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Revisioni Cochrane: gli interferoni  

Revisione Cochrane: Interferoni per la Sclerosi Multipla a decorso remittente

Gli interferoni alfa e beta sono agenti antivirali e agiscono sul sistema immunitario Gli interferoni beta sono stati approvati dai servizi sanitari per il trattamento della SM remittente. Nella pratica clinica sono utilizzati: interferone beta-1a (Avonex; Rebif ) e interferone beta 1-b (Betaferon). Sono definiti farmaci immunomodulatori, ma il loro meccanismo d’azione non è completamente conosciuto.

Obiettivi.
Valutare efficacia e frequenza di eventi avversi del trattamento con interferoni per la SM remittente.

Criteri di selezione.
Studi clinici randomizzati di confronto tra interferoni alfa o beta e placebo in persone con SM remittente. La selezione degli studi è stata fatta indipendentemente da quattro revisori.

Raccolta dei dati.
Quattro revisori hanno valutato la qualità degli studi ed hanno estratto i dati dagli articoli secondo i criteri definiti nel protocollo della revisione. Gli aspetti di qualità considerati sono stati:

a) metodo di randomizzazione e di assegnazione delle persone ai gruppi di trattamento a confronto;

b) cecità della persona e dei medici che avevano misurato gli esiti rispetto al trattamento (interferone o placebo);

c) analisi dei dati secondo il principio dell’intenzione al trattamento.

E’ stata effettuata una meta-analisi dei risultati. Sono stati calcolati i rischi relativi (RR, vedi il glossario) con i limiti di confidenza al 95% (LC 95%).

Risultati principali.
Sono stati analizzati sette studi per un totale di 1.215 persone trattate nel corso di due anni. I risultati sono che l’interferone riduce di circa un quarto il numero di pazienti che hanno ricadute nel primo anno di trattamento (RR: 0,79, LC 95%: 0,58–1,07), e che non si possono trarre conclusioni dopo un anno di trattamento. Infatti, il numero dei malati trattati che hanno avuto ricadute nel secondo anno è minore dei controlli (RR: 0,81, LC 95%: 0,74 – 0,89), ma questa riduzione perde significato dopo il test di sensitività, applicato dai revisori per interpretare il dato alla luce di una perdita del 20% nei pazienti al follow up, in altri termini, alla luce della mancanza di informazioni a due anni per un quinto dei pazienti. Il numero dei malati trattati che hanno avuto una progressione della disabilità nei due anni di trattamento è minore dei controlli (RR: 0,70; LC 95%: 0,55-0,88), ma questa riduzione perde significato dopo il test di sensitività (RR: 1,31; LC 95%: 0,60-2,89). Gli effetti avversi a breve termine del trattamento con interferone sono stati: reazioni cutanee, sindromi influenzali, stanchezza e dolori muscolari, effetti ematologici di ridotta funzione midollare e di innalzamento delle transaminasi epatiche. Tutti gli studi inclusi nella revisione hanno un follow up che termina a 2 anni, troppo breve per valutare gli effetti avversi di un trattamento che viene somministrato di norma per parecchi anni. Il numero di casi da trattare (NNT) nel primo anno, in base al rischio di partenza, è riportato nella figura 1 dove si può vedere, per esempio che 9 malati devono ricevere il trattamento con interferone perché uno di loro non presenti ricadute nel primo anno quando il rischio di ricaduta nella popolazione dei malati è del 40%.

Conclusioni dell’autore.
Gli interferoni beta hanno una modesta efficacia nel ridurre il numero di pazienti che hanno ricadute nel primo anno di trattamento. L’effetto clinico per un periodo superiore ad un anno rimane indeterminato e sono necessari nuovi trial per documentare l’efficacia di questo trattamento e gli effetti collaterali a lungo termine. Gli effetti avversi a breve termine sono reazioni cutanee, sindromi influenzali, stanchezza e dolori muscolari, effetti ematologici di ridotta funzione midollare e di innalzamento delle transaminasi epatiche.

Gruppo:
Gruppo Cochrane Sclerosi Multipla

Fonte:
Rice G PA et al. Interferon in relapsing-remitting multiple sclerosis.

The Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD002002. DOI: 10.1002/14651858.CD002002

Data: luglio 2001

Traduzione:
Liliana Coco, Gruppo Cochrane Sclerosi multipla, Istituto Nazionale Neurologico Carlo Besta, Milano; Diego Inghilleri Revisore scientifico: Graziella Filippini, Gruppo Cochrane Sclerosi multipla, Istituto Nazionale Neurologico Carlo Besta, Milano.


Revisione Cochrane: Interferon Beta for Primary Progressive Multiple Sclerosis

Rojas JIgnacio, Romano M, Ciapponi A, Patrucco L, Cristiano E

Summary

Treatments of patients with Primary Progressive Multiple Sclerosis (PPMS) with interferon beta (INF beta) seems not associated with a reduction of the disability progression

To date there is no proven or licensed disease-modifying treatments to slow the progression of PPMS. Studies on the effects of INF beta have mainly focused on Relapsing-Remitting MS and have demonstrated a modest reduction on the progression of the disease. The objective of this review was to assess the efficacy of INF beta also in patients with PPMS. Among the pertinent medical literature, only two studies, comprising a total of 123 participants, met the criteria of the methodological quality necessary for their inclusion in this review. Taking into account the disability progression, the analysis of the data showed that INF beta treatment in patients with PPMS was not associated with a reduction of this parameter during the first two years of therapy. Adverse effects, mainly flu-like symptoms and injection site reactions, occurred frequently and were the same as reported by the many studies on IFN beta treatments in MS patients with different types and at different stages of the disease. It is worth noting that the patients' population analysed was too small to allow a definitive conclusion on the efficacy of IFN beta therapy in PPMS.

This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2009 Issue 1, Copyright © 2009 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X). This record should be cited as: Rojas JIgnacio, Romano M, Ciapponi A, Patrucco L, Cristiano E. Interferon Beta for Primary Progressive Multiple Sclerosis. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006643. DOI: 10.1002/14651858.CD006643.pub2
Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD002002. DOI: 10.1002/14651858.CD002002.


This version first published online: January 21. 2009

Abstract

Background
Therapeutic trials with ß-interferon in Multiple Sclerosis (MS) have mainly focused on remitting-relapsing multiple sclerosis (RRMS), demonstrating a reduction in relapse rate. However, there is not enough evidence about their efficacy in patients with primary progressive multiple sclerosis (PPMS).

Objectives
Identify and summarize the evidence that ß-interferon is beneficial and safe in patients with PPMS.

Search strategy
We searched (until April 2008) the Cochrane MS Group Trials Register; The Cochrane Central Register of Controlled Trials (CENTRAL) The Cochrane Library, (2008, Issue 3,); MEDLINE (PubMed) (January 1966 to April 2008), EMBASE (January 1974 to April 2008); NICE (January 1999 to April 2008); LILACS (January 1986 to April 2008); Screening of reference lists of all primary studies found; Contact and inquiry of drug manufactures and multiple sclerosis experts.



Selection criteria
Randomized double or single blind, placebo-controlled trials of recombinant ß-interferon in patients with PPMS including trials of MS which report separate outcomes in subgroups of patients with PPMS.

Data collection and analysis
Two reviewers independently extracted and assessed trials' quality according to the criteria outlined in The Cochrane Handbook

Main results
Of 1280 potential studies evaluated, only two Randomized Control Trials (123 patients) were included. ß-interferon treatment compared to placebo did not show differences regarding the proportion of patients with progression of the disease (RR 0.89, 95% CI 0.55 to1.43), and it was associated with a greater frequency of treatment-related adverse events (RR 1.90, 95% CI 1.45-2.48). One of the trials evaluated the MRI secondary outcome pre-specified in the protocol. This trial showed that at two years the numbers of active lesions on brain MRI scan in ß-interferon arm were significantly lower than in placebo arm (weighted mean difference -1.3, 95% CI -2.15 to -0.45, P = 0.003); also, the number of participants with active lesions was significantly higher in placebo arm vs. ß-interferon arm at two years (RR 0.43, 95% CI 0.22 to 0.86, P = 0.02).

Authors' conclusions
Limited data on the effect of ß-interferon treatment on PPMS exists. Only two single-centre placebo controlled trials of interferon beta have been done. Based on this review, the included studies showed that ß-interferon treatment was not associated with reduced disability progression in PPMS patients. However, the trial population was too small to allow definitive conclusions on the efficacy of ß-interferon therapy in PPMS patients. Larger research studies need to be done in patients with PPMS in order to clarify whether ß-interferon is effective in this population.


Interferon beta for secondary progressive multiple sclerosis (protocol stage)

Title: Interferon beta for secondary progressive multiple sclerosis
Stage: Protocol
Date of creation: 17 November 2004
Last Updated: 22 September 2008
Author: Filippini, Graziella
Country: Italy
Entity: Multiple Sclerosis Group
Get full text on the Cochrane Library

Revisione Cochrane: Interferon in relapsing-remitting multiple sclerosis

Rice GP, Incorvaia B, Munari LM., Ebers G, Polman C, D'Amico R, Parmelli E, Filippini G

Summary

The use of interferons for treating people with the relapsing-remitting form of multiple sclerosis

Multiple sclerosis (MS) is a chronic disease of the nervous system which affects young and middle-aged adults. Repeated damage to the myelin sheaths and other parts of the nerves can lead to serious disability. MS may be related to the immune system. Interferons have several effects on the immune system, and act against viruses. Interferons can help to reduce disability and attacks for people with multiple sclerosis, but there is not enough evidence about their usefulness in the long term. The review of trials found that interferons administered intramuscularly or subcutaneously can lead to a moderate reduction in recurrences and disability in people who have MS with remissions. Interferon-1a administered by the oral route was not effective for prevention of relapses. Side effects were usually influenza-like symptoms, injection site-reactions, pains in the joints and muscles, fatigue and headacheb.

This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration,
currently published in The Cochrane Database of Systematic Reviews 2009 Issue 1, Copyright © 2009 The Cochrane Collaboration.
Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).
This record should be cited as: Rice G PA, Incorvaia B, Munari L, Ebers G, Polman C, D'Amico R, Parmelli E, Filippini G.
Interferon in relapsing-remitting multiple sclerosis.
Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD002002. DOI: 10.1002/14651858.CD002002.


This version first published online: October 23. 2001
Last assessed as up-to-date: April 30. 2007


Abstract

Background
Recombinant interferons have been shown to suppress both the clinical and magnetic resonance imaging (MRI) measures of disease activity in patients with relapsing remitting multiple sclerosis (RRMS).

Objectives
The objective of this review was to assess the effects of recombinant interferons in adults with RRMS.

Search strategy
We searched the Cochrane Multiple Sclerosis Group trials register (April 2007), MEDLINE (January 1966 April 2007), EMBASE (January 1985 to April 2007) and reference lists of articles. We also contacted manufacturers and researchers in the field

Selection criteria
The trials selected were double-blind, placebo-controlled, randomised trials of RRMS patients who were treated with recombinant interferon, given by the subcutaneous or the intramuscular route.

Data collection and analysis
All reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials.

Main results
Although eight trials involving 1301 participants were included in this review, only 919 (71%) contributed to the results concerning exacerbations and progression of the disease at two years. Specifically interferon significantly reduced the occurrence of exacerbations (Relative risk [RR] 0.80, 95% confidence interval [CI] 0.73 to 0.88, p < 0.001) and progression of the disease (RR 0.69, 95% CI 0.55 to 0.87, p = 0.002) two years after randomisation. However, the correct assignment of dropouts was essential to the demonstration of efficacy, most conspicuously concerning the effect of the drug on disease progression. If interferon-treated participants who dropped out were deemed to have progressed (worst case scenario) the significance of these effects was lost (RR 1.31, 95% CI 0.60 to 2.89, p = 0.5). The evolution in magnetic resonance imaging (MRI) technology in the decade in which these trials were performed and different reporting of data among trials made it impossible to perform a quantitative analysis of the MRI results. Both clinical and laboratory side effects reported in the trials were more frequent in treated participants than in controls; there was no information after two years of follow-up. The impact of interferon treatment (and its side effects) on the quality of life of patients was not reported in any trial included in this review.

Authors' conclusions
The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment. Interferon administered by the oral route was not effective for prevention of relapses. Longer follow-up and more uniform reporting of clinical and MRI outcomes among these trials might have allowed for a more convincing conclusion.


Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis

Clerico M, Faggiano F, Palace J, Rice GP, Tintorè Subirana M, Durelli L

Summary

Treatment of Multiple Sclerosis (MS) patients at a very early stage of the disease with recombinant interferon beta (IFN beta-1a and IFN beta-1b ) or glatiramer acetate (GA) could be useful in preventing irreversible damage in the central nervous system

Treatment of relapsing-remitting Multiple Sclerosis (RRMS) is currently based on immunomodulatory drugs such as recombinant interferon (IFN beta-1a and IFN beta-1b) or glatiramer acetate (GA) although these therapies have been shown to be only modestly effective. Recently it has been suggested that the nervous damage, supported by inflammation processes, is an early event in MS evolution which immunomodulatory drugs can only partially prevent. IFN and GA demonstrated only partial efficacy that could be ascribed to the fact that in the studies that lead to their approval they have been initiated in patients with a disease history of several years. The objective of this review was to assess IFN beta and GA efficacy in preventing the conversion to clinically defined multiple sclerosis in patients after the first demyelinating events. Among the pertinent literature, only three studies were found to test the efficacy of IFN beta including a total of 1160 participants (639 under treatment, 521 under placebo); while no published study testing the efficacy of GA was found. The review found that early interferon beta-1a treatment is effective in preventing the conversion of the first isolated demyelinating episodes into clinically definite MS both after one year and two years of follow-up. Side effects and adverse events occurrence was the same as reported by the many studies on IFN beta treatments in MS patients with different levels of the disease. More research is however needed to evaluate the long term preventing efficacy of these drugs and dosages

This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2009 Issue 1, Copyright © 2009 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X). This record should be cited as: Clerico M, Faggiano F, Palace J, Rice G, Tintorè M, Durelli L. Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD005278. DOI: 10.1002/14651858.CD005278.pub3.

This version first published online: April 16. 2008

Abstract

Background
Immunomodulatory drugs have been shown to be only modestly effective in clinically definite relapsing remitting multiple sclerosis (RRMS). It has been hypothesized that their efficacy could be higher if used at the first appearance of symptoms, that is in the clinically isolated syndromes (CIS) suggestive of demyelinating events, a pathology which carries a high risk to convert to clinically definite MS (CDMS).

Objectives
The objective of this review was to assess the effects of immunomodulatory drugs compared to placebo in adults in preventing conversion from CIS to CDMS which means the prevention of a second attack

Search strategy
We searched the Cochrane MS Group Trials Register (June 2007), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2007), MEDLINE (January 1966 to June 2007), EMBASE (January 1974 to June 2007) and reference lists of articles. We also contacted manufacturers and researchers in the field

Selection criteria
The trials selected were double-blind, placebo-controlled, randomised trials of CIS patients treated with immunomodulatory drugs.

Data collection and analysis
Study selection have been independently done by two reviewers. Two further reviewers independently assessed trial quality and extracted and analysed data. Study authors were contacted for additional informations. Adverse effects information was collected from the trials.

Main results
Only three trials tested the efficacy of interferon (IFN) beta including a total of 1160 participants (639 treatment, 521 placebo); no trial tested the efficacy of glatiramer acetate (GA). The metanalyses showed that the proportion of patients converting to CDMS was significantly lower in IFN beta-treated than in placebo-treated patients both after one year (pooled OR 0.53; 95% CI, 0.40 to 0.71; p <0.0001) as well as after two years of follow-up (pooled OR 0.52; 95% CI, 0.38 to 0.70; p <0.0001). Early treatment with IFN beta was associated with the side effect profile reported by the randomised controlled trials with this drug. Since side effects were reported with some heterogeneity in the three studies the metanalysis was possible only for the frequency of serious adverse events, not significantly different in IFN beta-treated or placebo-treated patients.

Authors' conclusions
The efficacy of IFN beta treatment on preventing the conversion from CIS to CDMS was confirmed over two years of follow-up. Since patients had some clinical heterogeneity (length of follow-up, clinical findings of initial attack), it could be useful for the clinical practice to further analyse the efficacy of IFN beta treatment in different patient subgroups.

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