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Original Investigation |

Interleukin 17F Level and Interferon Beta Response in Patients With Multiple Sclerosis FREE

Hans-Peter Hartung, MD1; Lawrence Steinman, MD4; Douglas S. Goodin, MD5; Giancarlo Comi, MD6; Stuart Cook, MD7; Massimo Filippi, MD6; Paul O’Connor, MD9; Douglas R. Jeffery, MD10; Ludwig Kappos, MD11; Robert Axtell, MS, PhD4; Volker Knappertz, MD1,12; Timon Bogumil, MD8; Susanne Schwenke, PhD2; Ed Croze, PhD8; Rupert Sandbrink, MD, PhD1,2; Christopher Pohl, MD2,3
[+] Author Affiliations
1Department of Neurology, Heinrich-Heine-Universität, Düsseldorf, Germany
2Bayer Pharma, Berlin, Germany
3University Hospital of Bonn, Bonn, Germany
4Department of Neurology, Stanford University, Stanford, California
5University of California, San Francisco
6University “Vita-Salute” San Raffaele, Milan, Italy
7New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark
8Bayer HealthCare, Montville, New Jersey
9Department of Neurology, St Michael’s Hospital, Toronto, Ontario, Canada
10Multiple Sclerosis Center, Advance Neurology and Pain, Cornerstone Health Care, Advance, North Carolina
11University Hospital, Basel, Switzerland
12MedImmune, Gaithersburg, Maryland
JAMA Neurol. 2013;70(8):1017-1021. doi:10.1001/jamaneurol.2013.192.
Text Size: A A A
Published online

Importance  High serum levels of interleukin 17F (IL-17F) at baseline have been associated with suboptimal response to interferon beta in patients with relapsing-remitting multiple sclerosis.

Objective  To further investigate the role of IL-17F in predicting treatment response to interferon beta-1b in patients with relapsing-remitting multiple sclerosis using the Singulex Erenna IL-17F immunoassay.

Design, Setting, and Patients  Serum samples were analyzed from 239 randomly selected patients treated with interferon beta-1b, 250 μg, for at least 2 years in the Betaferon Efficacy Yielding Outcomes of a New Dose Study.

Exposure  Treatment with interferon beta-1b, 250 μg, for at least 2 years.

Main Outcome Measures  Levels of IL-17F at baseline and month 6 as well as the difference between the IL-17F levels at month 6 and baseline were compared between the following: (1) patients with less disease activity vs more disease activity; (2) patients with no disease activity vs some disease activity; and (3) responders vs nonresponders.

Results  Levels of IL-17F measured at baseline and month 6 did not correlate with lack of response to treatment after 2 years using clinical and magnetic resonance imaging criteria. Relapses and new lesions on magnetic resonance imaging were not associated with pretreatment serum IL-17F levels. When patients with neutralizing antibodies were excluded, the results did not change. All patients with levels of IL-17F greater than 200 pg/mL were associated with poor response with some clinical or radiological activity.

Conclusions and Relevance  An increase of IL-17F before and early after treatment with interferon beta-1b was not associated with poor response. These data do not support the value of IL-17F as a treatment response indicator for therapy of patients with multiple sclerosis with interferon beta, although high levels of IL-17F greater than 200 pg/mL may predict nonresponsiveness.

Interleukin 17F (IL-17F) is one of the signature cytokines of helper T 17 cells that play a key role in the defense against pathogens and autoimmunity.13 Helper T 17 cells have been invoked as key determinants of aberrant immune responses in multiple sclerosis.3,4,

Interleukin 17F has been shown to function in part differently from another member of the IL-17 cytokine family, IL-17A.2 Interleukin 17F is a central mediator of cellular immunity governing the expression of critical cytokines that exert proinflammatory effects.3 High serum levels of IL-17F at baseline have been associated with suboptimal response to interferon beta-1b in patients with relapsing-remitting multiple sclerosis.5,6 To further investigate the role of IL-17F in predicting treatment response to interferon beta-1b, we used the Singulex Erenna IL-17F immunoassay to analyze serum samples collected at baseline and after 6 months of treatment from 239 patients who participated in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) Study.

Study Design

Serum samples were analyzed from 239 randomly selected patients treated with interferon beta-1b, 250 µg, for at least 2 years in the BEYOND Study.7 In these patients, IL-17F was measured at baseline and after 6 months of treatment using the Singulex Erenna immunoassay. The Erenna IL-17F immunoassay kit makes use of a microparticle-based single-molecule counting technology.8 Human serum samples were diluted in assay buffer and concentrations of IL-17F were determined using a reference and standard curve. The limit of detection of the assay was 0.5 pg/mL. The expected median value of IL-17F in human serum from healthy control subjects was 20 pg/mL. The low limit of quantification was 1.6 pg/mL (≤20% coefficient of variation and ±20% recovery). The short-term effects of interferon beta were confirmed by measuring 2 known interferon-inducible proteins (interferon gamma–induced protein 10 and interferon-inducible T-cell α chemoattractant) using the Human Discovery MAP250 version 1.0 Luminex-based, multianalytes profiling assay (Myriad RBM).

Statistical Analysis

Using the entire patient group (n = 239), IL-17F levels at baseline and month 6 as well as the difference between IL-17F at month 6 and baseline (ΔIL-17F) were compared between the following: (1) patients with less disease activity (no relapse and ≤4 lesions on magnetic resonance imaging [MRI]) vs more disease activity (≥1 relapse or >4 MRI lesions) within 2 years of treatment; (2) patients with no disease activity (no relapse and no MRI lesion) vs some disease activity (≥1 relapse or ≥1 MRI lesion); and (3) responders (no relapse and no confirmed progression on the Expanded Disability Status Scale) vs nonresponders (≥1 relapse and confirmed progression on the Expanded Disability Status Scale). Additional group comparisons excluded patients with neutralizing antibodies to interferon beta. Outcomes of patients having baseline IL-17F concentrations greater than 50 pg/mL or greater than 200 pg/mL were described in line with previous studies that found patients with pretreatment IL-17F values greater than 50 pg/mL to be clinical nonresponders.5 Finally, correlation of IL-17F serum levels with the number of new MRI lesions and the annualized relapse rate was determined for the entire population.

Nonparametric methods were used for all analyses: Wilcoxon rank sum test for group comparisons and Spearman ρ for correlation. Values were compared graphically by means of scatterplots. P values were not corrected for multiple comparisons.

Baseline characteristics and disease course during the first 2 years of interferon beta-1b treatment were similar between the patient group used for IL-17F measurements and the entire BEYOND Study cohort (Table 1). There was no statistically significant difference between IL-17F levels at baseline and month 6 (median, 16.5 vs 16.8 pg/mL, respectively; P = .22). However, levels of interferon gamma–induced protein 10 and interferon-inducible T-cell α chemoattractant increased significantly from baseline to month 6. There was a 2.4-fold increase of median interferon gamma–induced protein 10 levels (P < .001) and a 2.4-fold increase of median interferon-inducible T-cell α chemoattractant levels (P < .001) (data not shown).

Table Graphic Jump LocationTable 1.  Baseline Characteristics and Disease Course of Patients Receiving Interferon Beta-1b in the Original Cohort of the BEYOND Study vs Those Selected for Interleukin 17F Measurement

When clinical and MRI criteria were used to measure response to treatment, 115 patients (48.1%) had less disease activity (no relapse and ≤4 MRI lesions) and 124 (51.9%) had more disease activity (≥1 relapse or >4 MRI lesions). Fifty-six patients (23.4%) had no disease activity (no relapse and no MRI lesion) and 183 (76.6%) had some disease activity (≥1 relapse or ≥1 MRI lesion). Using clinical response criteria, 124 patients (51.9%) were responders (no relapse and no confirmed progression on the Expanded Disability Status Scale), while 27 (11.3%) were nonresponders (≥1 relapse and confirmed progression on the Expanded Disability Status Scale).

Levels of IL-17F at baseline and month 6 as well as ΔIL-17F did not differ significantly between patient groups (Table 2, and eTable 1 and eTable 2 in Supplement). Similar results were obtained for the 149 patients who did not develop neutralizing antibodies during the entire study (data not shown).

Table Graphic Jump LocationTable 2.  Comparison of Baseline Interleukin 17F Concentrations

The frequency of high (>50 pg/mL) or very high (>200 pg/mL) IL-17F values at baseline was similar for the different definitions of active vs inactive disease used in our study (Table 2). Of note, we found that no patients without any clinical or radiological disease activity with interferon beta-1b treatment demonstrated baseline IL-17F values higher than 200 pg/mL, whereas 8 (4.4%) of the patients with at least some disease activity showed such values.

There was no significant correlation between baseline IL-17F level and the annualized relapse rate (ρ = 0.08; P = .21) and the number of new MRI lesions observed within the first 2 years of interferon beta-1b treatment (ρ = −0.13; P = .06) (eFigure in Supplement). Finally, there was no significant correlation between the month 6 IL-17F level and the annualized relapse rate (ρ = 0.01; P = .91), between ΔIL-17F and the annualized relapse rate (ρ = −0.02; P = .70), between the month 6 IL-17F level and the number of new MRI lesions observed within the first 2 years of interferon beta-1b treatment (ρ = −0.10; P = .16), or between ΔIL-17F and the number of new MRI lesions observed within the first 2 years of interferon beta-1b treatment (ρ = 0.01; P = .92).

We found that serum concentrations of IL-17F alone did not predict response to interferon beta-1b therapy in patients with relapsing-remitting multiple sclerosis. Baseline IL-17F levels in the group of patients with higher disease activity were in the same range as the group having lower disease activity. Relapses and new MRI lesions occurring in the first 2 years of interferon beta-1b exposure did not correlate with pretreatment IL-17F levels. Negative results were also obtained for the comparison of responders and nonresponders defined on the basis of stringent clinical criteria. Similar results were obtained for IL-17F measured at month 6 and for ΔIL-17F. When patients with neutralizing antibodies were excluded, the results did not change. Finally, IL-17F levels in patient serum did not differ during administration of interferon beta-1b, in contrast to large and significant changes in levels of acute interferon beta-1b bioactivity markers interferon gamma–induced protein 10 and interferon-inducible T-cell α chemoattractant.

Of note, the proportions of patients with pretreatment IL-17F values higher than 50 pg/mL, which had been the threshold for nonresponse in the study by Axtell et al,5 were similar in our patient strata. When focusing on patients with even higher pretreatment IL-17F values, we found that all patients with values higher than 200 pg/mL had at least some clinical or radiological disease activity while being treated with interferon beta-1b. Analyses of extreme outcomes are often illuminating because such analyses often eliminate patients who may be misclassified.9,10 However, considering all our results makes it difficult to draw a robust conclusion from this finding.

Conceptual and methodological differences may have contributed to the discordance of findings between the study by Axtell et al5 and this study. Axtell and colleagues collected samples from a single center, and patients were treated with interferon beta-1a or interferon beta-1b. Our study was multicenter, and patients were treated with interferon beta-1b exclusively. The IL-17F serum concentrations were determined in our study using an assay optimized to measure IL-17F level in human serum, which is different from the multiplex assay used by Axtell et al.5 The Singulex IL-17F assay is recognized to be one of the most accurate, reproducible, and sensitive assays available for measuring IL-17F concentrations in human serum.11 Although Axtell et al5 found a positive correlation between pretreatment IL-17 serum concentrations and nonresponse to interferon beta, these results were based on a much smaller patient cohort (n = 26) and exclusively used clinical criteria for nonresponse. In a recent study, Bushnell et al12 were also unable to correlate IL-17F serum levels with treatment response to interferon beta. However, in their study, IL-17F values did not exceed 50 pg/mL, which makes it difficult to compare their results with those reported by Axtell et al5 and those from our study.

Because the biology of interferon beta is complex, it is not unexpected that serum IL-17F concentration by itself is inadequate to predict treatment response. It has also been demonstrated in mice that IL-17F and IL-17A as single factors do not contribute vitally to the development of autoimmune neuroinflammation.13 Measurement of a combination of other cytokines in concert with IL-17F may be required. Although predictors of response to interferon beta remain elusive, much progress has been made in this area.1420 Recognizing the synergistic interactions between IL-17F and other potent mediators on immune regulation, identification of predictors of response to interferon beta treatment may still be possible. Given the multifaceted pathophysiology associated with disease progression and response to treatment by patients with relapsing-remitting multiple sclerosis, using extreme patient cohorts in combination with immune-based biomarker signatures may actually be the most efficient way of initially identifying response markers. One approach might be to focus first on subjects with the highest levels of IL-17F (>200 pg/mL) in future studies.

Accepted for Publication: January 22, 2013.

Corresponding Author: Hans-Peter Hartung, MD, Department of Neurology, Heinrich-Heine-Universität, Moorenstrasse 5, D-40225 Düsseldorf, Germany (hans-peter.hartung@uni-duesseldorf.de).

Published Online: June 3, 2013. doi:10.1001/jamaneurol.2013.192

Author Contributions: Drs Sandbrink and Pohl contributed equally to this work.

Study concept and design: Hartung, Steinman, Comi, Filippi, Jeffery, Kappos, Axtell, Knappertz, Bogumil, Croze, Sandbrink, and Pohl.

Acquisition of data: Hartung, Steinman, Goodin, Comi, Filippi, Jeffery, Kappos, Croze, and Sandbrink.

Analysis and interpretation of data: Hartung, Steinman, Comi, Cook, Filippi, O’Connor, Jeffery, Kappos, Knappertz, Bogumil, Schwenke, Croze, Sandbrink, and Pohl.

Drafting of the manuscript: Hartung, Steinman, Comi, Knappertz, and Croze.

Critical revision of the manuscript for important intellectual content: Steinman, Goodin, Cook, Filippi, O’Connor, Jeffery, Kappos, Axtell, Knappertz, Bogumil, Schwenke, Croze, Sandbrink, and Pohl.

Statistical analysis: Steinman, Knappertz, Schwenke, and Croze.

Obtained funding: Knappertz and Sandbrink.

Administrative, technical, and material support: Hartung, Steinman, Comi, Cook, Filippi, Jeffery, Croze, and Sandbrink.

Study supervision: Hartung, Steinman, Comi, Jeffery, Knappertz, Bogumil, Croze, Sandbrink, and Pohl.

Conflict of Interest Disclosures: Dr Hartung received honoraria for consultancy and lectures with approval by the Rector of Heinrich-Heine-Universität from Bayer Pharma, Biogen Idec, Genzyme, Hoffman–La Roche, Merck Serono, Novartis Pharma, and Teva–sanofi-aventis. Dr Steinman has served as a consultant for Bayer, Novartis, MedImmune, sanofi-aventis, Teva, and Biogen Idec. Dr Comi has received honoraria for consultancy from Bayer, Novartis, Teva, sanofi-aventis, Merck Serono, Actelion, and Genzyme and has received honoraria for invited lectures from Bayer, Novartis, Teva, sanofi-aventis, Merck Serono, Biogen, Serono Symposia International Foundation, and Genzyme. Dr Cook has received research support from Bayer HealthCare and consultation fees from Bayer HealthCare, Merck Serono, Biogen Idec, Teva, and sanofi-aventis. Dr Filippi serves on scientific advisory boards for Teva and Genmab, has received funding for travel from Bayer Schering Pharma, Biogen Idec, Genmab, Merck Serono, and Teva; serves as a consultant to Bayer Schering Pharma, Biogen Idec, Genmab, Merck Serono, Pepgen Corp, and Teva; serves on speakers’ bureaus for Bayer Schering Pharma, Biogen Idec, Genmab, Merck Serono, and Teva; receives research support from Bayer Schering Pharma, Biogen Idec, Genmab, Merck Serono, Teva, Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, and CurePSP; is editor in chief of Journal of Neurology; and serves on the editorial boards of the American Journal of Neuroradiology, BMC Musculoskeletal Disorders, Clinical Neurology and Neurosurgery, Erciyes Medical Journal, Journal of Neuroimaging, Journal of Neurovirology, Magnetic Resonance Imaging, Multiple Sclerosis, Neurological Sciences, and Lancet Neurology. Dr Jeffery has received honoraria for speaking and consulting from Bayer, Biogen Idec, Teva, Serono, Pfizer, GlaxoSmithKline, Novartis, Acorda, Genzyme, and Questcor and has received research support from Bayer, Biogen Idec, Teva, Serono, Pfizer, and Novartis. The University Hospital Basel as employer of Dr Kappos has received and dedicated to research support fees for board membership, consultancy, or speaking, or grants, in the last 3 years from Actelion, Advancell, Allozyne, Bayer, Bayhill, Biogen Idec, BioMarin, CSL Behring, Eli Lilly, European Union, Genmab, GeNeuro, Gianni Rubatto Foundation. Glenmark, Merck Serono, MediciNova, Mitsubishi Pharma, Novartis, Novartis Research Foundation, Novonordisk, Peptimmune, Roche, Roche Research Foundation, Santhera, sanofi-aventis, Swiss MS Society, Swiss National Research Foundation, Teva, UCB, and Wyeth. Dr Sandbrink holds stocks and stock options in Bayer Pharma AG. Dr Pohl holds stock options in Bayer Pharma AG.

Funding/Support: This work was supported by Bayer Pharma AG, Berlin, Germany.

Role of the Sponsor: Bayer Pharma AG was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.

Additional Contributions: Editorial assistance for the development of the manuscript was provided by S. Dougherty, AxioMed Communications, Inc, and was supported by Bayer Healthcare Pharmaceuticals.

Kolls  JK, Lindén  A.  Interleukin-17 family members and inflammation. Immunity. 2004;21(4):467-476.
PubMed   |  Link to Article
Yang  XO, Chang  SH, Park  H,  et al.  Regulation of inflammatory responses by IL-17F. J Exp Med. 2008;205(5):1063-1075.
PubMed   |  Link to Article
Korn  T, Bettelli  E, Oukka  M, Kuchroo  VK.  IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485-517.
PubMed   |  Link to Article
Mitsdoerffer  M, Kuchroo  V.  New pieces in the puzzle: how does interferon-beta really work in multiple sclerosis? Ann Neurol. 2009;65(5):487-488.
PubMed   |  Link to Article
Axtell  RC, de Jong  BA, Boniface  K,  et al.  T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010;16(4):406-412.
PubMed   |  Link to Article
Bălaşa  R, Huţanu  A, Bajko  Z, Feier  C, Pascu  I.  Does the serum IL-17 titer influence the efficacy of interferon-β treatment in multiple sclerosis patients? Rev Rom Med Lab. 2011;19:381-389.
O’Connor  P, Filippi  M, Arnason  B,  et al; BEYOND Study Group.  250 microg or 500 microg interferon beta-1b vs 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8(10):889-897.
PubMed   |  Link to Article
Todd  J, Freese  B, Lu  A,  et al.  Ultrasensitive flow-based immunoassays using single-molecule counting. Clin Chem. 2007;53(11):1990-1995.
PubMed   |  Link to Article
Risch  N, Zhang  H.  Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science. 1995;268(5217):1584-1589.
PubMed   |  Link to Article
Ebers  GC, Kukay  K, Bulman  DE,  et al.  A full genome search in multiple sclerosis. Nat Genet. 1996;13(4):472-476.
PubMed   |  Link to Article
Greenberg J, Furer V, Lu QA, et al. Advanced single molecule detection accelerating biomarker development utilizing cytokines through ultrasensitive immunoassays. http://www.singulex.com/documents/CytoInflamm2012_FINAL.pdf. Accessed March 23, 2012.
Bushnell  SE, Zhao  Z, Stebbins  CC,  et al.  Serum IL-17F does not predict poor response to IM IFNβ-1a in relapsing-remitting MS. Neurology. 2012;79(6):531-537.
PubMed   |  Link to Article
Haak  S, Croxford  AL, Kreymborg  K,  et al.  IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest. 2009;119(1):61-69.
PubMed
Killestein  J, Hartung  HP.  Interferon β in multiple sclerosis: predicting response at an early stage. J Neurol Neurosurg Psychiatry. 2008;79(6):616-617.
PubMed   |  Link to Article
Comabella  M, Lünemann  JD, Río  J,  et al.  A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis. Brain. 2009;132(Pt 12):3353-3365.
PubMed   |  Link to Article
van Baarsen  LGM, Vosslamber  S, Tijssen  M,  et al.  Pharmacogenomics of interferon-β therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients. PLoS One. 2008;3(4):e1927.
PubMed   |  Link to Article
Croze  E, Yamaguchi  KD, Knappertz  V, Reder  AT, Salamon  H.  Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis [published online June 19, 2012]. Pharmacogenomics J. doi:10.1038/tpj.2012.27.
PubMed
Río  J, Nos  C, Tintoré  M,  et al.  Defining the response to interferon-β in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59(2):344-352.
PubMed   |  Link to Article
Río  J, Castilló  J, Rovira  A,  et al.  Measures in the first year of therapy predict the response to interferon β in MS. Mult Scler. 2009;15(7):848-853.
PubMed   |  Link to Article
Killestein  J, Polman  CH.  Determinants of interferon β efficacy in patients with multiple sclerosis. Nat Rev Neurol. 2011;7(4):221-228.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Baseline Characteristics and Disease Course of Patients Receiving Interferon Beta-1b in the Original Cohort of the BEYOND Study vs Those Selected for Interleukin 17F Measurement
Table Graphic Jump LocationTable 2.  Comparison of Baseline Interleukin 17F Concentrations

References

Kolls  JK, Lindén  A.  Interleukin-17 family members and inflammation. Immunity. 2004;21(4):467-476.
PubMed   |  Link to Article
Yang  XO, Chang  SH, Park  H,  et al.  Regulation of inflammatory responses by IL-17F. J Exp Med. 2008;205(5):1063-1075.
PubMed   |  Link to Article
Korn  T, Bettelli  E, Oukka  M, Kuchroo  VK.  IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485-517.
PubMed   |  Link to Article
Mitsdoerffer  M, Kuchroo  V.  New pieces in the puzzle: how does interferon-beta really work in multiple sclerosis? Ann Neurol. 2009;65(5):487-488.
PubMed   |  Link to Article
Axtell  RC, de Jong  BA, Boniface  K,  et al.  T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010;16(4):406-412.
PubMed   |  Link to Article
Bălaşa  R, Huţanu  A, Bajko  Z, Feier  C, Pascu  I.  Does the serum IL-17 titer influence the efficacy of interferon-β treatment in multiple sclerosis patients? Rev Rom Med Lab. 2011;19:381-389.
O’Connor  P, Filippi  M, Arnason  B,  et al; BEYOND Study Group.  250 microg or 500 microg interferon beta-1b vs 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8(10):889-897.
PubMed   |  Link to Article
Todd  J, Freese  B, Lu  A,  et al.  Ultrasensitive flow-based immunoassays using single-molecule counting. Clin Chem. 2007;53(11):1990-1995.
PubMed   |  Link to Article
Risch  N, Zhang  H.  Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science. 1995;268(5217):1584-1589.
PubMed   |  Link to Article
Ebers  GC, Kukay  K, Bulman  DE,  et al.  A full genome search in multiple sclerosis. Nat Genet. 1996;13(4):472-476.
PubMed   |  Link to Article
Greenberg J, Furer V, Lu QA, et al. Advanced single molecule detection accelerating biomarker development utilizing cytokines through ultrasensitive immunoassays. http://www.singulex.com/documents/CytoInflamm2012_FINAL.pdf. Accessed March 23, 2012.
Bushnell  SE, Zhao  Z, Stebbins  CC,  et al.  Serum IL-17F does not predict poor response to IM IFNβ-1a in relapsing-remitting MS. Neurology. 2012;79(6):531-537.
PubMed   |  Link to Article
Haak  S, Croxford  AL, Kreymborg  K,  et al.  IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest. 2009;119(1):61-69.
PubMed
Killestein  J, Hartung  HP.  Interferon β in multiple sclerosis: predicting response at an early stage. J Neurol Neurosurg Psychiatry. 2008;79(6):616-617.
PubMed   |  Link to Article
Comabella  M, Lünemann  JD, Río  J,  et al.  A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis. Brain. 2009;132(Pt 12):3353-3365.
PubMed   |  Link to Article
van Baarsen  LGM, Vosslamber  S, Tijssen  M,  et al.  Pharmacogenomics of interferon-β therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients. PLoS One. 2008;3(4):e1927.
PubMed   |  Link to Article
Croze  E, Yamaguchi  KD, Knappertz  V, Reder  AT, Salamon  H.  Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis [published online June 19, 2012]. Pharmacogenomics J. doi:10.1038/tpj.2012.27.
PubMed
Río  J, Nos  C, Tintoré  M,  et al.  Defining the response to interferon-β in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59(2):344-352.
PubMed   |  Link to Article
Río  J, Castilló  J, Rovira  A,  et al.  Measures in the first year of therapy predict the response to interferon β in MS. Mult Scler. 2009;15(7):848-853.
PubMed   |  Link to Article
Killestein  J, Polman  CH.  Determinants of interferon β efficacy in patients with multiple sclerosis. Nat Rev Neurol. 2011;7(4):221-228.
PubMed   |  Link to Article

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Supplement.

eTable 1. Comparison of month 6 IL17-F in patients with (A) less vs more disease activity, (B) no vs some disease activity, (C) clinically defined responders vs nonresponders

eTable 2. Comparison of change of IL17-F to month 6 in patients with (A) less vs more disease activity, (B) no vs some disease activity, (C) clinically defined responders vs nonresponders

eFigure. Baseline IL-17F vs number of new MRI lesions

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