aiha
TRANSCRIPT
Diagnosis dan Penatalaksanaan Anemia Hemolitik AutoimunR. Satriyo Budhi Susilo
Pembimbing : dr. H. Suradi Maryono, SpPD-KHOM, FINASIM
Tinjauan Pustaka
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DEFINISI AIHA :kelainan dimana autoantibodi
menempel pada antigen di membran sel darah merah
pemendekan masa hidup sel darah merah ± komplemen dan penghancuran di SRE
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Williams hematology. 8th 2010Diagnostic criteria in autoimmune diseases. 2008
Postgraduate haematology. 6th 2011
INSIDENSI AIHA :1 : 100.000 WARM AIHA1
1 : 1.000.000 COLD AIHA1
1.700 : 1.000.000 CKD2
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1Autoimmun Rev. 20102JAMA. 2007
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Warm-Autoantibody Type Primary or idiopathic warm AHA
Secondary warm AHA
Cold-Autoantibody TypeMediated by cold agglutinins
Idiopathic (primary) chronic cold agglutinin disease
Secondary cold agglutinin hemolytic anemia
Mediated by cold hemolysins
Idiopathic (primary) paroxysmal cold hemoglobinuria
Secondary
Mixed Cold and Warm AutoantibodiesPrimary or idiopathic mixed AHA
Secondary mixed AHA
Drug-Immune Hemolytic Anemia
KLASIFIKASI AIHA
Williams hematology. 8th 2010
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Tanda Frek. (%) Gejala Frek. (%)Splenomegali 82 Lemas 88Hepatomegali 45 Pusing 50Limfadenopati 34 Demam 37Ikterik 21 Perdarahan 10Edema 6 Sesak nafas 9Gagal jantung 5 Batuk 6Pucat 4 Berat badan turun 5
Gangguan GIT 5Anoreksia 4Urin warna gelap 3Angina 2
Tanda dan gejala pada AIHA
Williams hematology. 8th ed. 2010
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Penemuan laboratorium berdasarkan evidence based
Autoimmun Rev. 2010 Mar;9(5):A350-4.
Perkiraan Kasus Kondisi
Hiperbilirubinemia 80 %Indirek, prehepatik bilirubin meningkat
Peningkatan LDH 100 % Iso-form 5Retikulositosis 100 %Coombs test 90% (agglutinasi) 95% (Flow cytometri)
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DIAGNOSIS AIHA :
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KLINIS ANEMIA HEMOLITIK
POIN DIAGNOSIS AIHA
DIRECT ANTIGLOBULIN TEST
COLD atau WARM AIHA
AIHA PRIMER atau SEKUNDER10
ALUR DIAGNOSIS AIHAExpert Rev. Hematol. 4(6), 607–618 (2011)
ANEMIA HEMOLITIK
anemia normo/makrositik, retikulositosis, haptoglobin ↓, bilirubin indirek ↑, LDH ↑
DAT
POSITIF NEGATIF
AIHA
IgG±C3d C3d
WAIHA CAIHA
Cari underlying disease
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AIHA type Epidemiology/type of hemolysis
Autoantibody isotype
Optimal temperature DAT pattern
Warm AIHA ~70–80% of all AIHAs
Adults > childrenEV hemolysis,
IgG >> IgA, IgM 37°C IgG ± C3d
Cold agglutinin syndrome
~20–30% of all AIHAAge >50 years EV hemolysis
IgM >>> IgA or IgG titer >1/500 4°C C3d
Cold transient
AIHAChildren and adults
IV hemolysis Polyclonal IgM
titer ≥1/64 4°C C3d
Paroxysmal cold
hemoglobinuria
Children (rare ++), exceptional in adults Acute IV hemolysis
IgG (DL hemolysin) >30°C C3d
Mixed-type AIHA
Adult Mainly EV hemolysis
IgG, IgM ± AF ~1/500
Wide range (4–37°C) IgG ± C3d
Main characteristics of various types of autoimmune hemolytic anemia.
Expert Rev. Hematol. 4(6), 607–618 (2011)
Direct antiglobulin test differential diagnostic
Direct antiglobulintest pattern Differential diagnosis
IgG aloneWarm antibody autoimmune hemolytic anemiaDrug-immune hemolytic anemia of the Hapten-drug adsorptionor autoimmune type
Complement alone
Cold agglutinin syndromeWarm antibody autoimmune hemolytic anemia (IgM with a large thermal amplitude)Paroxysmal cold hemoglobinuriaDrug-immune hemolytic anemia: immune complex type
IgG+complement Warm antibody autoimmune hemolytic anemiaDrug-immune hemolytic anemia: autoimmune type (rare)
Williams hematology. 8th 2010
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ALUR TERAPI AIHA :
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16ALUR TERAPI COLD AIHAExpert Rev. Hematol. 4(6), 607–618 (2011)
COLD AIHA TRANSIEN
TRANFUSI PRC Bila Perlu
ANTIBIOTIK infeksi bakteri definitif
(M. pneumonia)
KORTIKOSTEROID jangka pendek (3 mg)
Pada AIHA berat
HINDARI PAPARAN DINGIN
COLD AIHA KRONIK
TERAPI INFEKSIVAKSINASI
ASAM FOLAT
WAIT & WATCH
TRANSFUSI PRCprewarmed
TERAPI RITUXIMAB±FLUDARABIN
KRONIK AKTIF atauRELAPS+SIMPTOMATIF
YA
TIDAK
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PREDNISON : 1-1.5mg/kg/hari (2-3minggu)IV metilpred 250-1000mg (1-3hr) anemia berat
PREDNISON ↑ : 2mg/kg/hari± danazol (2 minggu)
PREDNISON ↓ mulai minggu 4
TAPERING-STOP PREDNISON (6-12bln)
TERGANTUNG PREDNISON
SPLENEKTOMI RITUXIMAB
SPLENEKTOMIRITUXIMABIMUNOSUPRESAN (Aza, Cy, MMF, Cic)
Gagal Respon
Respon
Gagal
Respon Gagal Respon Gagal
atau
Gagal
ALUR TERAPI WARM AIHAExpert Rev. Hematol. 4(6), 607–618 (2011)
KESIMPULAN :
1. Klinis AIHA mirip anemia hemolitik lainnya kerjasama klinisi dan praktisi lab dalam diagnosis
2. Penatalaksanaan AIHA belum berdasar evidence based / RCT. Masing-masing center mengembangkan guideline sendiri.
3. Penatalaksanan berdasar tipe AIHA (cold atau warm) serta penyakit yang mendasari
4. Terapi lini pertama : kortikosteroidTerapi lini kedua : splenektomi atau rituximabTerapi lini ketiga : azatriopin, siklosporin, siklofosfamid, MMF
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Terima Kasih
Expert Rev. Hematol. 4(6), 607–618 (2011)
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Expert Rev. Hematol. 1(2), (2008)
Blood Reviews (2008) 22, 17–31
L.D. Petz, Immune hemolytic anemias , Elsevier. 2nd ed. 2004
L.D. Petz, Immune hemolytic anemias , Elsevier. 2nd ed. 2004
L.D. Petz, Immune hemolytic anemias , Elsevier. 2nd ed. 2004
L.D. PetzImmune hemolytic anemias
Elsevier. 2nd ed. 2004
27
Criteria for complete response (CR) for AIHA : resolution of both anemia (Hb 13g/dL [males], 12g/dL [females]) and signs of hemolysis off all therapy for at least 4 weeks after treatment.
A partial response (PR) :a stable increase in hemoglobin level of at least 2 g/dL and discontinuation of concomitant therapy.
haematologica 2005; 90:1273-1274
Monoclonal antibodies are produced in the following main forms:· Murine – 100% mouse protein· Chimeric – approximately 65% human and 35% mouse protein· Humanized – 95% human and 5% mouse protein· Fully human – 100% human protein
An antibody is a protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target.
Monoclonal antibodies (mAb) are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell.
Polyclonal antibodies are antibodies that are derived from different cell lines.
Current Trends in Monoclonal Antibody Development and Manufacturing2010, Springer
28
Therapeutic monoclonal antibodies: from the bench to the clinic, 2009, John Wiley&Sons 29
Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490-1498.
Cellular and molecular immunology, Abbas, 6th ed, 2007, Elsevier 31
CD20 is a transmembrane protein with four predicted hydrophobic regions that cross the membrane and two extracellular loops. It is a B-cell marker that is expressed from the pre-B-cell stage until the plasma cell stage. CD20 is not expressed on stem cells or plasma cells. Although the exact function of CD20 is still not completely understood, data indicate that it is possibly a Ca2þ channel (Bubien et al. 1993) and may be involved in B-cell growth and activation (Tedder et al. 1985). CD20 is also expressed in more than 90 percent of B-cell non-Hodgkin’s lymphomas and 10 to 15 percent of chronic lymphocytic leukemia B-cells (Almasri et al. 1992; Anderson et al. 1984).
Its antigen, CD52, is a small (21 to 28 kDa) glycosylphosphatidylinositol-anchored cell surface glycoprotein. CD52 is highly expressed (500,000 molecules/cell on lymphocytes) on B- and T-cells, as well as in monocytes, macrophages, eosinophils, natural killer cells, dendritic cells, and epithelial cells of the male reproductive tractTherapeutic monoclonal antibodies: from the bench to the clinic2009, John Wiley&Sons
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CD20 ideal target bagi terapi CLL
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Surface Molecule Targets on B Cells
slg
HLA-DR
CD52CD20
CD23
B lymphocyte
Adapted from Press O, et al. Cancer J Sci Am. 1998:4(suppl 2):s19–s26, and M Hallek.
Molecule Target mAb
HLA-DR Hu1D10
CD20 CDCADCCCaChannel
Rituximab
Ofatumumab
GA-101
CD22
CD23 FceRII Lumiliximab
CD25Denileukin diflitoxin
CD37 Tetraspan
CD38 ADP-riboC Humax-CD38
CD52 GPI-linked Alemtuzumab
CD80 Co-stim Galiximab
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36
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Cellular and molecular immunology, Abbas, 6th ed, 2007, Elsevier
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Cellular and molecular immunology, Abbas, 6th ed, 2007, Elsevier
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Anti-CD20: Mechanism of Action
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Complement-dependentCytotoxicityComplement-dependentCytotoxicity
FcRIIIACD20
CD20MAC
ApoptosisApoptosis
.Anti-CD20 antibody
Macrophage, monocyte, NK cell
University of Rochester Medical Center, 2009 40
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.
.
The structural-functional classification of cytokines Mechanical Stretch and Cytokines, Springer 2011
No Cytokine family Subfamilies and ligands Main biological functions
1 Interferons (IFN)
Interferons type I: IFNα, β,δ, κ, ω, τInterferon type II: IFNγInterferons type III: IFNλ1(IL-29), IFNλ2 (IL-28A),IFNλ3 (IL-28B)
Antiviral, antiproliferative,Immunomodulating action
2Hemopoietic cell Growth factors
Stem cells factor (kit-ligand,steel factor), Flt-3 ligand,G-CSF,M-CSF, IL-7,IL-11Ligands of gp140 receptorsubunit: IL-3, IL-5,GM-CSFErythropoietin, Thrombopoietin
Stimulation of different cell precursor types proliferation and differentiation in bone marrow, hematopoiesis Activation
3
Superfamilyof interleukin-1 (IL-1)and fibroblast Growth factor (FGF)
FGF family: acid FGF, basic FGF, FGF3-FGF23IL-1 family (F1–11): IL-1α,IL-1β, IL-1 receptor antagonist, IL-18, IL-33, IL-37 and others
Activation of fibroblast and epithelial cell Proliferation Proinflammatory effect, activation of specificImmunity
4Tumor necrosis factor (TNF) family
TNF, lymphotoxin α and β,Fas-ligand and others
Proinflammatory action, apoptosis regulation and immune cell intercellular Interaction
5 Interleukin-6 family
Ligands of gp130: IL-6, IL-11, IL-31,oncostatin-M, cardiotropin-1, leukemia inhibitory factor, ciliary neurotrophic factor
Proinflammatory and immunoregulatory Action
6 Chemokines Subclasses: SS, SHS, SH3S, S Different leukocyte types chemotaxis Regulation
7 Interleukin-10 family IL-10, -19, -20, -22, -24, -26Immunosupressive action, inflammation and tumor growthRegulation
8 Interleukin-12 family IL-12, -23, -27, -35 Regulation of T-helper differentiation
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Cytokines of T-helperclones and lymphocytefunction regulators
T-helpers type I: IL-2, IL-15, IL-21, IFNγ, TNF, T-helpers type II: IL-4,IL-5, IL-10, IL-13Ligands of IL-2 receptorγ-chain: IL-15, IL-21
Activation of cell ImmunityActivation of humoral immunity,Immunomodulation EffectsDifferentiation, proliferation andfunctional activity stimulation ofdifferent types of lymphocytes, DC, NK-cells, macrophages and others
10 Interleukin-17 family IL-17A, B, C, D, E, FProinflammatory cytokine synthesis Activation
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Superfamily of nervegrowth factor (NGF),platelet derivinggrowth factor (PDGF)and transforminggrowth factor (TGF)
NGF, brain neurotrophicFactor. PDGF, vascular endothelialgrowth factors (VEGF), TGFβ, activins, inhibins, nodal, bone morphogenicproteins, mullerian inhibitory substance
Regulation of inflammation,angiogenesis, neuron functioning,Embryonic development andtissue regeneration
12Epidermal growth factor (EGF) family EGF, TGFα and others
Stimulation of different cell type proliferation
13Insulin-like growth factor (IGF) family IGF-I, IGF-II
Stimulation of different cell type proliferation
The structural-functional classification of cytokinesNo Cytokine family Subfamilies and ligands Main biological functions
6 Chemokines Subclasses: SS, SHS, SH3S, S Different leukocyte types chemotaxis Regulation
7 Interleukin-10 family IL-10, -19, -20, -22, -24, -26Immunosupressive action, inflammation and tumor growthRegulation
8 Interleukin-12 family IL-12, -23, -27, -35 Regulation of T-helper differentiation
9
Cytokines of T-helperclones and lymphocytefunction regulators
T-helpers type I: IL-2, IL-15, IL-21, IFNγ, TNF, T-helpers type II: IL-4,IL-5, IL-10, IL-13Ligands of IL-2 receptorγ-chain: IL-15, IL-21
Activation of cell ImmunityActivation of humoral immunity,Immunomodulation EffectsDifferentiation, proliferation andfunctional activity stimulation ofdifferent types of lymphocytes, DC, NK-cells, macrophages and others
10 Interleukin-17 family IL-17A, B, C, D, E, FProinflammatory cytokine synthesis Activation
11
Superfamily of nervegrowth factor (NGF),platelet derivinggrowth factor (PDGF)and transforminggrowth factor (TGF)
NGF, brain neurotrophicFactor. PDGF, vascular endothelialgrowth factors (VEGF), TGFβ, activins, inhibins, nodal, bone morphogenicproteins, mullerian inhibitory substance
Regulation of inflammation,angiogenesis, neuron functioning,Embryonic development andtissue regeneration
12Epidermal growth factor (EGF) family EGF, TGFα and others
Stimulation of different cell type proliferation
13Insulin-like growth factor (IGF) family IGF-I, IGF-II
Stimulation of different cell type proliferation
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DIRECT COOMB TEST POSITIVE
Autoantibodies directed at RBC antigens (warm autoimmune hemolytic anemia [WAIHA], cold agglutinin syndrome [CAS])
Alloantibodies in a patient who was recently transfused antigen-positive RBCs (acute or delayed hemolytic transfusion reaction [AHTR, DHTR])
Passively transfused alloantibodies against the patient’s RBCs resulting from plasma-containing components (platelet component) or a plasma derivative (intravenous immunoglobulin [IVIG] or Rh immune globulin [RhIg])
Alloantibodies in the maternal circulation which cross the placenta and coat the fetal RBCs (hemolytic disease of the fetus and newborn [HDFN])Antibodies against drugs which bind to the RBC membrane (penicillin)Absorbed proteins (IgG) which attach to altered RBC membrane or RBCs modified by drugs (cephalosporins)
Immune complex or complement binding to RBCs after drug administration secondary to a drug/anti-drug interaction (quinidine, phenacetin)
Nonspecific uptake of protein, usually IgG (patients with hypergammaglobulinemia or recipients of high dose IVIG)
Antibodies derived from passenger lymphocytes as a result of either solid organ or HPC transplantation
Direct antiglobulin Test, Elsevier. 2009
De Novo Pathway
Salvage Pathway
Ribose 5P + ATP
PRPP synthetase
5-Phosphoribosyl-1-pyrophosphate (PRPP)
IMP
GMPGTP
RNA
GlycoproteinSynthesis
dGDPdGTP
DNAGuanine
HGPRTase
IMPD (Inosine Monophosphate Dehydrogenase)
Mycophenolic Mofetil acid(CELLCEPT)
CellCept©: Mechanism of Action
Guanosin nukleotida
Definition of Autoimmune
• Misperceptions of the immune system in the human body can not
distinguish whether the antigens in the body comes from outside or within
the patient's body itself.
• (Self and non self), so that the result will damage the immune system is
our body's own tissue, a condition termed as autoimmune diseases.
(Guntur, 2006)
Auto-immune Diseases
Failure of SELF RECOGNITION Failure of SELF TOLERANCE TOLERANCE
• CENTRAL (Death of self reactive lymphocytes)
• PERIPHERAL (anergy, suppression by T-cells, deletion by apoptosis, sequestration (Ag masking))
STRONG GENETIC PREDISPOSITION OFTEN RELATED TO OTHER AUTOIMMUNE DISEASES OFTEN TRIGGERED BY INFECTIONS
(Guntur, 2006)
Pathogenesis of Autoimmunity Genetic predisposition and environmental factors relevant
• Immunoglobulins, T cell receptors, major histocompatibilty complex T Cell Bypass- The requirement of T cells to activate B cells in order to
produce large amounts of antibodies is bypassed Molecular Mimicry- An exogenous antigen shares structural similarities with
host antigen and when an antibody is produced, it can bind to host antigen Idiotype Cross Reaction- A cross reaction between the idiotype (molecule
recognized by antigen) on an antiviral antibody and a host cell receptor for
the virus in question Cytokine Dysregulation- Certain cytokines have a role in the prevention of
the exaggeration of pro-inflammatory immune response Dendritic Cell Apoptosis- Defective dendritic cells can lead to inappropriate
systemic lymphocyte activation and a decline in self tolerance
(Guntur, 2006)
Calculation of normal transfusion requirements for a 70-kg male whose marrow is producing no RBCsNormal RBC volume = 30 mL/kg = 2100 mLIf the patient’s hemoglobin is 10 g/dL (two thirds of normal), the RBC volume is 1400 mL.If RBC survival is 100 days, 14 mL of RBCs must be replaced daily to maintain a hemoglobin of 10 g/dL.Because RBCs obtained from a blood donor are of all ages, average survival of transfused RBCs will be about 50 days.Therefore, to maintain a hemoglobin of 10 g/dL, 28 mL would have to be transfused daily, or 196 mL/wk.Each unit of RBCs contains about 180 mL of RBCs. Thus, about 1 unit of RBCs per week is a normal transfusion requirement for an adult producing no RBCs.In the absence of bleeding, a significantly increased transfusion requirement indicates hemolysis, i.e., a short RBC survival time of transfused RBCs.
L.D. Petz, Immune hemolytic anemias , Elsevier. 2nd ed. 2004
Plasmapheresis is a form of therapy to separate plasma from blood, remove pathogenic substances from plasma, and either replace it with substitution fluid or purify it. There are four main types of membrane plasmapheresis:plasma exchange (PE)double filtration plasmapheresis (DFPP)plasma adsorption (PA)immunoadsorption (IA).
FASE UJI KETERANGAN
Studi Preklinik Invitro utk menguji efikasi, toksisitas dan farmakokinetik
Fase 0 Uji pertama pada manusia (10-15 org)Farmakodinamik dan kinetik
Fase I 20-100 orgUji keamanan, dosis, efikasi obat
Fase IIKonfirmasi dari fase I dg subyek lebih besar (20-300 org)Uji keamanan, dosis, efikasi obat
Fase III RCT, multicenter, 300-3000 orgPerbandingan dengan gold standar tx
Fase IV Post Marketing Surveillance TrialEfek jangka panjang
Adapted from Clinicaltrials.gov, 2009 http://www.nlm.nih.gov/services/ctphases.html 52
Peran TGF beta
Peter Ten Dijke. Smad Signal Transduction Smads in Proliferation, Differentiation and Disease. Springer, 2006
5454
LPS bp
CD 14
IL 6
TNF -
IL -1
IL 8
APC
CD 4+ TCR
IFN -
SUPER ANTIGEN
IL - 10 IL - 4IL - 5IL - 6
Ig
NO ICAM -1
a
gTH - 2TH - 1
B cell
CD 8+
LPS
IMUNOCOM
SEPSIS
MOD
SHOCK
SEPTIC
IL-2
CSF
Compl.
N
NK
(Guntur, 2006)
C3a, C5a
PGE 2
TLR 4
TLR2
C7a MHC II
PAI-1
Imunopatogenesis
Kortikosteroid
54
5555
MD-2CD14
LPS bp
TLR4
My D88
TRAF6IRAK
NF-KB
ENDOTOKSIN
M
NIK/MKK
IKK
Target Genes
- Insulin Treatment
Guntur, 2008
- Metformin- Low dos Kortikosteroid
- Statin- ACE Inhibitor- AG II Blocker
- Anti ROS- NO
- Bradikinin
- Oestrogen
TNF-IL-6 IL-12
IL-1
IL-8
TGFβ-1
CYTOKINES
55
5656Dorren 200556
Biome-chanical
PCh
Cyto C
Jalur Zainal