Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis

Abstract

Background: There is a lack of high-quality meta-analyses and network meta-analyses of immunosuppressive drugs for lupus nephritis. Our objective was to assess the comparative benefits and harms of immunosuppressive drugs and corticosteroids in lupus nephritis.

Methods: We conducted a systematic review and network meta-analysis (NMA) of trials of immunosuppressive drugs and corticosteroids in patients with lupus nephritis. We calculated odds ratios (OR) and 95 % credible intervals (CrI).

Results: Sixty-five studies that met inclusion and exclusion criteria; data were analyzed for renal remission/response (37 trials; 2697 patients), renal relapse/flare (13 studies; 1108 patients), amenorrhea/ovarian failure (eight trials; 839 patients) and cytopenia (16 trials; 2257 patients). Cyclophosphamide [CYC] low dose (LD) and CYC high-dose (HD) were less likely than mycophenolate mofetil [MMF] and azathioprine [AZA], CYC LD, CYC HD and plasmapharesis less likely than cyclosporine [CSA] to achieve renal remission/response. Tacrolimus [TAC] was more likely than CYC LD to achieve renal remission/response. MMF and CYC were associated with a lower odds of renal relapse/flare compared to PRED and MMF was associated with a lower rate of renal relapse/flare than AZA. CYC was more likely than MMF and PRED to be associated with amenorrhea/ovarian failure. Compared to MMF, CYC, AZA, CYC LD, and CYC HD were associated with a higher risk of cytopenia.

Conclusions: In this systematic review and NMA, we found important differences between immunosuppressives used for the treatment of lupus nephritis. Patients and physicians can use this information for detailed informed consent in a patient-centered approach. Study limitations of between-study clinical heterogeneity and small sample size with type II error must be considered when interpreting these findings.

Prospero: CRD42016032965.

Keywords: Cyclophosphamide; Glucocorticoids; Immunosuppressive drugs; Lupus; Lupus nephritis; Mycophenolate mofetil; Network meta-analysis; Renal relapse; Renal remission; Tacrolimus.

Fig. 1

PRISMA study flow chart for study selection. Legend: none

Fig. 2

Network diagrams for composite study outcomes in lupus nephritis, renal remission or renal response (a), renal relapse or renal flare (b), fertility issues (c), and bone marrow toxicity (d). Legend: Each node shows the treatment compared along with the number of RCTs that provide evidence. The size of each node is proportional to the sample size. a shows only the direct evidence, while b–d show both direct and indirect evidence. Direct evidence is indicated by lines indicating the number of RCTs providing the evidence and indirect by lines without this information. This was done since there were several direct comparator studies available for a, and addition of connections based on indirect evidence to a would make the network diagram very complex and difficult to visualize and understand

Fig. 3

Rankograms for composite study outcomes in lupus nephritis, renal remission or renal response (a), renal relapse or renal flare (b), fertility issues (c), and bone marrow toxicity (d). Legend: This two-dimensional plot show on the x-axis (horizontal) the possible ranks of the treatment from best to the last ranks and on the y-axis (vertical) the probability of each of the treatments to assume those possible ranks for each outcome. For example, for renal relapse/flare (an undesired outcome), the highest probability was evident with corticosteroids alone, followed by MMF-AZA, followed by AZA and others