Skip to main content
Top

10-04-2016 | Systemic lupus erythematosus | Book Chapter | Article

17. Innovative Therapies in Systemic Lupus Erythematosus

Authors: Roberta Fenoglio, Fernando Fervenza, Dario Roccatello

Publisher: Springer International Publishing

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with unpredictable course, with periods of flares and remission. SLE is characterized by a broad spectrum of clinical manifestations and varying patterns of disease activity. The efficacy of current SLE medication has been questioned by treatment-related adverse side effects secondary to corticosteroid use and untargeted immunosuppression and by the increasing number of patients with refractory disease. Over the last decades, there has been major progress in the understanding of the immunopathology of SLE, paving the way for the development of new biological agents, potentially revolutionizing the treatment of SLE. A variety of novel therapeutic targets have been identified and there have been many studies in patients with SLE in an attempt to translate these new treatments into clinical practice.
Literature
1.
Jordan N, Lutalo PMK, D’Cruz D (2013) Novel therapeutic agents in clinical development for systemic lupus erythematosus. BMC J 11:120–130CrossRef
2.
Gottenberg J-E, Lorenzo N, Sordet C, Theulin A, Chatelus E, Sibilia J (2014) When biologics should be used in systemic lupus erythematosus? Presse Med 43:e181–e185CrossRefPubMed
3.
Ginzler EM, Moldovan I (2004) Systemic lupus erythematosus trials: successes and issues. Curr Opin Rheumatol 16:499–504CrossRefPubMed
4.
Andreoli L, Reggia R, Pea L, Frassi M, Zanola A, Cartella S, Franceschini F, Tincani A (2014) Belimumab for the treatment of refractory systemic lupus erythematosus: real-life experience in the first year of use in 18 Italian patients. IMAJ 16:651–653PubMed
5.
Zonana-Nacach A, Barr SG, Magder LS, Petri M (2000) Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 43:1801–1808CrossRefPubMed
6.
Dorner T, Radbruch A, Gerd R, Burmester GR (2009) B-cell-direct therapies for autoimmune disease. Nat Rev Rheumatol 5:433–441CrossRefPubMed
7.
Schiffer L, Bethunaickan R, Ramanujam M et al (2008) Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol 180:1938–1947CrossRefPubMedPubMedCentral
8.
Doria A, Iaccarino L (2013) Terapia del LES. Ital J Public Health 2(1):37–53
9.
Cragg MS, Walshe CA, Ivanov AO, Glennie MJ (2005) The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmune 8:140–174CrossRef
10.
Harvey PR, Gordon C (2013) B-cell targeted therapies in systemic lupus erythematosus: successes and challenges. BioDrugs 27(2):85–95CrossRefPubMed
11.
Zhou T, Zhang J, Carter R, Kimberly R (2003) BLyS and B cell autoimmunity. Curr Dir Autoimmun 6:21–37CrossRefPubMed
12.
Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA (2009) Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus 18(9):767–776CrossRefPubMed
13.
Anolik JH et al (2003) The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum 48:455–459CrossRefPubMed
14.
Leandro MJ, Cooper N, Cambridge G et al (2007) Bone marrow B lineage cells in patients with rheumatoid arthritis following rituximab therapy. Rheumatology 46:29–36CrossRefPubMed
15.
Beckwith H, Lightstone L (2014) Rituximab in systemic lupus erythematosus and lupus nephritis. Nephron Clin Pract 128:250–254CrossRefPubMed
16.
Favas C, Isenberg DA (2009) B-cell-depletion therapy in SLE – what are the current prospects for its acceptance? Nat Rev Rheumatol 5:711–716CrossRefPubMed
17.
Merrill JT, Neuwelt CM, Wallace DJ et al (2010) 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 62:222–233CrossRefPubMedPubMedCentral
18.
Merrill J et al (2011) Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER). Lupus 20:709–716CrossRefPubMed
19.
Rovin BH, Furie R, Latinis K et al (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 64:1215–1226CrossRefPubMed
20.
Lightstone L (2012) The landscape after LUNAR: rituximab’s crater-filled path. Arthritis Rheum 64:962–965CrossRefPubMed
21.
Weidenbusch M, Rommele C, Schrottle A, Anders HJ (2013) Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant 28:106–111CrossRefPubMed
22.
Diaz-Lagares C, Croca S, Sangle S et al (2012) Efficacy of rituximab in 164 pts with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 11:357–364CrossRefPubMed
23.
Hickman RA, Hira-Kazal R, Yee C-S, Toescu V (2015) The efficacy and safety of rituximab in a chart review study of 15 pts with systemic lupus erythematosus. Clin Rheumatol 34:263–271CrossRefPubMed
24.
Moroni G, Raffiotta F, Trezzi B, Giglio E, Mezzina N, Del Papa N, Meroni P, Messa P, Sinico AR (2014) Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study. Rheumatology (Oxford) 53(9):1570–1577CrossRef
25.
Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, Cairns TD, Lightstone L (2013) 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 72:1280–1286CrossRefPubMed
26.
Roccatello D, Sciascia S, Rossi D, Alpa M, Naretto C, Baldovino S, Menegatti E, La Grotta R, Modena V (2011) Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy. Nephrol Dial Transplant 26(12):3987–3992CrossRefPubMed
27.
Roccatello D, Sciascia S, Baldovino S, Rossi D, Alpa M, Naretto C, Di Simone D, Simoncini M, Menegatti E. 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):1123–1130
28.
Terrier B, Amoura Z, Ravaud P et al (2010) Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 pts from the French Autoimmunity and Rituximab registry. Arthritis Rheum 62:2458–2466CrossRefPubMed
29.
van Vollenhoven RF, Emery P, Bingham CO et al (2013) Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow up of the global clinical trial programme focus on adverse events of interest in RA pts. Ann Rheum Dis 72:1496–1502CrossRefPubMedPubMedCentral
30.
Molloi ES (2011) PML and rheumatology: the contribution of disease and drugs. Cleve Clin J Med 78:S28–S32CrossRef
31.
Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA et al (2013) Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-bind, phase III study. Arthritis Rheum 65:2368–2379CrossRefPubMed
32.
Dorner T, Kaufmann J, Wegener WA et al (2006) Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 8:R74CrossRefPubMedPubMedCentral
33.
Jacobi AM, Goldenberg DM, Hiepe F et al (2006) Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal control. Ann Rheum Dis 67:450–457CrossRef
34.
Al Rayes H, Touma Z (2014) Profile of epratuzumab and its potential in the treatment of systemic lupus erythematosus. Drug Des Devel Ther 8:2303–2310PubMedPubMedCentral
35.
Wallace DJ, Goldenberg DM (2013) Epratuzumab for systemic lupus erythematosus. Lupus 22(4):400–405CrossRefPubMed
36.
Traczewski P, Rudnicka L (2011) Treatment of systemic lupus erythematosus with epratuzumab. Br J Clin Pharmacol 71:175–182CrossRefPubMedPubMedCentral
37.
Strand V, Petri M, Kalunian K, Gordon C, Wallace DJ, Hobbs K et al (2014) Epratuzumab for patients with moderate to severe flaring SLE: health-related quality of life outcomes and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study SL0006. Rheumatology (Oxford) 53(3):502–511CrossRef
38.
ClinicalTrials.gov. Identifier NCT01262365, a phase 3, randomized, double-blind, placebo-controlled, multicenter study of the efficacy and safety of four 12-week treatment cycles (48 weeks total) of epratuzumab in systemic lupus erythematosus subjects with moderate to severe disease (EMBODY 1); 14th Dec 2010 – [cited 30th Mar 2014])
39.
Stohl W (2013) Future prospects in biologic therapy for systemic lupus erythematosus. Nat Rev Rheumatol 9:705–720CrossRefPubMed
40.
Stohl W (2014) Therapeutic targeting of the BAFF/APRIL axis in systemic lupus erythematosus. Expert Opin Ther Targets 18(4):473–489CrossRefPubMed
41.
Pisetsky DS, Grammer AC, Ning TC, Lipsky PE (2011) Are autoantibodies the target of B cell-direct therapy? Nat Rev Rheumatol 7:551–556CrossRefPubMed
42.
Navarra SV, Guzman RM, Gallacher AE et al (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, phase 3 trial. Lancet 377:721–731CrossRefPubMed
43.
Furie R, Petri M, Zamani O et al (2011) 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 63:3918–3930CrossRefPubMed
44.
Dooley MA, Houssiau F, Aranow C, D’Cruz DP, Askanase A, Roth DA, Zhong ZJ, Cooper S, Freimuth WW, Ginzler EM (2013) Effects of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus 22:63CrossRefPubMed
45.
Fried AJ, Bonilla FA (2009) Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev 22:396–414CrossRefPubMedPubMedCentral
46.
Kraaij T, Huizinga TW, Rabelink TJ, Teng YK (2014) Belimumab after rituximab as maintenance therapy in lupus nephritis. Rheumatology 53(11):2122–2124CrossRefPubMed
47.
Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C et al (2014) 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. http://​dx.​doi.​org/​10.​1136/​annrheumdis-2013-205144
48.
Kamala A, Khamashta M (2014) The efficacy of novel B cell biologics as the future of SLE treatment: a review. Autoimmun Rev 13(11):1094–1101CrossRef
49.
Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K et al (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404:995–999CrossRefPubMed
50.
Dall’Era M, Chakravarty E, Wallace D, Genovese M, Weisman M, Kavanaugh A et al (2007) Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum 56(12):4142–4150CrossRefPubMed
51.
Kayagaki N, Yan M, Seshasayee D, Wang H, Lee W, French DM et al (2002) BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. Immunity 17(4):515–524CrossRefPubMed
52.
Mok MY (2010) The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis 13(1):3–11CrossRefPubMed
53.
Cunane G, Chan OT, Cassafer G, Brindis S, Kaufman E, Yen TS, Daikh DI (2004) Prevention in renal damage in murine lupus nephritis by CTLA-4Ig and cyclophosphamide. Arthritis Rheum 50:1539–1548CrossRef
54.
Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace DJ, Bae SC, Sigal L, Becker JC, Kelly S, Raghupathi K, Li T, Peng Y, Kinaszczuk M, Nash P (2010) The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 62:3077–3087CrossRefPubMed
55.
Furie R, Nicholis K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL et al (2011) Efficacy and safety of abatecept over 12 months in patients with lupus nephritis: results from a multicenter, randomized, double blind, placebo-controlled phase II/III study. Arthritis Rheum 63:S 962–S 963CrossRef
56.
Wofsy D, Hillson JL, Diamond B (2013) Comparison of alternative primary outcome measures for use in a lupus nephritis trial. Arthritis Rheum 65(6):1586–1591CrossRefPubMedPubMedCentral
57.
Kalumian KC, Davis JC Jr, Merrill JT, Totoritis MC, Wofsy D (2002) Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double blind, placebo-controlled trial. Arthritis Rheum 46:3251–3258CrossRef
58.
Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A (2003) A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 48:719–727CrossRefPubMed
59.
Liang B, Gardner DB, Griswold DE et al (2006) Antiinterleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 119:296–305CrossRefPubMedPubMedCentral
60.
Illei GG, Shirota Y, Yarboro C et al (2010) Tocilizumab in systemic lupus erythematosus: data on safety, preliminarily efficacy, and impact on circulating plasma cells from an open label phase I dosage-escalation study. Arthritis Rheum 62:542–552CrossRefPubMedPubMedCentral
61.
Szepietowski JC, Nilganuwong S, Wozniacka A, Kuhn A et al (2013) Phase I randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of Sirukumab in cutaneous or systemic lupus erythematosus. Arthritis Rheum 65:2661–2671PubMed
62.
Rajadhyaksha AG, Mehra S, Nadkar MY (2013) Biologics in SLE: current status. JAPI 61:262–267PubMed
63.
Llorente L, Richaud-Patin Y, Garcia-Padilla C et al (2000) Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 43:1790–1800CrossRefPubMed
64.
Crow MK, Wohlgemuth J (2003) Microarray analysis of gene expression in lupus. Arthritis Rheum Ther 5:279–287CrossRef
65.
Merrill JT, Wallace DJ, Petri M et al (2011) 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 70(11):1905–1913CrossRefPubMed
66.
McBride JM, Jiang J, Abbas AR et al (2012) 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 64(11):3666–36769CrossRefPubMed
67.
Kirou KA, Gkrouzman E (2013) Anti-interferon alpha treatment in SLE. Clin Immunol 148(3):303–312CrossRefPubMed
68.
Hein E, Nielsen LA, Nielsen CT, Munthe-Fog L, Skjoedt MO, Jacobsen S, Garred P (2015) Ficolins and the lectin pathway of complement in patients with systemic lupus erythematosus. Mol Immunol 63(2):209–214CrossRefPubMed
69.
Cordeiro AC, Isenberg DA (2008) Novel therapies in lupus – focus on nephritis. Acta Reumatol Port 33:157–169PubMed
70.
Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P et al (2006) The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 355:1233–1243CrossRefPubMed
71.
Wang Y, Hu Q, Madri J, Rollins SA, Chodera A, Matis LA (1996) 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 Sci 93(16):8563–8568CrossRefPubMedPubMedCentral
72.
Barilla-Labarca ML, Toder K, Furie R (2013) Targeting the complement system in systemic lupus erythematosus and other diseases. Clin Immunol 148(3):313–321CrossRefPubMed
73.
Baumann U, Schimidt RE, Gessner JE (2003) New insights into the pathophysiology and in vivo Function of IgG Fc receptors through gene deletion studies. Arch Immunol Ther Exp 51:399–406
74.
Pradhan V, Patwardhan M, Ghosh K (2008) Fc gamma receptor polymorphisms in systemic lupus erythematosus and their correlation with the clinical severity of the disease. Indian J Hum Genet 14(3):77–78CrossRefPubMedPubMedCentral
75.
Michaelson JS, Wisniacki N, Burkly LC, Putterman C (2012) Role of TWEAK in lupus nephritis: a bench-to-bedside review. J Autoimmun 39(3):130–142CrossRefPubMedPubMedCentral
76.
Wisniacki NC, Codding CE (2011) Phase I, randomized, double-blind, placebo-controlled, single dose, dose escalation study to evaluate the safety, tolerability and pharmacokinetics of BIIB023 (Anti-TWEAK) in subjects with rheumatoid arthritis. Arthritis Rheum 63:S858
77.
Ghoreschi K, Gadina M (2014) Jakpot! New small molecules in autoimmune and inflammatory diseases. Exp Dermatol 23(1):7–11CrossRefPubMed
78.
Norman P (2014) Spleen tyrosine kinase inhibitors: a review of the patent literature 2010–2013. Expert Opin Ther Pat 24(5):573–595CrossRefPubMed
79.
Bahjat FR, Pine PR, Reitsma A, Cassafer G, Baluom M, Grillo S, Chang B, Zhao FF, Payan DG, Grossbard EB, Daikh DI (2008) An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine. Lupus 58(5):1433–1444
80.
Morales-Torres J (2012) The status of fostamatinib in the treatment of rheumatoid arthritis. Expert Rev Clin Immunol 8(7):609–615CrossRefPubMed
81.
Rovin BH, Parikh SV (2014) Lupus nephritis: the evolving role of novel therapeutics. Am J Kidney Dis 63(4):677–690CrossRefPubMedPubMedCentral
82.
Mishra MK, Wang J, Silva C, Mack M, Yong VW (2012) Kinetics of proinflammatory monocytes in a model of multiple sclerosis and its perturbation by laquinimod. Am J Pathol 181(2):642–651CrossRefPubMed
83.
Jolivel V, Luessi F, Masri J et al (2013) Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain 136:1048–1066CrossRefPubMed
84.
Keino H, Watanabe T, Sato Y, Okada AA (2011) Oral administration of retinoic acid receptor-alpha/beta-specific ligand Am80 suppresses experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 52(3):1548–1556CrossRefPubMed
85.
Klemann C, Raveney BJ, Klemann AK et al (2009) Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis. Am J Pathol 174(6):2234–2245CrossRefPubMedPubMedCentral
86.
Markopoulou A, Kyttaris VC (2013) Small molecules in the treatment of systemic lupus erythematosus. Clin Immunol 148(3):359–368CrossRefPubMedPubMedCentral
87.
Hiepe F, Dorner T (2011) Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol 7:170–178CrossRefPubMed
88.
Neubert K et al (2008) The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 14:748–755CrossRefPubMed
89.
Starke C, Frey S, Ubronaviciute V, Schett G, Winkler T, Voll R (2011) Depletion of autoreactive short- and long-lived plasma cells within nephritic kidneys of lupus mice by bortezomib. Ann Rheum Dis 2011;70:S91
90.
Hainz N et al (2012) The proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulo-interstitial architecture. Nephron Exp Nephrol 120:e47–e58CrossRefPubMed
91.
Alexander T, Sarfert R, Klotsche J, Kuhl A et al (2015) The proteasome inhibitor bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 0:1–5