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14-08-2018 | Lupus nephritis | Review | Article

Induction Therapy for Lupus Nephritis: the Highlights

Journal: Current Rheumatology Reports

Authors: Isabelle Ayoub, Jessica Nelson, Brad H. Rovin

Publisher: Springer US

Abstract

Purpose of Review

Lupus nephritis is a frequent complication of systemic lupus erythematosus and is more common and severe in children. This is a disease of the immune system characterized by T cell, B cell, and complement activation, as well as immune complex formation and deposition. The introduction of steroids and later cyclophosphamide transformed lupus nephritis from a fatal to a treatable condition. However, the standard therapies currently used for treatment carry significant toxicity and chronic kidney disease still remains a far too frequent outcome. To address these issues, we will review current and emerging induction therapies in LN.

Recent Findings

Several clinical trials have been undertaken to test more effective and safer drugs, often targeting mechanistic disease pathways.

Summary

At present, it is difficult to identify an induction regimen that is more effective and less toxic than the standard of care; however, we believe continuing efforts in drug development will bring breakthrough agents to clinics.
Literature
1.
Rovin B, Ayoub I. The clinical evaluation of kidney disease in systemic lupus erythematosus. Sytemic Lupus Erythematosus. 2016. Chapter 40 (Elsevier).
2.
Hanly JG, O’Keeffe AG, Su L, Urowitz MB, Romero-Diaz J, Gordon C, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford). 2016;55(2):252–62.CrossRef
3.
Dall’Era M. Treatment of lupus nephritis: current paradigms and emerging strategies. Curr Opin Rheumatol. 2017;29(3):241–7.CrossRefPubMed
4.
Bastian HM, Roseman JM, Mcgwin G Jr, Alarcón GS, Friedman AW, Fessler BJ, et al. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus. 2002;11(3):152–60.CrossRefPubMed
5.
Parikh SV, Rovin BH. Current and emerging therapies for lupus nephritis. J Am Soc Nephrol. 2016;27(10):2929–39.CrossRefPubMedPubMedCentral
6.
Heller BI, Jacobson WE, Hammarsten JF. The effect of cortisone in glomerulonephritis and the nephropathy of disseminated lupus erythematosus. J Lab Clin Med. 1951;37(1):133–42.PubMed
7.
Hahn BH, McMahon M, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res. 2012;64(6):797–808.CrossRef
8.
Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, 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(11):1771–82.CrossRefPubMed
9.
Cathcart ES, Idelson BA, Scheinberg MA, Couser WG. Beneficial effects of methylprednisolone “pulse” therapy in diffuse proliferative lupus nephritis. Lancet. 1976;1(7952):163–6.CrossRefPubMed
10.
Kountz SL, Cohn R. Initial treatment of renal allografts with large intrarenal doses of immunosuppressive drugs. Lancet. 1969;1(7590):338–40.CrossRefPubMed
11.
Woods JE, Anderson CF, DeWeerd J, Johnson WJ, Donadio JV Jr, Leary FJ, et al. High-dosage intravenously administered methylprednisolone in renal transplantation. A preliminary report. JAMA. 1973;223(8):896–9.CrossRefPubMed
12.
Dall’Era M, Cisternas MG, Smilek DE, Straub L, Houssiau FA, Cervera R, et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort. Arthritis Rheumatol. 2015;67(5):1305–13.CrossRefPubMed
13.
Ponticelli C, Locatelli F. Glucocorticoids in the treatment of glomerular diseases: pitfalls and pearls. Clin J Am Soc Nephrol. 2018;13(5):815–22.CrossRefPubMedPubMedCentral
14.
Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008;4(10):525–33.CrossRefPubMed
15.
Sciascia S, Mompean E, Radin M, Roccatello D, Cuadrado MJ. Rate of adverse effects of medium- to high-dose glucocorticoid therapy in systemic lupus erythematosus: a systematic review of randomized control trials. Clin Drug Investig. 2017;37(6):519–24.CrossRefPubMed
16.
Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 2004;50(11):3408–17.CrossRefPubMed
17.
Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J, et al. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant. 2008;8(2):307–16.CrossRefPubMed
18.
Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol. 2017;28(9):2756–67.CrossRefPubMedPubMedCentral
19.
Almaani S, Rovin B. B-cell therapy in lupus nephritis: an overview. Nephrol Dial Transplant. 2018.
20.
Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72(8):1280–6.CrossRefPubMed
21.
• Rovin B, Solomons N, Pendergraft FW III, Dooley MA, Tumulin J, Romero-Diaz J. et al. A randomized, controlled double-blind study comparing the efficacy and safety of voclosporin (23.7 mg BID, or 39.5 mg BID) with placebo in achieving remission in patients with active lupus nephritis. Kidney Int, 2018. In revision. This is a multination RCT looking at efficacy and safety of a novel CNI in multitargeted regimen.
22.
Ruiz-Irastorza G, Ugarte A, Saint-Pastou Terrier C, Lazaro E, Iza A, Couzi L, et al. Repeated pulses of methyl-prednisolone with reduced doses of prednisone improve the outcome of class III, IV and V lupus nephritis: an observational comparative study of the lupus-cruces and lupus-Bordeaux cohorts. Autoimmun Rev. 2017;16(8):826–32.CrossRefPubMed
23.
Austin HA 3rd, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986;314(10):614–9.CrossRefPubMed
24.
Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido ER, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121–31.CrossRefPubMed
25.
Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. 2010;69(1):61–4.CrossRefPubMed
26.
•• Wofsy D, Diamond B, Houssiau FA. Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America. Arthritis Rheumatol. 2015;67(5):1144–6. This study shows the efficacy of the Euro-lupus regimen not only in Caucasian but also in multi-racial ethnic groups. CrossRefPubMedPubMedCentral
27.
Hebert LA, Rovin BH. Oral cyclophosphamide is on the verge of extinction as therapy for severe autoimmune diseases (especially lupus): should nephrologists care? Nephron Clin Pract. 2011;117(1):c8–14.CrossRefPubMed
28.
Harward LE, Mitchell K, Pieper C, Copland S, Criscione-Schreiber LG, Clowse MEB. The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease. Lupus. 2013;22(1):81–6.CrossRefPubMed
29.
Mina R, von Scheven E, Ardoin SP, Eberhard BA, Punaro M, Ilowite N, et al. Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus. Arthritis Care Res. 2012;64(3):375–83.CrossRef
30.
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103–12.CrossRefPubMedPubMedCentral
31.
Rovin BH, Parikh SV, Hebert LA, Chan TM, Mok CC, Ginzler EM, et al. Lupus nephritis: induction therapy in severe lupus nephritis--should MMF be considered the drug of choice? Clin J Am Soc Nephrol. 2013;8(1):147–53.CrossRefPubMed
32.
Palmer SC, Tunnicliffe DJ, Singh-Grewal D, Mavridis D, Tonelli M, Johnson DW, et al. Induction and maintenance immunosuppression treatment of proliferative lupus nephritis: a network meta-analysis of randomized trials. Am J Kidney Dis. 2017;70(3):324–36.CrossRefPubMed
33.
Zavada J, Pešickova SS, Ryšava R, Olejarova M, Horák P, Hrnčíř Z, et al. Cyclosporine a or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Lupus. 2010;19(11):1281–9.CrossRefPubMed
34.
Mok CC. Towards new avenues in the management of lupus glomerulonephritis. Nat Rev Rheumatol. 2016;12(4):221–34.CrossRefPubMed
35.
Hannah J, Casian A, D’Cruz D. Tacrolimus use in lupus nephritis: a systematic review and meta-analysis. Autoimmun Rev. 2016;15(1):93–101.CrossRefPubMed
36.
Ekberg H, van Gelder T, Kaplan B, Bernasconi C. Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation. Transplantation. 2011;92(1):82–7.CrossRefPubMed
37.
• Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. 2015;162(1):18–26. This is the first RCT looking at multi-target therapy in an Asian population. CrossRefPubMed
38.
Zhang H, Liu Z, Zhou M, Liu Z, Chen J, Xing C, et al. Multitarget therapy for maintenance treatment of lupus nephritis. J Am Soc Nephrol. 2017;28(12):3671–8.CrossRefPubMedPubMedCentral
39.
Yoon KH. Efficacy and cytokine modulating effects of tacrolimus in systemic lupus erythematosus: a review. J Biomed Biotechnol. 2010;2010:686480.CrossRefPubMedPubMedCentral
40.
Ayoub I, Rovin BH. Calcineurin inhibitors in the treatment of lupus nephritis: a hare versus turtle story? J Am Soc Nephrol. 2017;28(12):3435–7.CrossRefPubMedPubMedCentral
41.
Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14(Suppl 1):s2–8.CrossRefPubMed
42.
Fu J, Wang Z, Lee K, Wei C, Liu Z, Zhang M, et al. Transcriptomic analysis uncovers novel synergistic mechanisms in combination therapy for lupus nephritis. Kidney Int. 2018;93(2):416–29.CrossRefPubMed
43.
Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, et al. Structural basis for the cyclophilin a binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr. 2011;67(Pt 2):119–23.CrossRefPubMedPubMedCentral
44.
Mayo PR, Ling SY, Huizinga RB, Freitag DG, Aspeslet LJ, Foster RT. Population PKPD of voclosporin in renal allograft patients. J Clin Pharmacol. 2014;54(5):537–45.CrossRefPubMed
45.
Chan OT, et al. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med. 1999;189(10):1639–48.CrossRefPubMedPubMedCentral
46.
Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001;2(9):764–6.CrossRefPubMed
47.
Dorner T, Burmester GR. The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets. Curr Opin Rheumatol. 2003;15(3):246–52.CrossRefPubMed
48.
Chang A, Henderson SG, Brandt D, Liu N, Guttikonda R, Hsieh C, et al. In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol. 2011;186(3):1849–60.CrossRefPubMed
49.
Hsieh C, Chang A, Brandt D, Guttikonda R, Utset TO, Clark MR. Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res. 2011;63(6):865–74.CrossRef
50.
Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med. 1994;180(4):1295–306.CrossRefPubMed
51.
Ahuja A, Shupe J, Dunn R, Kashgarian M, Kehry MR, Shlomchik MJ. Depletion of B cells in murine lupus: efficacy and resistance. J Immunol. 2007;179(5):3351–61.CrossRefPubMed
52.
Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;64(4):1215–26.CrossRefPubMed
53.
Roccatello D, Sciascia S, Baldovino S, Rossi D, Alpa M, Naretto C, et al. A 4-year observation in lupus nephritis patients treated with an intensified B-lymphocyte depletion without immunosuppressive maintenance treatment-clinical response compared to literature and immunological re-assessment. Autoimmun Rev. 2015;14(12):1123–30.CrossRefPubMed
54.
Ramos-Casals M, Brito-Zerón P, Muñoz S, Soto MJ, BIOGEAS STUDY Group. A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine (Baltimore). 2008;87(6):345–64.CrossRef
55.
Pollard RP, et al. Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjogren’s syndrome: data from a placebo-controlled clinical trial. Ann Rheum Dis. 2013;72(1):146–8.CrossRefPubMed
56.
Vallerskog T, Heimbürger M, Gunnarsson I, Zhou W, Wahren-Herlenius M, Trollmo C, et al. Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther. 2006;8(6):R167.CrossRefPubMedPubMedCentral
57.
Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, et al. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2015;74(9):1667–75.CrossRefPubMed
58.
Foster MH. T cells and B cells in lupus nephritis. Semin Nephrol. 2007;27(1):47–58.CrossRefPubMedPubMedCentral
59.
Daikh DI, Wofsy D. Treatment of autoimmunity by inhibition of T cell costimulation. Adv Exp Med Biol. 2001;490:113–7.CrossRefPubMed
60.
Schiffer L, Sinha J, Wang X, Huang W, von Gonsdorff G, Schiffer M, et al. Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. J Immunol. 2003;171(1):489–97.CrossRefPubMed
61.
Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL, et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol. 2014;66(2):379–89.CrossRefPubMed
62.
Group, A.T. Treatment of lupus nephritis with abatacept: the abatacept and cyclophosphamide combination efficacy and safety study. Arthritis Rheum. 2014;66(11):3096–104.CrossRef
63.
Chasset F, Arnaud L. Targeting interferons and their pathways in systemic lupus erythematosus. Autoimmun Rev. 2018;17(1):44–52.CrossRefPubMed
64.
Gallagher KM, et al. Type I interferon (IFN alpha) acts directly on human memory CD4+ T cells altering their response to antigen. J Immunol. 2009;183(5):2915–20.CrossRefPubMed
65.
Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity. 2003;19(2):225–34.CrossRefPubMed
66.
Ramos HJ, Davis AM, Cole AG, Schatzle JD, Forman J, Farrar JD. Reciprocal responsiveness to interleukin-12 and interferon-alpha specifies human CD8+ effector versus central memory T-cell fates. Blood. 2009;113(22):5516–25.CrossRefPubMedPubMedCentral
67.
Ronnblom L, Alm GV, Eloranta ML. The type I interferon system in the development of lupus. Semin Immunol. 2011;23(2):113–21.CrossRefPubMed
68.
Parikh SV, Malvar A, Song H, Alberton V, Lococo B, Vance J, et al. Characterising the immune profile of the kidney biopsy at lupus nephritis flare differentiates early treatment responders from non-responders. Lupus Sci Med. 2015;2(1):e000112.CrossRefPubMedPubMedCentral
69.
Parikh SV, Malvar A, Song H, Alberton V, Lococo B, Vance J, et al. Molecular imaging of the kidney in lupus nephritis to characterize response to treatment. Transl Res. 2017;182:1–13.CrossRefPubMed
70.
Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheum. 2017;69(2):376–86.CrossRef
71.
Kalunian KC, Merrill JT, Maciuca R, McBride JM, Townsend MJ, Wei X, et al. A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-alpha) in patients with systemic lupus erythematosus (ROSE). Ann Rheum Dis. 2016;75(1):196–202.CrossRefPubMed
72.
Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75(11):1909–16.CrossRefPubMed
73.
Song D, Guo WY, Wang FM, Li YZ, Song Y, Yu F, et al. Complement alternative pathways activation in patients with lupus nephritis. Am J Med Sci. 2017;353(3):247–57.CrossRefPubMed
74.
Burt RK, Traynor A, Statkute L, Barr WG, Rosa R, Schroeder J, et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA. 2006;295(5):527–35.CrossRefPubMed
75.
Jayne D, Passweg J, Marmont A, Farge D, Zhao X, Arnold R, et al. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus. 2004;13(3):168–76.CrossRefPubMed
76.
Fathollahi A, Gabalou NB, Aslani S. Mesenchymal stem cell transplantation in systemic lupus erythematous, a mesenchymal stem cell disorder. Lupus. 2018;27(7):1053–64.CrossRefPubMed
77.
Deng D, Zhang P, Guo Y, Lim TO. A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. Ann Rheum Dis. 2017;76(8):1436–9.CrossRefPubMed