New concept of Antiphospholipid syndrome

SYDNEY REVISION OF SAPPORO CRITERIA (2006)

Laboratory criteria
Classification of APS should be avoided if less than 12 weeks or more than 5 years separate the positive aPL test and the clinical manifestation. Anticardiolipin antibodies can be found in 2% to 5% of a normal population These antibodies increase in prevalence with increasing age, with IgG and IgM aCL being observed in 12% to 52% of an elderly population

aPL associated (individual diagnosis)

Cardiac valve disease Livido reticularis Thrombocytoponia Nephropathy

Non-APS criteria antiphospholipid antibodies

Anticardiolipin IgA Anti-2GPI IgA Antiphosphatidylserine Antiphosphatidylethanolamine Prothrombin alone (aPT-A) Phosphatidylserine-prothrombin (aPS/PT) complex

Antiphopholipid Syndrome
APS that no associated rheumatic disease APS that associated rheumatic disease Catastrophic APS (CAPS) aPL antibody (no symptoms)

Thrombosis
One or more confirmed episodes: venous, arterial or small vessel Exclude male 55+ female 65+ and other causes

Established risk factors for cardiovascular disease

Hypertension Diabetes mellitus Elevated LDL or low HDL Family history of premature cardiovascular disease Body mass index 30 kg/m2 Microalbuminuria or nephrotic syndrome GFR < 60 mL/min Inherited thrombophilias Oral contraceptives Cigarette smoking, Malignancy Immobilization Surgery

Pregnancy
One or more unexplained deaths >10 wk One or more pre-eclampsia/ placental insufficiency < 34wk 3 or more unexplained consecutive spontaneous abortion < 10 wk Exclude other causes

Features of placental insufficiency

Abnormal or nonreassuring fetal surveillance tests Abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia Oligohydramnios A postnatal birth weight less than the 10th percentile for the gestational age.

Explained mechanisms
Venous and arterial thrombosis Pregnancy loss

Pregnancy loss

C3a, C5a

Annexin V

Additive risk events

(Recurrent) Vascular Events

Risk factor Hypertention Diabetes Hypercholesteral Smoking HRT Surgery Pregnancy Malignancy Infection Thrombocytopenia Vascular thrombosis 77(%) 14 0 5 30 20 18 14 1 14 17 aPL 56(%) 20 5 7 16 10 5 0 2 16 5 P 0.4 0.07 0.4 0.07 0.12 0.04 0.005 1 0.8 0.06

A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome

Erkan,Rheumatology 2002;41:924-929

Venous/Arterial Events
Risk factor Hypertention Diabetes Hypercholesteral Smoking HRT Surgery Pregnancy Malignancy Infection Thrombocytopenia Venous 34 1 0 2 6 7 8 4 0 4 6 Arterial 43 10 0 1 17 6 6 5 1 7 7 P 0.011 0.42 0.037 0.44 0.27 0.98 0.37 0.57 0.91

Stroke manifestations
in the Antiphospholipid Syndrome

Risk for recurrent stroke was higher in patients with aPL after the first cerebral ischemic episode. Presence of aPL at the time of initial stroke increases the risk of recurrence in an unselected population ???
APASS Neurology 1997;48:914. Levine SR, JAMA 2004;291:57684.

Either LA or aCL in patients with ischemic stroke did not predict an increased risk for further thrombo-occlusive events. Routine screening for aPL did not appear warranted in patients with ischemic stroke.
Levine and the APASS investigators

limitation
A number of important limitations of this study have raised several concerns.
Average age of patients (62.5 years) was significantly higher than in previous studies of APS (34 years). Only a single measurement of aCL and LA. High proportion of patients was found positive for aPL (41%) ,but only 0.2% had high IgG levels.

6.7% tested positive for both aCL and LA.

Patients positive for both aCL and LA had a tendency to develop recurrent events.

Recent systematic review

LA is a risk factor for thrombosis, independent of the site (venous or arterial) and the type of event (first or recurrence). aCL were not such strong risk factors, unless the IgG isotype and medium and high titers were considered
Galli M, Blood 2003;101:182732.

Unexplained mechanisms
Livido UBOs Valve disease Thrombotic microangiopathy (nephropathy) Leg ulcers

Definition of aPL-associated cardiac valve disease

Valvular disease in antiphospholipid syndrome

Lesions most frequently involved left-sided valves, mitral more commonly affected than aortic. Higher prevalence of valve defects in patients suffering SLE with aPL than in those without these antibodies.

Exclude Libman-Sacks endocarditis, rheumatic fever and infective endocarditis

Valvular disease in antiphospholipid syndrome

Abnormalities in 33 of 40 (82%) of primary APS patients Mitral valve thickening most common abnormality (63%) Aortic valve thickening 32% Tricuspid valve thickening in 8%.
Turiel MLupus 2000;9(6):40612,

aPL are associated with mitral valve nodules in SLE

No aPL 158 AV nodule MV nodule 10 (6.3%) 7 (4.4%) aPL 42 1 (2.4%) 6 (14.3%) P 0.32 0.02

Farzaneh-Far, Arthritis Rheum, in press

Definition of aPL-associated nephropathy (APLN)

Organized thrombi

FIH

TMA

Exclude TTP/HUS ,other causes of TMP and lupus nephritis

Accelerated Atheroma in the Antiphospholipid Syndrome

Some studies aPLs correlate with atherosclerosis. Binding of oxLDL with b2GPI to form circulating complexes : atherogenic autoantigens. Enhanced macrophage uptake of oxLDL/b2GPI/antibody complexes. Macrophage Fc receptors that uptake of oxLDLcontaining complexes : foam cells

Prevalence of Atherosclerotic Plaque

Its still controversy

SLE

Roman, NEJM,2003 Dec 18;349(25):2399-406

Why aPL protect atherosclerotic plaque in SLE ?

Characteristic No plaque (N=124) aPL (%) 18 LA ACL 10.4 11.5 Plaque (N=73) 14.1 15.3 2.8 P value 0.48 0.37 0.04

Catastrophic APS

Roman, NEJM,2003 Dec 18;349(25):2399-406

Preliminary criteria for the classification of catastrophic APS

1.

Distinct differences of patients with catastrophic APS

Unusual organs affected (eg, ovaries, uterus, testes) ARDS or DAH SIR Early loss of consciousness DIC Abdominal pain : intraabdominal vascular complications Severe thrombocytopenia HELLP syndrome Poor prognosis

Evidence of involvement of three or more organs, systems, or tissues. Development of manifestations simultaneously or in less than a week. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue. Laboratory confirmation of the presence of antiphospholipid antibodies

2.

3.

4.

Precipitating factors according to the analysis of 250 patients from the CAPS Registry
Unknown Infections Trauma Anticoagulation problems Neoplasia Obstetric Lupus flares 40% 22% 14% 7.2% 6.8% 4.6% 3%

Treatment for CAPS

Prophylactic therapy Specific therapies Nonspecific therapies : ICU

Prophylactic therapy

Specific therapies
First-line therapies Intravenous heparin (1500 U/h) 7 - 10 days followed by oral anticoagulants (INR 3 ) Corticosteriods (1-2 mg/kg/day) : minimum 3 days Second-line therapies Intravenous immunoglobulins Plasma exchange Cyclosphosphamide Rituximab Prostacyclin Other fibrinolytics

APS : Relationship to SLE

SLE 30-40% have aPL 10% have APS

Prevalence of aPL in SLE

LAC is found in approximately one-third of SLE patients. aCL positivity in SLE vary from 23% to 47%. Anti-b2GPI is found in 20% of lupus patients

Clinical significance of aPL in SLE

1.

aPL-positive lupus patients have an increase in thrombotic or adverse pregnancy events ? Vascular and pregnancy-related manifestations that have been ascribed to lupus, are seen mainly or exclusively in those who have aPL ?

2.

Hypercoagulability, antiphospholipid antibodies, and systemic lupus erythematosus

aPL in SLE is associated with an increased prevalence of thromboembolism compared with patients who did not have aPL. Thromboembolic events occurred in 53% of 160 patients who had a LAC and in 12% of 338 patients who did not have this antibody Who were aCL positive, 40% of 300 had thrombotic events, compared with 18% of 364 patients who were antibody negative.

The prognosis of lupus appears to be impacted significantly by the presence of aPL.

Cumulative survival at 15 years to be lower in patients who had APS than in those who did not have APS (65% versus 90%, P=0.03)
Ruiz-Irastorza G, Arch Intern Med 2004

8-year survival in SLE-APS patients who have APS was 75% VS 98% in those who did not have APS
Reshetniak TM, Ter Arkh 2003

Pregnancy in systemic lupus erythematosus and antiphospholipid syndrome

Lupus patients who have a history of pregnancy loss : LAC 50% - 74% and up to 36% have aCL
J Obstet Gynaecol 1985 Clin Immunol Immunopathol 1986

Currently recommended treatments for antiphospholipid syndrome

Healthy women who have pregnancy loss : LAC 15% and aCL 12%
Am J Obstet Gynecol 1986
Placental thrombosis, placental insufficiency, IUGR

Recommendations for perioperative medical management of patients with APS

Erkan D, J Rheumatol 2002;29(4):8439

Recommendations for perioperative medical management of patients with APS

Recommendations for perioperative medical management of patients with APS III

Erkan D, J Rheumatol 2002;29(4):8439

Erkan D, J Rheumatol 2002;29(4):8439

Potential current and future treatments for antiphospholipid syndrome

Thank you

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