Huan XIE, Jin DENG, Lei LUO, Hongping XIE, Lin ZHU

Multitarget therapy versus intravenous cyclophosphamide in the induction treatment of lupus nephritis: a metaanalysis of randomized controlled trials

Background/aim: Multitarget therapy for lupus nephritis (LN) remains in its exploratory phrase and the recent evidence is insufficient.This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF), tacrolimus (TAC), and steroids (multitargettherapy) versus intravenous cyclophosphamide (IVC) and steroids in induction treatment of LN.Materials and methods: We searched for randomized controlled trials of MMF plus TAC versus IVC in LN using PubMed, EMBASE, theCochrane Central Register of Controlled Trials, the China Biology Medicine Database, and the China National Knowledge InfrastructureDatabase. We assessed the retrieved citations and selected studies according to predefined inclusion and exclusion criteria.Results: In total, we identified 8 trials including 801 patients. The metaanalysis revealed that overall multitarget therapy is more effectiveat inducing complete renal remission compared with IVC (RR: 1.94, 95% CI: 1.61–2.33; P < 0.00001). In terms of LN classification,multitarget therapy exhibited superiority compared with IVC for inducing complete remission of class IV LN (RR: 1.52, 95% CI: 1.10–2.08; P = 0.01), class V LN (RR: 4.24, 95% CI: 1.30–13.88; P = 0.02), and class V+IV LN (RR: 2.29, 95% CI: 1.45–3.62; P = 0.0004);however, no superiority was noted for class III LN or class V+III LN. The rates of gastrointestinal symptoms, abnormal liver function,leukopenia, and irregular menstruation were significantly reduced in the multitarget therapy group compared with the IVC group forLN. Nevertheless, the multitarget therapy group more frequently exhibited new-onset hypertension compared with the IVC group.Conclusion: Multitarget therapy is more effective than IVC in the induction treatment of LN in Chinese patients and exhibits a bettersafety profile.

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Jaryal A, Vikrant S. Current status of lupus nephritis. Indian J Med Res 2017; 145: 167-178.
Yap DY, Tang CS, Ma MK, Lam MF, Chan TM. Survival analysis and causes of mortality in patients with lupus nephritis. Nephrol Dial Transpl 2012; 27: 3248-3254.
Chen YE, Korbet SM, Katz RS, Schwartz MM, Lewis EJ. Value of a complete or partial remission in severe lupus nephritis. Clin J Am Soc Nephro 2008; 3: 46-53.
Hanaoka H, Kiyokawa T, Iida H, Ishimori K, Takakuwa Y, Okazaki T, Yamada H, Ichikawa D, Shirai S, Koike J et al. Comparison of renal response to four different induction therapies in Japanese patients with lupus nephritis class III or IV: a single-centre retrospective study. PLoS One 2017; 12: e0175152.
Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthrit Care Res 2012; 64: 797-808.
Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, Boletis J, Cervera R, Dorner T, Doria A et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012; 71: 1771-1782.
Mok CC, Yap DY, Navarra SV, Liu ZH, Zhao MH, Lu L, Takeuchi T, Avihingsanon Y, Yu XQ, Lapid EA et al. Overview of lupus nephritis management guidelines and perspective from Asia. Nephrology 2014; 19: 11-20.
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sanchez-Guerrero J, Solomons N et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20: 1103-1112.
Weng MY, Weng CT, Liu MF. The efficacy of low-dose mycophenolate mofetil for treatment of lupus nephritis in Taiwanese patients with systemic lupus erythematosus. Clin Rheumatol 2010; 29: 771-775.
Li X, Ren H, Zhang Q, Zhang W, Wu X, Xu Y, Shen P, Chen N. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transpl 2012; 27: 1467- 1472.
Najafi CC, Korbet SM, Lewis EJ, Schwartz MM, Reichlin M, Evans J. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int 2001; 59: 2156-2163.
Sloan RP, Schwartz MM, Korbet SM, Borok RZ. Long-term outcome in systemic lupus erythematosus membranous glomerulonephritis. Lupus Nephritis Collaborative Study Group. J Am Soc Nephrol 1996; 7: 299-305.
Liu CB, Hu WX, Xie HL, Zhang HT, Chen HP, Zeng CH, Liu ZH, Li LS. Mycophenolate mofetil versus intravenous pulse cyclophosphamide for class IV plus V lupus nephritis. Chin Nephrol Dail Transplant 2006; 15: 1-6.
Zhang HT, Hu WX, Xie HL, Zeng CH, Chen HP, Liu ZH, Li LS. Randomized controlled trial of tacrolimus versus intravenous cyclophosphamide in the induction therapy of class V plus IV lupus nephritis Chin Nephrol Dail Transplant 2006; 15: 508- 514.
Bargman JM. How did cyclophosphamide become the drug of choice for lupus nephritis? Nephrol Dial Transpl 2009; 24: 381- 384.
Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, Chen J, Lin H, Liu F, He Y et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 2015; 162: 18- 26.
Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J Am Soc Nephrol 2008; 19: 2001-2010.
Hu WX, Chen YH, Liu ZZ, Zhang HT, Chen HP, Zeng CH, Zhang LH, Liu ZH. A prospective clinical trial of corticosteroids in combination with mycophenolate mofetil dispersible tablets and tacrolimus for the induction treatment of lupus nephritis. Chin Nephrol Dail Transplant 2011; 20: 301-306.
Zhao WX, Xu H. Clinical efficacy and safety of lupus nephritis with multi-target therapy. Journal of Hebei Medical University in Chinese 2016; 37: 61-63.
Huang JP, Yu YZ, Gao W, Chen W, Hua DJ, Wu YZ, Jiang JY. Clinical study on the efficacy and safety of treatment of both proliferative and membranous lupus nephritis with multitarget therapy. Chin Clin Nephrol 2017; 17: 100-104.
Jang J, Guo Q, Duan R. Effects of mycophenolate mofetil combined with tacrolimus on immunological indexes and activity index of patients with lupus nephritis. Journal of Clinical and Experimental Medicine 2017; 16: 367-370.
Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5. 1. 0 [Updated March 2011]. London, UK: Cochrane Collaboration; 2011.
Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen, Denmark: The Nordic Cochrane Centre; 2014.
Li M. Efficacy and safety of corticosteroids in combination with mycophenolate mofetil dispersible tablets and tacrolimus for the induction treatment of lupus nephritis. Chinese Journal of Clinical Rational Drug Use 2014; 7: 51-52.
Zhang Y, Lin SP, Chen DZ, Liang J. Clinical therapeutic effects of multi-target treatment on type-IV lupus nephritis and the effects on serum IL-6, IL-13, and IL-18 levels. Chin Clin Nephrol 2016; 16: 8-11. 26. Chan TM. Treatment of severe lupus nephritis: the new horizon. Nat Rev Nephrol 2015; 11: 46-61.
Rovin BH, Parikh SV, Hebert LA, Chan TM, Mok CC, Ginzler EM, Hooi LS, Brunetta P, Solomons N. Lupus nephritis: induction therapy in severe lupus nephritis--should MMF be considered the drug of choice? Clin J Am Soc Nephro 2013; 8: 147-153.
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sanchez-Guerrero J, Solomons N et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20: 1103-1112.
Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. New Engl J Med 2011; 365: 1886-1895.
Sundel R, Solomons N, Lisk L. Efficacy of mycophenolate mofetil in adolescent patients with lupus nephritis: evidence from a two-phase, prospective randomized trial. Lupus 2012; 21: 1433-1443.
Chen Y, Sun J, Zou K, Yang Y, Liu G. Treatment for lupus nephritis: an overview of systematic reviews and metaanalyses. Rheumatol Int 2017; 37: 1089-1099.
Palmer SC, Tunnicliffe DJ, Singh-Grewal D, Mavridis D, Tonelli M, Johnson DW, Craig JC, Tong A, Strippoli GFM. Induction and maintenance immunosuppression treatment of proliferative lupus nephritis: a network meta-analysis of randomized trials. Am J Kidney Dis 2017; 70: 324-336.
Chen W, Tang X, Liu Q, Fu P, Liu F, Liao Y, Yang Z, Zhang J, Chen J, Lou T et al. Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial. Am J Kidney Dis 2011; 57: 235-244.
Li X, Ren H, Zhang Q, Zhang W, Wu X, Xu Y, Shen P, Chen N. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transpl 2012; 27: 1467- 1472.
Zhang X, Ji L, Yang L, Tang X, Qin W. The effect of calcineurin inhibitors in the induction and maintenance treatment of lupus nephritis: a systematic review and meta-analysis. Int Urol Nephrol 2016; 48: 731-743.
Ahsan N, Johnson C, Gonwa T, Halloran P, Stegall M, Hardy M, Metzger R, Shield C 3rd, Rocher L, Scandling J et al. Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years. Transplantation 2001; 72: 245.
Sun Q, Liu Z, Cheng Z, Chen J, Ji S, Zeng C, Li LS. Treatment of early mixed cellular and humoral renal allograft rejection with tacrolimus and mycophenolate mofetil. Kidney Int 2007; 71: 24-30.