Unità operativa di neurologia Centro sclerosi multipla

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1 Unità operativa di neurologia Centro sclerosi multipla Trattamento appropriato dei pazienti affetti da sclerosi multipla in terapia con interferone beta.

2 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

Caratterizzata da placche sclerotiche disseminate nella sostanza

3 Epidemiologia e latitudine Prevalenza fortemente dipendente dalla latitudine Fattori ambientali (habitat, alimentazione, infezioni) > 30/ / < 5/

4 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 Età di comparsa anni Australiani Bianchi sudafricani Sudeuropei Neri africani Orientali Compston A. Genetic susceptibility to Multiple Sclerosis in Mc Alpine s Multiple Sclerosis. 3 rd ed. London: Churchill Livingstone 1998.

Australiani Bianchi sudafricani Sudeuropei Neri africani Orientali Compston A.

5 Tipi di progressione della malattia SM recidivante remittente SM primariamente progressiva 10 % SM secondariamente progressiva SM recidivante progressiva < 5 % Adattata ddekker, Noseworthy J.H. et al. Medical Progress: Multiple Sclerosis N Engl J Med 2000; 343:

recidivante progressiva < 5 % Adattata ddekker, 2001. Noseworthy J.H.

6 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. 3 rd ed. London: Churchill Livingstone 1998.

7 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

8 Anti-IFNß antibodies in IFNß-treated MS patients NEUROLOGY 2003;61:S1-S 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

" The purpose of the meeting was to answer, based on the research literature and expert opinion, the following questions: 1.

9 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

The magnitude of decrease in bioactivity depends on the amplitude, avidity, and epitope-binding characteristics of the anti-ifnß antibody population.

10 NAbs delayed effects (2) PRISMS 4: Effect of NAbs on relapse counts Rebif 44 x3 Rate / Year NAb- NAb+ Years 3-4: NAb+ vs NAb- p = Pre-study 1st yr 2nd yr 3rd yr 4th yr

11 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.

Gavin Giovannoni, PhD; and Andrew Goodman, MD NEUROLOGY Jul 2005;65:6 8

12 Trattamento appropriato dei pazienti affetti da sclerosi multipla in terapia con interferone Paz Immunomodulanti Mitoxantrone Altro 20 0

con interferone. 140 120 100 80 60 40 Paz.

13 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 )

Ricerca anticorpi anti-interferon beta testati i

14 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)

di Virologia Dipartimento di Medicina sperimentale e patologia -

15 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.

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.

16 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

increasing evidence that NAbs abrogate or reduce the clinical efficacy of IFN on MRI outcomes, on

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