Prognostic biomarkers of IFNb therapy in multiple sclerosis patients.
BACKGROUND
Interferon beta (IFNb) reduces relapse frequency and disability progression in patients with multiple sclerosis (MS).


OBJECTIVE
Early identification of prognostic biomarkers of IFNb-treated patients will allow more effective management of MS.


METHODS
The IMPROVE study evaluated subcutaneous IFNb versus placebo in 180 patients with relapsing-remitting MS. Magnetic resonance imaging scans, clinical assessments, and blood samples were obtained at baseline and every 4 weeks from every participant. Thirty-nine biomarkers (32 transcripts; seven proteins) were studied in 155 patients from IMPROVE. Therapeutic response was defined by absence of new combined unique lesions, relapses, and sustained increase in Expanded Disability Status Scale over 1 year. A machine learning approach was used to examine the association between biomarker expression and treatment response.


RESULTS
While baseline levels of individual genes were relatively poor predictors, combinations of three genes were able to identify subjects with sub-optimal therapeutic responses. The triplet CASP2/IRF4/IRF6, previously identified in an independent dataset, was tested among other combinations. This triplet showed acceptable predictive accuracy (0.68) and specificity (0.88), but had relatively low sensitivity (0.22) resulting in an area under the curve (AUC) of 0.63. Other combinations of biomarkers resulted in AUC of up to 0.80 (e.g. CASP2/IL10/IL12Rb1).


CONCLUSIONS
Baseline expression, or induction ratios, of specific gene combinations correlate with future therapeutic response to IFNb, and have the potential to be prognostically useful.
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contribution sebaran@cgl.ucsf.edu.
Sergio E
SE
Baranzini
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contribution.
Lohith R
LR
Madireddy
Merck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the company.
Anne
A
Cromer
Merck Serono RBM S.p.A- Colleretto Giacosa, Turin, Italy.
Mauro
M
D'Antonio
Merck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the company.
Lorenz
L
Lehr
Merck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the company.
Manolo
M
Beelke
Merck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the company.
Pierre
P
Farmer
University of Siena, Siena, Italy.
Marco
M
Battaglini
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contribution.
Stacy J
SJ
Caillier
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contributionDepartment of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contributionMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyMerck Serono RBM S.p.A- Colleretto Giacosa, Turin, ItalyMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyUniversity of Siena, Siena, ItalyDepartment of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contributionMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyDepartment of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contribution.
Maria L
ML
Stromillo
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contributionDepartment of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contributionMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyMerck Serono RBM S.p.A- Colleretto Giacosa, Turin, ItalyMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyUniversity of Siena, Siena, ItalyDepartment of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contributionMerck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the companyDepartment of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contribution.
Nicola
N
De Stefano
Merck Serono S.A. - Geneva, Switzerland/During the completion of this study, Merck Serono closed its Geneva operations. These authors are no longer with the company.
Emmanuel
E
Monnet
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, USA/ Equal contribution.
Bruce A C
BA
Cree
D000328:Adult; D019540:Area Under Curve; D015415:Biomarkers / Q000032:analysis*; D053143:Caspase 2 / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D050835:Interferon Regulatory Factors / Q000235:genetics; D016899:Interferon-beta / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012372:ROC Curve; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D000099218:Interferon Regulatory Factor-4
D015415:Biomarkers; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D007155:Immunologic Factors; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D000099218:Interferon Regulatory Factor-4; C109803:IRF6 protein, human; C490360:CASP2 protein, human
Biomarker; RNA; bioinformatics; interferon beta; multiple sclerosis; prognostic