B-Cell-Attracting Chemokine CXCL13 As a Marker of Disease Activity in Systemic Lupus Erythematosus (SLE)

Abstract

Background A correlation was detected between the chemokine CXC ligand 13 (CXCL13) and lupus nephritis, but there is no data recorded in the literature about a relationship with other disease manifestations in systemic lupus erythematosus (SLE). Therefore, we sought to investigate the relationship between CXCL13 and overall disease activity and other disease manifestations in SLE.

Patients and Methods Fifty-seven SLE patients (51 female, 6 male) aged 18–60 years, fulfilling≥4 SLICC classification criteria for the classification of SLE, were enrolled in a cross-sectional study. Disease activity was scored using the SLE Disease Activity Index (SLEDAI) scoring system. The serological workup included routine lab investigations (full blood count, liver and kidney function tests, and urinalysis) as well as ESR, CRP, anti-ds DNA, C3, C4, 24-h urine protein, and creatinine clearance. Plasma CXCL13 levels were detected by ELISA.

Results CXCL13 levels were elevated in active SLE patients. A significant positive correlation was found between the total score of SLEDAI and CXCL13 levels (r=0.547, p-value <0.0001). A statistically significant difference was found regarding the mean CXCL13 levels between the patient groups (classified according to SLEDAI score) (inactive <3, mild/moderate ≥3–12, severe ˃12) (p-value<0.001). The anti-ds DNA antibody titre showed a significant positive correlation with CXCL13 levels (r=0.335, p-value<0.05). The complement levels (C3, C4) showed a significant negative correlation with CXCL13 levels (p-value<0.001). Also there was a significant positive correlation between 24-h urine protein and urinary casts and CXCL13 levels (p-value<0.05).

Conclusion Our study revealed elevated levels of serum CXCL13 in active SLE patients. We demonstrated a highly significant positive correlation between serum CXCL13 levels in active SLE patients and SLE disease activity, which supports the role of CXCL13 in the pathogenesis of SLE disease and its activity. Among the variants used in calculating the SLEDAI score, we detected significant relations between level of serum CXCL13 and each of total and extra-renal SLEDAI score.

Zusammenfassung

Hintergrund Eine Beziehung zwischen dem Chemokin-CXC-Liganden 13 (CXCL13) wurde festgestellt, um mit der Lupusnephritis zu korrelieren, aber es wurden keine Daten in der Literatur über ihre Beziehung mit anderen Krankheitsmanifestationen im systemischen Lupus erythematodes (SLE) aufgezeichnet. Deshalb haben wir versucht, die CXCL13-Relation mit der gesamten Krankheitsaktivität und ihrer Beziehung zu anderen Krankheitsmanifestationen in SLE zu untersuchen.

Patienten und Methoden Fünfundfünfzig SLE-Patienten (51 weiblich, 6 männlich) im Alter von 18–60 Jahren, die≥4 SLICC-Klassifizierungskriterien für die Klassifizierung von SLE erfüllen, wurden in einer Querschnittsstudie eingeschrieben. Die Krankheit Aktivität wurde mit dem SLE-Krankheit Aktivität Index (SLEDAI) Scoring-System bewertet. Die serologische Aufarbeitung umfasste die Routine-Laboruntersuchungen (Vollblutbild, Leber- und Nierenfunktionstests und Urinanalyse) neben ESR, CRP, Anti-ds-DNA, C3, C4, 24 h-Protein im Urin und Kreatinin-Clearance. Die Plasma-CXCL13-Spiegel wurden durch ELISA nachgewiesen.

Ergebnisse CXCL13-Werte wurden bei aktiven SLE-Patienten erhöht. Eine signifikante positive Korrelation zwischen der Gesamtpunktzahl der SLEDAI- und CXCL13-Werte (r=0,547, P-Wert<0,0001). Ein statistischer signifikanter Unterschied zu den mittleren CXCL13-Werten zwischen den Patientengruppen (klassifiziert nach SLEDAI-Score) (inaktiv<3, mild/mäßig ≥ 3–12, sever ˃12) (P-Wert<0,001). Der Anti-ds-DNA-Antikörper-Titer zeigte eine signifikante positive Korrelation mit den CXCL13-Werten (r=0,335, P-Wert<0,05). Die Komplement-Niveaus (C3, C4) zeigten eine signifikante negative Korrelation mit den CXCL13-Werten (P-Wert<0,001). Eine signifikante positive Korrelation zwischen Harn-24-Stunden-Protein und Harn-Casts und CXCL13-Konzentrationen (P-Wert<0,05).

Schlussfolgerung Unsere Studie ergab eine erhöhte Serum-CumCL13 bei aktiven SLE-Patienten. Wir zeigten eine signifikante positive Korrelation zwischen den Serum-CXCL13-Werten bei aktiven SLE-Patienten und der SLE-Erkrankung, die die Rolle von CXCL13 bei der Pathogenese der SLE-Erkrankung und ihrer Aktivität unterstützt. Unter den Varianten, die bei der Berechnung der SLEDAI-Punktzahl verwendet wurden, wurden signifikante Beziehungen zwischen dem Serum CXCL13 und jedem der gesamten und extra-renalen SLEDAI-Score nachgewiesen.

Schlüsselwörter

Chemokin-CXC-Liganden 13 (CXCL13) - Rolle von CXCL13 bei der Pathogenese der SLE-Krankheit und ihrer Aktivitat - SLE-Krankheit Aktivitat

Key words

role of CXCL13 in the pathogenesis of SLE disease and its activity - SLE disease activity - chemokine CXC ligand 13 (CXCL13)

• References

• 1 Dall’era M, Wofsy D. Clinical Features of Systemic Lupus Erythematosus. In: Firestein GS. et al. (eds) Kelley’s Textbook of Rheumatology. Elsevier; 2013: 1283-1303
• 2 Forster R, Mattis AE, Kremmer E. et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 1996; 87: 1037-1047
• 3 Ishikawa S, Sato T, Abe M. et al. Aberrant high expression of B lymphocyte chemokine (BLC/CXCL13) by C11b+ CD11c+ dendritic cells in murine lupus and preferential chemotaxis of B1 cells towards BLC. J Exp Med 2001; 193: 1393-1402
• 4 Takemura S, Braun A, Crowson C. et al. Lymphoid neogenesis in rheumatoid synovitis. J Immunol 2001; 167: 1072-1080
• 5 Adalid-Peralta L, Mathian A, Tran T. et al. Leukocytes and the kidney contribute to interstitial inflammation in lupus nephritis. Kidney Int 2008; 73: 172-180
• 6 Segerer S, Schlöndorff D. B cells and tertiary lymphoid organs in renal inflammation. Kidney Int 2008; 73: 533-537
• 7 Hoffmann MH, Trembleau S, Muller S. et al. Nucleic acid associated autoantigens: pathogenic involvement and therapeutic potential. J Autoimmun 2010; 34: 178-206
• 8 Silva JdA, Addobbati C, Sandrin-Garcia P. et al. Systemic Lupus Erythematosus: old and new susceptibility genes versus clinical manifestations. Curr Genomics 2014; 15: 52-65
• 9 Petri M, Orbai AM, Alarcόn GS. et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677-2686
• 10 Bombardier C, Gladman DD, Urowitz MB. et al. Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 1992; 35: 630-640
• 11 Petri M, Kim MY, Kalunian KC. et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 2005; 353: 2550-2558
• 12 Tassiulas IO, Boumpas DT. Clinical features and treatment of systemic lupus erythematosus. In: Firestein GS. et al. (eds) Kelley's Textbook of Rheumatology. Saunders; 2009: 1263-1301
• 13 Yee CS, Vernon T, David I. et al. The use of Systemic Lupus Erythematosus Disease Activity Index-2000 to define active disease and minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus patients. Rheumatology (Oxford) 2011; 50: 982-988
• 14 Gro E, Marijke V, Harald S. et al. Increased levels of BAFF in patients with systemic lupus erythematosus are associated with acute-phase reactants, independent of BAFF genetics. Arthritis and Rheumatism 2011; 50: 2197-2205
• 15 Schiffer L, Kümpers P, Davalos-Misslitz AM. et al. B-cell-attracting chemokine CXCL13 as a marker of disease activity and renal involvement in systemic lupus erythematosus (SLE). Nephrol Dial Transplant 2009; 24: 3708-3712
• 16 Stohl W, Metyas S, Tan S. et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus. Arthritis and Rheumatism 2003; 48: 3475-3486
• 17 Schiffer L, Kielstein JT, Haubitz M. et al. Elevation of serum CXCL13 in SLE as well as in sepsis. Lupus 2011; 20: 507-511
• 18 Wong CK, Wong PT, Tam LS. et al. Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity. J Clin Immunol 2010; 30: 45-52
• 19 Ezzat M, El-Gammasy T, Shaheen K. et al. Elevated production of serum B-cell-attracting chemokine-1 (BCA-1/CXCL13) is correlated with childhood-onset lupus disease activity, severity, and renal involvement. Lupus 2011; 20: 845-854
• 20 Hafez SS, Saad Wel S, Shedid NH. B-cell-attracting chemokine-1 (BCA-1/CXCL13) in systemic lupus erythematosus, its correlation to disease activity and renal involvement. Egypt J Immunol 2014; 21: 23-32
• 21 Worthmann K, Gueler F, von Vietinghoff S. et al. Pathogenetic role of glomerular CXCL13 expression in lupus nephritis. Clinical & Experimental Immunology 2014; 178: 20-27
• 22 George B, Ricard C, Dimitrios T. Systemic Lupus Erythematosus: Pathogenesis and Clinical Features. In: Bijlsma JWJ (ed) EULAR textbook of rheumatic diseases BMJ 2012; 476-505
• 23 Petri M, Stohl W, Chatham W. et al Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum 2008; 58: 2453-2459
• 24 McCarthy EM, Lee RZ, Gabhann JN. et al. Elevated B lymphocyte stimulator levels are associated with increased damage in an Irish systemic lupus erythematosus cohort. Rheumatology 2013; 52: 1279-1284
• 25 Rioja I, Hughes FJ, Sharp CH. et al. Potential novel biomarkers of disease activity in rheumatoid arthritis patients CXCL13, CCL23, transforming growth factor, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor. Arthritis Rheum 2008; 58: 2257-2267
• 26 Fathi Ahmed S, Badr T, Hosny SM. et al. Assessment of synovitis in early rheumatoid arthritis by CXCL13 serum levels and power Doppler ultrasonography: Correlation with disease activity. The Egyptian Rheumatologist 2013; 35: 21-27