Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis.
OBJECTIVE
To analyze the impact of neutralizing antibodies (NAbs) on the clinical efficacy of IFNbeta.


METHODS
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).


RESULTS
The incidence of persistent NAb+ patients was 35% for Betaferon, 20% for Rebif, and 3% for Avonex. During IFNbeta 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).


CONCLUSIONS
Persistent NAbs significantly reduce the clinical efficacy of IFNbeta.
Malucchi
S
S
Centro Riferimento Regionale Sclerosi Multipla (CReSM) & Neurobiologia Clinica, Ospedale Universitario San Luigi, Orbassano, Italy.
Sala
A
A
Gilli
F
F
Bottero
R
R
Di Sapio
A
A
Capobianco
M
M
Bertolotto
A
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D018450:Disease Progression; D018572:Disease-Free Survival; D004351:Drug Resistance; D004686:Encephalomyocarditis virus / Q000187:drug effects / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D007518:Isoantibodies / Q000276:immunology*; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology; D009500:Neutralization Tests; D011446:Prospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000998:Antiviral Agents; D007518:Isoantibodies; D000068576:Interferon beta-1b; D016899:Interferon-beta; D000068556:Interferon beta-1a