Effectiveness and safety of common therapeutic drugs for refractory lupus nephritis: A network meta-analysis

Abstract

Previous studies have indicated that various drugs may be beneficial for the treatment of patients with refractory lupus nephritis (RLN). The present study aimed to evaluate the effectiveness and safety of common therapeutic drugs for the treatment of RLN using a network meta-analysis (NMA). NMA was performed using Stata 14.0 software. The odds ratio (OR) and 95% CI were calculated. A total of 19 studies comprising 1,127 patients were included. Common therapeutic drugs for RLN included glucocorticoids (GC), cyclophosphamide (CTX), mycophenolate mofetil (MMF), tacrolimus (TAC), leflunomide (LEF), cyclosporine A and rituximab (RTX). Evaluation of the effectiveness revealed that MMF + GC produced significantly higher overall responses (i.e. complete remission plus partial remission) and that MMF + GC (OR=2.58; 95% CI, 1.67-3.97), CTX + RTX + GC (OR=3.89; 95% CI, 1.60-9.45), CTX + LEF + GC (OR=3.05; 95% CI, 1.05-8.84) and CTX + TAC + GC (OR=6.22; 95% CI, 1.93-20.05) had significantly higher overall responses compared with those to the traditional treatment regimen (CTX + GC). Ranking probability based on the surface under the cumulative ranking curve indicated that CTX + TAC + GC had the highest probability (80.6%) of being the best treatment for achieving an overall response. In the safety evaluation, MMF + GC had a lower risk of infection than CTX + GC (OR=0.32; 95% CI, 0.11,0.88). There were no statistically significant differences in adverse reactions, including gastrointestinal reactions and leukopenia between any two treatment regimens. In conclusion, the regimen of CTX + TAC + GC exhibited a trend in superiority regarding clinical efficacy among common therapeutic drug treatments for RLN, while the regimen of CTX + GC had a higher probability to cause adverse effects among the nine interventions compared.

Keywords: cyclophosphamide; mycophenolate mofetil; network meta-analysis; refractory lupus nephritis; tacrolimus.

Figure 1.

Flow diagram of the selection of included studies.

Figure 2.

Network diagram of evidence for treatment efficacy of each regimen. The size of each node is proportional to the sample size of the individual treatment regimen; the widths of the connecting lines are proportional to the number of studies compared between the two regimens. GC, glucocorticoid; CTX, cyclophosphamide; MMF, mycophenolate; TAC, tacrolimus; LEF, leflunomide; RTX, rituximab; CsA, cyclosporine A.

Figure 3.

Funnel plot for assessment of publication bias or small sample effect. A, GC; B, CTX+GC; C, MMF+GC; D, LEF+GC; E, FK506+GC; F, CsA+GC; G, CTX+RTX+GC; H, CTX+LEF+GC; I, CTX+FK506+GC. GC, glucocorticoid; CTX, cyclophosphamide; MMF, mycophenolate; TAC, tacrolimus; LEF, leflunomide; RTX, rituximab; CsA, cyclosporine A.

Figure 4.

Comparison of the therapeutic effects of the regimens. The OR and 95% CI for comparison of the efficacy of each treatment regimen are provided. The results of the plots are read from top to bottom and from left to right. An OR >1 indicates that the treatment on the top left is better than the comparative treatment. For instance, the effectiveness of TAC+CTX+GC is better than that of CTX+GC. The underlined and bold numbers indicate statistical significance. OR, odds ratio; GC, glucocorticoid; CTX, cyclophosphamide; MMF, mycophenolate; TAC, tacrolimus; LEF, leflunomide; RTX, rituximab; CsA, cyclosporine A.

Figure 5.

Comparison of infections after treatment according to each regimen. An OR <1 means that the possibility of infection after treatment on the top left was lower than that after the comparative treatment. For instance, MMF+GC treatment of RLN had a lower risk of infection than CTX+GC. OR, odds ratio; GC, glucocorticoid; CTX, cyclophosphamide; MMF, mycophenolate; TAC, tacrolimus; LEF, leflunomide; RTX, rituximab; CsA, cyclosporine A.

Figure 6.

Comparison of gastrointestinal reactions and leukopenia after treatment with each regimen. Green indicates the comparison of gastrointestinal reactions after treatment with each regimen; light blue indicates the comparison of leukopenia after treatment with each regimen. GC, glucocorticoid; CTX, cyclophosphamide; MMF, mycophenolate; TAC, tacrolimus; LEF, leflunomide; RTX, rituximab; CsA, cyclosporine A.