Breakthrough disease during interferon-[beta] therapy in MS: No signs of impaired biologic response

TY - JOUR

T1 - Breakthrough disease during interferon-[beta] therapy in MS: No signs of impaired biologic response

AU - Hesse, D

AU - Krakauer, M

AU - Lund, H

AU - Søndergaard, H B

AU - Langkilde, A

AU - Ryder, L P

AU - Sørensen, Per Soelberg

AU - Sellebjerg, F

AU - Langkilde, Annika

PY - 2010/5/4

Y1 - 2010/5/4

N2 - Background: Disease activity is highly variable in patients with multiple sclerosis (MS), both untreated and during interferon (IFN)-β 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 IFNβ 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 IFNβ 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)-β 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 IFNβ-treated patients with multiple sclerosis.

AB - Background: Disease activity is highly variable in patients with multiple sclerosis (MS), both untreated and during interferon (IFN)-β 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 IFNβ 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 IFNβ 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)-β 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 IFNβ-treated patients with multiple sclerosis.

U2 - 10.1212/wnl.0b013e3181dc1a94

DO - 10.1212/wnl.0b013e3181dc1a94

M3 - Journal article

SN - 0028-3878

VL - 74

SP - 1455

EP - 1462

JO - Neurology

JF - Neurology

IS - 18

ER -