Ελένη Ι. Καμπυλαυκά Μέτσοβο, Ιανουάριος 2011

Transcription

1 Παθολογική Φυσιολογία Ιατρική Σχολή Ελένη Ι. Καμπυλαυκά Μέτσοβο, Ιανουάριος 2011 Εθνικό & Καποδιστριακό Πανεπιστήμιο Αθηνών

2 Main Principles Pathogenetic Mechanisms Clinical Applications Immunodeficiencies- Transplantation- Sepsis Systemic Autoimmune Diseases Neurological Diseases of Autoimmune Origin Inflammatory Myopathies Cost- Effectiveness

3 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

4 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 Idiopathic Thrombocytopenic Purpura (ITP) Kawasaki disease Use in neurology: First reports on the use of IVIG in Multiple Sclerosis (MS) in 1982 and Successful treatment of Myasthenia Gravis in Chronic demyelinating polyneuropathy (CIDP) the first immune-mediated neuropathy to be responsive to IVIG in 1985 Guillain- Barré syndrome (GBS) in *Stangel et al, J Neurol 2006 **Hartung et al, J Neurol 2008

5 Innate Immunity-General DC-mediated T-cell activation Endocytosis Pro-inflammatory cytokines (IL-1, TNFa, IL-1b) Anti-inflammatory cytokines DC differentiation Expression of MHC class II & co-stimulatory molecules Expression of CD1d Expression of activating FcγRs Cell migration by ICAM-1, integrins T cells T cell activation & proliferation IL-2 production T cell apoptosis T cell differentiation Autoantibodies against CD4, CD8 Autoantibodies against superantigens Expansion of Treg cells Suppressive function of T cells NK cells NK-cell trafficking from cell to tissue NK-cell activation Anti-tumor activity Complement Cascade Binding of C1, C3a, C3b, C4, C5a Degradation of C3b MAC deposition Macrophages Expression of inhibitory FcγRIIB Macrophage acivation Expression of IFN-γR2 B cells B cell apoptosis Inhibitory FcγRIIB Blockade of activating FcγR B cell proliferation Inhibition of antibody production Neutralization of autoantibodies by anti-idiotypes Catabolism of antibodies via blockade of the protective intracellular FcRn IL-6 production Granulocytes Neutrophil death Neutrophil activation Neutrophil adhesion to endothelium *Durandy et al, Clin Exp Immunol 2009 **Stangel et al, J Neurol 2006

6 Usually minor- In less than 10% of the patients Common 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) Causes Unclear Activation of complement by aggregated immunoglobulin molecules or various stabilizing agents in the IVIg preparation have been implicated Less common Backache, 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

7 Approved 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) Solid clinical evidence Few data Difficulty in performing trials- Diseases with low prevalence Many off label indications *Kivity et al, Clinic Rev Allerg Immunol 2010

8 *AANEEM, Muscle & Nerve 2009

9 Primary immunodeficiencies [CL-I] ( mg/ kg/ 3-4 weeks) Secondary immunodeficiencies [CL-I] ( mg/ kg/ 2-4 weeks) Malignant lymphoma & Multiple myeloma with clinically relevant antibody deficiency HIV 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

10 otal cumulative dose of 2 g/ kg during 2 or 5 consecutive days rbitrarily chosen & proven to be efficient diopathic Thrombocytopenic Purpura [CL-I] (Cumulative dose 2gr/ kg, during 2 or 5 days) awasaki [CL-I] (2gr/ kg in acute phase) ther ANCA (+) vasculities [CL-III/IV] Efficient ucocutaneous blistering diseases [CL-I/IV] treatment (2g/kg/month) Second line or adjunctive *Kivity et al, Clinic Rev Allerg Immunol 2010 **Stangel et al, J Neurol 2006 ***Boletis et al, Lancet 1999

11 Adult Still Disease [CL-IV] Possible Improvement Mixed Connective Tissue Disease [CL-IV] Systemic Sclerosis [CL-IV] Rheumatoid Arthritis [CL-I/III] Sjögren s Syndrome [CL-IV] Congenital Heart Block (CHB) Multicenter, prospective, open-label study Replacement dose 400 mg/kg: Safe but not efficient Inflammatory Myopathies Possible improvement of skin lesions Improvement of fibrosis Not efficient on disease activity Possible improvement of vasculitis & neuropathy DM [CL-I] Second line or adjunctive treatment PM [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 12 patients with chronic ITP To avoid splenectomy Failed to respond Required maintenance Doses of corticosteroids or immunosupression The average platelet count increase to initial therapy was /μl (range ) 6 months after treatment 2 patients in remission, 4 patients stable requiring no therapy (PLT ~ ) 3 patients require maintenance IVIG therapy 3 patients have become refractory to lvig treatment. *Bussel et al, Blood 1983

13 Class of evidence supporting use of IVIG in the treatment of specific neuromuscular disorders: Class of evidence Neuromuscular disorder Guillain- Barré Syndrome in adults I Guillain-Barre syndrome in children II Chronic Inflammatory Demyelinating Polyradiculopathy I Multifocal motor neuropathy I Myasthenia gravis I Lambert-Eaton myasthenic syndrome I Dermatomyositis I Stiff person syndrome I Multiple Sclerosis: Conflicting results in RR- Negative in progressive *AANEEM, Muscle & Nerve 2009

14 Class of evidence supporting use of IVIG in the treatment of specific neuromuscular disorders: Class of evidence Neuromuscular disorder Fisher syndrome IV Neuropathies associated with monoclonal proteins IV Chronic auto-immune neuropathies IV Neuropathies associated with cryoglobulinemia IV Idiopathic neuropathies IV Polymyositis IV Inclusion Body Myositis None Idiopathic brachial plexopathy IV Diabetic lumbosacral radiculoplexopathy IV *AANEEM, Muscle & Nerve 2009

15 Dermatomyositis (DM) [CL-I] Double blind placebo-controlled trial: Dalakas et al, al N Eng J Med 1993 (*) Polymyositis (PM) [CL-IV] Efficient only in small groups of patients (**) Inclusion Body Myositis (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

16 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

17 Double 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 Immune Globulin baseline IVIG placebo 3month 3month s s baseline placebo IVIG 3month 3month s s Placebo baseline IVIG placebo baseline placebo IVIG 3month 3month 3month 3month s s s s *Dalakas et al, N Eng J Med 1993

18 Retrospective Study ( ) 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 Measures Medical Research Council scale (MRC) of proximal muscles of the upper & lower extremities [0-10] Cutaneous Involvement o Heliotrope rash, rash on chest & shoulders Definitions o Gottron papules Remission: MRC 9 & minimum or no skin lesions o Mechanic hands Relapse: Decrease of MRC by 3 &/ or Total- Muscular-Cutaneous Relapses reappearance of skin lesions

19 IVIG treated patients Non IVIG treated patients Total remission: 58.33% Muscular remission: 87.5% Cutaneous remission: 66.67% % 90.00% 80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% P. =0 Total remission: 27.78% Muscular remission: 44.44% Cutaneous remission: 33.33% 04 P. =0 01 P. =0 03 ivig control total remission muscular remission cutaneous remission

20 nt t0) e ( atm w up e tr f llo o o is s n ff o o o n i t g a a et i t1 i t s i d In On 6 months 1 year t2 1 year t3 1 year En f do f ow l l o u t4 ( p ) 1 year Median follow up time: 76 months During long term follow up, IVIG treated patients experienced relapses However, their muscular and cutaneous involvement scores were significantly better than their pre-treatment ones (P<0.001).

21 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.

22 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 vulgaris The true cost of conventional therapy was $US / pt/ year, vs. $US for IVIG therapy Cost-effective 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 IDP Incremental cost per QALY gained of IVIG: $687,287 value for money of a medical intervention. Not a cost-effective treatment *Daoud et al, Immunopharmacol 2006 **Blackhouse et al, Cost Effect & Res Alloc 2010

23 ulticenter clinical trials in large cohorts of patients onfirmation of effectiveness xpansion of clinical applications