title: Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy.
abstract: OBJECTIVE
  Lupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). B cells have a central role in the pathogenesis of SLE. B lymphocyte stimulator (BLyS) and a proliferation inducing ligand (APRIL) are pivotal in B cell homeostasis. We aimed to investigate a potential role of serum BLyS and APRIL as biomarkers in LN, especially as predictors of treatment response.
  
  
  METHODS
  Sixty-four patients with active LN (52 proliferative lupus nephritis (PLN); 12 membranous LN) were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of BLyS, APRIL and autoantibodies were measured on both biopsy occasions and in 64 individually matched controls. Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification, and scored for Activity Index and Chronicity Index. Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index.
  
  
  RESULTS
  Baseline BLyS levels were significantly higher in LN patients compared with controls (p<0.001) and remained unchanged following induction treatment. APRIL levels were significantly higher in patients compared with controls at baseline (p=0.005) and decreased following treatment (p<0.001). Among PLN patients, APRIL levels decreased significantly only in responders (CR: p=0.009; HR: p=0.01). Baseline BLyS levels <1.5 ng/mL predicted treatment response, attaining a positive predictive value of 92% for CR with PLN at baseline.
  
  
  CONCLUSIONS
  BLyS and APRIL were affected differently by immunosuppression; BLyS levels remained unchanged following therapy while APRIL levels decreased. Despite unchanged BLyS levels following therapy, low baseline levels predicted both clinical and histopathological improvement. Our data support APRIL as a candidate biomarker of renal disease activity in lupus patients with proliferative glomerulonephritis and point to low baseline BLyS levels predicting treatment response in LN, especially in PLN.
authors: Department of Medicine, Rheumatology Unit , Karolinska Institutet , Stockholm , Sweden.
authors: Ioannis
authors: 0000-0002-4875-5395
authors: I
authors: Parodis
authors: Department of Medicine, Rheumatology Unit , Karolinska Institutet , Stockholm , Sweden.
authors: Agneta
authors: A
authors: Zickert
authors: Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.
authors: Birgitta
authors: B
authors: Sundelin
authors: AlbaNova University Center, KTH Royal Institute of Technology , Stockholm , Sweden.
authors: Magnus
authors: M
authors: Axelsson
authors: Department of Medicine, Rheumatology Unit , Karolinska Institutet , Stockholm , Sweden.
authors: Jakob
authors: J
authors: Gerhardsson
authors: Department of Medicine, Rheumatology Unit , Karolinska Institutet , Stockholm , Sweden.
authors: Elisabet
authors: E
authors: Svenungsson
authors: Department of Medicine, Rheumatology Unit , Karolinska Institutet , Stockholm , Sweden.
authors: Vivianne
authors: V
authors: Malmström
authors: Department of Medicine, Rheumatology Unit , Karolinska Institutet , Stockholm , Sweden.
authors: Iva
authors: I
authors: Gunnarsson
keywords: B cells; Lupus Nephritis; Systemic Lupus Erythematosus
references: PLoS One. 2013 Aug 12;8(8):e71458
references: 23951169
references: Ann Rheum Dis. 2005 Jul;64(7):1065-7
references: 15576416
references: Arthritis Rheum. 2006 Mar;54(3):723-32
references: 16508933
references: Annu Rev Immunol. 2003;21:231-64
references: 12427767
references: Ann Rheum Dis. 2007 Mar;66(3):351-7
references: 16950808
references: Lupus. 2010 Nov;19(13):1534-49
references: 20974656
references: Medicine (Baltimore). 2003 Sep;82(5):299-308
references: 14530779
references: N Engl J Med. 2008 Feb 28;358(9):929-39
references: 18305268
references: Scand J Immunol. 2005 Nov;62(5):421-8
references: 16305638
references: J Clin Invest. 2002 Jun;109(12):1587-98
references: 12070306
references: Ann N Y Acad Sci. 2005 Jun;1050:34-9
references: 16014518
references: Clin Immunol. 2010 Apr;135(1):118-24
references: 20116334
references: Lancet. 1995 Jun 24;345(8965):1595-9
references: 7783536
references: Ann Intern Med. 1999 Mar 16;130(6):461-70
references: 10075613
references: Mod Pathol. 2011 Jan;24(1):98-107
references: 20890272
references: Arthritis Rheum. 2008 Aug;58(8):2453-9
references: 18668552
references: Lupus. 2013 Jan;22(1):63-72
references: 23263865
references: Arthritis Rheum. 2003 Dec;48(12):3475-86
references: 14673998
references: Lupus. 2013 Apr;22(4):372-80
references: 23553780
references: Arthritis Rheum. 1985 Apr;28(4):425-30
references: 3885960
references: Arthritis Res Ther. 2012 Feb 07;14 (1):R33
references: 22325903
references: Nat Rev Drug Discov. 2006 Mar;5(3):235-46
references: 16474316
references: J Exp Med. 2003 Sep 15;198(6):937-45
references: 12975458
references: J Immunol. 2001 Jan 1;166(1):6-10
references: 11123269
references: Arthritis Rheum. 2006 Feb;54(2):421-32
references: 16453282
references: J Exp Med. 2004 Jan 5;199(1):91-8
references: 14707116
references: Mol Immunol. 2005 May;42(7):763-72
references: 15829264
references: Arthritis Res Ther. 2012 Nov 21;14 (6):R252
references: 23171638
references: Immunity. 2004 Apr;20(4):441-53
references: 15084273
references: Lupus Sci Med. 2014 Aug 06;1(1):e000018
references: 25379188
references: Lancet. 1992 Sep 26;340(8822):741-5
references: 1356175
references: J Allergy Clin Immunol. 2010 Apr;125(4):814-20
references: 20371395
references: Arthritis Rheum. 1990 May;33(5):634-43
references: 2346519
references: Arthritis Rheum. 1979 Mar;22(3):226-35
references: 311204
references: J Exp Med. 1999 Dec 6;190(11):1697-710
references: 10587360
references: Arthritis Rheum. 2012 Jul;64(7):2328-37
references: 22275291
references: Arthritis Rheum. 1982 Nov;25(11):1271-7
references: 7138600
references: J Rheumatol. 2002 Feb;29(2):288-91
references: 11838846
references: Arthritis Rheum. 2012 Aug;64(8):2677-86
references: 22553077
references: Arthritis Res Ther. 2006;8(6):R167
references: 17092341
references: Arthritis Res Ther. 2006;8(1):R6
references: 16356193
references: Arthritis Rheum. 2007 Apr;56(4):1263-72
references: 17393458
references: J Clin Invest. 2003 Jul;112(2):286-97
references: 12865416
references: Ann Rheum Dis. 2008 Jul;67(7):1011-6
references: 17962238
references: Arthritis Rheum. 2010 May;62(5):1457-68
references: 20131293
references: Am J Med. 1983 Sep;75(3):382-91
references: 6351607
references: Arthritis Rheum. 2003 May;48(5):1332-42
references: 12746906
references: Arthritis Rheum. 2001 Jun;44(6):1313-9
references: 11407690
references: J Am Soc Nephrol. 2004 Feb;15(2):241-50
references: 14747370
references: Lupus. 2013 Aug;22(9):873-84
references: 23846230
references: Arthritis Rheum. 2003 Nov;48(11):3253-65
references: 14613291
references: Arthritis Rheum. 2002 Aug;46(8):2121-31
references: 12209517
references: Arthritis Rheum. 2013 Apr;65(4):853-63
references: 23280551
references: Nat Rev Rheumatol. 2014 Jun;10(6):365-73
references: 24614588