La terapia con immunoglobuline: efficacia clinica, quali attenzioni - - PowerPoint PPT Presentation

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

1952 Bruton treats first patient diagnosed with agammaglobulinemia with SC injections

• f immune serum globulin (ISG)1

1953 1980 Janeway and Gitlin prefer IM injections, and this becomes standard of care in US2 Renewed interest in SCIG as alternative to IV therapy, especially for home use5

• 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.

1955 Berger introduces battery- powered pumps to slowly administer IM ISG by SC route3 1990s IVIG introduced and becomes standard therapy due to reduction of bacterial and non-bacterial infections4 First SCIG First SCIG Licensed in US Licensed in US 2006

Il Consumo di immunoglobuline in Italia e nel mondo

Indicazioni cliniche

Condizione clinica Indicazione Immunodeficienze primitive Nei difetti di produzione anticorpale e nelle altre forma di immunodeficienza primitiva combinata Trombocitopenia idiopatica Nelle condizioni in cui è necessario ottenere un rapido aumento del numero di piastrine per il controllo di una emorragia. Sindrome di Kawasaki Nella prevenzione di aneurismi delle coronarie Leucemia linfoide cronica e mieloma Nella prevenzione di infezioni batteriche nei pazienti con ipogammaglobulinemia ed infezioni recidivanti batteriche Infezione da HIV In pediatria Trapianto di midollo In pazienti > 20 anni per ridurre il rischio di sepsi, polmonite interstiziale, GVH acuta nei primi 100 giorni dal trapianto Sindrome di Guillain Barré Efficacia clinica sovrapponibile alla plasmaferesi Neuropatia Motoria Multifocale CIDP (Registro AIFA) Autorizzazione limitata solo ad alcuni prodotti commerciali

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

FDA approved indications for the therapeutical usage of polyvalent human immunoglobulins.

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

Clinical conditions that might benefit from immunoglobulin treatment according to Food and Drugs Administration additional approved indications with criteria* *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

Adequate Patient’s Outcome Achieved with Short Immunoglobulin Replacement Intervals in Severe Antibody Deficiencies

Cinzia Milito & Federica Pulvirenti & Anna Maria Pesce & Maria Anna Digiulio & Franco Pandolfi & Marcella Visentini & Isabella Quinti

J Clin Immunol (2014) 34:813–819 DOI 10.1007/s10875-014-0081-9

• Keep IgG trough levels >500 mg/dL,
• Minimize of major infections (pneumonias and infections

requiring hospitalization),

• Minimize of adverse events (AE).

Objective: To determine for each patient the best interval between immune globulins administration in order to:

Individualizzare il trattamento

GROUP 1 High risk (56) STUDY DESIGN ENROLLMENT (108 patients) maintain standard treatment with 3 or 4 weeks interval (52) dosage adjusted to 2 weeks interval (48) GROUP 2 FEWER DISEASE-ASSOCIATED

(52)

SHIFT TO 1-WEEK

CUMULATIVE IVIG

MAINTAIN 2-WEEKS

Not achieved (6) Achieved (42) SHIFT TO 2-WEEKS INTERVAL MAINTAIN 3-/4- WEEKS

3 m

• n

t h s 9 m

• n

t h s

Not achieved (4) Achieved (48)

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

• utcomes.

Elucidating the effects of the system of care on patient outcomes requires new methodologic approaches in order to identify what works in which setting and under what conditions. Personalized health research presents further methodologic challenges, since emphasis is placed on the individual response rather than on the population

N Engl J Med 367;9, august 30, 2012

Individualizzare il trattamento

98% of patients achieved the objective of the study.

• 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.

• The adverse events were reduced by administrating low Ig dosages in a single setting.
• Patients without risk factors achieved the study objective with immune globulin replacement administered

with the widely used interval of 3 or 4 weeks.

Livelli di evidenza

Monitoraggio degli eventi avversi Monitoraggio degli eventi avversi

• mialgia
• febbre
• brividi
• cefalea
• nausea
• vomito
• difficoltà respiratoria
• manifestazioni a carico del sistema vascolare quali

variazione della pressione sanguigna, tachicardia

• reazioni gravi di tipo anafilattico
• insufficienza renale acuta (dopo alte dosi di IVIG)
• neutropenia
• anemia emolitica acuta
• aumento della viscosità del sangue (solo dopo alte dosi)
• aumento del rischio di aggregazione piastrinica tale da

giustificare episodi trombotici e vaso-occlusivi (solo dopo alte dosi)

• meningite asettica/encefalite

Le immunoglobuline sono un farmaco biologico e come per tutti i farmaci biologici la tollerabilità individuale ai diversi prodotti commerciali è ampiamente dimostrata. E’ quindi necessario avere a disposizione più prodotti in modo da poter mantenere la continuità terapeutica.

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)

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 e trombosi

Anti-A in Cohn like versus Modern Processes

• Cohn like processes have ≥ 2 titer step reduction capacity

20

Immunoglobuline ed emolisi

Acute haemolysis

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).

The eluted antibodies had the same specificity found in the lots of Ig infused at the time of the haemolytic episode.

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.

• Haemoglobin levels showed a mild decrease in

71% of patients – pre-infusion 13.8 ± 1.4 gr/dL, – 1 day post 13.0 ± 1.3 gr/dL – 7 days post 13.8 ± 1.2 gr/dL Hb levels returned to the same pre-infusion level after 21 days.

• A mild increase in serum total bilirubin levels

was observed following Ig administration: – pre-infusion 0.31 ± 0.24 mg/dL – 1 day post 0.75 ± 0.94 mg/dL – 7 days post 0.69 ± 0.92 mg/Dl

• Haptoglobin

and LDH levels remained unchanged.

• Reticulocyte counts were increased in 6/16

patients before Ig and in 8/16 after 7 days.

• 2 /16 patients before infusion and 24 hours post-
• infusion. Had a DAT positive test. Eluates from

patient’s RBCs showed An anti-A alloantibody

Haemolysis following IVIG administration?

baseline + 24 h + 7 days + 21 days baseline + 24 h + 7 days

Conclusioni

• Post-Immunoglobulin haemolysis can occurred in PAD patients receiving Ig at

replacement dosages.

• Haemolysis was due to anti-A in 6 patients, to anti-C and anti-D in 1 patient and to

anti-C antibodies in 2 patients, passively transferred through Ig

• Polyvalent Ig preparations can contain multiple clinically significant antibodies that

could have unexpected haemolytic consequences, as anti-C and anti-c

• Mild haemolytic reactions can be easily missed and the true incidence of such

reactions is difficult to document without careful clinical and laboratory follow-up.

• For PAD patients under Ig, the occurrence of mild adverse events are outweighed by

the benefits of IVIG and SCIG therapy; however, the clinical consequences of the passive transfer of blood group antibodies should be identified.

• In terms of safety the issue of acute and chronic haemolysis in long term recipients of

immunoglobulin treatment administered at replacement dosages should be more widely recognized

• The effects of the recent changes in the immunoglobulin production and schedules of

administration should be assessed in studies of drug surveillance

Conclusioni

La somministrazione delle immunoglobuline induce molteplici effetti sulle funzioni del sistema immunitario La conoscenza di tali effetti deve essere nota, deve guidare le scelte normative e le scelte terapeutiche, deve orientare la ricerca clinica e di base La terapia deve essere individualizzata Le immunoglobuline non possono essere considerate un farmaco generico E’ necessario formulare una dichiarazione europea sulla priorità assoluta della indicazione terapeutica nelle immunodeficienze primitive

UOD Centro di Riferimento Immunodeficienze Primitive Azienda Policlinico Umberto I Sapienza Università di Roma Grazie a: Commissione Europea Agenzia Italiana del Farmaco Jeffrey Modell Foundation isabella.quinti@uniroma1.it Tel 06-49972007