Differential Effects Of Three Interferon-betas On Neutralizing AntiBodies In Patients With Multiple Sclerosis: A Follow Up Study In An Independent Laboratory
Bertolotto A, Malucchi S, Sala A, Orefice G, Carrieri PB, Capobianco M, Milano E, Melis F, Giordana MT
Journal of Neurology NeuroSurgery and Psychiatry 2002;73:148-153
Centro di Riferimento Regionale Sclerosi Multipla & Laboratorio di NeuroBiologia Clinica, Divisione Universitaria di Neurologia, Azienda Ospedaliera S Luigi, Universita di Torino, Orbassano, Italy
To evaluate the incidence and the prevalence of Neutralizing AntiBodies (NABs) to three Interferon-ß (IFN-ß) products in patients with Multiple Sclerosis (MS).
Sera were tested from 125 patients with Relapsing/Remitting MS. Patients were treated with IFN-ß-1b (Betaferon, n = 29) 8 MIU subcutaneously every other day, IFN-ß-1a (Avonex, n = 44) 30 microg intramuscularly once weekly, or IFN-ß-1a (Rebif, n = 36) 22 microg subcutaneously three times weekly for 6 to 18 months.
An additional 16 patients were treated with Rebif 22 microg intramuscularly once or twice weekly. NABs were assessed using the cytopathic effect assay before treatment and every three months during treatment.
Patients with two or more consecutive positive samples were considered to be persistent NAB positive (NAB+).
At baseline, no patients were NAB+. NABs developed during the first three months of treatment and continued to develop until month 18.
Over 18 months of treatment, the risk of being persistent NAB+ was 31% for Betaferon, 15% for Rebif, and 2% for Avonex (Betaferon versus Avonex, p = 0.001; Betaferon versus Rebif, p = 0.19; Rebif versus Avonex, p = 0.04).
In all patients with one or more NAB+ samples, the risk of becoming NAB+ was 38% for Betaferon, 18% for Rebif, and 7% for Avonex (Betaferon versus Avonex, p = 0.0007; Betaferon versus Rebif, p = 0.10; Rebif versus Avonex, p = 0.07).
At month 18, the prevalence of persistent NAB+ patients was 31.6% for Betaferon, 18.7% for Rebif, and 4% for Avonex. Numbers of NAB+ patients observed were similar with intramuscular Rebif and with subcutaneous Rebif.
The three IFN-ß preparations have different degrees of immunogenicity, with Betaferon producing the highest incidence of NABs and Avonex the lowest.
These differences should be considered by Neurologists when selecting treatment for their patients with MS because NABs can reduce both BioAvailability and clinical efficacy of IFN-ß.
Biological Activity Of Interferon-beta In Multiple Sclerosis Is Affected By Treatment Regimen And Neutralizing AntiBodies
Bertolotto A, Sala A, Malucchi S, Marnetto F, Caldano M, Di Sapio A, Capobianco M, Gilli F
J Neurol NeuroSurg Psychiatry 2004 Sep;75(9):1294-9
Centro Riferimento Regionale Sclerosi Multipla (CReSM) and NeuroBiologia Clinica, ASO S. Luigi Gonzaga, Regione Gonzole 10, 10043, Orbassano, Torino, Italy
MxA gene expression is one of the most appropriate markers of biological activity of exogenous Interferon-beta (IFN-ß).
We quantified MxA mRNA for five consecutive days in 62 patients treated with IFN-ß (16, Avonex; 10, Betaferon; 24, Rebif 22; 12, Rebif 44), by quantitative-competitive polymerase chain reaction.
Every three months, IFN-ß induced Neutralizing AntiBodies (NABs) were evaluated in Sera using a cytopathic effect assay.
Two categories of patients were identified:
- One group (49/62) had a sharp post-injection increase in MxA expression
- Defined as "IFN-ß biological responder"
- The other group (13/62) had no MxA induction after IFN-ß administrations
- Defined as "IFN-ß biological non-responder"
In 11/13 biological non-responders, the persistent presence of NABs correlated with abolished biological activity, independently of treatment regimen. The two remaining IFN-ß biological non-responders were NAb-.
Among the 49 IFN-ß biological responders, biological activity was comparable between the four preparations on day 2 and 3 (+12 and +36 hours post-injection), but it was greater in Betaferon and both Rebif preparations on day 1, 4, and 5.
In biological responders treated three times a week, only 82% (59/72) of injections were considered effective, compared with 100% (13/13) of Avonex injections.
Our results suggest that an optimal IFN-ß regimen is not yet available: Avonex, given once a week, shows lower cumulative biological activity.
On the other hand, both Betaferon and Rebif, given three times a week, show 18% biologically ineffective injections and higher risk of developing NABs, which abolish biological activity.
Malucchi S, Sala A, Gilli F, Bottero R, Di Sapio A, Capobianco M, Bertolotto A
Neurology 2004 Jun 8;62(11):2031-7
Centro Riferimento Regionale Sclerosi Multipla (CReSM) & NeuroBiologia Clinica, Ospedale Universitario San Luigi, Orbassano, Italy
To analyze the impact of Neutralizing AntiBodies (NABs) on the clinical efficacy of IFN-ß.
This was an open-label study involving 78 patients with Multiple Sclerosis treated with Betaferon 8 million IU (MIU) subcutaneously (SC) every other day (n = 20), Rebif 22 micro g SC 3 times weekly (n = 25), or Avonex 30 micro g IM once weekly (n = 33).
Every 3 months, blood samples were collected and sera were analyzed for NABs using an AntiViral cytopathic effect assay.
Patients were categorized according to their NAB status: NAB negative (NAB-); isolated NAB positive (NAB+), patients with > or =1 positive sample (titer > or = 20); and persistent NAB+, patients with > or =2 consecutive positive samples (Titer > or = 20).
Patients who were NAB- and persistent NAB+ were compared for relapse rate, time between first and second relapse, percentage of relapse-free patients, and percentage of patients who had a sustained progression of > or =1 point on the Expanded Disability Status Scale (EDSS).
During IFN-ß treatment, both NAB+ and NAB- patients showed a reduction in relapse rate; this reduction (25%) was not significant in NAB+ patients but was significant (67%; p < 0.0001) in NAB- patients.
In addition, the mean relapse rate was higher (p = 0.039), mean time between first and second relapse was shorter (13 vs 21 months; p = 0.0064), and there was a trend suggesting that NABs affected the probability of remaining relapse free (p = 0.08).
A higher percentage of NAB+ patients versus NAB- patients had worsening of EDSS scores during follow-up (p = 0.013).
Persistent NABs significantly reduce the clinical efficacy of IFN-ß.