Multitarget Therapy: An Effective and Safe Therapeutic Regimen for Lupus Nephritis

- Introduction: We evaluated the effectiveness and safety of various multitarget therapies for inducing remission in lupus nephritis patients. Methods: Randomized controlled trials (RCT) were identified and extracted from the Embase, PubMed, Chinese Biomedical Literature Database (CBM), and the Cochrane Library until Oct 31, 2018, investigations meeting inclusion criteria were extracted, and data were analyzed by meta-analysis. The total remission (TR; complete to partial remission), complete remission (CR), albumin, proteinuria levels, negative rate of anti-double-stranded DNA antibody (ds-DNA), negative rate of anti-nuclear antibody (ANA), and systemic lupus erythematosus disease activity index (SLE-DAI) were calculated using the software of RevMan 5.3. Results: Eleven RCTs were included and analyzed. The multitarget therapy group exhibited a higher value of CR (OR=3.06, 95%CI: 2.35-3.99, P ﹤ 0.00001) as well as TR (OR=3.83, 95%CI: 2.77-5.31, P ﹤ 0.00001) than those in the cyclophosphamide (CYC) group. In addition, multitarget therapies had more albumin (WMD=3.50, 95%CI: 1.04-5.95, P=0.005), greater albumin increases (OR=1.96, 95%CI: 0.63-3.29, P=0.004) and higher negative rates of ds-DNA (OR=2.13, 95%CI: 1.51-3.01, P ﹤ 0.0001) and ANA (OR=2.82, 95%CI: 1.77-4.50, P ﹤ 0.0001) when compared with the CYC group. This group also had less proteinuria levels (WMD=-0.55, 95%CI: -0.79 to -0.30, P ﹤ 0.0001), lower degrees of SLE-DAI (OR=-1.80, 95%CI:-2.78 to -0.81, P=0.0004), and a lower adverse reaction rate. For example, gastrointestinal syndrome, irregular menstruation and leucopenia happened less frequently in the multitarget therapy group. However, hypertension was more prevalent in the multitarget therapy group. Conclusions: Multitarget therapy is an effective and safe intervention for inducing remission in lupus nephritis patients.


INTRODUCTION
Lupus nephritis (LN) is the most frequent major complication in patients with systemic lupus erythematosus (SLE), and the morbidity is approximately 30%-50% in SLE patients [1,2]. Immune activation of B cells and T helper cells can not only play a role in the pathogenesis of SLE, but also induce the inflammation, which is associated with the onset of LN [3]. B cells are also involved in T cell activation and cytokine production [4]. Persistent inflammation may induce permanent damage in the glomerulus and kidney tubules, resulting in chronic kidney disease. Without intervention, LN can develop into end stage renal disease.
Glucocorticoids (GC) plus cyclophosphamide (CYC) is the traditional therapy for LN, which is used to improve long-term prognosis of patients with LN. However, severe adverse effects are associated with this treatment, including sepsis, malignancy, hemorrhagic cystitis, and amenorrhea.
In the past decades, some new immunosuppressants such as tacrolimus (TAC), cyclosporine A (CsA), mycophenolate mofetil (MMF), and leflunomide are used to treat LN.
Multitarget therapies, such as TAC plus MMF or leflunomide plus MMF, are successfully used for immunosuppression in patients with kidney transplants, and these drugs have additive inhibitory effects on lymphocytes [2]. In this study, we conducted a meta-analysis to calculate the effectiveness and safety of multitarget therapies for the induction of remission of lupus nephritis patients.

________________________________________ MATERIALS AND METHODS
Search strategies for identified studies A search strategy of Cyclophosphamide, CYC, Tacrolimus, TAC, Mycophenolate mofetil, MMF, Leflunomide, LEF, systemic lupus erythematosus and lupus nephritis, were entered into Embase, PubMed, Chinese Biomedical Literature Database (CBM), and the Cochrane Library (up to Oct 31, 2018) to identify eligible studies without language limitations. Other resources such as the references cited in articles relevant to this update were also evaluated.

Selection of studies
By reviewing the titles, abstracts, and, if necessary, the full texts, two abstractors individually screened out relevant studies. Publications were included in the analysis if patients were diagnosed as lupus nephritis by renal biopsy, and the study type was limited to randomized controlled trials. Eligibility criteria required individuals to have received different types of immunosuppressants combinations as the multitarget therapies in one arm of the treatment and CYC in the other. On the contrary, retrospective studies, one-arm studies, case reports, letters, reviews, guidelines and comments were excluded from the study. Studies with unclear diagnostic criteria for lupus nephritis in the trials were also not included. Reviewers would discuss and resolve any discordant opinions. In the analysis, only those randomized controlled trials related to the multitarget therapies for LN were included.

Outcome measures
The primary outcomes, including the effectiveness and tolerance of multitarget therapy, were assessed. The efficacy was measured by related indices such as total remission (TR; complete remission (CR) plus partial remission (PR)), CR, rise of serum albumin, decrease of urinary protein excretion, negative rate of anti-double-stranded DNA antibody (ds-DNA) and anti-nuclear antibody (ANA), systemic lupus erythematosus disease activity index (SLE-DAI). The safety of multitarget therapies was measured by adverse reaction rate and side effects such as gastrointestinal syndrome, hypertension, hyperglycemia, leucopenia, infection of various organ systems, herpes zoster or varicella, alopecia, and irregular menstruation.

STATISTICAL ANALYSIS
Review Manager Version 5.3 software was used to pool the data extracted from the individual studies. I 2 statistics was used to detect the heterogeneity. When the p-value  0.1 for the heterogeneity test, a fixed effects model was chosen for a more conservative estimate. If not, a random effects model was used to pool the results. Continuous data were presented using weighted mean differences (WMDs), and the odds ratio (OR) was used to show the binary data. 95% confidence intervals (95% CI) were assessed in the included studies. A value of p < 0.05 was regarded as statistical significance.

DISCUSSION
In this meta-analysis, we assessed the effectiveness and safety of multitarget therapies in inducing remission in lupus nephritis patients. The results indicate that multitarget therapies can result in superior rates of TR, and CR, decreased rates of ds-DNA and ANA, and low proteinuria levels. The safety of multitarget therapy was also assessed, and the results indicated that the multitarget therapy group exhibited lower adverse reaction rates than that the CYC group. Adverse events including leucopenia, gastrointestinal syndrome and irregular menstruation were less prevalent in the multitarget therapy group. These results indicate that multitarget therapy is an effective and safe treatment for lupus nephritis patients.
In the sub-group analysis, the multitarget therapy regimen of TAC+MMF had greater values for TR, CR, albumin, and albumin increase, and decreased levels of ds-DNA, ANA, proteinuria and SLE-DAI compared to CYC. There were eight RCTs included for this meta-analysis. Furthermore, the comparison of the multitarget therapy regimen of leflunomide +MMF with CYC indicated that the multitarget therapy group had greater of TR and CR, and decreased levels of ds-DNA, ANA, proteinuria. There were only three RCTs included for this meta-analysis, and additional studies are needed to confirm these findings.
In a previous study, Deng et al [16] performed a meta-analysis and reported that multitarget therapy is more effective at inducing CR compared with CYC, and the rates of irregular menstruation, leukopenia, gastrointestinal symptoms and were significantly reduced in the multitarget therapy group compared with the CYC group. However, the multitarget therapy group exhibited a higher prevalence of new-onset hypertension than the CYC group. Our meta-analysis had similar results, and we also included a meta-analysis of leflunomide +MMF vs. CYC.
In the current meta-analysis, the results indicate that multitarget therapy is a valid therapeutic option for inducing remission in lupus nephritis patients. Additional RCTs are needed to confirm the effectiveness and safety of multitarget therapies for LN.