This position paper critically analyzes the available controlled data regarding biologic therapy in lupus nephritis (LN). Rather than an exhaustive review of all published evidence, the stress is put on the unmet medical needs in LN, the design of trials aimed at testing the effect of a biologic in LN, the possible reasons for LN trial failures and the future of biological therapy in LN.

Keywords:
Lupus, Lupus nephritis, Glomerular disease, Treatment, Biologics
1.
Houssiau FA, Lauwerys BR: Current management of lupus nephritis. Best Pract Res Clin Rheumatol 2013;27:319-328.
2.
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gül A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R: Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. Arthritis Rheum 2004;50:3934-3940.
3.
Gladman DD, Urowitz MB, Rahman P, Ibañez D, Tam LS: Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol 2003;30:1955-1959.
4.
Thamer M, Hernan MA, Zhang Y, Cotter D, Petri M: Prednisone, lupus activity, and permanent organ damage. J Rheumatol 2009;36:560-564.
5.
Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, Cairns TD, Lightstone L: 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;72:1280-1286.
6.
Houssiau FA, Isenberg D: Towards treating lupus nephritis without oral steroids: a dream-come-true ? Ann Rheum Dis 2013;72:1271-1272.
7.
Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, Bonnet C, Cacoub P, Cantagrel A, de Bandt M, Fain O, Fautrel B, Gaudin P, Godeau B, Harlé JR, Hot A, Kahn JE, Lambotte O, Larouche C, Léone J, Meyer O, Pallot-Prades B, Pertuiset E, Quartier P, Schaerverbeke T, Sibilia J, Somogyi A, Soubrier M, Vignon E, Bader-Meunier B, Mariette X, Gottenberg JE; Club Rhumatismes et Inflammation: Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French Autoimmunity and Rituximab Registry. Arthritis Rheum 2010;62:2458-2466.
8.
Witt M, Grunke M, Proft F, Baeuerle M, Aringer M, Burmester G, Chehab G, Fiehn C, Fischer-Betz R, Fleck M, Freivogel K, Haubitz M, Kötter I, Lovric S, Metzler C, Rubberth-Roth A, Schwarting A, Specker C, Tony HP, Unger L, Wassenberg S, Dörner T, Schulze-Koops H; German Registry of Autoimmune Disease (GRAID) Investigators: Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID). Lupus 2013;22:1142-1149.
9.
Diaz-Lagares C, Croca S, Sangle S, Vital EM, Catapao F, Martinez-Berriotxoa A, Garcia-Hernandez F, Callejas-Rubio JL, Rascon J, D'Cruz D, Jayne D, Ruiz-Irastorza G, Emery P, Isenberg D, Ramos-Casals M, Khamashta MA; UK-BIOGEAS Registry: Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 2012;11:357-364.
10.
Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G; LUNAR Investigator Group: 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.
11.
Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, Houssiau FA, Drappa J, Close D, Maciuca R, Rao K, Shahdad S, Brunetta P: Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum 2013;65:2368-2379.
12.
Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL, Hillson JL, Meadows-Shropshire S, Kinaszczuk M, Merrill JT: Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol 2014;66:379-389.
13.
Frogoso-Loyo HE, Dooley MA; ACCESS Trial Group, et al: Efficacy of the Euro-Lupus Nephritis regimen combined with abatacept vs placebo in a North American lupus nephritis population. Ann Rheum Dis 2014, DOI: 10.1136/annrheumdis-2014-eular.4435.
14.
Ginzler EM, Wax S, Rajeswaran A, Copt S, Hillson J, Ramos E, Singer NG: Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther 2012;14:R33.
15.
Jayne D, Appel G, Chan TM, Barkay H, Weiss R, Wofsy D: A randomized controlled study of laquinimod in active lupus nephritis patients in combination with standard of care. Ann Rheum Dis 2013;72(suppl 3):164.
16.
van Vollenhoven R, Aranow C, Rovin B, Wagner C, Zhou B: A phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study to evaluate the efficacy and safety of sirukumab in patients with active lupus nephritis. Ann Rheum Dis 2014, DOI: 10.1136/annrheumdis-2014-eular.3974.
17.
Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D: Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis 2014, DOI: 10.1136/annrheumdis-2013-205067.
18.
Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, Leon MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA; BLISS-52 Study Group: Lancet 2011;377:721-731.
19.
Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, Sanchez-Guerrero J, Schwarting A, Merril JT, Chatham WW, Stohl W, Ginzler EM, Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF; BLISS-76 Study Group: A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918-3930.
20.
Wofsy D, Hillson JL, Diamond B: Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis Rheum 2012;64:3660-3665.
21.
Stohl W: Future prospects in biologic therapy for systemic lupus erythematosus. Nat Rev Rheumatol 2013;9:705-720.
22.
Carter LM, Isenberg DA, Ehrenstein MR: Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum 2013;65:2672-2679.
23.
Ichikawa HT, Conley T, Muchamuel T, Jiang J, Lee S, Owen T, Barnard J, Nevarez S, Goldman BI, Kirk CJ, Looney RJ, Anolik JH: Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum 2012;64:493-503.
24.
Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M, Kilgallen B, Bongardt S, Barry A, Kelley L, Gordon C: Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis 2014;73:183-190.
25.
Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, Martin RS, Scheinberg MA; for the PEARL-SC Study: 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 2014, DOI: 10.1136/annrheumdis-2013-205144.
27.
Petri M, Wallace DJ, Spindler A, Chindalore V, Kalunian K, Mysler E, Neuwelt CM, Robbie G, White WI, Higgs BW, Yao Y, Wang L, Ethgen D, Greth W: Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study. Arthritis Rheum 2013;65:1011-1021.
28.
Tcherepanova I, Curtis M, Sale M, Miesowicz F, Nicolette C: Results of a randomized placebo controlled phase IA study of AGS-009, a humanized anti-interferon-α monoclonal antibody in subjects with systemic lupus erythematosus. Ann Rheum Dis 2012;71(suppl 3):536.
29.
McBride JM, Jiang J, Abbas AR, Morimoto A, Li J, Maciuca R, Townsend M, Wallace DJ, Kennedy WP, Drappa J: 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.
30.
Lauwerys BR, Hachulla E, Spertini F, Lazaro E, Jorgensen C, Mariette X, Haelterman E, Grouard-Vogel G, Fanget B, Dhellin O, Vandepapalière P, Houssiau FA: Down-regulation of interferon signature in systemic lupus erythematosus patients by active immunization with interferon α-kinoid. Arthritis Rheum 2013;65:447-456.
32.
Zimmer R, Scherbarth HR, Rillo OL, Gomez-Reino JJ, Muller S: Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann Rheum Dis 2013;72:1830-1835.
33.
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D; Aspreva Lupus Management Study Group: Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009;20:1103-1112.
© 2014 S. Karger AG, Basel
2014
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