PAS.LN (1).pdf

Antiphospholipid antibodies in
pediatric lupus nephritis
NHÓM CK1 TỔ 7 2022-2024: NHỮ THU HÀ, TRẦN THỊ DUNG, LÊ KHẢI HOÀN
HVCH: NGUYỄN THANH MINH
GVHD: Ths.BS ĐỖ ĐĂNG TRÍ

NỘI DUNG
1. Định nghĩa
2. Tiêu chuẩn phân loại APS
3. Cơ chế bệnh sinh trong APS
4. Biểu hiện lâm sàng APS
5. Tiêu chuẩn phân loại SLE
6. Tiêu chuẩn chẩn đoán LN
7. Antiphospholipid antibodies in pediatric lupus nephritis
8. Điều trị

ĐỊNH NGHĨA ( DEFINITION)
• Antiphospholipid antibody syndrome : is a systemic autoimmune
disorder that can manifest clinically as recurrent thrombosis.
• SLE : is a rheumatic disease characterized by autoantibodies directed
against self-antigens, immune complex formation, and immune
dysregulation, resulting in damage to essentially any organ. The
disease can affect, for example, the kidneys, skin, blood cells, and
nervous system
• Antiphospholipid antibodies in pediatric lupus nephritis

• Antiphospholipid (aPL) antibodies have been found in association with clinical
symptoms such as deep venous thrombosis, arterial occlusive events (eg, stroke,
myocardial infarction), and recurrent fetal loss. They are also associated with
vasospastic phenomena such as migraine headache, Raynaud phenomenon, and
transient ischemic attack (TIA).
• Antiphospholipid antibody syndrome (APS)
▪ Primary antiphospholipid antibody syndrome (PAPS) : Antiphospholipid
antibodies associated with vaso-occlusive events without any underlying disease
process
▪ Secondary antiphospholipid antibody syndrome (SAPS):
The presence of antiphospholipid antibodies and a vaso-occlusive
event superimposed on an underlying disease, such as SLE or malignancy.
https://emedicine.medscape.com/article/1006128-print

Primary versus secondary APS
• APS can occur in isolation as so-called “primary APS” or in conjunction
with another autoimmune condition, in which case it is referred to as
secondary APS.
• In the aforementioned Ped APS Registry, 60 cases (49.5%) were considered
primary APS, 60 (49.5%) were associated with a second autoimmune
condition, and one (1.0%) was associated with malignancy(21).
• Of the 60 cases associated with a second autoimmune condition, there
were 46 cases of lupus (76.7%), 4 of lupus-like disease (7.7%), 4 of
autoimmune thyroiditis (7.7%), 2 of rheumatic fever (3.3%), and 1 each
(1.7%) of immune thrombocytopenic purpura, hemolytic-uremic syndrome,
pauci-immune glomerulonephritis, and Behçet’s disease (21)
• somewhat higher rate of progression from primary APS to secondary APS in
children as compared with adults.

Classification criteria for antiphospholipid syndrome
updated Sapporo criteria (developed in 2006
and sometimes referred to as the Sydney
criteria),
Madison JA, Zuo Y, Knight JS. Pediatric antiphospholipid
syndrome. Eur J Rheumatol 2020; 7(Suppl1): S3-S12
The updated Sapporo criteria were developed with
adults in mind, and there are no specifc criteria for
pediatric APS. As will be discussed in more detail below,
potential limitations of these criteria in children include
the fact that most individuals under the age of 18 will
not have experienced pregnancy (and therefore have
no opportunity to meet that aspect of the criteria), as
well as that certain neurologic and hematologic
manifestations of APS (chorea, thrombocytopenia,
etc.) that are not part of the criteria may be
particularly common in children.

Madison JA, Zuo Y, Knight JS. Pediatric
antiphospholipid syndrome. Eur J Rheumatol 2020;
7(Suppl1): S3-S12
OVER AT LEAST 12 WEEKS ?

D Garcia, D Erkan. N Engl J Med 2018;378:2010-2021.
Summary of the Proposed Pathogenesis of Antiphospholipid-
Antibody–Mediated Clinical Problems.

-“các bẫy bạch cầu trung tính ngoại bào” (“neutrophil extracellular
traps” – NETS)
-trophoblasts : nguyên bào nuôi
-decidual cells : tb thuộc màng rụng
Figure 1. Summary of the Proposed Pathogenesis of Antiphospholipid-Antibody–Mediated Clinical
Problems.
In Panel A, antiphospholipid antibodies are produced by B cells; binding to anionic surfaces
converts the closed, nonimmunogenic β2-glycoprotein I (β2GPI) to the open, immunogenic β2GPI.
In Panel B (left), antiphospholipid antibodies bind to the immunogenic β2GPI, resulting in
endothelial-cell, complement, platelet, neutrophil, and monocyte activation (including the release
of neutrophil extracellular traps [NETosis]).
In Panel B (middle), antiphospholipid antibodies promote clot formation, and in Panel B (right),
antiphospholipid antibodies interfere with trophoblasts and decidual cells.
Panels C and D show that, on the basis of multiple mechanisms that are not mutually exclusive,
antiphospholipid antibodies result in inflammation, vasculopathy, thrombosis, and pregnancy
complications.

Clinical features
• What are the most common thrombotic manifestations in children with APS?
cardinal feature of pediatric APS is vascular thrombosis
• Again referencing the PedAPS Registry of 121 cases, the most common presenting
feature was venous thrombosis in 60% of children (21). Lower-limb deep venous
thrombosis (DVT) was the most common single form of thrombotic event (40%),
which was also the most common event (37%) in the large case series from China
(8, 21). The other venous thrombotic events that aﬀected more than one child
were cerebral venous sinus thrombosis (7%), portal vein thrombosis (3%), upper
extremity DVT (2%), superfcial vein thrombosis (2%), and left atrial thrombus
formation (2%) (21). There were also rare forms of venous thrombosis described
in just a single child including involvement of the jugular vein, inferior vena cava,
renal vein, and retinal vein .
Madison JA, Zuo Y,
Knight JS. Pediatric antiphospholipid
syndrome. Eur J Rheumatol 2020; 7(Suppl
1): S3-S12

Clinical features
• Arterial thrombosis aﬀected 32% of children, with ischemic stroke as
by far the most common in this category (79% of arterial events) (21).
Other rare forms of arterial thrombosis were peripheral artery
thrombosis, retinal artery thrombosis, myocardial infarction (MI),
renal artery thrombosis, and splenic infarction (21). Interestingly,
just 2% of children demonstrated a mixture of arterial and venous
thrombosis (21). Small-vessel thrombosis in the form of digital
ischemia or renal thrombotic microangiopathy aﬀected
approximately 6% of children (21)
Madison JA, Zuo Y,
Knight JS. Pediatric antiphospholipid
syndrome. Eur J Rheumatol 2020; 7(Suppl
1): S3-S12

Current Rheumatology Reports (2021) 23: 10
https://doi.org/10.1007/s11926-020-00976-7

Current Rheumatology Reports (2021) 23: 10
https://doi.org/10.1007/s11926-020-00976-7
other manifestations beyond thrombosis?

Laboratory studies
If the clinical features suggest an antiphospholipid antibody syndrome, a thorough evaluation to
detect the presence of at least one of these antibodies is essential. Evaluate the patient for the
following:
• Anticardiolipin
• Antiphosphatidylethanolamine
• Antiphosphatidylinositol
• Antiphosphatidylserine
• Antiphosphatidylglycerol
• Antiphosphatidic acid
Evaluate for lupus anticoagulant and anti–beta-2 glycoprotein I antibodies as well. Assessment for
abnormalities in phospholipid-dependent tests of coagulation is also recommended.

Imaging studies
Imaging studies are useful to confirm a thrombotic event. For example, in patients with venous
thrombotic events (eg, deep vein thrombosis), the following studies have been used:
• Doppler ultrasonography
• Venography
• Ventilation/perfusion scan (to document pulmonary emboli)
In patients with arterial thrombotic events, the following studies have been used:
• Computed tomography
• Nuclear imaging
• Magnetic resonance imaging
• Doppler ultrasonography
• Magnetic resonance arteriography
• Arteriography

Laboratory testing
Madison JA, Zuo Y, Knight JS. Pediatric antiphospholipid syndrome. Eur J
Rheumatol 2020; 7(Suppl 1): S3-S12

Approach to treatment
• In general, data specifc to pediatric APS are quite limited. Most
concepts are derived from small observational studies, extrapolation
from adult data, or expert opinion.
➢Prevention of Thrombosis.
➢Treatment after Thrombosis.
➢Treatment of CAPS.

DỰ PHÒNG HUYẾT KHỐI ĐIỀU TRỊ SAU KHI BỊ HUYẾT KHỐI
-aPL trước khi huyết khối (lupus):
low-dose aspirin ???
In aPL-positive children with lupus,
hydroxychloroquine will almost always
be employed, which may provide some
adjunctive properties for prevention of
APS complications as well (44, 97)
-Venous thrombosis and persistently-positive aPL :
+ kháng đông (anticoagulation) lâu dài
+ LMWH or unfractionated heparin.
+Chuyển sang kháng VitK (vitamin K antagonist) như warfarin
+INR mục tiêu : 2-3
-In arterial thrombosis:
+ thêm anti-aggregation : low-dose aspirin
+Nếu huyết khối tái phát trong lúc trẻ đang dùng chống đông kéo dài
với kháng VitK, thay đổi INR : 3-4 hoặc cân nhắc LMWH (low-molecular-
weight heparin)
-Tránh dùng DOACs (direct oral anticoagulants ) như first-line therapy,
cần thêm dữ liệu.
-there is no evidence to support the regular use of immunomodulatory
treatment in primary APS, although some ongoing protocols are
prospectively assessing hydroxychloroquine in this context for adults
Prevention of Thrombosis Treatment after Thrombosis
Madison JA, Zuo Y, Knight JS. Pediatric antiphospholipid syndrome. Eur J Rheumatol 2020; 7(Suppl 1): S3-S12

Catatrophic antiphospholipid antibody
syndrome (CAPS) (Asherson syndrome)
Tiêu chuẩn CAPS
1. Có từ 3 cơ quan bị tổn thương
2. Xảy ra trong vòng 1 tuần
3. Có bằng chứng thuyên tắc ở ít nhất 1 cơ quan
4. Có kháng thể kháng phospholipid (lupus anticoagulant, anticardiolipine)
- Chẩn đoán chắc chẳn khi đủ cả 4 tiêu chuẩn
- Chẩn đoán có thể: khi có tiêu chuẩn 1 kèm tiêu chuẩn 2 và 4, hoặc 3 và 4.

Điều trị CAPS
Nguyên tắc: CAPS gây ra do kích hoạt dòng thác đông máu ồ ạt, do đó
cần điều trị khẩn trương “quyết liệt”
Phối hợp: Thuốc kháng đông, glucocorticoids liều cao, thay huyết
tương (TPE), IVIG.
So với chỉ điều trị kháng đông đơn thuần của APS

Điều trị CAPS
Chống đông và chống kết tập tiểu cầu
- Chống đông đường tĩnh mạch: UFH hoặc LMWH khi nghi ngờ giảm
tiểu cầu do heparin
- Aspirin liều thấp: sử dụng ngay khi có chẩn đoán CAPS cùng với
kháng đông tĩnh mạch. Khởi đầu từ liều thấp 81mg đến tối đa 100mg
/ngày ( 3-6 mg/kg/ngày)
- Chuyển dần sang VKA: sau khi hồi phục, chuyển dần sau VKA với mục
tiêu INR 2-3 sau 2 ngày. Không sử dụng DOACs cho bệnh nhân CAPS
do nguy cơ tái phát huyết khối.

Điều trị CAPS
- -VKA (acenocoumaril) nên được bắt đầu 4-5 ngày trước khi ngừng heparin, mục tiêu INR từ 2.0 tới 3.0 trong 2 ngày liên tiếp
• Liều tấn công:
▪ Ngày 1: 0.2 mg/kg (liều tối đa 10mg)
▪ Ngày 2- 4:
+ Nếu INR = 1.1-1.3, lập lại liều nạp ban đầu
+ Nếu INR = 1.4-1.9, 50% liều nạp ban đầu
+ Nếu INR = 2-3, 50% liều nạp ban đầu
+ Nếu INR = 3.1-3.5, 25% liều nạp ban đầu
+ Nếu INR > 3.5, tạm ngưng warfarin và kiểm tra INR mỗi ngày cho tới khi INR < 3.5, sau đó bắt đầu lại liều 50% liều trước đó đang điều trị
• Liều duy trì (ngày 5 và những ngày sau)
+ Nếu INR = 1.1-1.4, tăng 20% liều trước đó
+ Nếu INR = 1.5-1.9, tăng 10% liều trước đó
+ Nếu INR = 2-3, không thay đổi liều
+ Nếu INR = 3.1-3.5, giảm 10% liều trước đó
+ Nếu INR > 3, tạm ngưng thuốcvà kiểm tra INR cho tới khi INR < 3.5, sau đó bắt đầu lại liều 50% liều trước đó đang điều trị.

Điều trị CAPS
• Glucocorticoids: liều cao glucocorticoids
- Methylprednisolone: Truyền tĩnh mạch 10-30 mg/kg/liều/ngày (tối đa
1g) trong 3 ngày sau đó giảm dần liều tương đương prednisone
1mg/kg/ngày từ 4-6 tuần.

Điều trị CAPS
Thay huyết tương(TPE) và/hoặc IVIG: hầu hết các bệnh nhân nên được
TPE hoặc IVIG phối hợp với kháng đông và GCS.
IVIG: 400 mg/kg/ngày trong 5 ngày
Các yếu tố giúp lựa chọn TPE hay IVIG bao gồm:
- Giảm tiểu cầu và tổn thương chức năng thận: ưu tiên TPE
- Chảy máu nặng, giảm tiểu cầu nghiêm trọng, sử dụng kháng đông liều
cao gây khó khan khi thực hiện TPE( nhưng không phải chống chỉ
định)

Điều trị CAPS
Điều trị cứu vãn: khi tình trạng không cải thiện hoặc xấu đi dù đã điều
trị phối hợp
- Kháng thể đơn dòng:
Rituximab: 375mg/m2 mỗi tuần trong 4 tuần
Eculizumab: 900 mg mỗi tuần trong 4 tuần sau đó 1200mg mỗi 2 tuần

TIÊU CHUẨN PHÂN LOẠI SLE
• ACR 1997 : satisfy 4 of 11 criteria
• SLICC 2012: Satisfy 4 of the criteria with at least 1 clinical criterion
and 1 immunologic criterion OR biopsy-proven LN with positive ANA
or anti-ds antibodies
• ACR/EULAR 2019 : At least one clinical criterion and 10 points
BN : SLICC 2012 : 7/17

Chẩn đoán
viêm thận
lupus (LN)
Chẩn đoán SLE
Chẩn đoán LN
Sinh thiết thận

CHẨN ĐOÁN LN
• The clinical identification of LN can be challenging because patients often
lack overt signs of kidney disease, especially early.
• Instead, LN is most commonly discovered after careful examination of urine
and laboratory data in patients with lupus. Assessment of serum creatinine
level, urine dipstick testing, and urine sediment examination are necessary
screening tools for LN evaluation.
• Many patients will have findings suggestive of LN at the initial diagnosis of
SLE, and patients with SLE should undergo screening for LN at diagnosis, at
least yearly thereafter, and any time there is concern for a lupus flare.
• The gold standard for diagnosis and classification of LN is the percutaneous
kidney biopsy.
TEXTBOOK OF PEDIATRIC RHEUMATOLOGY, EIGHTH EDITION

Biểu hiện lâm sàng LN:
• In general, the presentation of LN can be grouped into the following
broad clinical syndromes:
1. Isolated asymptomatic hematuria and/or nonnephrotic proteinuria:
generally seen in class II LN,
2. Acute nephritic syndrome
3. Nephrotic syndrome
4. Chronic kidney disease (CKD)

PEDIATRIC
NEPHROLOGY
ON-THE –GO
Fourth Edition

Kidney biopsy
PEDIATRIC
NEPHROLOGY
ON-THE –GO
Fourth Edition

Indications for Kidney Biopsy
• The ACR has suggested the following indications for biopsy in the
initial evaluation of LN:
+ increasing serum creatinine without compelling alternative causes
(such as sepsis hypovolemia, or medication);
+proteinuria of 1 g or greater per 24 hours (24-hour urine or random
urine protein/creatinine is acceptable);
+proteinuria of 0.5 g or greater per 24 hours with hematuria, 5 red
blood cell (RBC) count or greater per high power feld (HPF);
+ or proteinuria of 0.5 g or greater per 24 hours with cellular casts in
urine.

• Given the consequences of missing and undertreating LN, and given the
possibility of clinically silent LN with minimal laboratory findings and
severe histology, it is the authors’ practice to have a low threshold for
biopsy, which is consistent with the SHARE initiative.
• We recommend biopsy with
+ any urinary abnormalities, such as urine casts, persistent proteinuria (urine
protein/creatinine > 0.2 mg/mg),and/or persistent microhematuria (≥5
RBC/HPF) in addition to the more clinically overt presentations.
+Additionally, we recommend kidney biopsy when urine testing has not
been performed prior to initiation of treatment.
+In a new patient with cSLE, no prior corticosteroid or other
immunosuppressive therapy, normal serum creatinine, and normal
urinalysis, a kidney biopsy is not indicated

Management
Antiphospholipid antibodies in pediatric lupus nephritis
Thrombosis attributable to APS
anticoagulation
❖ Lowmolecular-weight heparin (LMWH)
❖ Unfractionated heparin
Perform
kidney biospy
The ISN/RPS 2018 classification of lupus nephritis

Update on Lupus Nephritis: Core Curriculum 2020

A proposed treatment protocol for the induction and maintenance management of histologically class III, IV, and V lupus nephritis in
children as based on published recommendations [14,15,16,17,18]. CR, complete response (UPCR < 50 mg/mmol, normal kidney function);
PR, partial response (> 50% reduction in proteinuria, not nephrotic, normal kidney function). UPCR, urine protein:creatinine ratio; LN, lupus
nephritis; DMARD, disease modifying anti-rheumatic drug; CR, complete response; PR, partial response; MMF mycophenolate mofetil;
AZA, azathioprine; IV, intravenous; CNI, calcineurin inhibitor
Pediatric Nephrology (2021) 36:1377–1385

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