Urinary neopterin and nitric oxide metabolites as markers of interferon beta-1a activity in primary progressive multiple sclerosis.
BACKGROUND
Interferon beta has not been demonstrated to be effective in exploratory phase 2 clinical trials in primary progressive multiple sclerosis. However, using more sensitive indicators of a treatment response, such as biomarkers, might help to identify sub-groups of patients who may benefit from therapy.


OBJECTIVE
To assess the utility of measuring urinary neopterin and nitric oxide metabolite excretion for monitoring interferon beta-1a (IFNbeta-1a) treatment in patients with primary progressive multiple sclerosis.


METHODS
Fifty patients from a phase II trial of IFNbeta-1a (Placebo n = 20; Avonex 1 x 30 microg/week (IFN-30), n = 15; Avonex 1 x 60 microg/week (IFN-60), n = 15), were enrolled. Patients were assessed using the Expanded Disability Status Scale. Urine samples were collected on each visit, 3 months apart, for a period of 24 months. Nitric oxide metabolites, nitrite/nitrate (NOx), were measured by colorimetric assay and neopterin and creatinine (Cr) were assayed using a high-performance liquid chromatography technique. NOx/creatinine ratio (NOxCR) and urinary neopterin/creatinine ratio (UNCR) quotients were calculated.


RESULTS
There was no significant difference between pre-dose, baseline levels of UNCR or NOxCR between the study groups. On the intention-to-treat analysis, there was a significant difference in UNCR levels between the placebo compared with IFN-30 (p = 0.03) or IFN-60 (p = 0.002) groups. The IFN-30 and IFN-60 groups did not differ. Within IFNbeta-1a-treated patients with primary progressive multiple sclerosis, median UNCR values were significantly higher in clinically stable (no Expanded Disability Status Scale change) compared with progressive patients (p = 0.002). IFNbeta-1a treatment did not significantly influence NOx excretion in patients with primary progressive multiple sclerosis.


CONCLUSIONS
Urinary neopterin is a potential biomarker to monitor the in vivo effects of IFNbeta-1a in primary progressive multiple sclerosis and other multiple sclerosis sub-types.
Rejdak
K
K
Department of Neurology, Medical University of Lublin, Lublin, Poland. krejdak@europe.com
Leary
S M
SM
Petzold
A
A
Thompson
A J
AJ
Miller
D H
DH
Giovannoni
G
G
D000328:Adult; D015415:Biomarkers / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003124:Colorimetry; D003404:Creatinine / Q000652:urine; D004185:Disability Evaluation; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis / Q000188:drug therapy* / Q000652:urine; D019798:Neopterin / Q000652:urine*; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000652:urine*; D009573:Nitrites / Q000652:urine; D011044:Poland; D011237:Predictive Value of Tests; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
D015415:Biomarkers; D007155:Immunologic Factors; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D019798:Neopterin; D016899:Interferon-beta; D003404:Creatinine; D000068556:Interferon beta-1a