on follow-up. Forest plots comparing tofacitinib plus MTX and MTX monotherapy for RA. Abbreviations: AEs, adverse events; MTX, methotrexate; RA, rheumatoid arthritis.
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