La terapia con immunoglobuline: efficacia clinica, quali attenzioni Isabella Quinti Dipartimento di Medicina Molecolare Centro di Riferimento per le Immunodeficienze Primitive Sapienza Università di Roma
Landmarks in the History of Immunoglobulin Replacement Therapy Landmarks in the History of Immunoglobulin Replacement Therapy IVIG introduced and becomes Renewed interest Janeway and Gitlin prefer IM standard therapy due to in SCIG as alternative to injections, and this becomes reduction of bacterial and IV therapy, especially for standard of care in US 2 non-bacterial infections 4 home use 5 1980 1953 1955 1952 1990s 2006 Bruton treats first patient diagnosed Berger introduces battery- First SCIG First SCIG with agammaglobulinemia with SC injections powered pumps to slowly Licensed in US Licensed in US of immune serum globulin (ISG) 1 administer IM ISG by SC route 3 1. Bruton OC. Pediatrics. 1952;9:722-728. 2. Berger M. Clin Immunol . 2004;112:1-7. 3. Berger M. et al. Ann Intern Med. 1980;98:55-56. 4. Quartier P. et al. Jour Pediatrics. 1999;134:5:589-596. 5. Abrahamsen TG . Et al. Pediatrics. 1996;98:1127-1131.
Il Consumo di immunoglobuline in Italia e nel mondo
Indicazioni cliniche Condizione clinica Indicazione Nei difetti di produzione anticorpale e nelle Immunodeficienze primitive altre forma di immunodeficienza primitiva combinata Nelle condizioni in cui è necessario ottenere Trombocitopenia idiopatica un rapido aumento del numero di piastrine per il controllo di una emorragia. Nella prevenzione di aneurismi delle Sindrome di Kawasaki coronarie Nella prevenzione di infezioni batteriche nei Leucemia linfoide cronica e mieloma pazienti con ipogammaglobulinemia ed infezioni recidivanti batteriche Infezione da HIV In pediatria In pazienti > 20 anni per ridurre il rischio di Trapianto di midollo sepsi, polmonite interstiziale, GVH acuta nei primi 100 giorni dal trapianto Efficacia clinica sovrapponibile alla Sindrome di Guillain Barr é plasmaferesi Neuropatia Motoria Multifocale Autorizzazione limitata solo ad alcuni prodotti commerciali CIDP (Registro AIFA)
FDA approved indications for the therapeutical usage of polyvalent human immunoglobulins . Primary Immune Deficiencies Chronic lymphocytic leukaemia Paediatric HIV infection Kawasaki disease Allogeneic bone marrow transplantation Chronic inflammatory demyelinating polyneuropathy Kidney transplantation involving a recipient with a high titre or an ABO- incompatible donor Multifocal motor neuropathy
Clinical conditions that might benefit from immunoglobulin treatment according to Food and Drugs Administration additional approved indications with criteria* FDA additional approved indications with criteria Neuromuscular disorders Guillain-Barré syndrome Relapsing-remitting multiple sclerosis Myasthenia gravis Refractory polymiositis Polyradiculoneuropathy Lambert Eaton myasthenic syndrome Opsoclonus-myoclonus Birdshot retinopathy Refractory dermatomyositis Haematologic disorders Autoimmune haemolytic anaemia Severe anaemia associated with parvovirus B19 Autoimmune neutropenia Neonatal alloimmune thrombocytopenia HIV-associated thrombocytopenia Graft-versus-Host disease CMV infection or interstitial pneumonia in patients undergoing BMT Dermatologic disorders Pemphigus vulgaris Pemphigus foliaceous Bullous pemphigoid Mucous-membrane pemphigoid Epidermolysis bullosa acquisita Stevens-Johnson syndrome *Requiring documentation of contraindications or lack of response to conventional therapies
Le indicazioni cliniche all’uso delle immunoglobuline: vecchi criteri e nuove evidenze -Individualizzare il trattamento -Livelli di evidenza -Monitoraggio degli eventi avversi -Monitoraggio dei rischi associati ai nuovi metodi di preparazione delle immunoglobuline
Individualizzare il trattamento Adequate Patient’s Outcome Achieved with Short Immunoglobulin Replacement Intervals in Severe Antibody Deficiencies Cinzia Milito & Federica Pulvirenti & Anna Maria Pesce & J Clin Immunol (2014) 34:813–819 Maria Anna Digiulio & Franco Pandolfi & DOI 10.1007/s10875-014-0081-9 Marcella Visentini & Isabella Quinti Objective: To determine for each patient the best interval between immune globulins administration in order to: • Keep IgG trough levels >500 mg/dL, • Minimize of major infections (pneumonias and infections requiring hospitalization), • Minimize of adverse events (AE).
STUDY DESIGN ENROLLMENT (108 patients) GROUP 2 GROUP 1 F EWER DISEASE - ASSOCIATED s High risk h COMPLICATIONS (56) ( 52) t n o m D ROP OUT (8) maintain standard R EFUSE TO dosage adjusted to 2 3 treatment with 3 or 4 weeks REDUCE weeks interval IVIG interval (48) (52) INTERVAL Patients assessment relative to the Patients assessment relative to the study objective study objective Not achieved Achieved Not achieved Achieved s (6) (42) (4) (48) h n t o m S HIFT TO 1- WEEK M AINTAIN M AINTAIN S HIFT TO 2- WEEKS 3-/4- WEEKS 9 INTERVAL 2- WEEKS INTERVAL C UMULATIVE IVIG INTERVAL AND INTERVAL DOSE ADJUSTED DOSAGE UNTIL THE STUDY OBJECTIVE
Individualizzare il trattamento Health care delivery systems are quickly changing in response to economic pressures and concerns about quality of care. The system of care is itself an important determinant of patient outcomes. Elucidating the effects of the system of care on patient outcomes 98% of patients achieved the objective of the study. requires new methodologic approaches in order to identify what works in which setting and under what conditions. - Patients who had low switched memory B cells and low IgA serum levels and/or are affected by bronchiectasis and/or enteropathy and/or continued to experience adverse events despite premedications, achieved the study objective by shortening the administration intervals to 2-weeks or to 1-week without the need to increase the monthly cumulative immunoglobulin dosage and its relative cost. Personalized health research presents further methodologic challenges, since emphasis is placed on the individual response - The adverse events were reduced by administrating low Ig dosages in a single setting. rather than on the population - Patients without risk factors achieved the study objective with immune globulin replacement administered with the widely used interval of 3 or 4 weeks. N Engl J Med 367;9, august 30, 2012
Livelli di evidenza
Monitoraggio degli eventi avversi Monitoraggio degli eventi avversi -mialgia Le immunoglobuline -febbre sono un farmaco -brividi biologico e come per -cefalea tutti i farmaci biologici -nausea la tollerabilità -vomito individuale ai diversi -difficoltà respiratoria prodotti commerciali è -manifestazioni a carico del sistema vascolare quali ampiamente variazione della pressione sanguigna, tachicardia -reazioni gravi di tipo anafilattico dimostrata. -insufficienza renale acuta (dopo alte dosi di IVIG) -neutropenia E’ quindi necessario -anemia emolitica acuta avere a disposizione -aumento della viscosità del sangue (solo dopo alte dosi) più prodotti in modo da -aumento del rischio di aggregazione piastrinica tale da poter mantenere la giustificare episodi trombotici e vaso-occlusivi (solo dopo continuità terapeutica. alte dosi) -meningite asettica/encefalite
Monitoraggio dei rischi associati ai nuovi metodi di preparazione delle immunoglobuline
Production Processes Cohn like Modern ≥ 2.5 g / L ≥ 3.5 g / L References: J. Am. Chem. Soc., 68:459-475 (1946); J. Am. Chem. Soc., 71:541-550 (1946)
Immunoglobuline e trombosi 24 Settembre 2010 EMA/CHMP/591722/2010 Comunicato stampa L’ Agenzia Europea dei Medicinali raccomanda la sospensione di Octagam in tutti gli Stati Membri della UE Raccomandazioni del CHMP basate sul rischio di reazioni tromboemboliche . L’Agenzia Europea dei Medicinali ha raccomandato la sospensione dell’autorizzazione all’immissione in commercio per Octagam (immunoglobulina normale umana), di Octapharma GmbH e il richiamo di tutti i lotti attualmente disponibili sul mercato in Europa.
Immunoglobuline ed emolisi Anti-A in Cohn like versus Modern Processes • Cohn like processes have ≥ 2 titer step reduction capacity 20
Acute haemolysis The eluted antibodies had the same specificity found in the lots of Ig infused at the time of the haemolytic episode. Comment: Patients with acute haemolysis due to passive transfer of to irregular antibodies had a more severe haemoglobin drop and higher reticulocyte percentages than patients who received Ig products containing anti-A blood group antibodies ( 5,7 ± 1 g/L vs 1,3 ± 0.2 g/L; 9.8 ± 2.5 % vs 3.2 ± 1.1%, respectively ).
Blood group antibodies and irregular antibodies in IVIG and SCIG 1.Reactive RBCs IgG antibodies without conventional specificity were present in 15/16 lots. 2.The titers of blood group anti-A and anti-B antibodies in the Ig preparations were within those recommended by the European Pharmacopoeia (<1:64 dilution at 5% (w/v)) 3.2/2 lots from one brand were positive for anti-C and anti-D. 4.2/3 lots from one brand were positive for anti-c. The European Pharmacopoeia does not recommend the test for the presence of anti-C anti-c and anti- D antibodies.
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