Trattamento appropriato dei pazienti affetti da sclerosi ... - ASL Viterbo

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Trattamento appropriato dei pazienti affetti da sclerosi ... - ASL Viterbo

Trattamento appropriato dei pazienti

affetti da sclerosi multipla in terapia con

interferone beta.

Viterbo 1.12.05

Unità operativa di neurologia

Centro sclerosi multipla


Sclerosi Multipla

• Malattia infiammatoria cronica

demielinizzante del SNC

• Descritta per la prima volta da Charcot e

Vulpian nel 1866

• Caratterizzata da placche sclerotiche

disseminate nella sostanza bianca

dell’encefalo e del midollo spinale, e da

variabilità dei sintomi

Viterbo 1.12.05


Epidemiologia e latitudine

> 30/100 000

5-30/100 000

< 5/100 000

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Prevalenza fortemente

dipendente dalla latitudine

Fattori ambientali

(habitat, alimentazione, infezioni)


Suscettibilità alla SM in base a sesso,

età e origine etnica

Sesso

Rapporto tra sessi:

2F/1M

Alto

rischio

Origine etnica

Nordeuropei

Bianchi USA

Canadesi

Australiani

Bianchi sudafricani

Sudeuropei

Neri africani

Orientali

Età di comparsa

20 - 40 anni

Compston A. Genetic susceptibility to Multiple Sclerosis in Mc Alpine’s Multiple Sclerosis. 3 rd ed. London: Churchill Livingstone 1998.


Tipi di progressione della

malattia

SM recidivante remittente

SM secondariamente

progressiva

Adattata dDekker, 2001.

Noseworthy J.H. et al. Medical Progress: Multiple Sclerosis N Engl J Med 2000; 343: 938-52.

SM primariamente progressiva

10 %

SM recidivante

progressiva

< 5

%


I diversi tipi di trattamento

Trattamenti

sintomatici

Gestione

della ricaduta acuta

Corticoterapia

Trattamento dei sintomi

Trattamenti che

modificano il decorso

Compston A. Treatment and management of Multiple Sclerosis in Mc Alpine’s Multiple Sclerosis. 3 rd 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

Viterbo 1.12.05


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 anti-

IFNß 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


Rate / Year

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NAbs delayed effects (2)

PRISMS 4: Effect of NAbs on relapse counts Rebif

44 x3

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

NAb- NAb

NAb+

Pre-study 1st yr 2nd yr 3rd yr 4th yr

Years 3-4: NAb+ vs NAb- p = 0.002


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 )

Viterbo 1.12.05


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)

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”

“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

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