anti-phospholipid syndrome (aps)€¦ · anti-phospholipid syndrome (aps) a focus on renal...

ANTI-PHOSPHOLIPID SYNDROME (APS)

A focus on renal involvement

Anti-phospholipid syndrome

APS is an autoimmune disease characterized by the

presence of anti-phospholipid antibodies (aPL) and

various clinical manifestation related to arterial or

venous thrombosis

It can be further divided into primary and

secondary APS

Making the diagnosis requires both clinical and

laboratory criteria

Pathogenesis

The antiphospholipid antibodies target β2-glycoprotein I or anticardiolipin detected by ELISA

or antibodies detected by lupus anticoagulant

assay

The risk of a first thrombotic event among

asymptomatic persons who are positive for lupus

anticoagulant, anticardiolipin antibodies, and anti–

β2-glycoprotein I antibodies (triple +ve) is

5.3%/year

Giannakopoulos B, Krilis SA. N Eng J Med. 2013;368:1033-44..

Pathogenesis

“Two-hit” model

Initial first hit disrupts the endothelium

Second hit potentiates thrombus formation

First hit may not be identified

Infection or recent surgery in CAPS

Smoking β2-glycoprotein I

Giannakopoulos B, Krilis SA. N Eng J Med. 2013;368:1033-44.

Giannakopoulos B, Krilis SA. N Eng J Med. 2013;368:1033-44.

Pathogenesis

Recent study revealed that the activation of mTOR

enzymes stimulates intimal hyperplasia leading to

chronic vascular lesion

Merashli M et al_Eur J Clin Invet. 2015;45(6):653-62.

Clinical criteria

Miyakis S et al_J Thromb Haemost. 2006;4:295-306

Laboratory criteria

Miyakis S et al_J Thromb Haemost. 2006;4:295-306

Specific clinical entity

http://slideplayer.com/slide/10696917/

http://www.westernreserveheartcare.com/vp/echo-cardio.htm

Livedo reticularis

aPL-associated cardiac valve disease

aPL-associated thrombocytopenia

Catastrophic APS (CAPS)

Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27

aPL-associated nephropathy

(APS nephropathy)

Epidemiology

Epidemiology

APS

Prevalence: 40-50 cases per 100000 persons

Incidence: 5 new cases per 100000 persons per year

Positive aPL

Prevalence: 1-5% in general population

13% with stroke

11% with myocardial infraction

9.5% with DVT

6% with pregnancy morbidity

Gómez-Puerta JA, Cervera R. Journal of Autoimmunity 2014;48:20-

5.

Epidemiology

Sex distribution

Adult: Female : Male = 4.5: 1 (n=1000)

Children: Female : Male = 1.2: 1 (n=121)

Mean age

Adult: 34 ± 13 years

Children: 10.7 years (Range: 1-17.9 years)

Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27

Acvin T et al. Pediatrics 2008;122:e1100–07

Primary vs Secondary

aPL is associated with various conditions

Gómez-Puerta JA, Cervera R. Journal of Autoimmunity 2014;48:20-

5.

n=1000

European adults

98.5% Caucasian

n=121

US, South American,

European children

Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27

Acvin T et al. Pediatrics 2008;122:e1100–07

Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27

Our patient

Clinical manifestation

Clinical presentation

Variable

Depends on the site of thrombosis

Arterial vs venous

Recurrent fetal loss in women

Thrombocytopenia

Livedo reticularis

Adult cohort

Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27

Paediatric cohort

Acvin T et al. Pediatrics 2008;122:e1100–07

*Evans syndrome: Autoimmune haemolytic anaemia and ITP

Budd-Chiari syndrome (BCS) in APS

Budd-Chiari syndrome (BCS) in APS

Among 43 patients with APS presented with BCS

Female: Male = 2:1

Mean age: 30.8 years

Primary APS: 74%

BCS as first clinical manifestation of APS: 65%

Thrombocytopenia: 53% (?Related to the underlying

portal hypertension)

Espinosa G et al. Medicine (Baltimore). 2001;80(6):345-54.

How about the kidney?

aPL-associated nephropathy

Also called APS nephropathy

Renal involvement in APS

Renal vein thrombosis

Renal artery stenosis and thrombosis

Renal infraction

Systemic hypertension

Thrombotic microangiopathy

Glomerular microthrombosis associated with SLE

It can be the first presentation of APS

Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.

Abeysekera RA et al. Journal of Medical Case Reports. 2015;9:28

Presentation

??CKD / ESRF

Proteinuria Haematuria Loin pain Hypertension

(New or worsened) AKI

Renal vein

thrombosis

Renal artery stenosis

or thrombosis Renal infraction TMA

Investigations:

- Imaging

- Biochemistry

- Histology

- Immunology

Definition

Miyakis S et al_J Thromb Haemost. 2006;4:295-306

George JN, Nester CM. N Eng J Med. 2014;371:654-6.

Systemic lupus

erythematosis

Anti-

phospholipid

syndrome

APS

nephropathy

Thrombotic

microangiopathy

How prevalent?

Acvin T et al. Pediatrics 2008;122:e1100–07

Prevalence of renal

manifestation: 5%

Underestimation due to low

prevalence of renal biopsy

Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27

F:M = 7:1; Mean age = 35±12 years

Renal involvement: 8.7%

Proteinuria 100% (Nephrotic range 35%)

AKI: 15%

CKD / ESRF: 35%

Hypertension: 57%

10/14 subjects had a renal biopsy performed

Membranous GN: 40%

Proliferative GN: 20%

TMA: 20%

Vascular lesion compatible with APS nephropathy: 20%

Sinico RA et al. CJASN. 2010;5:1211-7.

Tektonidou MG et al. Arthritis and Rheumatism. 2004;50(8):2569-79.

151 White SLE patients

aPL +ve (n=81)

APSN

39.5%

No APSN

60.5%

aPL –ve (n=70)

APSN

4.3%

No APSN

95.7%

- More arterial thrombosis, stroke, PE, hypertension, raised Cr and +ve LA

- 66% had acute changes and 87.5% had chronic changes

- Hypertension was more associated with acute APSN and raised Cr was more

associated with chronic APSN. Both were associated with CKD at end of study.

- No associated between WHO class and any APSN (p=0.2)

- No difference in risk of CKD or ESRF between those with / without APSN (mean

duration of FU = 5.3±4.1 years)

In fact…

Conflicting data on whether

aPL is associated with worse renal outcome among SLE patients

Coexisting APS nephropathy and lupus nephritis carries worse prognosis

Still it is advised to distinguish between lupus nephritis (immune-complex disease) alone or with additional APSN (thrombotic disease and vascular lesions)

Additional anticoagulation may be required

Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.

QEH Paediatrics

Anticardiolipin IgG Lupus

anticoagulant Lupus nephritis APSN Thrombosis

F/10 28.2 -ve Class IV ?? No

M/17 <13.3 -ve Class IV No No

F/15 19.3 Detected Class III No No

M/16 36.2 → 21.1 → <13.3 -ve Class IV No No

F/15 N/A N/A Class III + V *+/- No

F/16 <13.3 → <13.3 Detected Class IV *+/- No

*arterial mild fibroelastic intimal hyperplasia

- Inclusion:

- Patients underwent renal biopsy with pathological diagnosis of SLE

- Age: ≤18 years old

- Source: CDARS (using procedure code of renal biopsy)

- Year: 9/2011-8/2016

MANAGEMENT

Management

Primary and Secondary thromboprophylaxis

Control cardiovascular risk factors

Primary: Aspirin, LMWH, Statin, hydroxychloroquine (especially those with SLE)

Secondary: Warfarin (INR 2-3 for venous thrombosis and INR 3-4 for recurrent thrombosis or arterial thrombosis)

Renal artery stenosis and hypertension

Anti-hypertensive agents in addition to anticoagulants

Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.

Merashli M et al. Eur J Clin Inves 2015;45(6):653-62.

Management

Therapeutic options

Steroid

IVIG

Plasmapheresis

Cyclophosphamide

Rituximab

Complement inhibition (Eculizumab)

The role of all these agents in long term outcome of APS is yet to be determined

As APS is a systemic disease, the extent and severity of other organ involvement should also be considered

Steroid

Patients with APS secondary to SLE with lupus nephritis may have been treated with steroid

In CAPS, it is commonly employed with other measures like IVIG / plasmapheresis

Lack of data evaluating its independent effect

In patients with primary APS with APSN, steroid plus azathioprine / cyclophosphamide has been reported. But it is not routinely recommended

?Due to low awareness of APSN in the past

?Low renal biopsy rate in patients with APS

Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.

Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27

IVIG

It has been reported that F(ab’)2 fragment from IVIG

can neutralize the binding of aCL to cardiolipin and inhibit LA activity

IVIG itself carries risk of thrombosis

Most studies were carried out in obstetric APS or CAPS

May have a role in preventing recurrent thrombosis in addition to convention therapy from a recent review

To prevent thrombosis

More days of infusion (Usually 2g/kg over 4-5 days)

Slow infusion using concentration <5%

Tenti S et al_Autoimmunity Reviews. 2016;15:226.

Plasmapheresis

Extended from the known benefit of plasmapheresis for various forms of microangiopathy

CAPS are frequently treated with combination of steroid, plasmapheresis and/or IVIG

Lack of prospective study to evaluate its effectiveness

?Indication, optimal number of sessions and dose

?Usefulness in other clinical entity of APS

Consideration:

Manpower / Availability / Cost

IVIG is better to be given after plasmapheresis

Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27

Rituximab

Anti-CD 20 monoclonal antibody that depletes

CD20+ B-lymphocytes

Mechanism of its action in APS is unclear

Usually used in refractory cases, especially those

with refractory thrombocytopenia and haemolytic

anaemia

Data in APS nephropathy is limited

Katikaneni M et al. The Open Urology and Nephrology Journal. 2015;8(Suppl 1:M6):27-38

Cyclophosphamide

Usually in patients with coexisting SLE who develops

CAPS

In a retrospective review of patients with CAPS,

non-SLE patients who received cyclophosphamide

actually had increased mortality (OR = 9.5,

p=0.005)

Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27

Eculizumab

Recombinant humanized monoclonal antibody binds

to the terminal complement protein C5

Complement contributes to the activation of the

endothelial cells and induces thrombosis

Isolated case reports on its use in CAPS

Some of them were used in patients with renal

transplantation

Lonze BE et al. N Eng J Med. 2010;362(18):1744-5.

Hadaya K et al. American Journal of Transplantation 2011;11(11):2523-7.

Merashli M et al. Eur J Clin Inves 2015;45(6):653-62.

Back to our patient…

Primary APS

Thrombosis

Persistent thrombocytopenia

APS nephropathy with hypertension, proteinuria and

impaired renal function