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Congreso Internacional de Anticuerpos Antifosfolipidos.
Rio de Janeiro 2013
Grupo de trabajo de SAF: diagnostico de laboratorio y nuevos marcadores
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1955 - 2013
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Subgroup 1: Harmonization of aCL and anti-b2GPIReference material: Dr Rohan Willis• To establish international consensus units (IU) for the
measurement for aβ2GPI antibodies• RM serum was assigned an IU value• Sent with 30 samples to six commercial companies (INOVA,
Bio-Rad, Corgenix, Phadia, Human and Instrumentation Laboratory)
• Tested on 8 kits eight, according to an approved protocol • linearity, unit equivalency and commutability (CLSI guideline
C53-A)
APS Task force 3:Laboratory diagnostics and trends
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• The new polyclonal and monoclonal RMs for IgG and IgM aβ2GPI are an excellent and promising tools for harmonizing aβ2GPI IgG and IgM results across different methods
• These studies contribute significantly to the much-needed standardization of aβ2GPI immunoassays
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Monoclonal reference material: HCAL
• MoRM demonstrates excellent
linearity and produces results
highly correlated with other
calibrant materials
• Commutability studies suggest
that this material is suitable for
use in a wide array of aβ2GPI
assays
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Subgroup 1: Harmonization of aCL and anti-b2GPI
APS Task force 3:Laboratory diagnostics and trends
Low titers/cut off: Dr Gabriella Lakos
• Clinical view has changed: diagnostic antibodies risk factors. Risk associated to the “presence” of antibodies-Quantitative risk is to be studied
• New analytical technologies have introduced a new level of variability
• Low, medium and high antibody level cannot be defined as a universally applicable value as they are “assay specific”, even when using the same units
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Subgroup 2: Lupus anticoagulant
APS Task force 3:Laboratory diagnostics and trends
Weak Lupus anticoagulant: Prof Thomas Ortel
“weak” positive LA results should be considered positive when making clinical decisions
• We have no data to state that “weak” positive results are not clinically significant
• we have no data to state at what level of detection a lupus anticoagulant becomes “weak”
• we have assays that vary in their sensitivity in detecting these “weak” antibodies
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Subgroup 2: Lupus anticoagulant
APS Task force 3:Laboratory diagnostics and trends
Lupus anticoagulant testing: Prof Philip de Groot• Mixing is only necessary when there is a suspicion of APS
but the screen is negative
• Low levels of clotting factors and β2-Glycoprotein I (prothrombin) can mask the presence of the auto-antibodies
Prop
osal
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APS Task force 3:Laboratory diagnostics and trends
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APS Task force 3:Laboratory diagnostics and trends
GRADE: QUALITY OF EVIDENCEThe extent to which our confidence in an estimate of the
treatment effect is adequate to support a particular recommendation
4 categories of quality:• High• Moderate• Low• Very low
Balshem H et al. J Clin Epidemiol 2011 64 (4): 401–6. http://www.cc-ims.net/gradepro . GRADE handbook for grading quality of evidence and strength of recommendation
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• High Quality: low probability of further research completely changing the presented conclusions
• Moderate Quality: Estimate lies close to the true value, but further research may completely change the conclusions
• Low Quality: Estimate and the true value may be substantially different. Further research is likely to change the presented conclusions completely
• Very low quality: The authors do not have any confidence in the estimate
Grade: Quality of evidence
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Determinants of qualityWhat lowers quality of evidence?
Methodological limitations
Inconsistency of results
Indirectness of evidence
Imprecision of results
Publication bias
APS Task force 3:Laboratory diagnostics and trends
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Publ
ishe
d Ig
A aC
L
12 descriptive studies showing +ve associations with APS
SG3: IgA aPL testsProf Angela Tincani
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Publ
ishe
d Ig
A aC
L
16 descriptive studies showing no associations with APS
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Publ
ishe
d Ig
A an
ti-b
2GPI
14 descriptive -1 case control studies showing +ve associations with APS
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Published IgA anti-b2GPI
4 descriptive studies showing no associations with APS
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Unpublished IgA aPL
4 descriptive studies showing no associations with APS1 animal model
SG3: IgA aPL testsDr Anne Tebo
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IgA anti-domain IV-V b2GPI
4 descriptive studies showing correlation with IgA aCL and associations with APS
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Subgroup 3: IgATesting for IgA aCL:• Can contribute to identifying patients with thrombosis and
pregnancy morbidity
Testing for IgA anti-b2GPI:• Can contribute to the assessment of risk for thrombosis and/or
pregnancy morbidity in APS• Can contribute to a better identification of patients with APS
Testing for domain IV-V anti-b2GPI:• Correlation with IgA aCL and some associations but only 4
descriptive studies
Level of evidence III-Low quality evidence
APS Task force 3:Laboratory diagnostics and trends
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Published: Dr Anne Tebo
4 descriptive studies showing correlation with aCL and associations with APS
SG4: Tests for antibodies to negatively charged phospholipids
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Unpublished: Dr Mittermayer Santiago
Studies report aPhL specificity and sensitivity against aCL
SG4: Tests for antibodies to negatively charged phospholipids
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aPE: Dr Marc Lambert
2 studies showing association
6 studies showing no association
SG4: Tests for antibodies to negatively charged phospholipids
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Subgroup 4: Other aPL and aPETesting for other negatively charged aPL:• aPI and aPS may identify additional women with recurrent
pregnancy loss
Testing for aPhL:• More specific than standard aCL discriminating better APS
from non-APS• Confirmatory tests? Alternative to aCL?
Level of evidence III-Low quality evidence
APS Task force 3:Laboratory diagnostics and trends
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Subgroup 4: Other aPL and aPETesting for aPE:• Most of the studies do not support an association between
aPE and thrombosis or PM, making the assumption of “NO NEED TO TEST” a valid one.
• However, the level of evidence is even low for this recommendation and further well designed studies may probably change the presented conclusions completely
Level of evidence III-Very Low quality evidence
APS Task force 3:Laboratory diagnostics and trends
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SG5: Tests for antibodies to prothrombin and aPS/PT
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Antiprothrombin detection
irradiated plate
PT
aPT
PS
non-irradiated plate
PT
aPS/PT
non-irradiated plate
ab
protein
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IgG aPT
200100504030201054321
IgG
aPS
-PT
200
100
504030
20
10
543
2
1
aPT vs. aPS-PT
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Intrinsic Pathway
Extrinsic Pathway
VIICommon Pathway
VIIIa
TF
Prothrombin
Fibrinogen Fibrin
X Xa
Thrombin
Va
IXa
VIIa
Protein C
APC
Protein S
XIa
XIIa
Fragment 1+2
Ca++
PL
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Prothrombin antigen level
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Prothrombin antigen activity%
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Bertolaccini et al. Thromb Hemost 2013
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APS Thrombosis Pregnancy loss
Antibodies AUC OR [CI 95%] p AUC OR [CI 95%] p AUC OR [CI 95%] p
LA+aCL .612 3.22 [1.41-7.36] 0.0041 .620 3.04 [1.67-5.52] 0.0002 .613 1.70 [0.99-2.91] 0.0543
LA+aCL+anti-β2GPI .612 3.22 [1.41-7.36] 0.0041 .620 3.04 [1.67-5.52] 0.0002 .613 1.70 [0.99-2.91] 0.0543
LA+aCL+anti-β2GPI+aPS/PT .610 1.69 [0.89-2.96] NS .599 3.05 [1.61-5.75] 0.0004 .620 4.03 [1.50-10.79] 0.0033
LA+aCL+aPS/PT .610 1.70 [0.88-2.97] NS .599 3.04 [1.67-5.52] 0.0002 .620 4.03 [1.50-10.79] 0.0033
LA +anti-β2GPI+aPS/PT .712 3.73 [1.82-5.38] 0.0001 .709 3.75 [2.13-6.62] 0.0001 .677 4.82 [2.17-10.72] 0.0007
aCL+anti-β2GPI+aPS/PT .614 1.76 [1.04-2.99] 0.0357 .606 2.79 [1.54-5.08] 0.0006 .612 3.13 [1.31-7.46] 0.0076
Anti-β2GPI+aPS/PT+aPT .658 3.63 [2.07-6.36] 0.0001 .643 3.35 [1.91-5.88] 0.0001 .643 3.38 [1.59-7.19] 0.001
aPT+aPS/PT+aCL .590 1.70 [1.00-2.89] 0.0482 .589 2.58 [1.38-4384] 0.0026 .578 2.34 [0.98-5.60] 0.0516
aPT+aPS/PT+LAC .618 2.31 [1.36-3.93] 0.0018 .609 2.58 [1.47-4.54] 0.0009 .619 2.87 [1.32-6.22] 0.006
Anti-β2GPI+aPE+aPS/PT .627 2.49 [1.46-4.24] 0.0007 .609 2.58 [1.47-4.54] 0.0009 .632 3.29 [1.48-7.32] 0.0024
aPE+aPS/PT+LAC .610 2.08 [1.23-3.52] 0.0062 .612 2.65 [1.50-4.68] 0.0007 .611 2.68 [1.24-5.81] 0.0104
aPE+aPS/PT+aCL .581 1.59 [0.94-2.81] NS .582 2.44 [1.30-4.57] 0.0049 .591 2.81 [1.12-7.07] 0.0234
Diagnostic accuracy of combinations
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Thrombotic risk in SLE
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Unpublished: Prof Tatsuya Atsumi
6 studies on aPT
9 studies on aPS/PT
2 in-vitro studies
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Published aPT: Dr Ricardo Forastiero
30 retrospective studies 4 cross-sectional 2 case-control 1 prospective
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11 studies: 10 retrospective
1 case control
Published aPS/PT: Dr Ricardo Forastiero
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Subgroup 5: aPT and aPS/PTTesting for aPT:• Results widely differ between groups suggesting a true
difference• Most data retrospective studies• Not possible to identify the role of aPT alone• Lack of multivariate adjustment
Level of evidence IIILow quality evidence
APS Task force 3:Laboratory diagnostics and trends
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Subgroup 5: aPT and aPS/PTTesting for aPS/PT:• Can contribute to assess the risk of thrombosis• Can contribute to a better identification of patients with APS• Multivariate analysis confirm aPS/PT as independent risk
factors• Results do not substantially differ between groups• Association with LA deserves further study
Level of evidence IIILow/Moderate quality evidence
APS Task force 3:Laboratory diagnostics and trends
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SG6: Tests for antibodies to Domain I
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Anti-b2GPI
de Laat et al. Nat Clin Pract Rheumatol 2008
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De Laat et al. Blood 2005
2 types of anti-b2GPI:
A - recognize domain I
- cause lupus anticoagulant activity
- are associated with thrombosis
B - heterogeneous reactivity for all domains
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De Laat et al. Blood 2006
• Pathogenic anti-b2GPI bind to a cryptic epitope
in domain I of b2GPI
• This epitope (G40-R43) is only expressed after
the molecule suffers a conformational change
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Anti-domain I antibodies• Present in 243/442 patients (55%)
• 83% had thrombosis [OR3.5 (2.3-5.4)]
• Associated with pregnancy morbidity
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Published: Prof Anisur Rahman
11 studies
SG6: Tests for antibodies to Domain I
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Unpublished: Dr Gabriela Lakos
13 studies – 3 on animal models
SG6: Tests for antibodies to Domain I
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Subgroup 6: Antibodies to domain I• Cross-sectional retrospective data show that IgG anti-DI
positivity is associated with thrombosis and pregnancy morbidity
• Animal models show pathogenicity• No prospective data• Frequency of patients positive for DI and negative for anti-b2GPI is not established
• Value of anti-DI as the sole antibody still to be determined
Level of evidence III-Low/Moderate quality evidence
APS Task force 3:Laboratory diagnostics and trends
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How do we assess the risk
• Full thrombophilia screen• History of other autoimmune diseases• Other cardiovascular risk factors• Presence of aPL
• LA is the strongest risk factor Galli et a. Blood 2003
• Double or triple aPL positivity the riskPengo et al. JTH
2010
• Testing for LA+anti-b2GPI+aPS/PT has the best diagnostic accuracy Sciascia et al. JTH 2012
SG7: aPL as risk factors
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Subgroup 7: aPL as risk factors
APS Task force 3:Laboratory diagnostics and trends
Assessing risk in APS: the global APS score - Savino Sciascia
• GAPSS is score model based on six clinical factors that has been proven to represent the “probability” or likelihood of having thrombosis or pregnancy loss in SLE
• Derived from the combination of independent risk factors for thrombosis and pregnancy loss:
- aPL profile (including criteria and non-criteria aPL)- conventional cardiovascular risk factors- autoimmune antibodies profile.
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• Risk score derived from the combination of independent risk factors • Each variable was assigned points proportional to its regression coefficient
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Development and Validation of GAPSS
• Patients were filtered by the criterion of the diagnosis in order to equally distribute the disease prevalence (SLE and APS, SLE and aPL positivity or SLE alone)
• Efficacy of randomization was confirmed by computing the prevalence of the variables in the 2 sets where no statistical differences were found
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Development and Validation of GAPSS(n=211)
Thrombosis+ve Thrombosis-ve(n=106)
Thrombosis+ve Thrombosis-ve(n=105)
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Higher values of GAPSS were seen in patients who experienced thrombosis compared to those with pregnancy loss alone
GAPSS in PAPS (N=62)
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Patients with thrombotic recurrences showed higher values of GAPSS
GAPSS in PAPS (N=62)
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GAPSS in PAPS (N=62)
GA
PS
S
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GAPSS: prospective validation
Increased GAPSS (entry vs. last visit) was seen in patients who developed thrombosis
P3-28
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Subgroup 7: aPL as risk factors
APS Task force 3:Laboratory diagnostics and trends
Assessing risk in APS: the global APS score - Savino Sciascia
• GAPSS is a valid tool for risk stratification for thrombosis and its recurrences
• GAPSS has been prospectively validated as a valid tool for accurate prediction of thrombosis in SLE patients with aPL
• The application of GAPSS leads to a substantial improvement in risk prediction of thrombosis or pregnancy loss
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Subgroup 7: aPL as risk factors
APS Task force 3:Laboratory diagnostics and trends
Designing the perfect study: how best to assess risks-Robert Roubey
Proposed Action Points:
• Identify and develop collaborations with existing large, population-based, prospective cohorts with data on thrombosis, pregnancy outcomes
• Evaluate traditional and newer aPL tests
• Proper analysis of aPL tests as continuous variables with attention to analytical sensitivity
• Consider, analyze, and test combinations of aPL tests, e.g., “triple positivity,” global aPL score
• Cluster analysis, techniques from microarray analysis, etc.
• Confirm risk models on out-of-sample data
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Task force membersSubgroup 1 Harmonisation of aCL and anti-b2GPI Subgroup 5 Antibodies to prothrombin and aPS/PT
Pierluigi Meroni Angela Tincani Tatsuya Atsumi Vittorio Pengo
Maria Orietta Borghi Gabriella Lakos Olga Amengual Luis Lopez
Katrien Devreese Melissa Snyder Ricardo Forastiero Ken Oku
Rohan Willis Nigel Harris Gary Norman Maria Orietta Borghi
Richard Wong Piet Meijer PierLuigi Meroni Savino Sciascia
Subgroup 2 Lupus anticoagulant Subgroup 6 Antibodies to domain 1 of B2GPI
Thomas Ortel Pierre Meijer Anisur Rahman Angela Tincani
Philip deGroot Elaine Gray Ian Giles Hilde Kelchterman
Dorothy Adcock Vittorio Pengo Charis Pericleous Michael Mahler
Jeffrey Dlott Helen Wilmot Gabriella Lakos Savino Sciascia
Subgroup 3 IgA aPL Jacob Rand John Ioannou
Gary Norman Angela Tincani Bas de Laat Angela Tincani
Anne Tebo Laura Andreoli PierLuigi Meroni Jacob Rand
Rohan Willis David Murray Subgroup 7 aPL as risk factors for thrombosis
Michelle Petri Yu Zuo Robert Roubey
Subgroup 4 Test for antibodies to negatively charged PL K Otomo
Dawn Wagenknecht William Kutteh Savino Sciascia
Nigel Harris Benjamin Leader Vittorio Pengo
Anne Tebo Marc Lambert Jakub Swadźba
Savino Sciascia Mittermayer Santiago
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