Neue Wege in der Diagnostik des Antiphospholipid Syndroms

Zusammenfassung

Die Diagnose des Antiphospholipid Syndroms (APS) stellt unverändert eine klinische Herausforderung insbesondere bezüglich der Bestimmung der sogenannten Antiphospholipid Antikörper (aPLAk) und deren Einfluss auf die Diag­nosestellung dieser klinischen Entität dar. Die vor Kurzem revidierten Klassifikationskriterien für APS empfehlen bei klinischem Verdacht die Verwendung von enzyme-linked immunosorbent assays (ELISAs) für die Bestimmung von anti-beta 2 Glykoprotein I (β2GPI) und Cardiolipin-abhängigen anti-β2GPI IgG und IgM. Zusätzlich können aPLAk als Lupusantikoagulanz mittels eines funktionellen Gerinnungstestes als Laborkriterium zur Diagnosestellung ermittelt werden. Entsprechend den Klassifikationskriterien ist ohne positives Laborkriterium keine Diagnose des APS möglich. Andere aPLAk mit Reaktivitäten gegen unterschiedliche Phospholipide und deren Kofaktoren wurden beschrieben und deren potentieller Nutzen für die APS Serologie hervorgehoben. Antikörperprofiling verschiedener aPLAk wird als ein neuer Ansatz für die Risikoabschätzung der Entwicklung von thrombotischen Ereignissen für Patienten mit APS diskutiert. Je mehr aPLAk Spezifitäten gegen unterschiedliche Phospholipid- bzw. Kofaktorepitope vorkommen, desto höher ist das Risiko für das Auftreten von klinischen Komplikationen des APS wie zum Beispiel thrombotische Ereignisse. Daher können neue Wege für die gleichzeitige Bestimmung von mehreren aPLAk in einer Patientenprobe sinnvoll sein, um zusätzliche Information für die Diagnose und letztendlich Risikoabschätzung von APS zu liefern. Multiplextechnologien zur Bestimmung von aPLAk können eine Alternative dafür sein. Insbesondere Line-Immunoassays (LIAs) mit Membranen als Festphase für die Immobilisierung von Phospholipiden und deren Kofaktoren sind als Alternative zu ELISA für die Bestimmung von aPLAk kürzlich beschrieben worden. Diese Übersichtsarbeit diskutiert die neuen Entwicklungen auf dem Gebiet des aPLAk Profilings und die entsprechende Verwendung von LIAs in der APS Serologie.

Abstract

The diagnosis of antiphospholipid syndrome (APS) remains a clinical challenge in particular with regard to the assessment of so called antiphospholipid (aPL) antibodies and their impact on the diagnosis of this autoimmune clinical entity. The recently revised classification criteria for APS recommend, when there is a clinical suspicion, the use of an enzyme-linked immunosorbent assay (ELISA) for the detection of anti-beta 2 glycoprotein I (β2GPI) and cardiolipin-dependent anti-β2GPI IgG and IgM. In addition, aPL antibodies can be determined as lupus anticoagulant by a functional coagulation assay as laboratory criterion. According to the classification criteria, a diagnosis of APS requires at least one positive laboratory criterion. However, other aPL antibodies are reactive with differing phospholipids and corresponding cofactors have been reported to be useful for the serological diagnosis of APS while the jury is still out concerning the possibility to reliably identify the full range of true APS cases. Antibody profiling of several aPL antibodies appears to pave the way for a new understanding of the risk assessment of thrombotic events in APS patients. The more different aPL antibodies occur in a patient the higher is the risk for the development of clinical APS manifestations such as thrombotic events. Thus, new approaches to multiparametric aPL antibody detection are required to provide the necessary information regarding diagnosis and eventually outcome in APS patients. Multiplex analysis of aPL antibodies candidates as an alternative thereof. In particular, line immunoassays (LIAs) employing membranous solid phases for the immobilisation of phospholipids and their respective cofactors are reported to detect the corresponding antibodies efficiently and represent an alternative to ELISA. Novel developments in the field of aPL antibody profiling and the currently available data on LIAs for APS serology are summarised in this review.

Schlüsselwörter

Antiphospholipid Syndrom - Antiphospholipid Antikörper - Line-Immunoassay

Key words

antiphospholipid syndrome - antiphospholipid antibodies - line immunoassay

• Literatur

• 1 Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed). 1983. 287. 1088-1089
• 2 Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-1311
• 3 Cervera R, Khamashta MA, Shoenfeld Y et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2009; 68: 1428-1432
• 4 Asherson RA, Cervera R, DE Groot PG et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003; 12: 530-534
• 5 Miyakis S, Lockshin MD, Atsumi T et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295-306
• 6 Tan EM, Cohen AS, Fries JF et al. The1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-1277
• 7 Devreese K, Hoylaerts MF. Challenges in the diagnosis of the antiphospholipid syndrome. Clin Chem 2010; 56: 930-940
• 8 Prinz N, Hauser F, Lorenz M et al. Structural and functional characterization of a human IgG monoclonal antiphospholipid antibody. Immunobiology 2011; 216: 145-151
• 9 de LB, DE Groot PG. Autoantibodies directed against domain I of beta2-glycoprotein I. Curr Rheumatol Rep 2011; 13: 70-76
• 10 Horstman LL, Jy W, Bidot CJ et al. Antiphospholipid antibodies: paradigm in transition. J Neuroinflammation 2009; 6: 3
• 11 Egerer K, Roggenbuck D, Buttner T et al. Single-step autoantibody profiling in antiphospholipid syndrome using a multi-line dot assay. Arthritis Res Ther 2011; 13: R118
• 12 Matsuura E, Igarashi Y, Fujimoto M et al. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-178
• 13 McNeil HP, Simpson RJ, Chesterman CN et al. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4124
• 14 Galli M, Comfurius P, Maassen C et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-1547
• 15 Forastiero RR, Martinuzzo ME, Kordich LC et al. Reactivity to beta 2 glycoprotein I clearly differentiates anticardiolipin antibodies from antiphospholipid syndrome and syphilis. Thromb Haemost 1996; 75: 717-720
• 16 Mirarabshahi P, Abdelatti M, Krilis S. Post-translational oxidative modification of beta2glycoprotein I and its role in the pathophysiology of the antiphospholipid syndrome. Autoimmun Rev. 2011
• 17 Petrovas C, Vlachoyiannopoulos PG, Kordossis T et al. Anti-phospholipid antibodies in HIV infection and SLE with or without anti-phospholipid syndrome: comparisons of phospholipid specificity, avidity and reactivity with beta2-GPI. J Autoimmun 1999; 13: 347-355
• 18 Lackner KJ, Peetz D, von Landenberg P. Revision of the Sapporo criteria for the antiphospholipid syndrome – coming to grips with evidence and Thomas Bayes?. Thromb Haemost 2006; 95: 917-919
• 19 Meroni PL, Borghi MO, Raschi E et al. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011; 7: 330-339
• 20 Rauch J, Dieude M, Subang R et al. The dual role of innate immunity in the antiphospholipid syndrome. Lupus 2010; 19: 347-353
• 21 Martinez-Zamora MA, Peralta S, Creus M et al. Risk of thromboembolic events after recurrent spontaneous abortion in antiphospholipid syndrome: a case-control study. Ann Rheum Dis 2012; 71: 61-66
• 22 Cohen D, Berger SP, Steup-Beekman GM et al. Diagnosis and management of the antiphospholipid syndrome. BMJ 2010; 340: c2541
• 23 Tripodi A, DE Groot PG, Pengo V. Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment. J Intern Med 2011; 270: 110-122
• 24 Otomo K, Atsumi T, Amengual O et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum 2012; 64: 504-512
• 25 Andreoli L, Tincani A. Beyond the “syndrome”: Antiphospholipid antibodies as risk factors. Arthritis Rheum 2012; 64: 342-345
• 26 Cervera R, Conti F, Doria A et al. Does seronegative antiphospholipid syndrome really exist?. Autoimmun Rev. 2011
• 27 Iaccarino L, Ghirardello A, Canova M et al. Anti-annexins autoantibodies: their role as biomarkers of autoimmune diseases. Autoimmun Rev 2011; 10: 553-558
• 28 Pengo V, Biasiolo A, Pegoraro C et al. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005; 93: 1147-1152
• 29 von Landenberg P, Scholmerich J, von Kempis J et al. The combination of different antiphospholipid antibody subgroups in the sera of patients with autoimmune diseases is a strong predictor for thrombosis. A retrospective study from a single center. Immunobiology 2003; 207: 65-71
• 30 Conrad K, Roggenbuck D, Reinhold D et al. Autoantibody diagnostics in clinical practice. Autoimmun Rev 2012; 11: 207-211
• 31 Roggenbuck D, Egerer K, von Landenberg P et al. Antiphospholipid antibody profiling – Time for a new technical approach?. Autoimmun Rev 2012; 11: 1-6
• 32 Harris EN, Gharavi AE, Boey ML et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2: 1211-1214
• 33 Arvieux J, Roussel B, Jacob MC et al. Measurement of anti-phospholipid antibodies by ELISA using beta 2-glycoprotein I as an antigen. J Immunol Methods 1991; 143: 223-229
• 34 Matsuura E, Igarashi Y, Yasuda T et al. Anticardiolipin antibodies recognize beta 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-462
• 35 de LB, DE Groot PG. Autoantibodies directed against domain I of beta2-glycoprotein I. Curr Rheumatol Rep 2011; 13: 70-76
• 36 Metzger J, Von LP, Kehrel M et al. Biosensor analysis of beta2-glycoprotein I-reactive autoantibodies: evidence for isotype-specific binding and differentiation of pathogenic from infection-induced antibodies. Clin Chem 2007; 53: 1137-1143
• 37 Lakos G, Favaloro EJ, Harris EN et al. International consensus guidelines on anticardiolipin and anti-beta(2) glycoprotein I testing: A report from the APL task force at the 13(th) international congress on antiphospholipid antibodies. Arthritis Rheum. 2011
• 38 DE Groot PG, Derksen RH, de LB. Twenty-two years of failure to set up undisputed assays to detect patients with the antiphospholipid syndrome. Semin Thromb Hemost 2008; 34: 347-355
• 39 Grossmann K, Roggenbuck D, Schroder C et al. Multiplex assessment of non-organ-specific autoantibodies with a novel microbead-based immunoassay. Cytometry A 2011; 79: 118-125
• 40 Pierangeli SS, Silva LK, Harris EN. A flow cytometric assay for the detection of antiphospholipid antibodies. Am Clin Lab 1999; 18: 18-19
• 41 Roggenbuck D, Egerer K, Feist E et al. Antiphospholipid antibody profiling – association with the clinical phenotype in APS?. Arthritis Rheum 2012; 64: 2807-2808
• 42 Schoenherr G, Roggenbuck D, Seifert M et al. Technical problems arising from the use of the immunoblot for determination of the reactivity of natural antibodies with different lipopolysaccharides (LPS). J Immunol Methods 1996; 190: 185-188
• 43 Conrad K, Schneider H, Ziemssen T et al. A new line immunoassay for the multiparametric detection of antiganglioside autoantibodies in patients with autoimmune peripheral neuropathies. Ann N Y Acad Sci 2007; 1109: 256-264
• 44 Seifert M, Schoenherr G, Roggenbuck D et al. Generation and characterization of a human monoclonal IgM antibody that recognizes a conserved epitope shared by lipopolysaccharides of different gram-negative bacteria. Hybridoma 1996; 15: 191-198
• 45 Chabraoui F, Derrington EA, Mallie-Didier F et al. Dot-blot immunodetection of antibodies against GM1 and other gangliosides on PVDF-P membranes. J Immunol Methods 1993; 165: 225-230
• 46 Forastiero RR, Martinuzzo ME, Carreras LO. Binding properties of antibodies to prothrombin and beta2-glycoprotein I (beta2-GPI) assayed by ELISA and dot blot. Clin Exp Immunol 1999; 118: 480-486
• 47 Nash MJ, Camilleri RS, Kunka S et al. The anticardiolipin assay is required for sensitive screening for antiphospholipid antibodies. J Thromb Haemost 2004; 2: 1077-1081
• 48 Lakos G, Favaloro EJ, Harris EN et al. International consensus guidelines on anticardiolipin and anti-beta(2) glycoprotein I testing: A report from the APL task force at the 13(th) international congress on antiphospholipid antibodies. Arthritis Rheum 2011; 64: 1-10
• 49 Conrad K, Roggenbuck D, Ittenson A et al. A new dot immunoassay for simultaneous detection of celiac specific antibodies and IgA-deficiency. Clin Chem Lab Med 2012; 50: 337-343
• 50 Danowski A, de Azevedo MN, de Souza Papi JA et al. Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus. J Rheumatol 2009; 36: 1195-1199
• 51 Miesbach W. Neurologic symptoms as a feature of the antiphospholipid syndrome. Semin Thromb Hemost 2008; 34: 286-289