La sindrome da aPL : up to date La sindrome da aPL : up to date PL - PowerPoint PPT Presentation

La sindrome da aPL : up to date La sindrome da aPL : up to date PL Meroni Div. of Rheumatology, Dept. Clinical Sciences & Community Health, Univ. of Milan, Ist. G Pini – Milan

Classification criteria for APS Classification criteria for APS Clinical criteria Clinical criteria – Vascular thrombosis: > 1 episode – Pregnancy morbidity: - Abortions (<10 sem.): > 3 - Fetal death (>10 sem.): > 1 - Prematures (<34 sem.): > 1 Classification Diagnostic criteria Classification Diagnostic criteria – Laboratory criteria Laboratory criteria – aCL (IgG/IgM): > 2 determ. (med/high titre) – Anti- β β β 2GPI (IgG/IgM) : > 2 determ. (med/high titre) β – LAC: > 2 determ. Classification: 1 clinical criteria + 1 laboratory criteria Classification: 1 clinical criteria + 1 laboratory criteria Myiakis et al JTH ‘06

aPL assays Specificity/ Sensitivity Predictive value aCL + +++ Anti- β β 2GPI β β ++ ++ LAC +++ +

LA activity is mediated by different autoaAbs 2/3 anti-prothrombin 2/3 anti-prothrombin 95% Anti-PT Abs can be detected by the PS-PT assay 1/3 anti-b2GPI An additional formal classification lab tool? Protein C autoAbs against (Oosting GD 1993) Protein S other PL-binding 5% Factor V ( Kapur A 1993) proteins ………………. ………………. Exner T, Blood Coagul Fibrinolysis 5: 281-289, 1994.

PL- -binding proteins bound by autoAbs in the binding proteins bound by autoAbs in the PL solid- -phase assays phase assays solid β β 2GPI β β Bovine β β β β 2GPI Anionic PL aCL assay Bovine Anionic PL aCL assay β β β β 2GPI γ γ - γ γ β 2GPI assay β β β Human β β β β γ γ γ γ - β β β β 2GPI -irr.plates irr.plates anti- 2GPI assay Human anti Human prothrombin Anionic PL (PS) Anti- -PT assay PT assay Human prothrombin Anionic PL (PS) Anti Protein C, Protein S Protein C, Protein S and C4b- -binding protein binding protein and C4b Anionic PL Anionic PL aCL assay +/- aCL assay +/ - Activated Protein C Activated Protein C Thrombomodulin Anionic PL aCL assay +/- - Thrombomodulin Anionic PL aCL assay +/ Annexin V Anionic PL aCL assay +/- - Annexin V Anionic PL aCL assay +/ High molecular weight kininogen Neutral PL (PE) anti- -PE assay PE assay High molecular weight kininogen Neutral PL (PE) anti

� β 2GPI-mediated LA more strongly correlated with thrombosis than anti-PT mediated LA � Domain I anti- β 2GPI Abs confer LA activity with the highest risk for thrombosis De Laat et al. Blood ‘04 Devreese et al. Blood ‘10

β β 2GPI domain I autoAbs - β β β β β β Anti- 2GPI domain I autoAbs De Laat et al Curr Rheumatol Rep ‘ 11 Anti

Human anti- β β β β 2GPI MoAb reacts with DI * MoAb & murine β 2GPI MoAb & human β 2GPI Irr MoAb &murine β 2GPI Irr MoAb & human β 2GPI Same reactivity with: a)INOVA DI plates ( Mahler et al Autoimmun Rev ‘12 ) b)39-43 aa peptide DI epitope ( Ioannou et al Lupus ‘10 )

Anti- -DI hu MoAb is pathogenic DI hu MoAb is pathogenic Anti MoAb A B 120 4 P = 0.0049 Fetal resorption frequency (%) 3,5 100 3 80 fetal weight (g) 2,5 60 2 1,5 40 1 20 P = 0.0286 0,5 0 0 MoAb Irr MoAb MBB2 MB unrelated C D MBB2 MB unrelated MoAb Irr MoAb

• DE Laat et al Blood ’05. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. • De Laat B et al JTH ’09 : IgG against D1 of β 2GPI more strongly associated with thrombosis/obstetric complications than those detected by the standard anti- β 2GPI Ab assay. • De Angelis et al Lupus (Abst)‘10: solid phase assay for D1. Anti- D1 Abs seem specific for APS pats but not associated with increased risk of arterial thrombosis in the general population. • Andreoli et al ARD ’10: Children born to mothers with systemic autoimmune disorders or children with atopic dermatitis display preferential IgG reactivity for D4/5, whereas APS patients are mainly positive for D1. • Banzato et al. Thromb. Res . ‘11 Antibodies to domain I of beta(2)glycoprotein I are in close relation to patients risk categories in antiphospholipid syndrome (APS).

Anti-DI – IV/V in our series (58 PAPS sera and 15 aPL carriers) % pos Triple negative D IV-V Whole 9% 4% β 2GPI/D IV-V 21% 4% 21% 41% Whole β 2GPI Whole β 2GPI/D I

Autoantibodies to Domain 1 of Beta 2 glycoprotein 1: A promising candidate biomarker for risk management in antiphospholipid syndrome M. Mahler, G.L. Norman, P.L. Meroni, M. Khamashta 2012 , 12:313-17 Take home messages � The hypothesis of anti- β 2GP1-D1 antibodies as promising biomarker in diagnosis /risk assessment of APS is scientifically sound, but needs further verification � Efforts are needed to standardize assays to detect β 2GP1-D1 antibodies � Prospective, multi-centric, longitudinal studies are necessary to clearly define the clinical utility of anti- β 2GP1-D1 antibodies

Main therapeutic targets Vascular � Avoiding recurrences Obstetric � Preventing comorbidities : APS nephropathy, cognitive dysfunction(?), atherothrombosis.

Treatment of vascular APS Treatment of vascular APS manifestations manifestations

Risk- -stratification stratification Risk � aPL autoAb profile Test Triple positivity LA Isotype Higher risk IgG > IgM Titer Medium/high titer Age, diabetes, arterial hypePA, dyslipidemia, BMI, smoking, sedentary lifestyle, hyperhomocyst, � Concomitant thrombotic risk-factors Protein C, Protein S and ATIII deficiency , Factor V � Underlying autoimmune diseases Leyden, PT and MHTFR mutations

Venous events Venous events

Oral anticoagulant therapy Oral anticoagulant therapy � INR target: � INR target: Standard intensity Very low frequency of recurrent (INR 2.0-3.0) events in both trials within all groups Ruiz-Irastorza G, Lupus 2011 Limitations: versus � Patients with history of recurrent High intensity thrombosis were excluded (INR 3.1-4.0) Crowther MA, N Engl J Med 2003 � Patients in the high intensity group had an Finazzi G, J Thromb Haemost 2005 INR below the target 40% of the follow-up time � Duration of anticoagulation: � Duration of anticoagulation: � The highest rate of recurrent thrombosis occurs in APS patients who had withdrawn their anticoagulants within the preceding 6 months. Khamashta, N Engl J Med 1995 Indefinitely � aPL positivity at least doubles the risk for recurrent disease. Indefinitely � Mandatory in high-risk patients versus 3- -6 months 6 months 3

Arterial events Arterial events

� Higher efficacy of high-intensity anticoagulation in Standard Intensity Standard Intensity preventing reccurrent thrombosis Khamashta MA,N Engl J Med 1995 anticoagulation anticoagulation � Recurrence rate over a 6-year period of 30% in patients in + + standard intensity anticoagulant Pengo V, J Thromb Haemost 2010 � Recurrent thromboses infrequent when INR > 3.0 Antiplatelet agent Antiplatelet agent Ruiz-Irastorza G, Arthritis Rheum 2007; Tan BE, Lupus 2009 � � Recommended treatment Recommended treatment Ruiz-Irastorza G, Lupus 2011 High Intensity High Intensity Lower incidence of recurrent stroke compared to aspirin (cumulative stroke-free survival: 74 versus 25% Okuma H, Int J Med Sci anticoagulation anticoagulation 2009 � Recommended treatment � Recommended treatment Ruiz-Irastorza G, Lupus 2011 No differences between aspirin and standard intensity anticoagulation for Antiplatelet Antiplatelet secondary stroke prevention APASS, 2004 agent � Recommended in patients without SLE and low agent � Recommended in patients without SLE and low- -risk aPL profile risk aPL profile Ruiz- Ruiz -Irastorza G, Lupus 2011 Irastorza G, Lupus 2011 Consider also: Consider also: Standard Intensity anticoagulation Standard Intensity anticoagulation � Higher bleeding risk when rising anticoagulation intensity Bleeding risk in APS: 0.57-10% per year � Standard intensity anticoagulation more effective than Ruiz-Irastorza G, Arthritis Rheum 2007 low-dose aspirin and no therapy Pengo V, J Thromb Haemost 2010 � Higher difficulties in keeping INR in the � Standard intensity anticoagulation not inferior to high 3.1-4.0 than in the 2.0-3.0 range intensity anticoagulation in preventing recurrency Crowther MA, N Engl J Med 2003 Crowther MA, N Engl J Med 2003; Finazzi G, J Thromb Haemost 2005

Anticoagulant Agents Anticoagulant Agents Limits: � Oral Vitamin K Antagonists Oral Vitamin K Antagonists � Slow onset of action of 3-5 days � Narrow therapeutic window � warfarin � Drugs and dietary interaction � INR monitoring � acenocoumarol � LA intereference on PT-INR Limits: � SC administration � UFH/LMWH � UFH/LMWH � Heparin-induced thrombocytopenia � Osteoporosis Limits: � Fondaparinux � Fondaparinux � SC administration � New Oral Anticoagulant Agents � New Oral Anticoagulant Agents � dabigatran � rivaroxaban Ongoing prospective randomised controlled phase II/III clinical trial � apixaban