Cross-sectional study of plasma Axl,ferritin,IGFBP4 and sTNFR2 as biomarkers of disease activity in childhood-onset SLE: A study of the Pediatric Nephrology Research Consortium
Restricted accessResearch articleFirst published online August, 2021
Cross-sectional study of plasma Axl,ferritin,IGFBP4 and sTNFR2 as biomarkers of disease activity in childhood-onset SLE: A study of the Pediatric Nephrology Research Consortium
To evaluate the performance of 4 plasma protein markers for detecting disease activity in childhood-onset systemic lupus erythematosus (SLE) patients.
Methods
Eighty-three consecutive pediatric patients fulfilling ≥4 ACR criteria for SLE and twenty-five healthy controls were prospectively recruited for serological testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, IGFBP4 and sTNFR2. SLE disease activity was assessed using SLEDAI-2000 score. Fifty-seven patients had clinically active SLE (SLEDAI score ≥4, or having a flare).
Results
The plasma concentrations of Axl and ferritin were significantly higher in patients with active SLE than inactive SLE. Plasma Axl levels were significantly higher in active renal versus active non-renal SLE patients. Levels of Axl, ferritin and IGFBP4 correlated significantly with SLEDAI scores. Levels of Axl, IFGBP4 and sTNFR2 inversely correlated with plasma complement C3 levels. Only plasma Axl and ferritin levels correlated with degree of proteinuria. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA antibody titer or decreased C3. Ferritin and IGFBP4 levels were more specific for concurrent active lupus nephritis than anti-dsDNA or C3. Plasma ferritin was the best monitor of global SLE activity, followed by C3 then Axl, while both Axl and C3 were best monitors of clinical lupus nephritis activity.
Conclusion
In childhood-onset SLE patients, plasma ferritin and Axl perform better than traditional yardsticks in identifying disease activity, either global or renal. The performance of these plasma markers should be explored further in longitudinal cohorts of SLE patients.
SolimanSMohamedFAIsmailFMStanleySSaxenaRMohanC.Urine angiostatin and VCAM-1 surpass conventional metrics in predicting elevated renal pathology activity indices in lupus nephritis. Int J Rheum Dis2017;
20: 1714–1727.
3.
TuckerLBUribeAGFernandezM, et al.
Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII). Lupus2008;
17: 314–322.
MokCC.Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol2010;
2010: 638413.
10.
ArriensCMohanC.Systemic lupus erythematosus diagnostics in the 'omics' era. Int J Clin Rheumtol2013;
8: 671–687.
11.
WuTDingHHanJ, et al.
Antibody-array-based proteomic screening of serum markers in systemic lupus erythematosus: a discovery study. J Proteome Res2016;
15: 2102–2114.
12.
MokCCDingHHKharboutliMMohanC.Axl, ferritin, IGFBP2 and TNFR2 as biomarkers in systemic lupus erythematosus. Arthritis Care Res (Hoboken)2016;
68: 1303–1309.
13.
HochbergMC.Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997;
40: 1725.
GladmanDGinzlerEGoldsmithC, et al.
The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus. Arthritis Rheum1996;
39: 363–369.
16.
BajemaIMWilhelmusSAlpersCE, et al.
Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int2018;
93: 789–796.
17.
AustinHAMuenzLRJoyceKMAntonovychTTBalowJE.Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int1984;
25: 689–695.
18.
HiramatsuNKuroiwaTIkeuchiH, et al.
Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions. Rheumatology (Oxford, England)2008;
47: 702–707.
19.
BossuytPMReitsmaJBBrunsDE, et al.
STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. BMJ2015;
351: h5527.
20.
O'BryanJPFridellYWKoskiRVarnumBLiuET.The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage. J Biol Chem1995;
270: 551–557.
21.
KanlikilicerPOzpolatBAslanB, et al.
Therapeutic targeting of AXL receptor tyrosine kinase inhibits tumor growth and intraperitoneal metastasis in ovarian cancer models. Mol Ther Nucleic Acids2017;
9: 251–262.
22.
StauferKDenglerMHuberH, et al.
The non-invasive serum biomarker soluble Axl accurately detects advanced liver fibrosis and cirrhosis. Cell Death Dis2017;
8: e3135.
23.
LiuYWYangQFZuoPYXiaoCLChenXLLiuCY.Elevated serum levels of soluble Axl in acute coronary syndrome. Am J Med Sci2015;
349: 124–129.
24.
LeeIJHilliardBAUlasM, et al.
Monocyte and plasma expression of TAM ligand and receptor in renal failure: links to unregulated immunity and chronic inflammation. Clin Immunol2015;
158: 231–241.
25.
OrmeJJDuYVanarsaK, et al.
Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE. Clin Immunol2016;
169: 58–68.
26.
EkmanCJönsenASturfeltGBengtssonAADahlbäckB.Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus. Rheumatology (Oxford, England)2011;
50: 1064–1069.
27.
GheitaTABassyouniIHBassyouniRH.Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl in patients with systemic lupus erythematosus and Behcets disease. J Clin Immunol2012;
32: 1279–1286.
28.
KellDBPretoriusE.Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics2014;
6: 748–773.
29.
JiYFaddyHHylandCFlowerR.A plasma ferritin is not always a serum ferritin. Pathology2015;
47: S89–S90.
30.
LipschitzDAAllegreACookJD.The clinical significance of ferritinuria. Blood1980;
55: 260–264.
31.
Zandman-GoddardGShoenfeldY.Ferritin in autoimmune diseases. Autoimmun Rev2007;
6: 457–463.
32.
LimMKLeeCKJuYS, et al.
Serum ferritin as a serologic marker of activity in systemic lupus erythematosus. Rheumatol Int2001;
20: 89–93.
33.
VanarsaKYeYHanJXieCMohanCWuT.Inflammation associated anemia and ferritin as disease markers in SLE. Arthritis Res Ther2012;
14: R182.
34.
TripathyRPandaAKDasBK.Serum ferritin level correlates with SLEDAI scores and renal involvement in SLE. Lupus2015;
24: 82–89.
35.
PradhanVPanditPRajadhyakshaA, et al.
Association of serum ferritin levels with hematological manifestations in systemic lupus erythematosus patients from Western India. J Assoc Physicians India2016;
64: 14–18.
36.
BeyanEBeyanCDemirezerAErtugrulEUzunerA.The relationship between serum ferritin levels and disease activity in systemic lupus erythematosus. Scand J Rheumatol2003;
32: 225–228.
37.
ForbesBEMcCarthyPNortonRS.Insulin-like growth factor binding proteins: a structural perspective. Front Endocrinol (Lausanne)2012;
3: 38.
38.
RadettiGPaganiniCAntoniazziF, et al.
Growth hormone-binding proteins, IGF-I and IGF-binding proteins in children and adolescents with type 1 diabetes mellitus. Horm Res1997;
47: 110–115.
39.
HjortebjergRTarnowLJorsalA, et al.
IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy. J Clin Endocrinol Metab2015;
100: 3032–3040.
40.
TaveraCAbribatTReboulP, et al.
IGF and IGF-binding protein system in the synovial fluid of osteoarthritic and rheumatoid arthritic patients. Osteoarthr Cartil1996;
4: 263–274.
41.
WuTXieCHanJ, et al.
Insulin-like growth factor binding protein-4 as a marker of chronic lupus nephritis. PLoS ONE2016;
11: e0151491.
42.
MahmoudRAEl-GendiHIAhmedHH.Serum neopterin, tumor necrosis factor-alpha and soluble tumor necrosis factor receptor II (p75) levels and disease activity in Egyptian female patients with systemic lupus erythematosus. Clin Biochem2005;
38: 134–141.
43.
HagaTEfirdJTTugizovSPalefskyJM.Increased TNF-alpha and sTNFR2 levels are associated with high-grade anal squamous intraepithelial lesions in HIV-positive patients with low CD4 level. Papillomavirus Res2017;
3: 1–6.
44.
BessaTFCordeiroCAGoncalvesRM, et al.
Increased serum levels of soluble tumor necrosis factor receptor-2 (sTNFR2) in patients with active toxoplasmic retinochoroiditis. Braz J Infect Dis2012;
16: 540–544.
45.
KudoNYamamoriHIshimaT, et al.
Plasma levels of soluble tumor necrosis factor receptor 2 (sTNFR2) are associated with hippocampal volume and cognitive performance in patients with schizophrenia. Int J Neuropsychopharmacol2018;
21: 631–639.
SvenungssonEGunnarssonIFeiG-ZLundbergIEKlareskogLFrostegårdJ.Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum2003;
48: 2533–2540.
