Breakthrough disease during interferon-[beta] therapy in MS: No signs of impaired biologic response.
BACKGROUND
Disease activity is highly variable in patients with multiple sclerosis (MS), both untreated and during interferon (IFN)-beta therapy. Breakthrough disease is often regarded as treatment failure; however, apart from neutralizing antibodies (NAbs), no blood biomarkers have been established as reliable indicators of treatment response, despite substantial, biologically measurable effects. We studied the biologic response to treatment in a cohort of NAb-negative patients to test whether difference in responsiveness could segregate patients with and without breakthrough disease during therapy.


METHODS
Gene expression in blood cells from 23 patients with relapsing-remitting MS was analyzed by microarray and PCR. Samples were collected pretreatment and 9-12 hours after IFNbeta injection at 3 and 6 months' treatment. Definition of breakthrough disease was based on the occurrence of relapses, disability progression, or subclinical activity on 3T MRI at 3 and 6 months.


RESULTS
Sixteen patients had breakthrough disease and 7 patients were stable. Microarray and PCR showed marked effects of IFNbeta on gene expression profiles, but biologic responses did not differ between patients with breakthrough disease and stable patients. However, pretreatment variables did differ: patients with breakthrough disease had lower baseline IL10 expression, more gadolinium-enhancing lesions, and a higher number and volume of T2 lesions.


CONCLUSIONS
Breakthrough disease during interferon (IFN)-beta treatment is not paralleled by differences in biologic responsiveness to treatment in NAb-negative patients; most likely, the spontaneously occurring variation in underlying disease activity between patients causes the varying level of breakthrough disease observed in IFNbeta-treated patients with multiple sclerosis.
Hesse
D
D
Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet. dan.hesse@get2net.dk
Krakauer
M
M
Lund
H
H
Søndergaard
H B
HB
Langkilde
A
A
Ryder
L P
LP
Sorensen
P S
PS
Sellebjerg
F
F
D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000627:therapeutic use; D016899:Interferon-beta / Q000276:immunology / Q000627:therapeutic use; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
D057134:Antibodies, Neutralizing; D007155:Immunologic Factors; D016899:Interferon-beta