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ANTIPHOSPHOLIPID SYNDROME: UPDATE ON PATHOGENESIS,
DIAGNOSIS AND MANAGEMENT
Ricard Cervera, MD, PhD, FRCPDepartment of Autoimmune Diseases
Hospital Clínic Barcelona
ANTIPHOSPHOLIPID SYNDROME(1983-2011)
ANTIPHOSPHOLIPID SYNDROME
Epidemiology
ANTIPHOSPHOLIPID SYNDROME
Epidemiology
• 20% of deep vein thrombosis• 10% of recurrent abortions• 10% of recurrent abortions• 30% of cerebro-vascular accidents in
<50 yr-olds
NIH, 2001NIH, 2001
ANTIPHOSPHOLIPID SYNDROME
• DIAGNOSIS• DIAGNOSIS
• TREATMENT
• PATHOGENESIS
APS-2011: DIAGNOSIS
• Classical, unusual and silent clinical manifestationsmanifestations
• Catastrophic antiphospholipid syndrome
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
European Forum on Antiphospholipid Antibodies
2002Antiphospholipid Antibodies
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
EURO -PHO SPHO LIP ID PRO JECTPRO JECTN euro logic m an ifesta tions
0 5 1 0 1 5 2 0
M ig r a i n e
S t r o k e
T IA
E p i l e p s y
M u l t i i n f d e m e n t i a
V e n o u s t h r o m b o s i s
E n c e p h a l o p a t h
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
EURO -PHOSPHOLIPID PRO JECTPRO JECTCardiac m anifestations
0 2 4 6 8 1 0
V a lv e l e s io n s
M I
A n g in a
V e g e t a t i o n s
C h ro n i c m y o c a rd
A c u t e m y o c a rd
B y p a s s o c c lu s io n s
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROMEClinical manifestations:
Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROMEClinical manifestations:
Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROMEClinical manifestations:
Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROMEClinical manifestations:
Classical, unusual and silent
ANTIPHOSPHOLIPID SYNDROME
Clinical manifestations: Classical, unusual and silent
STROKE
PULMONARY EMBOLISM
RENAL MICROANGIOPATHYBUDD-CHIARI
VALVE LESIONS
JUGULAR V. THROMB.
LIVEDO RETICULARIS
LEG ULCERS
FETAL MORBIDITY
DVT
DIGITAL ISCHEMIA
“SYSTEMIC”ANTIPHOSPHOLIPID SYNDROME
2006
J Thromb Haemostas 2006; 4:295-306
Revised criteria for APS
– Vascular thrombosis: > 1 episode– Pregnancy morbidity:
- Abortions (<10 sem.): > 3- Fetal death (>10 sem.): > 1- Prematures (<28 sem.): > 1
Clinical criteriaClinical criteria
- Prematures (<28 sem.): > 1
– Anticardiolipin antibodies (IgG/IgM): > 2 determ.
– Lupus anticaogulant: > 2 determ.
– Anti-beta-2-glycoprotein I (IgG/IgM) : > 2 determ.
Laboratory criteriaLaboratory criteria
Definite APS: Definite APS: 1 1 clínical criteria + clínical criteria + 1 1 laboratory criteria laboratory criteria
Features of probable APS
• aPL-associated cardiac valve disease
• aPL-associated livedo reticularis• aPL-associated livedo reticularis
• aPL-associated thrombocytopenia
• aPL-associated nephropathy
aPL-associated cardiac valve disease
aPL-associated cardiac valve disease
aPL-associated livedo reticularis
aPL-associated livedo reticularis
aPL-associated nephropathy
aPL-associated thrombocytopenia
aPL-associated thrombocytopenia
Pre-Conference Workshop on CAPS and non-criteria APS manifestationsand non-criteria APS manifestations
April 13, 2010
Smita Vaidya, Horacio Adrogué Doruk Erkan, Gerard Espinosa,
Maria Tektonidou, Antonio Cabral Yehuda Shoenfeld, Emilio González
Chair: Ricard Cervera
APS NEPHROPATHYRECOMMENDATIONS
• 1. Routine performance of renal biopsy is not recommended in APS.
• 2. In APS patients with clinical and laboratory findings that suggest renal involvement (new onset of hypertension, proteinuria, hematuria or renal insufficiency), renal biopsy should be performed (Evidence level II). proteinuria, hematuria or renal insufficiency), renal biopsy should be performed (Evidence level II).
• 3. In patients with APS nephropathy, especially in SLE and in the absence of other causes associated with similar lesions, aPL testing is recommended (Evidence level II).
• 4. In patients with APS nephropathy and persistently positive aPL, the diagnosis of APS should be considered, provided that other conditions resulting in similar renal lesions are excluded.
HEART VALVE LESIONSRECOMMENDATIONS
1.In patients with APS and previous thrombosis, mainly witharterial involvement, a TTE is recommended (Evidence levelII)
2.1.With normal valves and in the absence of atheroscleroticfactors, follow up controls might not benecessary.factors, follow up controls might not benecessary.2.2.If VHD exists, serial echocardiographic follow up controls arewarranted (1 prospective study) (Evidence level II)
3.1.No attempt to treat VHD with curative intention isrecommended (Evidence level II)3.2. A trial of steroids might be considered in APS-related VHD(Evidence level IV)
THROMBOCYTOPENIARECOMMENDATIONS
• 1. Multicentric, international, prospective long-term follow-up study of patients with ITP (APIgG, aPL, LAC, anti-β2GP-I…), thrombosis being the primary outcome.
• 2. International Registry of aPL-positive “ITP” patients (“Hematologic APS”).
• 2. International Registry of aPL-positive “ITP” patients (“Hematologic APS”).
• 3. We suggest that TCP may be incorporated as an isolated clinical criteria for APS.
APS-2011: DIAGNOSIS
• Classical, unusual and silent clinical manifestationsmanifestations
• Catastrophic antiphospholipid syndrome
CATASTROPHICANTIPHOSPHOLIPID SYNDROME
Epidemiology
CAPS: 1% of APS
THE "CAPS" REGISTRYInternational Registry of Patients with
Catastrophic APS
European Forum on Antiphospholipid Antibodies
Catastrophic APS
www.med.ub.es/MIMMUN/FORUM/CAPS.HTM
1. Clinical evidence of vessel occlusions affecting 3 or more organs or systems.
2. Development of the manifestations simultaneously or in less than a week.
2003
week.3. Confirmation by histopathology of small vessel occlusion in at least
one organ.4. Laboratory confirmation of the presence of aPL (LA and/or aCL).
-Definite catastrophic APS: All 4 criteria.-Probable catastrophic APS:-1, 2 & 4-1, 3 & 4 and the development of the third event in more thana week but less than a month, despite anticoagulation
• Sensitivity 90.3%
2005
• Sensitivity 90.3%
• Specificity 99.4%
• Positive predictive value 99.4 %
• Negative predictive value 91.1 %
Pre-Conference Workshop on CAPS and non-criteria APS manifestationsand non-criteria APS manifestations
April 13, 2010
Smita Vaidya, Horacio Adrogué Doruk Erkan, Gerard Espinosa,
Maria Tektonidou, Antonio Cabral Yehuda Shoenfeld, Emilio González
Chair: Ricard Cervera
A B
C
ANTIPHOSPHOLIPID SYNDROME
• DIAGNOSIS• DIAGNOSIS
• TREATMENT
• PATHOGENESIS
APS-2011: TREATMENT
• High/moderate INR controversy• High/moderate INR controversy• Heparin/aspirin for pregnancy
controversy• Treatment of catastrophic APS
APS-2011: TREATMENT
• High/moderate INR controversy• High/moderate INR controversy• Heparin/aspirin for pregnancy
controversy• Treatment of catastrophic APS
n=100 oralanticoagulant
aspirin none
events 37 36 23events 37 36 23
recurrences 7(19%)* 15(42%) 21(91%)
median time(months)
96* 75 48
p=0.0007
APS-2011: TREATMENT
• High/moderate INR controversy• High/moderate INR controversy• Heparin/aspirin for pregnancy
controversy• Treatment of catastrophic APS
APS - 2011: Heparin/aspirin for pregnancy controversy
S P E C IF IC S IT U A TIO N S : S P E C IF IC S IT U A TIO N S : S P E C IF IC S IT U A TIO N S : S P E C IF IC S IT U A TIO N S : A N T IP H O S P H O L IP ID S Y N D R O M EA N T IP H O S P H O L IP ID S Y N D R O M E
T heT he H o sp ita lH o sp ita l C lín ic o fC lín ic o f B arce lon aB arce lon a E xp e rienceE xp erienceM E D IC A L TR E A TM E N TM E D IC A L TR E A T M E N T
N oN o p re vio u s trea tm en t p re vio u s trea tm en t A s p irinAs p irin 100 m g /100 m g / d a yd a yfro mfro m 11 m o n th b e fo re a ttem p tin g co n cep tio nm o n th b e fo re a ttem p tin g co n cep tio n
F a ilu re o f asp irinF a ilu re o f asp ir in in in p re v io u s p reg n an cyp re vio u s p reg n an c yA s p irinAs p irin p lu s L M W p lu s L M W hep arinhep arin
H is to ry o f th ro m bo s isH is to ry o f th ro m bo s isA s p irin As p irin p lu s L M W p lu s L M W hep arinhep arin
P red n iso n eP red n iso n e d u rin gdu rin g p reg n an c y p reg n an c y O n ly if req u ired fo rO n ly if req u ired fo r m ed ica lm ed ica l co m p lica tion sco m p lica tio n s
APS - 2011: Heparin/aspirin for pregnancy controversy
SPECIFIC SITUATIONS: SPECIFIC SITUATIONS: ANTIPHOSPHOLIPID SYNDROMEANTIPHOSPHOLIPID SYNDROMETheThe HospitalHospital Clínic ofClínic of BarcelonaBarcelona ExperienceExperience
100n:137(78%)n:137(78%)
n=63 (81%)n=63 (81%)
0
10
20
30
40
50
60
70
80
90
Beforetreatment
Aftertreatment
ABORTION/FETALDEATHLIVEBORN
n=39 (22%)n=39 (22%)
n=63 (81%)n=63 (81%)
n=14 (19%)n=14 (19%)
APS - 2011: Heparin/aspirin for pregnancy controversy
SPECIFIC SITUATIONS: SPECIFIC SITUATIONS: ANTIPHOSPHOLIPID SYNDROMEANTIPHOSPHOLIPID SYNDROMETheThe HospitalHospital Clínic ofClínic of BarcelonaBarcelona ExperienceExperience
RESULTS (V)RESULTS (V)RESULTS (V)RESULTS (V)
Normal Normal livebornlivebornAAS AAS beforebefore conceptionconception(n=59 (n=59 patientspatients)) 52 cases (88.1%)52 cases (88.1%)AAS AAS afterafter conceptionconception(n=18 (n=18 patientspatients)) 11 cases11 cases(61.1%)(61.1%)
p=0.01 OR (IC):4.7 (1.3p=0.01 OR (IC):4.7 (1.3--16.2)16.2)
APS-2011: TREATMENT
• High/moderate INR controversy• High/moderate INR controversy• Heparin/aspirin for pregnancy
controversy• Treatment of catastrophic APS
CATASTROPHIC APSOutcome
RECOVERY 50%Plasma exchange 65%
Anticoagulants 63%Anticoagulants 63%
Steroids 54%
IV Gammaglobulins 50%
Cyclophosphamide 41%
AC+St+Pl/IV-GG 70%
AC+St+Pl/IV-GG+Cyclo 50% (p=0.02)
CAPS Registry, 2011
TRATAMIENTO
STEROIDS ANTICOAGULATIONPLASMA EXCHANGE
+/- IV IMMUNOGLOBULINS
CATASTROPHIC APSTriple Therapy
Infections
SIRS
Asherson RA, Cervera et al. Medicine (Baltimore) 2001; 80:355-376
140
160
20%
2006
53%
33%
0
20
40
60
80
100
120
140
1992-2000 2001-2005
DiedSurvived
p=0.005
20%
Year of Diagnosis
SB1
Diapositiva 57
SB1 The mortality rate wsfifty-three percent in the first period, before two thousand and one.
whilst the mortality rate was thirty-three percent from 2001.In other word the mortality decresed twenty percent from two thounsand and one with a p statistically significant. What does depend on?sbucciarelli; 05/03/2006
First periodp=0.025
13%
29%
AC+CS+PE and/or IVIG
First period
Second period
SB3
Diapositiva 58
SB3 When we use the logistic regression anlysis including age, precipitating factor and rate use of combinated therapyThe precipitanting factor dissapeared.
the mortality decrease in the second period was associated with the age and the higher rate use of combinated treatment.
Likely the age is a statistical factor, because there is a little difference between two age.This difference is not enough for explaining so significant reduction of mortality
Therefore the main reason for explaining the mortality decrese was the higher use rate of combinated therapy
In other word the reduction of twenty percent of mortality from two thounsand and one depends on the higher use rate of combinated treatment wit AC+CS+PE and/or IVIG.sbucciarelli; 05/03/2006
ANTIPHOSPHOLIPID SYNDROME
• DIAGNOSIS• DIAGNOSIS
• TREATMENT
• PATHOGENESIS
APS - 2011: PATHOGENESIS
• Role of infections• Peptide homology
APS - 2011: Role of infections
J Rheumatol 2000; 27:238-240
CATASTROPHIC APSPrecipitating Factors (I)
INFECTIONS 36 (24%)
Respiratory 15 (10%)Cutaneous 6 (4%)Urinary 6 (4%)Gastrointestinal 3 (2%)Sepsis 2 (1%)Other 4 (3%)
CAPS Registry, 2011
APS - 2011: Role of infections
APS - 2011: Peptide homology
Arthritis & Rheumatism 2002 (in press)
APS - 2011: Peptide homology
APS - 2011: Peptide homology
J Clin Immunol 2003; 23: 377-383
APS - 2011: Peptide homology
J Clin Immunol 2003; 23: 377-383
MOLECULAR MIMICRY
J Clin Immunol 2004; 24: 12-23
J Clin Immunol 2004; 24: 12-23
J Clin Immunol 2004; 24: 12-23
EULAR PRIZE 2005Yehuda ShoenfeldPier Luigi MeroniRicard Cervera
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