1.
Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. 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(12):3918–30.
CrossRefPubMedPubMedCentral
2.
Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721–31.
CrossRefPubMed
3.
Isenberg DA, Urowitz MB, Merrill JT, Hoffman RW, Linnik MD, Morgan-Cox M, et al., editors. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus (SLE): results from 2 phase 3, 52-week, multicenter, randomized, double-blind, placebo-controlled trials. Boston, MA: American College of Rheumatology Annual Meeting; 2014.
4.
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.
5.
Ginzler EM, Wax S, Rajeswaran A, Copt S, Hillson J, Ramos E, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther. 2012;14(1):R33.
CrossRefPubMedPubMedCentral
6.
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. 2015;74(11):2006–15.
7.
Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572–81.
CrossRefPubMed
8.
Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA. Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus. 2009;18(9):767–76.
CrossRefPubMed
9.
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
10.
Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, 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(1):222–33.
CrossRefPubMedPubMedCentral
11.
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.
CrossRefPubMedPubMedCentral
12.
Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum. 2013;65(9):2368–79.
CrossRefPubMed
13.
Wallace DJ, Gordon C, Strand V, Hobbs K, Petri M, Kalunian K, et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up. Rheumatology (Oxford). 2013;52(7):1313–22.
CrossRef
14.
Clowse ME, Wallace DJ, Furie RA, Petri MA, Pike MC, Leszczynski P, et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: results from two phase III randomized, double-blind, placebo-controlled trials. Arthritis Rheumatol. 2017;69(2):362–75.
15.
Kurosaki T. Regulation of BCR signaling. Mol Immunol. 2011;48(11):1287–91.
CrossRefPubMed
16.
Jongstra-Bilen J, Puig Cano A, Hasija M, Xiao H, Smith CI, Cybulsky MI. Dual functions of Bruton’s tyrosine kinase and Tec kinase during Fcgamma receptor-induced signaling and phagocytosis. J Immunol. 2008;181(1):288–98.
CrossRefPubMed
17.
Kenny EF, Quinn SR, Doyle SL, Vink PM, van Eenennaam H, O’Neill LA. Bruton’s tyrosine kinase mediates the synergistic signalling between TLR9 and the B cell receptor by regulating calcium and calmodulin. PLoS One. 2013;8(8):e74103.
CrossRefPubMedPubMedCentral
18.
Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science. 1993;261(5119):355–8.
CrossRefPubMed
19.
Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–37.
CrossRefPubMedPubMedCentral
20.
Rankin AL, Seth N, Keegan S, Andreyeva T, Cook TA, Edmonds J, et al. Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. J Immunol. 2013;191(9):4540–50.
CrossRefPubMed
21.
Hutcheson J, Vanarsa K, Bashmakov A, Grewal S, Sajitharan D, Chang BY, et al. Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus. Arthritis Res Ther. 2012;14(6):R243.
CrossRefPubMedPubMedCentral
22.
Slifka MK, Ahmed R. Long-lived plasma cells: a mechanism for maintaining persistent antibody production. Curr Opin Immunol. 1998;10(3):252–8.
CrossRefPubMed
23.
Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med. 2008;14(7):748–55.
CrossRefPubMed
24.
Ichikawa HT, Conley T, Muchamuel T, Jiang J, Lee S, Owen T, et al. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum. 2012;64(2):493–503.
CrossRefPubMedPubMedCentral
25.
Seavey MM, Lu LD, Stump KL, Wallace NH, Ruggeri BA. Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE. Int Immunopharmacol. 2012;12(1):257–70.
CrossRefPubMed
26.
• Alexander T, Sarfert R, Klotsche J, Kuhl AA, Rubbert-Roth A, Lorenz HM, et al. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis. 2015;74(7):1474–8.
This proof of concept study demonstates the effectiveness of plasma cell inhibition in patients with refractory SLE.
CrossRefPubMedPubMedCentral
27.
Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, 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(5):2610–5.
CrossRefPubMedPubMedCentral
28.
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.
CrossRefPubMedPubMedCentral
29.
• 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.
This article shows evidence of the clinical usefulness of interferon alpha inhibition in SLE patients.
CrossRefPubMed
30.
Morehouse C, Chang L, Wang L, Brohawn P, Ueda S, Illei G, et al. Target Modulation of a Type I Interferon (IFN) Gene Signature with Sifalimumab or Anifrolumab in Systemic Lupus Erythematosus (SLE) Patients in Two Open Label Phase 2 Japanese Trials. Boston, MA: American College of Rheumatology Annual Meeting; 2014.
31.
Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017;69(2):376–86.
32.
Balomenos D, Rumold R, Theofilopoulos AN. Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest. 1998;101(2):364–71.
CrossRefPubMedPubMedCentral
33.
Welcher AA, Boedigheimer M, Kivitz AJ, Amoura Z, Buyon J, Rudinskaya A, et al. Blockade of interferon-gamma normalizes interferon-regulated gene expression and serum CXCL10 levels in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2015;67(10):2713–22.
CrossRefPubMedPubMedCentral
34.
Werth VP, Fiorentino D, Cohen SB, Fivenson D, Hansen C, Zoog S, et al. A Phase I Single-Dose Crossover Study To Evaluate The Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy Of AMG 811 (anti-IFN-gamma) In Subjects With Discoid Lupus Erythematosus. Boston, MA: American College of Rheumatology Annual Meeting; 2014.
35.
Martin D, Amoura Z, Romero-Diaz J, Chong Y, Sanchez-Guerrero J, Chan T, et al. A multiple dose study of AMG 811 (anti-IFN-gamma) in subjects with systemic lupus erythematosus and active nephritis. Ann Rheum Dis. 2015;74(Suppl2):337.
36.
Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 2003;48(3):719–27.
CrossRefPubMed
37.
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
38.
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.
CrossRefPubMed
39.
Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med. 1998;338(18):1272–8.
CrossRefPubMed
40.
• Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055–66.
First evidence that low dose IL-2 can act as an immuno-regulatory cytokine increasing the numbers of Treg.
CrossRefPubMedPubMedCentral
41.
Mizui M, Koga T, Lieberman LA, Beltran J, Yoshida N, Johnson MC, et al. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells. J Immunol. 2014;193(5):2168–77.
CrossRefPubMedPubMedCentral
42.
He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991–3.
CrossRefPubMed
43.
Crispin JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol. 2008;181(12):8761–6.
CrossRefPubMedPubMedCentral
44.
Zhang Z, Kyttaris VC, Tsokos GC. The role of IL-23/IL-17 axis in lupus nephritis. J Immunol. 2009;183(5):3160–9.
CrossRefPubMedPubMedCentral
45.
Kyttaris VC, Zhang Z, Kuchroo VK, Oukka M, Tsokos GC. Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol. 2010;184(9):4605–9.
CrossRefPubMedPubMedCentral
46.
Kyttaris VC, Kampagianni O, Tsokos GC. Treatment with anti-interleukin 23 antibody ameliorates disease in lupus-prone mice. Biomed Res Int. 2013;2013:861028.
CrossRefPubMedPubMedCentral
47.
Schmidt T, Paust HJ, Krebs CF, Turner JE, Kaffke A, Bennstein SB, et al. Function of the Th17/interleukin-17A immune response in murine lupus nephritis. Arthritis Rheumatol. 2015;67(2):475–87.
CrossRefPubMed
48.
Mok CC, Ying KY, Yim CW, Siu YP, Tong KH, To CH, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis. 2016;75(1):30–6.
CrossRefPubMed
49.
Dooley MA, Pendergraft W III, Ginzler EM, Olsen NJ, Tumlin J, Rovin BH, et al. Speed of remission with the use of voclosporin, MMF and low dose steroids: results of a global lupus nephritis study [abstract]. Arthritis Rheumatol. 2016;68(suppl 10).
50.
Sarbassov DD, Sabatini DM. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex. J Biol Chem. 2005;280(47):39505–9.
CrossRefPubMed
51.
Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011;334(6056):678–83.
CrossRefPubMedPubMedCentral
52.
Warner LM, Adams LM, Sehgal SN. Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Arthritis Rheum. 1994;37(2):289–97.
CrossRefPubMed
53.
Fernandez D, Bonilla E, Mirza N, Niland B, Perl A. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(9):2983–8.
CrossRefPubMedPubMedCentral
54.
Lai ZW, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012;64(9):2937–46.
CrossRefPubMedPubMedCentral
55.
Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25–36.
CrossRefPubMed
56.
Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495–507.
CrossRefPubMed
57.
Kahl L, Patel J, Layton M, Binks M, Hicks K, Leon G, et al. Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus. Lupus. 2016;25(13):1420–30.
58.
Hedrich CM, Rauen T, Apostolidis SA, Grammatikos AP, Rodriguez Rodriguez N, Ioannidis C, et al. Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc Natl Acad Sci U S A. 2014;111(37):13457–62.
CrossRefPubMedPubMedCentral
59.
Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007;40(1):1–8.
CrossRefPubMed
60.
Edwards LJ, Mizui M, Kyttaris V. Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice. Clin Immunol. 2015;158(2):221–30.
CrossRefPubMedPubMedCentral
61.
Ding C, Chen X, Dascani P, Hu X, Bolli R, Zhang HG, et al. STAT3 signaling in B cells is critical for germinal center maintenance and contributes to the pathogenesis of murine models of lupus. J Immunol. 2016;196(11):4477–86.
CrossRefPubMed
62.
Liu K, Liang C, Liang Z, Tus K, Wakeland EK. Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes. J Immunol. 2005;174(3):1630–7.
CrossRefPubMed
63.
Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996;392(2):189–93.
CrossRefPubMed
64.
Li Y, Harada T, Juang YT, Kyttaris VC, Wang Y, Zidanic M, et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus. J Immunol. 2007;178(3):1938–47.
CrossRefPubMed
65.
Biswas PS, Gupta S, Chang E, Song L, Stirzaker RA, Liao JK, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest. 2010;120(9):3280–95.
CrossRefPubMedPubMedCentral
66.
Biswas PS, Gupta S, Stirzaker RA, Kumar V, Jessberger R, Lu TT, et al. Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity. J Exp Med. 2012;209(3):581–96.
CrossRefPubMedPubMedCentral
67.
Stirzaker RA, Biswas PS, Gupta S, Song L, Bhagat G, Pernis AB. Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice. Lupus. 2012;21(6):656–61.
CrossRefPubMed
68.
Vicari RM, Chaitman B, Keefe D, Smith WB, Chrysant SG, Tonkon MJ, et al. Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J Am Coll Cardiol. 2005;46(10):1803–11.
CrossRefPubMed
69.
Fukumoto Y, Yamada N, Matsubara H, Mizoguchi M, Uchino K, Yao A, et al. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J. 2013;77(10):2619–25.
CrossRefPubMed
70.
Fava A, Wung PK, Wigley FM, Hummers LK, Daya NR, Ghazarian SR, et al. Efficacy of Rho kinase inhibitor fasudil in secondary Raynaud’s phenomenon. Arthritis Care Res (Hoboken). 2012;64(6):925–9.
CrossRef
71.
Andersen O, Lycke J, Tollesson PO, Svenningsson A, Runmarker B, Linde AS, et al. Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology. 1996;47(4):895–900.
CrossRefPubMed
72.
Bjork P, Bjork A, Vogl T, Stenstrom M, Liberg D, Olsson A, et al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009;7(4):e97.
CrossRefPubMed
73.
Lood C, Stenstrom M, Tyden H, Gullstrand B, Kallberg E, Leanderson T, et al. Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus. Arthritis Res Ther. 2011;13(2):R60.
CrossRefPubMedPubMedCentral
74.
Loser K, Vogl T, Voskort M, Lueken A, Kupas V, Nacken W, et al. The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med. 2010;16(6):713–7.
CrossRefPubMed
75.
Lourenco EV, Wong M, Hahn BH, Palma-Diaz MF, Skaggs BJ. Laquinimod delays and suppresses nephritis in lupus-prone mice and affects both myeloid and lymphoid immune cells. Arthritis Rheumatol. 2014;66(3):674–85.
CrossRefPubMed
76.
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(Suppl3):164.
77.
Bengtsson AA, Sturfelt G, Lood C, Ronnblom L, van Vollenhoven RF, Axelsson B, et al. Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR-215757), a new quinoline-3-carboxamide derivative: studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64(5):1579–88.
CrossRefPubMed
78.
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(11):1830–5.
CrossRefPubMed