Unità operativa di neurologia
Centro sclerosi multipla
Trattamento appropriato dei pazienti
affetti da sclerosi multipla in terapia con
interferone beta.
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Sclerosi Multipla
•
Malattia infiammatoria cronica
demielinizzante del SNC
• Descritta per la prima volta
Vulpian nel 1866
da Charcot e
• Caratterizzata
da
placche
sclerotiche
disseminate
nella
sostanza
bianca
dell’encefalo e del midollo spinale, e da
variabilità dei sintomi
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Epidemiologia e latitudine
Prevalenza fortemente
dipendente dalla latitudine
Fattori ambientali
(habitat, alimentazione, infezioni)
> 30/100 000
5-30/100 000
< 5/100 000
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Suscettibilità alla SM in base a sesso,
età e origine etnica
Sesso
Rapporto tra sessi:
2F/1M
Origine etnica
Alto
rischio
Nordeuropei
Bianchi USA
Canadesi
Età di comparsa
20 - 40 anni
Australiani
Bianchi sudafricani
Sudeuropei
Neri africani
Orientali
Compston A. Genetic susceptibility to Multiple Sclerosis in Mc Alpine’s Multiple Sclerosis. 3rd ed. London: Churchill Livingstone 1998.
Tipi di progressione della
malattia
SM recidivante remittente
SM primariamente progressiva
10 %
SM secondariamente
progressiva
SM recidivante
progressiva
<5
%
Adattata dDekker, 2001.
Noseworthy J.H. et al. Medical Progress: Multiple Sclerosis N Engl J Med 2000; 343: 938-52.
I diversi tipi di trattamento
Trattamenti
sintomatici
Gestione
della ricaduta acuta
Trattamenti che
modificano il decorso
Corticoterapia
Trattamento dei sintomi
Compston A. Treatment and management of Multiple Sclerosis in Mc Alpine’s Multiple Sclerosis. 3rd ed. London: Churchill
Livingstone 1998.
TERAPIE
IMMUNOMODULANTI E IMMUNOSOPPRRESSIVE
• BETAFERON
(interferon-beta-1b) 1996
• AVONEX
(interferon-beta-1a) 1996
• REBIF
(interferon beta-1a) 1997
• COPAXONE
(glatimer-acetate ) 2002
• NOVANTRONE (mitoxantrone) 2000
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Anti-IFNß antibodies in IFNß-treated MS patients
NEUROLOGY 2003;61:S1-S5
© 2003 American Academy of Neurology
The Consortium of MS Centers organized a conference in London, England
on May 16 and 17, 2003 titled "Anti-IFN Antibodies in IFN-treated MS
Patients—Current Knowledge and Future Directions." The purpose of the
meeting was to answer, based on the research literature and expert
opinion, the following questions:
1. What is currently known about anti-interferon (IFN) antibodies and their
effects on patients with multiple sclerosis (MS) treated with IFN therapies ?
2. What are the tests available to detect antibodies ?
3. How accurate are they; and what is the best method for their detection in
clinical care?
4. What are the research priorities in advancing our knowledge in this field?
In an attempt to avoid, as much as possible, any potential bias from
pharmaceutical companies, employees of pharmaceutical companies were
not invit
Consensus statements (>70% agreement)
NEUROLOGY 2003;61:S1-S5
• High levels of anti-IFNß antibodies in the sera of MS patients interfere with the bioactivity of injected
IFNß
• IFNß-1b is more immunogenic than IFNß-1a.
• Antibody-mediated decreased bioactivity (ADB) is a graduated phenomenon rather than an all-or-nothing
effect. The magnitude of decrease in bioactivity depends on the amplitude, avidity, and epitope-binding
characteristics of the anti-IFNß antibody population.
• ADB of injected IFNß in patients with multiple sclerosis (MS) can be reliably detected by decreased
levels of MxA, an IFNß-induced gene product
• The clinical sequelae of ADB depend on the duration and severity of decreased bioactivity and the
underlying activity of the patient’s MS. Thus, the persistence of high levels of anti-IFNß antibodies in
patients with active MS will eventually lead to clinical evidence of loss of efficacy of IFNß.
• Because the therapeutic effects of IFNß may be delayed, analysis of the clinical effects of ADB would
best be performed in a period delayed several months after demonstration of persistent ADB
• Immunogenicity of an IFNß preparation should be one of the factors considered in selecting an IFNß
preparation for an MS patient
• Assays for binding and neutralizing antibodies should be standardized.
• Kawade 10-fold reduction method for determining units of a neutralization antibody assay should be
used when expressing results of neutralizing antibody assays.
• Controls for endogenous toxicity of serum and residual IFN activity in serum should be used in all antiIFNß NAb assays.
• Clinicians
need to change their approach to the patient if the patient is NAb
positive, and they need to consider discontinuing IFNß or changing therapy
• Research should be performed on when and how to manage ADB so that clinical sequelae can be
avoided or reversed; the optimal therapy of ADB has not yet been determined
NAbs delayed effects (2)
PRISMS 4: Effect of NAbs on relapse counts Rebif
44 x3
1.6
NAbNAb+
Rate / Year
1.4
Years 3-4: NAb+ vs NAb- p = 0.002
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Pre-study
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1st yr
2nd yr
3rd yr
4th yr
Neutralizing anti-IFN- antibodies
How much more evidence do we need to use them
in practice?
Gavin Giovannoni, PhD; and Andrew Goodman, MD NEUROLOGY Jul 2005;65:6–8 Editorial
“At present there is little evidence to guide
clinicians on how to manage persistently
NAb+ subjects who are doing well clinically”.
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Trattamento appropriato dei pazienti affetti da sclerosi
multipla in terapia con interferone.
140
120
100
80
60
40
20
0
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Paz. 2004-05
Immunomodulanti
Mitoxantrone
Altro
Trattamento appropriato dei pazienti affetti da sclerosi
multipla in terapia con interferone.
Ricerca anticorpi anti-interferon beta
testati i sieri di 4 pazienti
• 2 negativi
• 2 positivi ( titoli elevati 9386 t1/10 )
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Trattamento appropriato dei pazienti affetti da sclerosi
multipla in terapia con interferone
• Individuazione laboratorio di riferimento
Servizio di Virologia Dipartimento di Medicina sperimentale e
patologia - Policlinico Umberto 1° Università La Sapienza - Roma
• Invio campioni (coinvolgimento famigliari)
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Neutralizing anti-IFN- antibodies
How much more evidence do we need to use them
in practice?
Gavin Giovannoni, PhD; and Andrew Goodman, MD NEUROLOGY Jul 2005;65:6–8 Editorial
“Despite the increasing evidence that NAbs abrogate or reduce the
clinical efficacy of IFN on MRI outcomes, on relapse rate, and now
on disability progression, NAb testing has not been part of routine
clinical practice”
“In conclusion, it is well established that NAbs reduce
the biologic and clinical efficacy of IFN. The
efficacy of IFN and hence the cost-effectiveness of
treatment will be improved if the development of
NAbs can be prevented or reversed. Subjects with
MS who develop NAbs are likely to become IFN
nonresponders. They are by definition at higher risk
of having relapses in the future (if they have not
already had them) and can now be considered to be
at increased risk of disease progression”.”
Viterbo 1.12.05
Neutralizing anti-IFN- antibodies
How much more evidence do we need to use them
in practice?
Gavin Giovannoni, PhD; and Andrew Goodman, MD NEUROLOGY Jul 2005;65:6–8 Editorial
“Despite the increasing evidence that NAbs
abrogate or reduce the clinical efficacy of IFN
on MRI outcomes, on relapse rate, and now on
disability progression, NAb testing has not been
part of routine clinical practice”
Viterbo 1.12.05