Predictive markers for response to interferon therapy in patients with multiple sclerosis.
BACKGROUND
Prolonged therapy with interferon beta (IFN beta) often leads to the development of anti-IFN beta binding antibodies (BAbs). A subset of the BAbs is of a neutralizing nature (neutralizing antibodies, NAbs) and is associated with reduced clinical efficacy of therapy. Myxovirus-resistance-protein A (MxA) has proven to be a reliable biomarker of IFN beta bioactivity. We analyzed the prognostic value of MxA mRNA, NAbs, and BAbs on the risk of having a new relapse in IFN beta-treated patients.


METHODS
A 3-year study was conducted in 137 IFN beta-treated patients. Blood samples for BAbs, NAbs, and MxA mRNA measurements were taken after 12 +/- 3 months of therapy. Analysis of relapse-free survival (RFS) was performed for all measures by using known thresholds, generating "positive" and "negative" groups. Also, time between sampling and following relapse and risk of new relapses were calculated.


RESULTS
The MxA-negative group showed poorer RFS rates than the MxA-positive group [p < 0.0001, hazard ratio (HR) = 2.87]. Likewise, the NAb-positive group showed poorer RFS rates than the NAb-negative group (p =0.0013; HR = 2.49). On the contrary, BAb measurement did not show a clear clinical significance.


CONCLUSIONS
Findings indicate that measurements of both myxovirus-resistance-protein A (MxA) and neutralizing antibodies (NAbs) predict the risk of new relapses; however, the slightly stronger prognostic significance of MxA mRNA and the easier method for it measurement make MxA mRNA the preferred biomarker for monitoring interferon beta (IFN beta)-treated patients. This information can be used to better tailor treatment to the individual patient with MS.
Malucchi
S
S
Centro di Riferimento Regionale Sclerosi Multipla and Neurobiologia Clinica, ASO S. Luigi Gonzaga, Regione Gonzole 10, I-10043 Orbassano, Torino, Italy.
Gilli
F
F
Caldano
M
M
Marnetto
F
F
Valentino
P
P
Granieri
L
L
Sala
A
A
Capobianco
M
M
Bertolotto
A
A
D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000032:analysis / Q000097:blood / Q000276:immunology; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D018572:Disease-Free Survival; D004351:Drug Resistance / Q000276:immunology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy*; D064547:Myxovirus Resistance Proteins; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000097:blood*; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
D000906:Antibodies; D015415:Biomarkers; D007155:Immunologic Factors; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D016899:Interferon-beta; D019204:GTP-Binding Proteins