Efficacy and safety of total glucosides of paeony combined with methotrexate and leflunomide for active rheumatoid arthritis: a meta-analysis

Abstract

Purpose: Total glucosides of paeony (TGP) have been confirmed to reduce hepatotoxicity caused by methotrexate (MTX) and leflunomide (LEF) in rheumatoid arthritis (RA). Nevertheless, high-quality evidence-based meta-analysis data on the issue are unavailable. This study aimed to evaluate the efficacy and safety of this combination treatment for RA. Materials and methods: PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials, Chinese Biomedical Literature database, China National Knowledge Internet, Wan Fang, and VIP were searched up to February 2019. Randomized controlled trials (RCTs) on the efficacy and safety of TGP combined MTX and LEF for RA were included. Results: Eight RCTs were included in the final meta-analysis. Pooled results showed better therapeutic effects against RA in the TGP-treated group (RR =1.10, 95% CI: 1.04 -1.16). The TGP+MTX+LEF group showed a reduced erythrocyte sedimentation rate (MD = -2.80 mm/h, 95% CI: -5.08 - -0.52), C-reactive protein level (MD = -4.17 mg/L, 95% CI: -7.84 - -0.51), and rheumatoid factor (MD = -12.09 IU/mL, 95% CI: -14.05 - -10.14). Besides, the combination treatment tended to benefit lipid profiles (total cholesterol: 95% CI: -1.27-0.06; triglycerides: 95% CI: -0.49 - -0.08; high-density lipoprotein cholesterol: 95% CI: 0.15-0.83; and low-density lipoprotein cholesterol: 95% CI: -0.54 - -0.02). Adverse events, hepatotoxicity in particular, significantly decreased (RR =0.55, 95% CI: 0.38-0.80) in the TGP group. Conclusion: Compared to MTX and LEF therapy, TGP combination treatment may be a more effective and safer strategy. It is advisable to apply TGP as an adjuvant given its hepatoprotective and possible lipid-regulating effect. However, further large-scale and high-quality clinical trials are warranted, and the efficacy of TGP in terms of its effect on lipid profiles should be further confirmed.

Keywords: leflunomide; meta-analysis; methotrexate; rheumatoid arthritis; total glucosides of paeony.

Figure 1

Flow diagram of study selection.

Figure 2

Risk of bias assessment. Note: +, low risk of bias; ?, unclear risk of bias.

Figure 3

The pooled effects of TGP combined with MTX and LEF on TE, ESR, CRP, RF, DAS28, SJC, and TJC in cases of RA. Forest plots comparing TGP plus MTX and LEF with MTX and LEF. (A) TE; (B) ESR; (C) CRP; (D) RF; (E) DAS28; (F) SJC; (G) TJC. Abbreviations: TGP, total glucosides of paeony; MTX, methotrexate; LEF, leflunomide; TE, therapeutic effect; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; RF, rheumatoid factor; DAS28, disease activity score in 28 joints; SJC, swollen joint count; TJC, tender joint count.

Figure 4

Subgroup analysis of TE, ESR, and CRP based on the dosage of TGP. Forest plots comparing TGP plus MTX and LEF with MTX and LEF. (A) TE; (B) ESR; (C) CRP. Abbreviations: TGP, total glucosides of paeony; MTX, methotrexate; LEF, leflunomide; TE, therapeutic effect; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Figure 5

Subgroup analysis of TE, ESR, and CRP based on follow-up. Forest plots comparing TGP plus MTX and LEF with MTX and LEF. (A) TE; (B) ESR; (C) CRP. Abbreviations: TGP, total glucosides of paeony; MTX, methotrexate; LEF, leflunomide; TE, therapeutic effect; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; w, weeks.

Figure 6

Pooled effects of TGP combined with MTX and LEF on TC, TG, HDL-C, and LDL-C in cases of RA. Forest plots comparing TGP plus MTX and LEF with MTX and LEF. (A) TC; (B) TG; (C) HDL-C; (D) LDL-C. Abbreviations: TE, therapeutic effect; TGP, total glucosides of paeony; MTX, methotrexate; LEF, leflunomide; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Figure 7

Pooled effects of AEs of TGP combined with MTX and LEF for RA. Forest plots comparing TGP plus MTX and LEF with MTX and LEF treatment. (A) AE; (B) Abnormal liver function; (C) Leukopenia; (D) Nausea and vomiting; (E) Gastrointestinal disorder; (F) Diarrhoea. Abbreviations: AE, adverse event; TGP, total glucosides of paeony; MTX, methotrexate; LEF, leflunomide.

Figure 8

Sensitivity analysis. (A) ESR; (B) CRP; (C) DAS28; (D) SJC; (E) TJC; (F) AE. Abbreviations: ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; SJC, swollen joint count; TJC, tender joint count; AE, adverse event.

Figure 9

Begg’s regression analyses for publication bias. (A) TE; (B) ESR; (C) CRP; (D) RF; (E) DAS28; (F) SJC; (G) TJC; (H) AE. Abbreviations: ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; RF, rheumatoid factor; DAS28, disease activity score in 28 joints; SJC, swollen joint count; TJC, tender joint count; AE, adverse event.