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American Journal of Kidney Diseases

Lupus Nephritis: The Evolving Role of Novel Therapeutics

Published:January 09, 2014DOI:https://doi.org/10.1053/j.ajkd.2013.11.023
      Immune complex accumulation in the kidney is the hallmark of lupus nephritis and triggers a series of events that result in kidney inflammation and injury. Cytotoxic agents and corticosteroids are standard of care for lupus nephritis treatment, but are associated with considerable morbidity and suboptimal outcomes. Recently, there has been interest in using novel biologic agents and small molecules to treat lupus nephritis. These therapies can be broadly categorized as anti-inflammatory (laquinamod, anti–tumor necrosis factor–like weak inducer of apotosis, anti-C5, and retinoids), antiautoimmunity (anti-CD20, anti–interferon α, and costimulatory blockers), or both (anti–interleukin 6 and proteasome inhibitors). Recent lupus nephritis clinical trials applied biologics or small molecules of any category to induction treatment, seeking short-term end points of complete renal response. These trials in general have not succeeded. When lupus nephritis comes to clinical attention during the inflammatory stage of the disease, the autoimmune stage leading to kidney inflammation will have been active for some time. The optimal approach for using novel therapies may be to initially target kidney inflammation to preserve renal parenchyma, followed by suppression of autoimmunity. In this review, we discuss novel lupus nephritis therapies and how they fit into a combinatorial treatment strategy based on the pathogenic stage.

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      References

        • Austin H.A.
        • Klippel J.H.
        • Balow J.E.
        • et al.
        Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.
        N Engl J Med. 1986; 314: 614-619
        • Houssiau F.A.
        • Vasconcelos C.
        • D'Cruz D.
        • 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: 2121-2131
        • Appel G.B.
        • Contreras G.
        • Dooley M.A.
        • et al.
        Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
        J Am Soc Nephrol. 2009; 20: 1103-1112
        • Sanz A.B.
        • Sanchez-Nino M.D.
        • Ortiz A.
        TWEAK, a multifunctional cytokine in kidney injury.
        Kidney Int. 2011; 80: 708-718
        • Houssiau F.A.
        • Vasconcelos C.
        • D'Cruz D.
        • et al.
        The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose versus high-dose intravenous cyclophosphamide.
        Ann Rheum Dis. 2010; 69: 61-64
        • Dooley M.A.
        • Jayne D.
        • Ginzler E.M.
        • et al.
        Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.
        N Engl J Med. 2011; 365: 1886-1895
        • Rovin B.H.
        • Stillman I.E.
        The kidney in systemic lupus erythematosus.
        in: Lahita R.G. Systemic Lupus Erythematosus. 5th ed. Academic Press, London, UK2011: 769-814
        • Rovin B.H.
        • Furie R.
        • Latinis K.
        • 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: 1215-1226
        • Wofsy D.
        • Hillson J.L.
        • Diamond B.
        Abatacept for lupus nephritis.
        Arthritis Rheum. 2012; 64: 3660-3665
        • Kalaaji M.
        • Mortensen E.
        • Jorgensen L.
        • Olsen R.
        • Rekvig O.P.
        Nephritogenic lupus antibodies recognize glomerular basement membrane-associated chromatin fragments released from apoptotic intraglomerular cells.
        Am J Pathol. 2006; 168: 1779-1792
        • Kalaaji M.
        • Sturfelt G.
        • Mjelle J.E.
        • Nossent H.
        • Rekvig O.P.
        Critical comparative analyses of anti-alpha-actinin and glomerulus-bound antibodies in human and murine lupus nephritis.
        Arthritis Rheum. 2006; 54: 914-926
        • Kalaaji M.
        • Fenton K.A.
        • Mortensen E.S.
        • et al.
        Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis.
        Kidney Int. 2007; 71: 664-672
        • Manson J.J.
        • Ma A.
        • Rogers P.
        • et al.
        Relationship between anti-dsDNA, anti-nucleosome and anti-alpha-actinin antibodies and markers of renal disease in patients with lupus nephritis: a prospective longitudinal study.
        Arthritis Res Ther. 2009; 11: R154
        • Marchini M.
        • Antonioli R.
        • Lleo A.
        • et al.
        HLA class II antigens associated with lupus nephritis in Italian SLE patients.
        Hum Immunol. 2003; 64: 462-468
        • Taylor K.E.
        • Chung S.A.
        • Graham R.R.
        • et al.
        Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes.
        PLoS Genet. 2011; 7: e1001311
        • Steinmetz O.M.
        • Velden J.
        • Kneissler U.
        • et al.
        Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis.
        Kidney Int. 2008; 74: 448-457
        • Chang A.
        • Henderson S.G.
        • Brandt D.
        • et al.
        In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis.
        J Immunol. 2011; 186: 1849-1860
        • Ronnblom L.
        • Alm G.V.
        • Eloranta M.L.
        The type I interferon system in the development of lupus.
        Semin Immunol. 2011; 23: 113-121
        • Gao Y.
        • Majchrzak-Kita B.
        • Fish E.N.
        • Gommerman J.L.
        Dynamic accumulation of plasmacytoid dendritic cells in lymph nodes is regulated by interferon-beta.
        Blood. 2009; 114: 2623-2631
        • Jego G.
        • Palucka A.K.
        • Blanck J.P.
        • Chalouni C.
        • Pascual V.
        • Banchereau J.
        Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6.
        Immunity. 2003; 19: 225-234
        • Gallagher K.M.
        • Lauder S.
        • Rees I.W.
        • Gallimore A.M.
        • Godkin A.J.
        Type I interferon (IFN alpha) acts directly on human memory CD4+ T cells altering their response to antigen.
        J Immunol. 2009; 183: 2915-2920
        • Ramos H.J.
        • Davis A.M.
        • Cole A.G.
        • Schatzle J.D.
        • Forman J.
        • Farrar J.D.
        Reciprocal responsiveness to interleukin-12 and interferon-alpha specifies human CD8+ effector versus central memory T-cell fates.
        Blood. 2009; 113: 5516-5525
        • Baechler E.C.
        • Batliwalla F.M.
        • Karypis G.
        • et al.
        Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.
        Proc Natl Acad Sci U S A. 2003; 100: 2610-2615
        • Feng X.
        • Wu H.
        • Grossman J.M.
        • et al.
        Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus.
        Arthritis Rheum. 2006; 54: 2951-2962
        • Diebold S.S.
        • Kaisho T.
        • Hemmi H.
        • Akira S.
        • Reis e Sousa C.
        Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.
        Science. 2004; 303: 1529-1531
        • Hemmi H.
        • Takeuchi O.
        • Kawai T.
        • et al.
        A Toll-like receptor recognizes bacterial DNA.
        Nature. 2000; 408: 740-745
        • Kaser A.
        • Kaser S.
        • Kaneider N.C.
        • Enrich B.
        • Wiedermann C.J.
        • Tilg H.
        Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression.
        Blood. 2004; 103: 648-655
        • Tucci M.
        • Quatraro C.
        • Lombardi L.
        • Pellegrino C.
        • Dammacco F.
        • Silvestris F.
        Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18.
        Arthritis Rheum. 2008; 58: 251-262
        • Biesecker G.
        • Katz S.
        • Koffler D.
        Renal localization of the membrane attack complex in systemic lupus erythematosus nephritis.
        J Exp Med. 1981; 154: 1779-1794
        • Watanabe H.
        • Garnier G.
        • Circolo A.
        • et al.
        Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B.
        J Immunol. 2000; 164: 786-794
        • Elliott M.K.
        • Jarmi T.
        • Ruiz P.
        • Xu Y.
        • Holers V.M.
        • Gilkeson G.S.
        Effects of complement factor D deficiency on the renal disease of MRL/lpr mice.
        Kidney Int. 2004; 65: 129-138
        • Bao L.
        • Haas M.
        • Quigg R.J.
        Complement factor H deficiency accelerates development of lupus nephritis.
        J Am Soc Nephrol. 2011; 22: 285-295
        • Sekine H.
        • Reilly C.M.
        • Molano I.D.
        • et al.
        Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice.
        J Immunol. 2001; 166: 6444-6451
        • Wenderfer S.E.
        • Ke B.
        • Hollmann T.J.
        • Wetsel R.A.
        • Lan H.Y.
        • Braun M.C.
        C5a receptor deficiency attenuates T cell function and renal disease in MRLlpr mice.
        J Am Soc Nephrol. 2005; 16: 3572-3582
        • Sekine H.
        • Ruiz P.
        • Gilkeson G.S.
        • Tomlinson S.
        The dual role of complement in the progression of renal disease in NZB/W F(1) mice and alternative pathway inhibition.
        Mol Immunol. 2011; 49: 317-323
        • Wang Y.
        • Hu Q.
        • Madri J.A.
        • Rollins S.A.
        • Chodera A.
        • Matis L.A.
        Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5.
        Proc Natl Acad U S A. 1996; 93: 8563-8568
        • Korb L.C.
        • Ahearn J.M.
        C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited.
        J Immunol. 1997; 158: 4525-4528
        • Pickering M.C.
        • Botto M.
        • Taylor P.R.
        • Lachmann P.J.
        • Walport M.J.
        Systemic lupus erythematosus, complement deficiency, and apoptosis.
        Adv Immunol. 2000; 76: 227-324
        • Birmingham D.J.
        • Irshaid F.
        • Nagaraja H.N.
        • et al.
        The complex nature of serum C3 and C4 as biomarkers of lupus renal flare.
        Lupus. 2010; 19: 1272-1280
        • Sekine H.
        • Kinser T.T.
        • Qiao F.
        • et al.
        The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice.
        Arthritis Rheum. 2011; 63: 1076-1085
        • Weidenbusch M.
        • Rommaie C.
        • Schrottie A.
        • Anders H.J.
        Beyond the LUNAR trial: rituximab for refractory lupus nephritis.
        Nephrol Dial Transplant. 2013; 28: 106-111
        • Sanz I.
        • Lee F.E.-H.
        B Cells as therapeutic targets in SLE.
        Nat Rev Rheumatol. 2010; 6: 326-337
        • Townsend M.J.
        • Monroe J.G.
        • Chan A.C.
        B-Cell targeted therapies in human autoimmune diseases: an updated perspective.
        Immunol Rev. 2010; 237: 264-283
        • Anderson C.L.
        Human IgG Fc receptors.
        Clin Immunol Immunopathol. 1989; 53: 63-71
        • Li X.
        • Ptacek T.S.
        • Brown E.E.
        • Edberg J.C.
        Fcgamma receptors: structure, function and role as genetic risk factors in SLE.
        Genes Immun. 2009; 10: 380-389
        • Rovin B.H.
        Chemokines as therapeutic targets in renal inflammation.
        Am J Kidney Dis. 1999; 34: 761-764
        • Rovin B.H.
        The chemokine network in systemic lupus erythematosis nephritis.
        Front Biosci. 2007; 13: 904-922
        • Peterson K.S.
        • Huang J.F.
        • Zhu J.
        • et al.
        Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli.
        J Clin Invest. 2004; 113: 1722-1733
        • Chan R.W.
        • Lai F.M.
        • Li E.K.
        • et al.
        Intrarenal cytokine gene expression in lupus nephritis.
        Ann Rheum Dis. 2007; 66: 886-892
        • Malide D.
        • Russo P.
        • Bendayan M.
        Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients.
        Hum Pathol. 1995; 26: 558-564
        • Herrera-Esparza R.
        • Barbosa-Cisneros O.
        • Villalobos-Hurtado R.
        • Avalos-Diaz E.
        Renal expression of IL-6 and TNFalpha genes in lupus nephritis.
        Lupus. 1998; 7: 154-158
        • Uhm W.S.
        • Na K.
        • Song G.W.
        • et al.
        Cytokine balance in kidney tissue from lupus nephritis patients.
        Rheumatology (Oxford). 2003; 42: 935-938
        • Masutani K.
        • Akahoshi M.
        • Tsuruya K.
        • et al.
        Predominance of Th1 immune response in diffuse proliferative lupus nephritis.
        Arthritis Rheum. 2001; 44: 2097-2106
        • Crispin J.C.
        • Oukka M.
        • Bayliss G.
        • et al.
        Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys.
        J Immunol. 2008; 181: 8761-8766
        • Schwartz N.
        • Su L.
        • Burkly L.
        • et al.
        Urinary TWEAK and the activity of lupus nephritis.
        J. Autoimmun. 2006; 27: 242-250
        • Tackey E.
        • Lipsky P.E.
        • Illei G.G.
        Rationale for interleukin-6 blockade in systemic lupus erythematosus.
        Lupus. 2004; 13: 339-343
        • Tucci M.
        • Lombardi L.
        • Richards H.B.
        • Dammacco F.
        • Silvestris F.
        Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis.
        Clin Exp Immunol. 2008; 154: 247-254
        • Ge D.
        • You Z.
        Expression of interleukin-17RC protein in normal human tissues.
        Int Arch Med. 2008; 1: 1-19
        • Weaver C.T.
        • Hatton R.D.
        • Mangan P.R.
        • Harrington L.E.
        IL-17 family cytokines and the expanding diversity of effector T cell lineages.
        Annu Rev Immunol. 2007; 25: 821-852
        • Qiu Z.
        • Dillen C.
        • Hu J.
        • et al.
        Interleukin-17 regulates chemokine and gelatinase B expression in fibroblasts to recruit both neutrophils and monocytes.
        Immunobiology. 2009; 214: 835-842
        • Bettelli E.
        • Carrier Y.
        • Gao W.
        • et al.
        Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
        Nature. 2006; 441: 235-238
        • Baecher-Allan C.
        • Brown J.A.
        • Freeman G.J.
        • Hafler D.A.
        CD4+CD25 high regulatory cells in human peripheral blood.
        J Immunol. 2001; 167: 1245-1253
        • Kuhn A.
        • Beissert S.
        • Krammer P.H.
        CD4(+)CD25(+) regulatory T cells in human lupus erythematosus.
        Arch Dermatol Res. 2009; 301: 71-81
        • Lim H.W.
        • Hillsamer P.
        • Banham A.H.
        • Kim C.H.
        Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells.
        J Immunol. 2005; 175: 4180-4183
        • Iikuni N.
        • Lourenco E.V.
        • Hahn B.H.
        • La Cava A.
        Cutting edge: regulatory T cells directly suppress B cells in systemic lupus erythematosus.
        J Immunol. 2009; 183: 1518-1522
        • Gerli R.
        • Nocentini G.
        • Alunno A.
        • et al.
        Identification of regulatory T cells in systemic lupus erythematosus.
        Autoimmun Rev. 2009; 8: 426-430
        • Sanz A.B.
        • Justo P.
        • Sanchez-Nino M.D.
        • et al.
        The cytokine TWEAK modulates renal tubulointerstitial inflammation.
        J Am Soc Nephrol. 2008; 19: 695-703
        • Border W.A.
        Transforming growth factor-beta and the pathogenesis of glomerular diseases.
        Curr Opin Nephrol Hypertens. 1994; 3: 54-58
        • Tesch G.H.
        • Maifert S.
        • Schwarting A.
        • Rollins B.J.
        • Kelley V.R.
        Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-faslpr mice.
        J Exp Med. 1999; 190: 1813-1824
        • Perez de Lema G.
        • Maier H.
        • Franz T.J.
        • et al.
        Chemokine receptor CCR2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice.
        J Am Soc Nephrol. 2005; 16: 3592-3601
        • Hasegawa H.
        • Kohno M.
        • Sasaki M.
        • et al.
        Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice.
        Arthritis Rheum. 2003; 48: 2555-2566
        • Kiberd B.A.
        Interleukin-6 receptor blockage ameliorates murine lupus nephritis.
        J Am Soc Nephrol. 1993; 4: 58-61
        • Liang B.
        • Gardner D.B.
        • Griswold D.E.
        • Bugelski P.J.
        • Song X.Y.
        Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus.
        Immunology. 2006; 119: 296-305
        • Donadio J.V.
        • Holley K.E.
        • Ferguson R.H.
        • Ilstrup D.M.
        Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide.
        N Engl J Med. 1978; 23: 1151-1155
        • Moschella F.
        • Torelli G.F.
        • Valentini M.
        • et al.
        Cyclophosphamide induces a type I interferon-associated sterile inflammatory response signature in cancer patients' blood cells: implications for cancer chemoimmunotherapy.
        Clin Cancer Res. 2013; 19: 4249-4261
        • Kawabata D.
        • Venkatesh J.
        • Ramanujam M.
        • Davidson A.
        • Grimaldi C.M.
        • Diamond B.
        Enhanced selection of high affinity DNA-reactive B cells following cyclophosphamide treatment in mice.
        PLoS One. 2010; 5: e8418
      1. Parikh SV, Nagaraja H, Hebert LA, Rovin BH. Renal flare as a predictor of incident and progressive chronic kidney disease in patients with Lupus Nephritis [published online ahead of print November 21, 2013]. Clin J Am Soc Nephrol. http://dx.doi.org/10.2215/CJN. 05040513.

        • Mishra M.K.
        • Wang J.
        • Silva C.
        • Mack M.
        • Yong V.W.
        Kinetics of proinflammatory monocytes in a model of multiple sclerosis and its perturbation by laquinimod.
        Am J Pathol. 2012; 181: 642-651
        • Schulze-Topphoff U.
        • Shetty A.
        • Varrin-Doyer M.
        • et al.
        Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that modulate central nervous system autoimmunity.
        PLoS One. 2012; 7: e33797
        • Jolivel V.
        • Luessi F.
        • Masri J.
        • et al.
        Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis.
        Brain. 2013; 136: 1048-1066
        • Gurevich M.
        • Gritzman T.
        • Orbach R.
        • Tuller T.
        • Feldman A.
        • Achiron A.
        Laquinimod suppresses antigen presentation in relapsing-remitting multiple sclerosis: in-vitro high-throughput gene expression study.
        J Neuroimmunol. 2010; 221: 87-94
        • Keino H.
        • Watanabe T.
        • Sato Y.
        • Okada A.A.
        Oral administration of retinoic acid receptor-alpha/beta-specific ligand Am80 suppresses experimental autoimmune uveoretinitis.
        Invest Ophthalmol Vis Sci. 2011; 52: 1548-1556
        • Klemann C.
        • Raveney B.J.
        • Klemann A.K.
        • et al.
        Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis.
        Am J Pathol. 2009; 174: 2234-2245
        • Hillmen P.
        • Young N.S.
        • Schubert J.
        • et al.
        The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.
        N Engl J Med. 2006; 355: 1233-1243
        • Barilla-Labarca M.L.
        • Toder K.
        • Furie R.
        Targeting the complement system in systemic lupus erythematosus and other diseases.
        Clin Immunol. 2013; 148: 313-321
        • Chicheportiche Y.
        • Bourdon P.R.
        • Xu H.
        • et al.
        TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.
        J Biol Chem. 1997; 272: 32401-32410
        • Michaelson J.S.
        • Wisniacki N.
        • Burkly L.C.
        • Putterman C.
        Role of TWEAK in lupus nephritis: a bench-to-bedside review.
        J Autoimmun. 2012; 39: 130-142
        • Liu Z.C.
        • Zhou Q.L.
        Tumor necrosis factor-like weak inducer of apoptosis and its potential roles in lupus nephritis.
        Inflamm Res. 2012; 61: 277-284
        • Schwartz N.
        • Rubinstein T.
        • Burkly L.
        • et al.
        Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study.
        Arthritis Res Ther. 2009; 11: R143
        • Gao H.X.
        • Campbell S.R.
        • Burkly L.C.
        • et al.
        TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells.
        Cytokine. 2009; 46: 24-35
        • Zhao Z.
        • Burkly L.C.
        • Campbell S.
        • et al.
        TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus.
        J Immunol. 2007; 179: 7949-7958
        • Xia Y.
        • Campbell S.R.
        • Broder A.
        • et al.
        Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis.
        Clin Immunol. 2012; 145: 108-121
        • Molano A.
        • Lakhani P.
        • Aran A.
        • Burkly L.C.
        • Michaelson J.S.
        • Putterman C.
        TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis.
        Immunol Lett. 2009; 125: 119-128
        • Kitani A.
        • Hara M.
        • Hirose T.
        • et al.
        Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with systemic lupus erythematosus: analysis of IL-6 production and IL-6R expression.
        Clin Exp Immunol. 1992; 88: 75-83
        • Kitani A.
        • Hara M.
        • Hirose T.
        • et al.
        Heterogeneity of B cell responsiveness to interleukin 4, interleukin 6 and low molecular weight B cell growth factor in discrete stages of B cell activation in patients with systemic lupus erythematosus.
        Clin Exp Immunol. 1989; 77: 31-36
        • Tilg H.
        • Trehu E.
        • Atkins M.B.
        • Dinarello C.A.
        • Mier J.W.
        Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55.
        Blood. 1994; 83: 113-118
        • Linker-Israeli M.
        • Deans R.J.
        • Wallace D.J.
        • Prehn J.
        • Ozeri-Chen T.
        • Klinenberg J.R.
        Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis.
        J Immunol. 1991; 147: 117-123
        • Peterson E.
        • Robertson A.D.
        • Emlen W.
        Serum and urinary interleukin-6 in systemic lupus erythematosus.
        Lupus. 1996; 5: 571-575
        • Ryffel B.
        • Car B.D.
        • Gunn H.
        • Roman D.
        • Hiestand P.
        • Mihatsch M.J.
        Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice.
        Am J Pathol. 1994; 144: 927-937
        • Illei G.G.
        • Shirota Y.
        • Yarboro C.H.
        • et al.
        Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.
        Arthritis Rheum. 2010; 62: 542-552
        • Morimoto A.M.
        • Flesher D.T.
        • Yang J.
        • et al.
        Association of endogenous anti-interferon-alpha autoantibodies with decreased interferon-pathway and disease activity in patients with systemic lupus erythematosus.
        Arthritis Rheum. 2011; 63: 2407-2415
        • Kirou K.A.
        • Gkrouzman E.
        Anti-interferon alpha treatment in SLE.
        Clin Immunol. 2013; 148: 303-312
        • McBride J.M.
        • Jiang J.
        • Abbas A.R.
        • et al.
        Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study.
        Arthritis Rheum. 2012; 64: 3666-3676
        • Merrill J.T.
        • Wallace D.J.
        • Petri M.
        • et al.
        Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study.
        Ann Rheum Dis. 2011; 70: 1905-1913
        • Petri M.
        • Wallace D.J.
        • Spindler A.
        • et al.
        Sifalimumab, a human anti-interferon-alpha monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study.
        Arthritis Rheum. 2013; 65: 1011-1021
        • Weidenbusch M.
        • Rommele C.
        • Schrottle A.
        • Anders H.J.
        Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis.
        Nephrol Dial Transplant. 2013; 28: 106-111
        • Rovin B.H.
        Targeting B-cells in lupus nephritis: should cautious optimism remain?.
        Nephrol Dial Transplant. 2013; 28: 7-9
        • Merrill J.T.
        • Neuwelt C.M.
        • Wallace D.J.
        • et al.
        Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial.
        Arthritis Rheum. 2010; 62: 222-233
        • Pollard R.P.
        • Abdulahad W.H.
        • Vissink A.
        • et al.
        Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjögren's syndrome: data from a placebo-controlled clinical trial.
        Ann Rheum Dis. 2013; 72: 146-148
        • Vallerskog T.
        • Heimburger M.
        • Gunnarsson I.
        • 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: R167
        • Iwata Y.
        • Matsushita T.
        • Horikawa M.
        • et al.
        Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells.
        Blood. 2011; 117: 530-541
        • Horikawa M.
        • Minard-Colin V.
        • Matsushita T.
        • Tedder T.F.
        Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice.
        J Clin Invest. 2011; 121: 4268-4280
        • Serreze D.V.
        • Chapman H.D.
        • Niens M.
        • et al.
        Loss of intra-islet CD20 expression may complicate efficacy of B-cell-directed type 1 diabetes therapies.
        Diabetes. 2011; 60: 2914-2921
        • Seavey M.M.
        • Lu L.D.
        • Stump K.L.
        • Wallace N.H.
        • Ruggeri B.A.
        Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE.
        Int Immunopharmacol. 2012; 12: 257-270
        • Weng J.
        • Lai P.
        • Lv M.
        • et al.
        Bortezomib modulates regulatory T cell subpopulations in the process of acute graft-versus-host disease.
        Clin Lab. 2013; 59: 51-58
        • Hainz N.
        • Thomas S.
        • Neubert K.
        • et al.
        The proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulointerstitial architecture.
        Nephron Exp Nephrol. 2012; 120: e47-e58
        • Bontscho J.
        • Schreiber A.
        • Manz R.A.
        • Schneider W.
        • Luft F.C.
        • Kettritz R.
        Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis.
        J Am Soc Nephrol. 2011; 22: 336-348
        • Corthals S.L.
        • Kuiper R.
        • Johnson D.C.
        • et al.
        Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients.
        Haematologica. 2011; 96: 1728-1732
        • Stohl W.
        Biologic differences between various inhibitors of the BLyS/BAFF pathway: should we expect differences between belimumab and other inhibitors in development?.
        Curr Rheumatol Rep. 2012; 14: 303-309
        • Dooley M.A.
        • Houssiau F.
        • Aranow C.
        • et al.
        Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE.
        Lupus. 2013; 22: 63-72
        • Jones R.B.
        • Tervaert J.W.
        • Hauser T.
        • et al.
        Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.
        N Engl J Med. 2010; 363: 211-220
        • Stone J.H.
        • Merkel P.A.
        • Spiera R.
        • et al.
        Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
        N Engl J Med. 2010; 363: 221-232
        • Specks U.
        • Merkel P.A.
        • Seo P.
        • et al.
        Efficacy of remission-induction regimens for ANCA-associated vasculitis.
        N Engl J Med. 2013; 369: 417-427
        • Daikh D.I.
        • Wofsy D.
        Cutting edge: reversal of murine lupus nephritis with CTLA4Ig and cyclophosphamide.
        J Immunol. 2001; 166: 2913-2916
        • Schiffer L.
        • Sinha J.
        • Wang X.
        • 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: 489-497
      2. Rovin BH, for the Access Investigators. Treatment of lupus nephritis with abatacept and low-dose pulse cyclophosphamide: the results of the ACCESS trial [abstract]. Presented at: American Society of Nephrology Meeting, November 4-10, 2013; Atlanta, GA.

        • Marti L.
        • Golmia R.
        • Golmia A.P.
        • et al.
        Alterations in cytokine profile and dendritic cells subsets in peripheral blood of rheumatoid arthritis patients before and after biologic therapy.
        Ann N Y Acad Sci. 2009; 1173: 334-342
        • Hsieh C.
        • Chang A.
        • Brandt D.
        • Guttikonda R.
        • Utset T.O.
        • Clark M.R.
        Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring.
        Arthritis Care Res. 2011; 63: 865-874
        • Trachtman H.
        • Fervenza F.C.
        • Gipson D.S.
        • et al.
        A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis.
        Kidney Int. 2011; 79: 1236-1243
        • Benigni A.
        • Zoja C.
        • Campana M.
        • et al.
        Beneficial effect of TGFbeta antagonism in treating diabetic nephropathy depends on when treatment is started.
        Nephron Exp Nephrol. 2006; 104: e158-e168
        • Sam R.
        • Wanna L.
        • Gudehithlu K.P.
        • et al.
        Glomerular epithelial cells transform to myofibroblasts: early but not late removal of TGF-beta1 reverses transformation.
        Transl Res. 2006; 148: 142-148
        • Singh N.N.
        • Ramji D.P.
        The role of transforming growth factor-beta in atherosclerosis.
        Cytokine Growth Factor Rev. 2006; 17: 487-499