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  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. • 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
  5. 5. 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.
  6. 6. 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.
  7. 7. Madison JA, Zuo Y, Knight JS. Pediatric antiphospholipid syndrome. Eur J Rheumatol 2020; 7(Suppl1): S3-S12 OVER AT LEAST 12 WEEKS ?
  8. 8. D Garcia, D Erkan. N Engl J Med 2018;378:2010-2021. Summary of the Proposed Pathogenesis of Antiphospholipid- Antibody–Mediated Clinical Problems.
  9. 9. -“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.
  10. 10. 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
  11. 11. 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
  12. 12. Current Rheumatology Reports (2021) 23: 10 https://doi.org/10.1007/s11926-020-00976-7
  13. 13. Current Rheumatology Reports (2021) 23: 10 https://doi.org/10.1007/s11926-020-00976-7 other manifestations beyond thrombosis?
  14. 14. 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. https://emedicine.medscape.com/article/1006128-print
  15. 15. 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 https://emedicine.medscape.com/article/1006128-print
  16. 16. Laboratory testing Madison JA, Zuo Y, Knight JS. Pediatric antiphospholipid syndrome. Eur J Rheumatol 2020; 7(Suppl 1): S3-S12
  17. 17. 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.
  18. 18. 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
  19. 19. 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.
  20. 20. 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
  21. 21. 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.
  22. 22. 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.
  23. 23. 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.
  24. 24. 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)
  25. 25. 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
  26. 26. Điều trị CAPS
  27. 27. 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
  28. 28. Chẩn đoán viêm thận lupus (LN) Chẩn đoán SLE Chẩn đoán LN Sinh thiết thận
  29. 29. 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
  30. 30. 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)
  31. 31. PEDIATRIC NEPHROLOGY ON-THE –GO Fourth Edition
  32. 32. Kidney biopsy PEDIATRIC NEPHROLOGY ON-THE –GO Fourth Edition
  33. 33. 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. TEXTBOOK OF PEDIATRIC RHEUMATOLOGY, EIGHTH EDITION
  34. 34. • 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 TEXTBOOK OF PEDIATRIC RHEUMATOLOGY, EIGHTH EDITION
  35. 35. 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
  36. 36. Update on Lupus Nephritis: Core Curriculum 2020
  37. 37. 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
  38. 38. Update on Lupus Nephritis: Core Curriculum 2020
  39. 39. Thank You !