Ελένη Ι. ΚαμπυλαυκάΕλένη Ι. ΚαμπυλαυκάΜέτσοβο, Ιανουάριος 2011Μέτσοβο, Ιανουάριος 2011

Εθνικό & Καποδιστριακό Πανεπιστήμιο

Αθηνών

Παθολογική Παθολογική ΦυσιολογίαΦυσιολογία

Ιατρική ΣχολήΙατρική Σχολή

Main Principles

Pathogenetic Mechanisms

Clinical ApplicationsImmunodeficiencies- Transplantation- SepsisSystemic Autoimmune DiseasesNeurological Diseases of Autoimmune OriginInflammatory Myopathies

Cost- Effectiveness

Therapeutic preparations of pooled polyspecific IgG obtained from the plasma of a large number of healthy individuals.

U.S. Food and Drug Administration (FDA) guidelines

Prepared out of at least 1,000 different human donors.All four IgG subgroups (1-4) should be present.The IgG should maintain biological activity and lifetime of at least 21 days.Does not contain samples which are HIV, hepatitis B, hepatitis C positive.Screened and treated in a manner that destroys viruses.

*Stangel et al, J Neurol 2006

First used by E. Behring (1980) Treatment of sepsis Primary Immunodeficiencies- After description of agammaglobulinemia in 1952

Intramuscular administration Very limited dose/ Painful irritation of the muscle/ Local proteolytic degradation

Intravenous administration Activation of the complement cascade- Severe adverse reactions/ Adequate purification in the early 1980s

Use in autoimmune diseases 1981 Idiopathic Thrombocytopenic Purpura (ITP) 1986 Kawasaki disease

Use in neurology: First reports on the use of IVIG in Multiple Sclerosis (MS) in 1982 and 1983. Successful treatment of Myasthenia Gravis in 1985. Chronic demyelinating polyneuropathy (CIDP) the first immune-mediated neuropathy

to be responsive to IVIG in 1985 Guillain- Barré syndrome (GBS) in 1988.

*Stangel et al, J Neurol 2006 **Hartung et al, J Neurol 2008

*Durandy et al, Clin Exp Immunol 2009**Stangel et al, J Neurol 2006

Innate Immunity-GeneralDC-mediated T-cell activationEndocytosisPro-inflammatory cytokines(IL-1, TNFa, IL-1b)Anti-inflammatory cytokinesDC differentiationExpression of MHC class II & co-stimulatory moleculesExpression of CD1dExpression of activating FcγRsCell migration by ICAM-1, integrins

NK cellsNK-cell trafficking from cell to tissueNK-cell activation Anti-tumor activity

MacrophagesExpression of inhibitory FcγRIIBMacrophage acivationExpression of IFN-γR2

GranulocytesNeutrophil deathNeutrophil activationNeutrophil adhesion to endothelium

T cellsT cell activation & proliferation

IL-2 productionT cell apoptosis

T cell differentiationAutoantibodies against CD4, CD8

Autoantibodies against superantigensExpansion of Treg cells

Suppressive function of T cells

B cellsB cell apoptosisInhibitory FcγRIIBBlockade of activating FcγRB cell proliferationInhibition of antibody productionNeutralization of autoantibodies by anti-idiotypesCatabolism of antibodies via blockade of the protective intracellular FcRnIL-6 production

Complement CascadeBinding of C1, C3a, C3b, C4, C5aDegradation of C3bMAC deposition

Usually minor- In less than 10% of the patientsUsually minor- In less than 10% of the patients

CommonCommon Mild to moderate headache (Responds to NSAIDS) Chills, Myalgia, Chest discomfort (Within the first hour of the infusion). Post-infusion fatigue, fever, or nausea (Up to 24 hours)

CausesCauses Unclear Activation of complement by aggregated immunoglobulin molecules or

various stabilizing agents in the IVIg preparation have been implicated

Less commonLess commonBackache, Lightheadedness, Headache migraine, Serum viscosity, Thromboembolic

events, Transient leukopenia or neutropenia, Aseptic meningitis, Acute renal failure, Proteinuria, Dyspnea, Hypotension, Rash, Urticaria, Immune complex-mediated arthritis, Anaphylaxia

*Dalakas et al, Pharmacol Ther 2004**GBS Trial Group, Lancet 1997

Approved by FDA & EMEAApproved by FDA & EMEA Primary immunodeficiencies Immune Thrombocytopenic Purpura (ITP) Kawasaki disease Hematopoietic stem cell transplantation Chronic B cell lymphocytic leukemia Pediatric HIV Guillain- Barré Syndrome (*only by EMEA)

Many off label indications Solid clinical evidence Few data Difficulty in performing trials- Diseases with low prevalence

*Kivity et al, Clinic Rev Allerg Immunol 2010

*AANEEM, Muscle & Nerve 2009

Primary immunodeficiencies [CL-I] (400-800 mg/ kg/ 3-4 weeks)

Secondary immunodeficiencies [CL-I] (200-400 mg/ kg/ 2-4 weeks)Malignant lymphoma & Multiple myeloma with clinically relevant

antibody deficiencyHIV infection in children

Renal transplant rejection [CL-IV]

Stem cell/bone marrow transplantation- Not recommended

Sepsis- Not recommended

*Hartung et al, Clin & Exp Immunol 2009**Kivity et al, Clinic Rev Allerg Immunol 2010

***Stangel et al, J Neurol 2006

otal cumulative dose of 2 g/ kg during 2 or 5 consecutive days

rbitrarily chosen & proven to be efficient

diopathic Thrombocytopenic Purpura [CL-I] [CL-I] (Cumulative dose 2gr/ kg, during 2 or 5 days)

awasaki [CL-I][CL-I] (2gr/ kg in acute phase)

ther ANCA (+) vasculities [CL-III/IV][CL-III/IV] Efficient

ucocutaneous blistering diseases [CL-I/IV] [CL-I/IV] Second line or adjunctive treatment (2g/kg/month)

LE [CL-III/IV][CL-III/IV] Usually not recommended/ Only when other treatments fail SLE systemic flare, SLE myocarditis, SLE and thrombocytopenia, Lupus nephritis,

Subacute cutaneous lupus erythematosus

*Kivity et al, Clinic Rev Allerg Immunol 2010**Stangel et al, J Neurol 2006***Boletis et al, Lancet 1999

Adult Still Disease [CL-IV][CL-IV] Possible Improvement

Mixed Connective Tissue Disease [CL-IV][CL-IV] Possible improvement of skin lesions

Systemic Sclerosis [CL-IV] [CL-IV] Improvement of fibrosis

Rheumatoid Arthritis [CL-I/III] [CL-I/III] Not efficient on disease activity

Sjögren’s Syndrome [CL-IV] [CL-IV] Possible improvement of vasculitis & neuropathy

Congenital Heart Block (CHB) Multicenter, prospective, open-label study Replacement dose 400 mg/kg: Safe but not efficient

Inflammatory Myopathies DM [CL-I] [CL-I] Second line or adjunctive treatment PM [CL-IV] [CL-IV] Efficient IBM Not efficient in 2 clinical trials

*Kivity et al, Clinic Rev Allerg Immunol 2010**Stangel et al, J Neurol 2006

***Friedman et al, Arthr & Rheum 2010

12 patients with chronic ITP 12 patients with chronic ITP To avoid splenectomy Failed to respond Required maintenance

The average platelet count increase to initial therapy was 239.500/μl (range 23.000-790.000)

≥6 months after treatment 2 patients in remission, 4 patients stable requiring no therapy (PLT ~

30.000-50.000) 3 patients require maintenance IVIG therapy 3 patients have become refractory to lVIG

treatment.

*Bussel et al, Blood 1983

Doses of corticosteroids or immunosupression

Neuromuscular disorderNeuromuscular disorder Class ofClass ofevidenceevidence

Guillain- Barré Syndrome in adults IGuillain-Barre syndrome in children IIChronic Inflammatory Demyelinating Polyradiculopathy IMultifocal motor neuropathy IMyasthenia gravis ILambert-Eaton myasthenic syndrome IDermatomyositis IStiff person syndrome I

Class of evidence supporting use of IVIG in the treatment of specific neuromuscular disorders:

Multiple Sclerosis: Conflicting results in RR- Negative in progressiveMultiple Sclerosis: Conflicting results in RR- Negative in progressive

*AANEEM, Muscle & Nerve 2009

Neuromuscular disorderNeuromuscular disorder Class ofClass ofevidenceevidence

Fisher syndrome IVNeuropathies associated with monoclonal proteins IVChronic auto-immune neuropathies IVNeuropathies associated with cryoglobulinemia IVIdiopathic neuropathies IVPolymyositis IVInclusion Body Myositis NoneIdiopathic brachial plexopathy IVDiabetic lumbosacral radiculoplexopathy IV

Class of evidence supporting use of IVIG in the treatment of specific neuromuscular disorders:

*AANEEM, Muscle & Nerve 2009

Dermatomyositis (DM) Dermatomyositis (DM) [CL-I]Double blind placebo-controlled trial: Dalakas et alDalakas et al, N Eng J Med 1993 (*)

Polymyositis (PM) Polymyositis (PM) [CL-IV] Efficient only in small groups of patients (**)

Inclusion Body Myositis (Inclusion Body Myositis (ΙΒΜ) ΙΒΜ) 2 placebo-controlled trials failed to show effectiveness of treatment

(***)

IVIG could also be considered in life-threatening esophageal impairment complicating steroid-resistant PM/DM. (‡)

*Dalakas et al, N Eng J Med 1993**Jann et al, J Neurol Neurosurg Psych 1992

***Dalakas et al, Neurol 1997 & 2001‡Marie et al, Arthritis Care Res 2010

Inhibition of the complement

cascade

Reduction of their production & expression on

tissues

Anti-idiotypic antibodies deactivate the

pathogenetic ones & send inhibitory signals to

B cells

Double blind placebo controlled trialDouble blind placebo controlled trial 15 patients (8 IVIG- 7 placebo) 3 monthly infusions 2g/ kg (++ 3 more infusions) Improvement of muscle strength, neuromuscular symptoms &

histological picture

*Dalakas et al, N Eng J Med 1993

Immune Globulin Placebo

baseline baseline baselineIVIG3month

s

IVIG3month

s

IVIG3month

s

IVIG3month

s

placebo3month

s

placebo3month

s

placebo3month

s

placebo3month

s

baseline

Retrospective Study (1994-2005)Retrospective Study (1994-2005)

42 dermatomyositis patients (43±19 yrs, 40.5% males)

24 patients: IVIG + conventional treatments (corticosteroids, MTX, AZA, hydroxychloroquine)

6 monthly pulses 2g/ kg (range: 4- 18 IVIG pulses)

18 patients: conventional immunosupression

Documented MeasuresDocumented Measures Medical Research Council scale (MRC) of proximal muscles of the upper & lower extremities [0-10] Cutaneous Involvement

o Heliotrope rash, rash on chest & shoulderso Gottron papuleso Mechanic hands

Total- Muscular-Cutaneous Relapses

DefinitionsDefinitionsRemission: MRC ≥ 9 & minimum or no skin lesionsRelapse: Decrease of MRC by ≥ 3 &/ or reappearance of skin lesions

IVIG treated patientsIVIG treated patients Non IVIG treated patientsNon IVIG treated patients

Total remission: 58.33% Muscular remission: 87.5% Cutaneous remission: 66.67%

Total remission: 27.78% Muscular remission: 44.44% Cutaneous remission: 33.33%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

total remission muscular remission

cutaneous remission

ivig

control

P=0.04

P=0.03

P=0.01

Initiatio

n of treatm

ent

t1 t2 t3End of fo

llow up (t4)

Onset of fo

llow up (t0)

diagnosis

6months 1 year 1 year 1 year 1 year

Median follow up time: 76 months

During long term follow up, IVIG treated patients experienced relapses During long term follow up, IVIG treated patients experienced relapses

However, their muscular and cutaneous involvement scores were However, their muscular and cutaneous involvement scores were significantly better than their pre-treatment ones significantly better than their pre-treatment ones (P<0.001)(P<0.001)..

The total number of muscular relapses was inversely associated with the number of pulses (P=0.06).

A larger number of IVIG infusions could maintain disease remission for a longer period of time, reducing the total number of muscular relapses.

he costs associated with IVIG use are often perceived to be high.

onflicting results concerning the calculation of the true costs of conventional therapy, including costs of side effects and hospitalizations vs. costs of IVIG therapy

S analysis for pemphigus vulgarisS analysis for pemphigus vulgaris The true cost of conventional therapy was $US 123 133/ pt/ year, vs. $US 76 249 for IVIG therapy

Cost-effective

IDPIDP Incremental cost per QALY gained of IVIG: $687,287 Not a cost-effective treatment

*Daoud et al, Immunopharmacol 2006**Blackhouse et al, Cost Effect & Res Alloc 2010

Quality-adjusted life year (QALY): A measure of disease burden, including both the quality and the quantity of life lived. It is used in assessing the value for money of a medical intervention.

ulticenter clinical trials in large cohorts of patients

onfirmation of effectiveness onfirmation of effectiveness

xpansion of clinical applicationsxpansion of clinical applications