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.
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%).
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 Cochrane Sclerosi Multipla
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
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.
Cochrane: Interferon Beta for Primary Progressive Multiple Sclerosis
Rojas JIgnacio, Romano M, Ciapponi A, Patrucco
L, Cristiano E
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 version first published online: January
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
Identify and summarize the evidence that ß-interferon is beneficial and
safe in patients with PPMS.
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
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
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).
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.
beta for secondary progressive multiple sclerosis (protocol
Interferon beta for secondary progressive multiple sclerosis
Cochrane: Interferon in relapsing-remitting multiple sclerosis
Rice GP, Incorvaia B, Munari LM., Ebers G, Polman
C, D'Amico R, Parmelli E, Filippini G
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 version first published online: October
Last assessed as up-to-date: April 30. 2007
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).
The objective of this review was to assess the effects of recombinant
interferons in adults with RRMS.
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
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.
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.
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.
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
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 version first published online: April
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).
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
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
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.
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.
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.