Biology and Treatment of ITP

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Biology and Treatment of ITP

• 2003.9.18 ?????
• R2 ???

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ITP an autoimmune disorder

• Immune thrombocytopenic purpura
  autoimmune thrombocytopenic purpura
  idiopathic thrombocytopenic
  purpura
• One of autoimmune disease due to anti-platelet
  autoantibody
• Obscured precise pathogenesis and antigenic
  epitope
• Dilemma risk of life-theatening bleeding vs
  treatment-related morbidity
• Novel therapy monoclonal antibody and stem cell
  transplantation

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Pathophysiology

• Transient thrombocytopenia after passive transfer
  of plasma of ITP patient disease mediated by
  autoantibody
• Anti-platelet Ig G specific for platelet-
  surface glycoprotein
• GP IIb/IIIa especially, GP Ib/IX, GP V, GP IV
• Antibody-coated platelet cleared by macrophage
  of reticuloendothelial system, especially spleen

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Step of Epitope Spread

• 1) glycoprotein recognized by autoantibody and
  platelet is coated with autoantibody
• 2) antibody-coated platelet bind to Fc receptor
  of APC(antigen-presenting cells, mainly splenic
  macrophage), internalized and degraded
• 3) APC express cryptic epitopes form platelet
  glycoprotein and T-cell recognize epitopes along
  with costimulatory help (CD40-CD154) and T-cell
  proliferative cytokine(IL-2, IFN-gamma.)
• 4) B-cell recognize autoantigens and clonal
  expansion of B-cell and production of antibody
  for cryptic epitopes occurs

NEJM 2002346995-1008
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glycoprotein recognized by autoantibody and
platelet is coated with autoantibody

• 4) B-cell recognize autoantigens and clonal
  expansion of B-cell and production of antibody
  for cryptic epitopes occurs

antibody-coated platelet bind to Fc receptor of
APC(antigen-presenting cells, mainly splenic
macrophage), internalized and degraded

• APC express cryptic epitopes form platelet
  glycoprotein and T-cell recognize epitopes along
  with costimulatory help (CD40-CD154) and T-cell
  proliferative cytokine(IL-2, IFN-gamma.)

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cryptic epitope

• Native GPIIbIIIa do not stimulate T-cell line
• Trypsin-digested fragment or recombinent peptide
  of GPIIbIIIa can stimulate autoreactive T-cell
  and antibody production
• Autoreactive T cell recognize recognize
  cryptic epitopes on GPIIb-IIIa that are not
  produced from native GPIIb-IIIa by the normal
  processing pathway
• carboxyterminal(cytoplasmic domain) of GPIIbIIIa
  molecule? amino-terminal portions of both GPIIba
  and GPIIIa?
• the precise locations of these cryptic epitopes
  have not been reported.

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T-cell stimulation native, disgested,
recombinant GP IIbIIIa
Blood. 200198130-139
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T-cell mediated immunity in ITP

• Activation of helper T cell increased level of
  IL-2, IFN-gamma, soluble CD40 ligand
• Undetected level of IL-4, IL-6
• Elevated Th1/Th2 ratio (decreased Th2 cell count)

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Acts at the level of T-cell nonspecific
immunosuppressive agents (azathioprine,
cyclophosphamide)
Blockade of Fc receptor of macrophage or
neutralization of autoantibody IVIG,
anti-Rh(D) Fc receptor down regulation danazol
Impede antibody production at the level of
B-cell Anti-CD20(rituximab)
Imparing macrophage in BM corticosteroid
Direct removal of autoantibody plasma
pheresis
Monoclonal antibody against CD 154 in clinical
trial
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Treatment of ITP

• Treatment vs observation
• First line treatment
• 1) corticosteroid
• 2) splenectomy
• 3) IVIG
• Second line treatment
• Novel therapeutic strategy monoclonal antibody,
  SCT
• H-pylori eradication

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Treatment vs Observation

• Risk of life-threatening bleeding vs morbidity of
  treatment
• Fatal hemorrhage at pltlt30K 0.0162-0.0389/yr
• Long-term morbidity and mortality assessment
  More patient die of infection than bleeding
• If pltgt30K for first 3months from presentation
  no further severe thrombocytopenia or bleeding
  complication for 10yrs
• maintaining pltgt30K without treatment mortality
  is no more than general population.

Blood 2001972349-2554
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Corticosteroid first-line treatment

• Start with prednisone 1mg/kg/day for 2-4wks
  response rate 50-75
• Frequent relapse after dose reduction or
  cessation
• Long-term remission 30
• Mechanism
• 1) increase platelet production by impairing
  the ability of macrophages within the bone marrow
  to destroy platelets
• 2) Induction of Th2 cell differenciation and
  stimulation of Th2 cytokine normalization of
  Th1/Th2 ratio

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Initial Steroid Pulse therapy

• Dexamethasone 40mg for 4days, 125 patients
• Initial response rate(within 3days) 80(106/125)
• 101,40053,200 /mm3 after 1wk
• sustained response(after 6mo) 50(53/106) with
  plt count gt50,000/mm3
• Fewer side effects than conventional dose of
  prednisone

N Engl J Med 2003349831-6.
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Splenectomy

• The only treatment of curative effects
• Mechanism removal of
  1) site of
  antibody-coated platelet destruction
• 2) production of anti-platelet antibody at
  germinal center
• Long-term response rate 65-80
• Risk of overwhelming sepsis Pneumovax, Hib,
  meningococcal vaccination at least 2weeks before
  surgery
• Preop preparation with IVIG or high-dose
  corticosteroid

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Predicting Response to Splenectomy

• Response to IVIG correlated with response to
  splenectomy than corticosteroid
• Indium-labeled autologous platelet scan 96
  expect to obtain a remission if mainly splenic
  platelet destruction()

Clin J Invest.199797547-550
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IVIG

• Mechanism
• 1) saturation of phagocyte Fc receptor
• 2) Neutralization of anti-platelet antibody
• 1g/kg for 2-3 consecutive days
• Anti-Rh(D) immunoglobulin
• 1) Fc blackade with anti-D-coated RBC, sparing
  autoantibody-coated platelet
• 2) Lower side effects, convenient infusion
  than IVIG

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Second line treatment

• High-dose Corticosteroid
• Danazol
• Vinca alkaloid
• Nonspecific immunosuppressive angent
  Azathioprine, Cyclophosphamide

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High-dose Corticosteroid

• Dexamethasone 40mg daily for 4days repeated every
  28days for 6 cycles, for 10 refractory ITP
  patients 10 patients (100) achieved platelet
  countgt100K after 12months (Anderson, NEJM
  19943301520-1564)
• Plt countgt50K in 10 (1/10) (Caulier, 1995)
• No one showed significant increment of platelet
  count (Demiroglu, 1997)

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Danazol

• Response rate 10-80
• Down-regulation of of macrophage Fc receptor
• Hepatotoxicity, rash, headache,
• dose reduction of steroid if there is need for
  unacceptably high dose for maintenance of safe
  platelet count

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Azathioprine and Cyclosporine

• Azathioprine
• 1-4mg/kg, 150mg/day
• Sustained response rate 20
• Reversible leukopenia, risk of malignancy
• Generally tolerable

• Cyclosporine
• Daily oral regimen(1-2mg/kg) or intermittent IV
  dose(1-1.5g/m2 q 4wks)
• Dose-related marrow suppression, infertility,
  teratogenecity, hemorrhagic cystitis
• Leukemia ( threshold of total dose 20g),
  myelodysplatic syndrome

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Mycophenolate mofetil

• Potent inhibitor of inosine 5-monophosphate
  dehydrogenase in purine synthesis
• Suppression of lymphocyte proliferation
• Immunosuppressive agent generally used in solid
  organ transplantation
• 250mg bid, maintenance above 20K in 5/6 patients

Br J Haematol. 2002117(3)712-715
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Rituximab

• Anti-CD20 monoclonal antibody selective
  obsonization of B-cell
• 2 phase of response early response by macrophage
  Fc receptor blockade by opsonized B-cell ?
  decreased production of anti-platelet antibodies
  accounts for the late and sustained response.
• 375mg/m2 once weekly for 4 weeks.
• Overall response rate 52 (CR in 5, PR in 5, MR
  in 3) of 25 refractory ITP patients. In 7 cases,
  response sustained (6 months or longer) (Stasi.
  Blood 200198952-957)
• Overall response rate 75(CR in 5 (41), PR in
  2(17), MR in 2(17)) in 12 refractory ITP
  patients (Eur J Haematol 2002 69 95-100)

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Response to rituximab
splenectomy
rituximab

• Eur J Haematol 2002 69 95-100)

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Etanercept

• Antagonist of TNF-alpha RA, psoriatic arthritis
• Elevated TNF-alpha level in ITP patients
  Cytokine related to macrophage activation and
  platelet destruction
• 3 case report of maintenance above 200K after
  25mg twice per week (Am J Hematol. 2003
  73(2)135-40)

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Autologous stem cell transplantation

• High-dose cyclophosphamide immunosuppression
  stem cell support
• Purging Depletion of autoreactive T-cell from
  stem cells and selection of CD 34 cell
• Overall response rate 57 CR ( gt100k 6/14) PR
  (gt50K, 2/14) (Blood 200310171-77)

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H.Pylori eradication

• High prevalence of H.pylori infection in ITP
  patients and Triple H.pylori eradication improves
  platelet count in all infected patients(95K?150K)
  (Lancet 1998352878)
• Antigenic mimicry between H.pylori bacterial
  antigen(CagA) and platelet antigen
• variable response rate of remission (13-50)
• Low cost and convenience, free from side effect!

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H.Pylori eradication in Japan

• High prevalence of H.pylori in Japan (70-80,
  born before 1950s)
• 63 response rate and decreased PAIgG in
  Japanese?then in Korea?
• H.pylori serological assay is recommanded in
  patients refractory to therapy (Guidelines for
  the investigation and management of ITP. Br J
  Haematol. 2003120574-596)

Bri J Haematol, 2002, 118, 584588
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