cervera ricard antiphospholipid syndrome update on pathogenesis diagnosis and management-torino...

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