Interferon beta-1b

Interferon-β-1b: a review of its use in multiple sclerosis.

Zist Daru, 2010

Accessed on 28 Mar 2012 from http://www.zistdaru.ir/01.html..

Class:

Immunomodulator

(2)

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Target:

T lymphocytes

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

Blood-brain barrier (?)

(6)

Long-term experience with interferon beta-1b (Betaferon)in multiple sclerosis.

Arnason BGW

J Neurol. 2005 Sep; 252 Suppl 3:iii28-iii33. PMID: 16170497. Abstract

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

(21)

Interferon-beta-1b protects against multiple sclerosis-induced endothelial cells apoptosis.

Haghjooy Javanmard S, Saadatnia M M, Homayouni V V, Nikoogoftar M M, Maghzi AH, Etemadifar M, Chaitanya VG, McGee JC, Minagar A, Alexander SJ

Front Biosci (Elite Ed). 2012; 4:1368-74. PMID: 22201961. Abstract

T cell trafficking (?)

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

(43)

Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis.

Leppert D, Waubant E, Bürk MR, Oksenberg JR, Hauser SL

Ann Neurol. 1996 Dec; 40(6):846-52. PMID: 9007089. Abstract

Matrix metalloproteinases

(43)

Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis.

Leppert D, Waubant E, Bürk MR, Oksenberg JR, Hauser SL

Ann Neurol. 1996 Dec; 40(6):846-52. PMID: 9007089. Abstract

(44)

Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9.

Stuve O, Chabot S, Jung SS, Williams G, Yong VW

J Neuroimmunol. 1997 Dec; 80(1-2):38-46. PMID: 9413258. Abstract

(45)

Changes of serum sICAM-1 and MMP-9 induced by rIFNbeta-1b treatment in relapsing-remitting MS.

Trojano M, Avolio C, Liuzzi GM, Ruggieri M, Defazio G, Liguori M, Santacroce MP, Paolicelli D, Giuliani F, Riccio P, et al.

Neurology. 1999 Oct 22; 53(7):1402-8. PMID: 10534242. Abstract

(46)

IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS.

Waubant E, Goodkin D, Bostrom A, Bacchetti P, Hietpas J, Lindberg R, Leppert D

Neurology. 2003 Jan 14; 60(1):52-7. PMID: 12525717. Abstract

Inflammatory cytokines

(47)

Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b.

Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, McGee J, Jennings MH, Gonzalez-Toledo E, Minagar A

Mult Scler. 2010 Jul; 16(7):801-9. PMID: 20621951. Abstract

Inflammasome

(66)

Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.

Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML

Sci Signal. 2012 May 22; 5(225):ra38. PMID: 22623753. Abstract

Status for MS:

Approved in US, EU, and other countries for relapsing forms of MS

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

(5)

10 years of interferon beta-1b (Beta feron therapy.

Kappos L, Hartung H-P

J Neurol. 2005 Sep; 252 Suppl 3:iii1-iii2. PMID: 16170493. Abstract

(15)

Berlex continues legal challenge to FDA over MS drug.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

(38)

Glaser V

Nat Biotechnol. 1996 Jul; 14(7):811-2. PMID: 9630997. Abstract

Approved in EU for CIS, RRMS, and SPMS with active disease

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

First disease-modifying therapy approved by the US Food and Drug Administration for use in MS (July, 1993)

(30)

Interferon-beta1b for the treatment of multiple sclerosis.

Lam S, Wang S, Gottesman M

Expert Opin Drug Metab Toxicol. 2008 Aug; 4(8):1111-7. PMID: 18680445. Abstract

(38)

Berlex continues legal challenge to FDA over MS drug.

Glaser V

Nat Biotechnol. 1996 Jul; 14(7):811-2. PMID: 9630997. Abstract

Administration:

For Betaseron, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer

(15)

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

For Extavia, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer

(40)

Patient Satisfaction with the New Interferon Beta-1b Autoinjector (BETACONNECT™).

Novartis, Aug 2009

Accessed on 28 Mar 2012 from http://www.pharma.us.novartis.com/product/pi/pdf/extavia.pdf.

The Betaconnect autoinjector was associated with a high level of patient satisfaction in an industry-funded study involving 118 individuals with MS

(195)

Ziemssen T, Sylvester L, Rametta M, Ross A P

Neurol Ther. 2015 Dec; 4(2):125-36. Epub 2015 Oct 27. PMID: 26662362. Abstract

Commercial:

Betaferon/Betaseron was developed by Schering AG (which operated as Berlex Laboratory in North America), a company that was taken over by Bayer HealthCare

(39)

PrescriptionDrug-Info.com, 26 Jan 2012

Accessed on 28 Mar 2012 from http://www.prescriptiondrug-info.com/drug_details.asp?title=Extavia&page=1008148&ad=true.

Betaferon/Betaseron is marketed by Bayer HealthCare

(39)

PrescriptionDrug-Info.com, 26 Jan 2012

Accessed on 28 Mar 2012 from http://www.prescriptiondrug-info.com/drug_details.asp?title=Extavia&page=1008148&ad=true.

Novartis introduced Extavia in 2009; Extavia is manufactured by Bayer HealthCare and distributed by Novartis

(39)

PrescriptionDrug-Info.com, 26 Jan 2012

Accessed on 28 Mar 2012 from http://www.prescriptiondrug-info.com/drug_details.asp?title=Extavia&page=1008148&ad=true.

(40)

Novartis, Aug 2009

Accessed on 28 Mar 2012 from http://www.pharma.us.novartis.com/product/pi/pdf/extavia.pdf.

Zist Daru Danesh Ltd (Iran) began producing ZIFERON in 2010

(36)

Iran mass produces MS drug Ziferon

Zist Daru, 2010

Accessed on 28 Mar 2012 from http://www.zistdaru.ir/01.html..

(37)

PRESSTV, 18 Sep 2010

Accessed on 28 Mar 2012 from http://www.presstv.ir/detail/143010.html.

Mountain View Pharmaceuticals received a European patent for polyethylene glycol conjugates of interferon beta-1b with enhanced biological potency (press release, June 2012)

(51)

Mountain View Pharmaceuticals receives European patent on potential long-acting drug for multiple sclerosis

Mountain View Pharmaceuticals, 11 Jun 2012

Accessed on 12 Jun 2012 from http://www.mvpharm.com/Documents/MVP%20Receives%20European%20Patent%20on%20Long-Acting%20MS%20Drug%20June%2011,%202012.pdf.

Filing of a supplemental Biologics License Application by Bayer for Betaconnect, a new means of delivering Betaseron, has been accepted by the US Food and Drug Administration (22 April 2015)

(169)

FDA Accepts Filing of BETACONNECT™* for Relapsing-Remitting Multiple Sclerosis Patients Taking BETASERON® (interferon beta-1b)

PR Newswire, 22 Apr 2015

Accessed on 28 Apr 2015 from http://www.prnewswire.com/news-releases/fda-accepts-filing-of-betaconnect-for-relapsing-remitting-multiple-sclerosis-patients-taking-betaseron-interferon-beta-1b-300070199.html.

Betaconnect, the first electronic autoinjector for use in treating RRMS, has been approved by the US Food and Drug Administration; this device is used for delivering Betaseron (September 25, 2015)

(187)

Bayer Receives FDA Approval for BETACONNECT - First and Only Electronic Autoinjector in Relapsing-Remitting Multiple Sclerosis (RRMS) Treatment

PR Newswire, 25 Sep 2015

Accessed on 29 Sep 2015 from http://www.prnewswire.com/news-releases/bayer-receives-fda-approval-for-betaconnect---first-and-only-electronic-autoinjector-in-relapsing-remitting-multiple-sclerosis-rrms-treatment-300149438.html.

Names

Name:

Interferon beta-1b

Trade name:

Betaseron (in the US)

(5)

10 years of interferon beta-1b (Beta feron therapy.

Kappos L, Hartung H-P

J Neurol. 2005 Sep; 252 Suppl 3:iii1-iii2. PMID: 16170493. Abstract

(30)

Interferon-beta1b for the treatment of multiple sclerosis.

Lam S, Wang S, Gottesman M

Expert Opin Drug Metab Toxicol. 2008 Aug; 4(8):1111-7. PMID: 18680445. Abstract

Betaferon (in Europe)

(5)

10 years of interferon beta-1b (Beta feron therapy.

Kappos L, Hartung H-P

J Neurol. 2005 Sep; 252 Suppl 3:iii1-iii2. PMID: 16170493. Abstract

Extavia

(35)

Multiple sclerosis: pathogenesis and treatment.

Loma I, Heyman R

Curr Neuropharmacol. 2011 Sep; 9(3):409-16. PMID: 22379455. Abstract

ZIFERON

(36)

Zist Daru, 2010

Accessed on 28 Mar 2012 from http://www.zistdaru.ir/01.html..

Synonyms:

17-L-Serine-2-166-interferon beta1 (human fibroblast reduced)

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

BAY 86-5046

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

BAY86-5046

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Betaferon

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Betaseron

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

DRG-0054

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Extavia

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

IFN-beta (sub ser)

(1)

Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials.

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

IFNB-1b

(25)

Kappos L, Weinshenker B, Pozzilli C, Thompson AJ, Dahlke F, Beckmann K, Polman C, McFarland H, European(EU-SPMS) Interferon beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committee and Independent Advis, North American(NA-SPMS) Interferon beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committee and Independent

Neurology. 2004 Nov 23; 63(10):1779-87. PMID: 15557490. Abstract

IFNbeta-1b

(14)

Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study.

Panitch H, Miller A, Paty D, Weinshenker B, North American Study Group on Interferon beta-1b in Secondary Progressive MS

Neurology. 2004 Nov 23; 63(10):1788-95. PMID: 15557491. Abstract

Interferon beta-1b

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Interferon-1b

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

UNII-TTD90R31WZ

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

ZIFERON

(36)

Zist Daru, 2010

Accessed on 28 Mar 2012 from http://www.zistdaru.ir/01.html..

Systematic name:

2-166-Interferon beta1 (human fibroblast reduced), 17-L-serine-

(1)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Interferon beta1, 17-L-serine-, (2S-(2R*,5R*))-

(1)

Interferon-β-1b: a review of its use in multiple sclerosis.

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Physiology

Class:

Immunomodulator

(2)

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Target:

T lymphocytes

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

Blood-brain barrier (?)

(6)

Long-term experience with interferon beta-1b (Betaferon)in multiple sclerosis.

Arnason BGW

J Neurol. 2005 Sep; 252 Suppl 3:iii28-iii33. PMID: 16170497. Abstract

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

(21)

Interferon-beta-1b protects against multiple sclerosis-induced endothelial cells apoptosis.

Haghjooy Javanmard S, Saadatnia M M, Homayouni V V, Nikoogoftar M M, Maghzi AH, Etemadifar M, Chaitanya VG, McGee JC, Minagar A, Alexander SJ

Front Biosci (Elite Ed). 2012; 4:1368-74. PMID: 22201961. Abstract

T cell trafficking (?)

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

(43)

Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis.

Leppert D, Waubant E, Bürk MR, Oksenberg JR, Hauser SL

Ann Neurol. 1996 Dec; 40(6):846-52. PMID: 9007089. Abstract

Matrix metalloproteinases

(43)

Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis.

Leppert D, Waubant E, Bürk MR, Oksenberg JR, Hauser SL

Ann Neurol. 1996 Dec; 40(6):846-52. PMID: 9007089. Abstract

(44)

Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9.

Stuve O, Chabot S, Jung SS, Williams G, Yong VW

J Neuroimmunol. 1997 Dec; 80(1-2):38-46. PMID: 9413258. Abstract

(45)

Changes of serum sICAM-1 and MMP-9 induced by rIFNbeta-1b treatment in relapsing-remitting MS.

Trojano M, Avolio C, Liuzzi GM, Ruggieri M, Defazio G, Liguori M, Santacroce MP, Paolicelli D, Giuliani F, Riccio P, et al.

Neurology. 1999 Oct 22; 53(7):1402-8. PMID: 10534242. Abstract

(46)

IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS.

Waubant E, Goodkin D, Bostrom A, Bacchetti P, Hietpas J, Lindberg R, Leppert D

Neurology. 2003 Jan 14; 60(1):52-7. PMID: 12525717. Abstract

Inflammatory cytokines

(47)

Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b.

Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, McGee J, Jennings MH, Gonzalez-Toledo E, Minagar A

Mult Scler. 2010 Jul; 16(7):801-9. PMID: 20621951. Abstract

Inflammasome

(66)

Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.

Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML

Sci Signal. 2012 May 22; 5(225):ra38. PMID: 22623753. Abstract

Properties:

Interferons are naturally-occurring cytokines that are secreted in response to pathogens

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

(30)

Interferon-beta1b for the treatment of multiple sclerosis.

Lam S, Wang S, Gottesman M

Expert Opin Drug Metab Toxicol. 2008 Aug; 4(8):1111-7. PMID: 18680445. Abstract

Betaseron is a recombinant protein that is produced by fermentation of a strain of Escherichia coli containing a plasmid for expression of human interferon beta(ser17) (in which serine is substituted for cysteine at position 17)

(15)

Multiple sclerosis: pathogenesis and treatment.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Extavia is identical to Betaseron

(35)

Loma I, Heyman R

Curr Neuropharmacol. 2011 Sep; 9(3):409-16. PMID: 22379455. Abstract

Unlike the natural protein, is not glycosylated

(15)

Interferon-beta1b for the treatment of multiple sclerosis.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Lyophilized, 165-residue protein

(30)

Lam S, Wang S, Gottesman M

Expert Opin Drug Metab Toxicol. 2008 Aug; 4(8):1111-7. PMID: 18680445. Abstract

Molecular weight, 18,500 daltons

(15)

Interferon-β-1b: a review of its use in multiple sclerosis.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Serum concentrations are very low or undetectable after subcutaneous administration at the recommended dose

(2)

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Pharmacokinetic properties have been determined in healthy volunteers

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Controlled release, PEGylated version has been studied in mice

(56)

Enzon presents pre-clinical data on controlled release of PEGylated interferon-beta-1b and PEGylated anti-TNF-a antibody fragment at the Controlled Release Society annual meeting

Market Watch, The Wall Street Journal, 16 Jul 2012

Accessed on 16 Jul 2012 from http://www.marketwatch.com/story/enzon-presents-pre-clinical-data-on-controlled-release-of-pegylated-interferon-beta-1b-and-pegylated-anti-tnf-a-antibody-fragment-at-the-controlled-release-society-annual-meeting-2012-07-16.

Analysis has been performed to determine residues where covalent modification with polyethylene glycol does not inhibit (or improves) bioactivities in vitro (in contrast, random modification decreases the bioactivity)

(101)

Site-Specific PEGylation Enhances the Pharmacokinetic Properties and Antitumor Activity of Interferon Beta-1b.

Lee JI, Eisenberg SP, Rosendahl MS, Chlipala EA, Brown JD, Doherty DH, Cox GN

J Interferon Cytokine Res. 2013 Aug 20. PMID: 23962003. Abstract

Betaseron (interferon beta-1b) and Rebif (interferon beta-1a), which are formulated with human serum albumin, contain more aggregated protein and particles than does Avonex (interferon beta-1a), and the high levels of aggregates correlate with higher reported rates of neutralizing-antibody formation for Betaseron and Rebif

(72)

Characterization and quantitation of aggregates and particles in interferon-β products: Potential links between product quality attributes and immunogenicity.

Barnard JG, Babcock K, Carpenter JF

J Pharm Sci. 2012 Dec 11. PMID: 23233295. Abstract

A single injection can induce anti-drug antibodies in immune tolerant transgenic mice, and the titer increases with increasing frequency of treatment and dose

(76)

Effect of Treatment Regimen on the Immunogenicity of Human Interferon Beta in Immune Tolerant Mice.

Kijanka G, Jiskoot W, Schellekens H, Brinks V

Pharm Res. 2013 Jan 30. Epub 2013 Jan 30. PMID: 23361590. Abstract

Induces anti-drug antibodies in immune tolerant transgenic mice, such that intravenous delivery is the most immunogenic route; intramuscular, subcutaneous, and intraperitoneal delivery are similar to each other in their immunogenic effects

(76)

Effect of Treatment Regimen on the Immunogenicity of Human Interferon Beta in Immune Tolerant Mice.

Kijanka G, Jiskoot W, Schellekens H, Brinks V

Pharm Res. 2013 Jan 30. Epub 2013 Jan 30. PMID: 23361590. Abstract

Mechanisms/Effects

Human:

Mechanism in MS is unknown

(30)

Interferon-beta1b for the treatment of multiple sclerosis.

Lam S, Wang S, Gottesman M

Expert Opin Drug Metab Toxicol. 2008 Aug; 4(8):1111-7. PMID: 18680445. Abstract

Suppresses the development of inflammatory brain lesions in MS patients

(7)

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group.

Neurology. 1993 Apr; 43(4):655-61. PMID: 8469318. Abstract

(16)

Magnetic resonance imaging effects of interferon beta-1b in the BENEFIT study: integrated 2-year results.

Barkhof F, Polman CH, Radue E-W, Kappos L, Freedman MS, Edan G, Hartung H-P, Miller DH, Montalbán X, Poppe P, et al.

Arch Neurol. 2007 Sep; 64(9):1292-8. PMID: 17846268. Abstract

Decreases the expected number of contrast enhancing lesions (CELs) seen in MRI, such that new CEL formation is inhibited, but the resolution of previously-formed CELs is not enhanced, as shown by a population analysis using datasets from two different studies involving 24 individuals

(181)

A Population Approach to Characterize Interferon Beta-1b Effect on Contrast Enhancing Lesions in Patients With Relapsing Remitting Multiple Sclerosis.

Gulati A, Bagnato F, Villoslada P, Velez de Mendizabal N

CPT Pharmacometrics Syst Pharmacol. 2015 May; 4(5):295-304. Epub 2015 Apr 24. PMID: 26225255. Abstract

Stabilizes the blood-brain barrier (BBB), based on experiments in which serum from RRMS patients treated with interferon beta-1b reduced the permeability of an in vitro BBB model (human endothelial cells co-cultured with rat astrocytes) as compared with serum from untreated patients

(3)

Serum from interferon-β-1b-treated patients with early multiple sclerosis stabilizes the blood-brain barrier in vitro.

Müller M, Frese A, Nassenstein I, Hoppen M, Marziniak M, Ringelstein E B, Kim K S, Schäbitz W-R, Kraus J

Mult Scler. 2012 Feb; 18(2):236-9. Epub 2011 Aug 15. PMID: 21844066. Abstract

Downregulates expression of the integrin VLA-4/CD49d (which is implicated in MS pathology) on CD8+ T cells and on primed but not naïve CD4+ cells in MS patients, in agreement with the idea that the drug influences the interaction of immune cells and the blood-brain barrier

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

Increases the plasma concentration of soluble vascular cell adhesion molecule-1 (the soluble form of the VLA-4 integrin ligand) in MS patients

(20)

Cytokines and adhesion molecules in multiple sclerosis patients treated with interferon-beta1b.

Jensen J, Krakauer M, Sellebjerg F

Cytokine. 2005 Jan 7; 29(1):24-30. PMID: 15579375. Abstract

Inhibits MS-induced apoptosis of endothelial cells (potentially indicating a role in preserving the blood-brain barrier), as shown by experiments in which apoptosis of human umbilical endothelial cells was induced by sera from exacerbating MS patients and blocked by interferon beta-1b

(21)

Interferon-beta-1b protects against multiple sclerosis-induced endothelial cells apoptosis.

Haghjooy Javanmard S, Saadatnia M M, Homayouni V V, Nikoogoftar M M, Maghzi AH, Etemadifar M, Chaitanya VG, McGee JC, Minagar A, Alexander SJ

Front Biosci (Elite Ed). 2012; 4:1368-74. PMID: 22201961. Abstract

Inhibits interleukin-2–induced secretion of gelatinases (matrix metalloproteinases that digest subendothelial basement membrane components) and migration across an artificial basement membrane by human T cells, suggesting that the drug might interfere with the migration of activated T cells to the central nervous system

(43)

Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis.

Leppert D, Waubant E, Bürk MR, Oksenberg JR, Hauser SL

Ann Neurol. 1996 Dec; 40(6):846-52. PMID: 9007089. Abstract

Inhibits chemokine-induced expression of matrix metalloproteinase-9 and migration of human peripheral blood mononuclear cells across a fibronectin matrix

(44)

Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9.

Stuve O, Chabot S, Jung SS, Williams G, Yong VW

J Neuroimmunol. 1997 Dec; 80(1-2):38-46. PMID: 9413258. Abstract

Decreases serum matrix metalloproteinase-9 activity in MS patients

(45)

Changes of serum sICAM-1 and MMP-9 induced by rIFNbeta-1b treatment in relapsing-remitting MS.

Trojano M, Avolio C, Liuzzi GM, Ruggieri M, Defazio G, Liguori M, Santacroce MP, Paolicelli D, Giuliani F, Riccio P, et al.

Neurology. 1999 Oct 22; 53(7):1402-8. PMID: 10534242. Abstract

Increases serum levels of intercellular adhesion molecule-1 in MS patients

(45)

Changes of serum sICAM-1 and MMP-9 induced by rIFNbeta-1b treatment in relapsing-remitting MS.

Trojano M, Avolio C, Liuzzi GM, Ruggieri M, Defazio G, Liguori M, Santacroce MP, Paolicelli D, Giuliani F, Riccio P, et al.

Neurology. 1999 Oct 22; 53(7):1402-8. PMID: 10534242. Abstract

Reduces the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 (a ratio that is a predictor of new gadolinium-enhancing lesions) in SPMS patients

(46)

IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS.

Waubant E, Goodkin D, Bostrom A, Bacchetti P, Hietpas J, Lindberg R, Leppert D

Neurology. 2003 Jan 14; 60(1):52-7. PMID: 12525717. Abstract

Reduces serum levels of inflammatory cytokines that are associated with MS pathogenesis (interleukin-12 p40 and interleukin-23) in RRMS patients

(47)

Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b.

Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, McGee J, Jennings MH, Gonzalez-Toledo E, Minagar A

Mult Scler. 2010 Jul; 16(7):801-9. PMID: 20621951. Abstract

Affects cytokine release differently in cultured CD4+ and CD8+ T cells from RRMS and PPMS patients, such that the drug inhibits interferon-gamma and induces interleukin (IL)-4 selectively in CD4+ T cells from RRMS patients; induces IL-10 in all RRMS cell populations but only slightly in PPMS cells; always inhibits IL-5; and does not affect IL-17A

(62)

Differential effects of interferon-β1b on cytokine patterns of CD4+ and CD8+ T cells derived from RRMS and PPMS patients.

Skrzipek S, Vogelgesang A, Bröker BM, Dressel A

Mult Scler. 2012 May; 18(5):674-8. Epub 2011 Oct 24. PMID: 22025329. Abstract

Reduces serum levels of interferon-gamma (a sign of the intensity of an immune reaction) during relapses, based on a study of 35 women with RRMS

(141)

Cytokines and Disability in Interferon-β-1b Treated and Untreated Women with Multiple Sclerosis.

Trenova AG, Slavov GS, Manova MG, Kostadinova II

Arch Med Res. 2014 Aug 14. PMID: 25130430. Abstract

Interferon beta increases serum levels of interleukin-7, a cytokine that has been associated with MS, but decreases IL-7 receptor alpha chain expression and IL-7 consumption in peripheral blood leukocytes, indicating that interferon beta impairs IL-7 responsiveness

(130)

Interferon beta treatment of multiple sclerosis increases serum interleukin-7.

Lundström W, Hermanrud C, Sjöstrand M, Brauner S, Wahren-Herlenius M, Olsson T, Karrenbauer V, Hillert J, Fogdell-Hahn A

Mult Scler. 2014 May 12. PMID: 24821684. Abstract

Natalizumab or interferon beta treatment is associated with significantly reduced serum levels of a "cytokine signature" [a summed value of levels of tumor necrosis factor-alpha, interferon gamma, S100B, interleukin-1beta (IL-1beta), IL-6, IL-8, IL-17, and IL-23] in individuals with MS as compared with levels in drug naïve individuals with MS

(135)

The use of cytokine signature patterns: separating drug naïve, interferon and natalizumab-treated multiple sclerosis patients.

O'Connell KE, Mok T, Sweeney B, Ryan AM, Dev KK

Autoimmunity. 2014 Jun 30:1-7. PMID: 24974887. Abstract

Interferon beta treatment is associated with higher serum levels of pro-inflammatory cytokines as compared with natalizumab treatment in individuals with MS

(135)

The use of cytokine signature patterns: separating drug naïve, interferon and natalizumab-treated multiple sclerosis patients.

O'Connell KE, Mok T, Sweeney B, Ryan AM, Dev KK

Autoimmunity. 2014 Jun 30:1-7. PMID: 24974887. Abstract

Associated with increased serum levels of brain-derived neurotrophic factor, which are inversely correlated with the degree of disability (measured by the Expanded Disability Status Scale score), as shown in a study of 82 individuals with MS

(190)

Increased Serum Brain-derived Neurotrophic Factor in Multiple Sclerosis Patients on Interferon-β and Its Impact on Functional Abilities.

Mehrpour M, Akhoundi FH, Delgosha M, Keyvani H, Motamed MR, Sheibani B, Meysamie A

Neurologist. 2015 Oct; 20(4):57-60. PMID: 26468869. Abstract

In vitro treatment decreases CXCR4-dependent chemotaxis of T cells from individuals with RRMS or healthy individuals

(178)

Effect of IFN β-1b on CXCR4-dependent chemotaxis in T cells from multiple sclerosis patients.

Wostradowski T, Gudi V, Pul R, Gingele S, Lindquist JA, Stangel M, Lindquist S

Clin Exp Immunol. 2015 Jul 25. PMID: 26212126. Abstract

Reduces expression of CXCR4 mRNA, as well as surface expression of CXCR4, by primary human T cells

(178)

Effect of IFN β-1b on CXCR4-dependent chemotaxis in T cells from multiple sclerosis patients.

Wostradowski T, Gudi V, Pul R, Gingele S, Lindquist JA, Stangel M, Lindquist S

Clin Exp Immunol. 2015 Jul 25. PMID: 26212126. Abstract

Three major forms of interferon beta therapy (Avonex, Betaseron, and Rebif) are associated with a robust gene expression signature from blood that involves 25 upregulated genes; all of the drugs induce a similar maximum interferon beta activation state, although the average effect of Avonex is less than that of the other drugs

(164)

A robust type I interferon gene signature from blood RNA defines quantitative but not qualitative differences between three major IFNβ drugs in the treatment of multiple sclerosis.

Harari D, Orr I, Rotkopf R, Baranzini SE, Schreiber G

Hum Mol Genet. 2015 Feb 26. PMID: 25721402. Abstract

Interferon beta does not affect the frequency of CD27+CD43+ B1 cells, which is reduced in RRMS

(131)

B1 cells are unaffected by immune modulatory treatment in remitting-relapsing multiple sclerosis patients.

Rovituso D, Heller S, Schroeter M, Kleinschnitz C, Kuerten S

J Neuroimmunol. 2014 Apr 24. PMID: 24814390. Abstract

Decreases plasma concentrations of nitrogen dioxide + nitrate radical, 3-nitrotyrosine, and S-nitrosothiol, increases plasma concentrations of asymmetric and symmetric dimethyl-L-arginine, and increases plasma arginase activity in patients with RRMS

(85)

INF-β1b therapy modulates L-arginine and nitric oxide metabolism in patients with relapse remittent multiple sclerosis.

Stojanovic I, Vojinovic S, Ljubisavljevic S, Pavlovic R, Basic J, Pavlovic D, Ilic A, Cvetkovic T, Stukalov M

J Neurol Sci. 2012 Dec 15; 323(1-2):187-92. Epub 2012 Sep 28. PMID: 23026532. Abstract

Reduces serum nitrite levels (by 71%) and the annual relapse rate (by 71%), but does not affect cytokine levels or ratios in a manner that reflects effects on disease course, based on a 3-year longitudinal study of 18 RRMS patients receiving subcutaneous interferon beta-1b as monotherapy

(89)

Effects of Interferon β-1a and Interferon β-1b Monotherapies on Selected Serum Cytokines and Nitrite Levels in Patients with Relapsing-Remitting Multiple Sclerosis: A 3-Year Longitudinal Study.

Stępień A, Chalimoniuk M, Lubina-Dąbrowska N, Chrapusta SJ, Galbo H, Langfort J

Neuroimmunomodulation. 2013 May 24; 20(4):213-222. Epub 2013 May 24. PMID: 23711618. Abstract

Affects the expression of multiple genes (including CD20, a target of B cell depletion therapy), as shown by DNA microarray experiments to examine genome-wide RNA expression profiles of peripheral mononuclear blood cells from RRMS patients

(48)

Long-term genome-wide blood RNA expression profiles yield novel molecular response candidates for IFN-beta-1b treatment in relapsing remitting MS.

Goertsches RH, Hecker M, Koczan D, Serrano-Fernandez P, Moeller S, Thiesen H-J, Zettl UK

Pharmacogenomics. 2010 Feb; 11(2):147-61. PMID: 20136355. Abstract

Affects the expression of a variety of genes, including genes with roles in antioxidant activity, mitochondrial fatty acid metabolism, and immune regulation, as shown by analysis of patient gene expression profiles; greater changes were seen in long-term versus acute dosing

(53)

Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis.

Croze E, Yamaguchi KD, Knappertz V, Reder AT, Salamon H

Pharmacogenomics J. 2012 Jun 19. PMID: 22711062. Abstract

Increases the expression of mRNAs encoding Toll-like receptors TLR3 and TLR7 and MyD88 (a TLR adaptor molecule) in vitro in peripheral blood mononuclear cells from healthy volunteers and in vivo in individuals with RRMS

(100)

Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells.

Derkow K, Bauer JMJ, Hecker M, Paap BK, Thamilarasan M, Koczan D, Schott E, Deuschle K, Bellmann-Strobl J, Paul F, et al.

PLoS One. 2013; 8(8):e70626. Epub 2013 Aug 12. PMID: 23950974. Abstract

Increases the expression of Toll-like receptor 7 (TLR7) and MyD88 (a TLR adaptor molecule) proteins in plasmacytoid dendritic cells (DCs), but not in monocytes, myeloid DCs, B cells, CD4+ T cells, or CD8+ T cells

(100)

Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells.

Derkow K, Bauer JMJ, Hecker M, Paap BK, Thamilarasan M, Koczan D, Schott E, Deuschle K, Bellmann-Strobl J, Paul F, et al.

PLoS One. 2013; 8(8):e70626. Epub 2013 Aug 12. PMID: 23950974. Abstract

Treatment is associated with an increase in the expression of Toll-like receptor 7 in plasmacytoid dendritic cells of individuals with CIS or RRMS

(100)

Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells.

Derkow K, Bauer JMJ, Hecker M, Paap BK, Thamilarasan M, Koczan D, Schott E, Deuschle K, Bellmann-Strobl J, Paul F, et al.

PLoS One. 2013; 8(8):e70626. Epub 2013 Aug 12. PMID: 23950974. Abstract

Increases the expression Toll-like receptor 7 (TLR7) in plasmacytoid dendritic cells from healthy volunteers; subsequent stimulation of these cells with a TLR7-specific ligand then strongly increases production of interferon-alpha as compared to production in cells not pretreated with interferon beta-1b

(100)

Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells.

Derkow K, Bauer JMJ, Hecker M, Paap BK, Thamilarasan M, Koczan D, Schott E, Deuschle K, Bellmann-Strobl J, Paul F, et al.

PLoS One. 2013; 8(8):e70626. Epub 2013 Aug 12. PMID: 23950974. Abstract

Decreases the expression of mRNAs encoding Toll-like receptors TLR6 and TLR9 in vitro in peripheral blood mononuclear cells from healthy volunteers and decreases TLR9 (but not TLR6) mRNA expression in vivo in individuals with RRMS

(100)

Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells.

Derkow K, Bauer JMJ, Hecker M, Paap BK, Thamilarasan M, Koczan D, Schott E, Deuschle K, Bellmann-Strobl J, Paul F, et al.

PLoS One. 2013; 8(8):e70626. Epub 2013 Aug 12. PMID: 23950974. Abstract

Does not significantly affect the expression of mRNAs encoding Toll-like receptors TLR1, TLR2, TLR4, TLR8, and TLR10 in peripheral blood mononuclear cells from healthy volunteers

(100)

Multiple Sclerosis: Modulation of Toll-Like Receptor (TLR) Expression by Interferon-β Includes Upregulation of TLR7 in Plasmacytoid Dendritic Cells.

Derkow K, Bauer JMJ, Hecker M, Paap BK, Thamilarasan M, Koczan D, Schott E, Deuschle K, Bellmann-Strobl J, Paul F, et al.

PLoS One. 2013; 8(8):e70626. Epub 2013 Aug 12. PMID: 23950974. Abstract

Increases intracellular levels of Cu Zn superoxide dismutase (SOD1) in peripheral blood mononuclear cells (PBMCs); levels of SOD1 are reduced in cerebrospinal fluid and PBMCs in individuals with RRMS versus healthy controls

(183)

The IFN-β 1b effect on Cu Zn superoxide dismutase (SOD1) in peripheral mononuclear blood cells of relapsing-remitting multiple sclerosis patients and in neuroblastoma SK-N-BE cells.

Damiano S, Sasso A, De Felice B, Terrazzano G, Brescia Morra V, Carotenuto A, Orefice NS, Orefice G, Vacca G, Belfiore A, et al.

Brain Res Bull. 2015 Sep 3; 118:1-6. PMID: 26327496. Abstract

Increases intracellular and extracellular levels of Cu Zn superoxide dismutase (SOD1) in SK-N-BE neuroblastoma cell culture; levels of SOD1 are reduced in cerebrospinal fluid and PBMCs in individuals with RRMS versus healthy controls

(183)

The IFN-β 1b effect on Cu Zn superoxide dismutase (SOD1) in peripheral mononuclear blood cells of relapsing-remitting multiple sclerosis patients and in neuroblastoma SK-N-BE cells.

Damiano S, Sasso A, De Felice B, Terrazzano G, Brescia Morra V, Carotenuto A, Orefice NS, Orefice G, Vacca G, Belfiore A, et al.

Brain Res Bull. 2015 Sep 3; 118:1-6. PMID: 26327496. Abstract

Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start), in peripheral blood mononuclear cells from both healthy individuals and individuals with MS, as well as fetal brain cells and tumor cells; this transcript contains a unique first exon and the last 5 exons of full-length NCOA7

(149)

Induction of a Unique Isoform of the NCOA7 Oxidation Resistance Gene by Interferon β-1b.

Yu L, Croze E, Yamaguchi KD, Tran T, Reder AT, Litvak V, Volkert MR

J Interferon Cytokine Res. 2014 Oct 20. PMID: 25330068. Abstract

Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start); the encoded protein displays oxidation resistance activity

(149)

Induction of a Unique Isoform of the NCOA7 Oxidation Resistance Gene by Interferon β-1b.

Yu L, Croze E, Yamaguchi KD, Tran T, Reder AT, Litvak V, Volkert MR

J Interferon Cytokine Res. 2014 Oct 20. PMID: 25330068. Abstract

Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start); this induction requires activation of the interferon receptor as well as the JAK-STAT pathway

(149)

Induction of a Unique Isoform of the NCOA7 Oxidation Resistance Gene by Interferon β-1b.

Yu L, Croze E, Yamaguchi KD, Tran T, Reder AT, Litvak V, Volkert MR

J Interferon Cytokine Res. 2014 Oct 20. PMID: 25330068. Abstract

Increases the relative proportion of CD4+ T cells and decreases the proportion of CD8+ T cells in MS patients

(19)

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Muraro PA, Leist T, Bielekova B, McFarland HF

J Neuroimmunol. 2000 Nov 1; 111(1-2):186-94. PMID: 11063837. Abstract

Increases CD8+ regulatory T cell function in MS patients to levels similar to those in patients without MS

(6)

Long-term experience with interferon beta-1b (Betaferon)in multiple sclerosis.

Arnason BGW

J Neurol. 2005 Sep; 252 Suppl 3:iii28-iii33. PMID: 16170497. Abstract

Increases the proportion of CD56(bright) (immature) natural killer cells and decreases the proportion of cytotoxic CD56(dim) (mature) natural killer cells in the periphery

(83)

The role of natural killer cells in multiple sclerosis and their therapeutic implications.

Chanvillard C, Jacolik RF, Infante-Duarte C, Nayak RC

Front Immunol. 2013; 4:63. Epub 2013 Mar 13. PMID: 23493880. Abstract

Interferon beta reduces expression of natural killer cell receptor 1 in peripheral blood mononuclear cells; such expression is increased in individuals with MS relative to healthy controls

(142)

Are natural killer cells involved in multiple sclerosis etiology? Evidences from NKp46/NCR1 receptor modulation in an observational study.

Galuppo M, Giacoppo S, Sessa E, Bramanti P, Mazzon E

J Neurol Sci. 2014 Jul 30. PMID: 25115502. Abstract

Interferon beta (either -1a or -1b) treatment increases the frequncy of naïve T cells and decreases the frequency of central memory T cells (which is increased in MS) in RRMS patients

(79)

Immunoregulatory T cells in multiple sclerosis and the effect of interferon beta and glatiramer acetate treatment on T cell subpopulations.

Praksova P, Stourac P, Bednarik J, Vlckova E, Mikulkova Z, Michalek J

J Neurol Sci. 2012 Aug 15; 319(1-2):18-23. Epub 2012 Jun 05. PMID: 22676847. Abstract

Interferon beta increases serum levels of endogenous secretory receptor for advanced glycation end-products (esRAGE); serum esRAGE levels are reduced during clinical relapse

(153)

Disease modifying drugs modulate endogenous secretory receptor for advanced glycation end-products, a new biomarker of clinical relapse in multiple sclerosis.

Sternberg Z, Sternberg D, Drake A, Chichelli T, Yu J, Hojnacki D

J Neuroimmunol. 2014 Sep 15; 274(1-2):197-201. Epub 2014 Jul 15. PMID: 25064498. Abstract

Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS as compared with the number in treatment-naïve individuals or those treated with glatiramer acetate

(162)

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity.

Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, et al.

J Immunol. 2015 Mar 1; 194(5):2110-2116. Epub 2015 Feb 02. PMID: 25646307. Abstract

Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS; such cells are a significant source of interleukin-10 in these individuals and in healthy controls

(162)

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity.

Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, et al.

J Immunol. 2015 Mar 1; 194(5):2110-2116. Epub 2015 Feb 02. PMID: 25646307. Abstract

Interferon beta does not induce the secretion of interleukin-10 from unstimulated peripheral blood mononuclear cells from healthy individuals, but does enhance secretion when the cells are stimulated

(162)

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity.

Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, et al.

J Immunol. 2015 Mar 1; 194(5):2110-2116. Epub 2015 Feb 02. PMID: 25646307. Abstract

Interferon beta increases blood levels of B-cell activating factor (BAFF, the primary survival factor for B cells); BAFF levels are higher in individuals with MS than in healthy controls, but those with MS who do not relapse have higher BAFF levels than those who do, as shown in a prospective longitudinal study of 170 individuals with MS over 2.3 years

(194)

Changes in Blood B Cell-Activating Factor (BAFF) Levels in Multiple Sclerosis: A Sign of Treatment Outcome.

Kannel K, Alnek K, Vahter L, Gross-Paju K, Uibo R, Kisand KV

PLoS One. 2015; 10(11):e0143393. Epub 2015 Nov 23. PMID: 26600308. Abstract

Induces the proliferation and differentiation of human neural stem/progenitor cells in vitro

(18)

Interferon β-1b directly modulates human neural stem/progenitor cell fate.

Arscott TW, Soltys J, Knight J, Mao-Draayer Y

Brain Res. 2011 Sep 21; 1413:1-8. Epub 2011 Jul 23. PMID: 21855056. Abstract

Induces the development of anti-interferon antibodies in about one-third of MS patients, which usually disappear over time, but the effect of these antibodies on the response to treatment is unclear

(6)

Long-term experience with interferon beta-1b (Betaferon)in multiple sclerosis.

Arnason BGW

J Neurol. 2005 Sep; 252 Suppl 3:iii28-iii33. PMID: 16170497. Abstract

Interferon beta treatment can cause the production of antibodies that bind the drug, and their prevalence varies depending on the drug preparation; in one study of 124 individuals, 38.1% of those receiving Betaferon, 21.9% receiving Rebif, and 26.8% receiving CinnoVex produced binding antibodies

(114)

Antibodies to Interferon beta in Patients with Multiple Sclerosis Receiving CinnoVex, Rebif, and Betaferon.

Zare N, Zarkesh-Esfahani S H, Gharagozloo M, Shaygannejad V

J Korean Med Sci. 2013 Dec; 28(12):1801-6. Epub 2013 Nov 26. PMID: 24339712. Abstract

Interferon beta is associated with the formation of neutralizing antibodies; in a cross-sectional study in which serum samples from 2711 individuals with MS were submitted to the same independent laboratory, such antibodies occurred at a frequency of 35% for Rebif 44 microg (subcutaneous interferon beta-1a), 22% for Betaseron (interferon beta-1b) and Rebif 22 microg, and 7.5% for Avonex (intramuscular interferon beta-1a)

(176)

Frequency and magnitude of interferon β neutralizing antibodies in the evaluation of interferon β immunogenicity in patients with multiple sclerosis.

Grossberg SE, Oger J, Grossberg LD, Gehchan A, Klein JP

J Interferon Cytokine Res. 2011 Mar; 31(3):337-44. Epub 2011 Jan 12. PMID: 21226608. Abstract

Interferon beta is associated with the formation of neutralizing antibodies; in one study of 2711 individuals with MS, in those with detectable neutralizing antibodies, the titer was very high in 42% to 47% of individuals treated with interferon beta-1a but in only 22% of those treated with beta interferon-1b

(176)

Frequency and magnitude of interferon β neutralizing antibodies in the evaluation of interferon β immunogenicity in patients with multiple sclerosis.

Grossberg SE, Oger J, Grossberg LD, Gehchan A, Klein JP

J Interferon Cytokine Res. 2011 Mar; 31(3):337-44. Epub 2011 Jan 12. PMID: 21226608. Abstract

Interferon beta is associated with the formation of neutralizing antibodies; a systematic review and meta-analysis of randomized and non-randomized controlled trial data indicated that interferon beta-1a (Avonex) is least likely to lead to the formation of such antibodies (2.0 to 18.9% of individuals, as compared with 16.5 to 35.4% of individuals for interferon beta-1a (Rebif) and 27.3% to 53.3% for interferon beta-1b (Betaferon/Betaseron)

(182)

Development of interferon beta-neutralising antibodies in multiple sclerosis-a systematic review and meta-analysis.

Govindappa K, Sathish J, Park K, Kirkham J, Pirmohamed M

Eur J Clin Pharmacol. 2015 Aug 14. Epub 2015 Aug 14. PMID: 26268445. Abstract

Inhibits the activity of the ubiquitin/proteasome system (which is elevated in MS patients), as shown by analysis of plasma from MS patients; the level of inhibition correlates with the reduction in the number of T1-weighted enhancing lesions

(54)

Plasma ubiquitin?proteasome system profile in patients with multiple sclerosis: correlation with clinical features, neuroimaging, and treatment with interferon-beta-1b.

Minagar A, Ma W, Zhang X, Wang X, Zhang K, Alexander SJ, Gonzalez-Toledo E, Albitar M

Neurol Res. 2012 Jun 16. PMID: 22709658. Abstract

During interferon beta treatment, new inflammatory events are more likely in individuals with MS who display a distinct RNA profile, with increased expression of RNAs involved in lymphocyte signaling pathways

(98)

An RNA profile identifies two subsets of multiple sclerosis patients differing in disease activity.

Ottoboni L, Keenan BT, Tamayo P, Kuchroo M, Mesirov JP, Buckle GJ, Khoury SJ, Hafler DA, Weiner HL, De Jager PL

Sci Transl Med. 2012 Sep 26; 4(153):153ra131. PMID: 23019656. Abstract

Additively enhances the effects of 25-hydroxyvitamin D [25(OH)D] on MS activity, as shown in a study that measured serum levels of 25(OH)D and global gene expression profiles in individuals who began interferon beta-1b treatment after a CIS, who were monitored for ≤2 years

(148)

Molecular mechanism underlying the impact of vitamin D on disease activity of MS.

Munger KL, Köchert K, Simon KC, Kappos L, Polman CH, Freedman MS, Hartung HP, Miller DH, Montalbán X, Edan G, et al.

Ann Clin Transl Neurol. 2014 Aug; 1(8):605-17. Epub 2014 Aug 22. PMID: 25285313. Abstract

Effectiveness of interferon beta (measured in terms of a lack of relapses and disease progression), in individuals lacking neutralizing antibodies against the drug, correlates with a decrease in the titer of IgG antibodies against human herpes virus 6A/B, whereas an increase predicts relapse, as shown in a 2-year longitudinal study

(140)

Anti-Human Herpesvirus 6A/B IgG Correlates with Relapses and Progression in Multiple Sclerosis.

Ortega-Madueño I, Garcia-Montojo M, Dominguez-Mozo M I, Garcia-Martinez A, Arias-Leal A M, Casanova I, Arroyo R, Alvarez-Lafuente R

PLoS One. 2014; 9(8):e104836. Epub 2014 Aug 11. PMID: 25110949. Abstract

Response to interferon beta treatment correlates with levels of IgM antibodies against Epstein-Barr viral capsid antigen, as shown in a study of 87 individuals with MS

(192)

Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis.

Kvistad S, Myhr K-M, Holmøy T, Bakke S, Beiske AG, Bjerve KS, Hovdal H, Løken-Amsrud KI, Lilleås F, Midgard R, et al.

Mult Scler. 2014 May 19. PMID: 24842958. Abstract

Together with the anticoagulant agent warfarin, was used successfully to treat an individual with Baló's concentric sclerosis (a rare form of MS) and antiphospholipid syndrome

(161)

Combination Treatment of Interferon β-1b and Warfarin for a Patient With Baló's Concentric Sclerosis and Antiphospholipid Syndrome.

Tso A-C, Tsao W-L, Chen C-Y, Yang C-F, Peng G-S

Neurologist. 2015 Jan; 19(2):46-8. PMID: 25607332. Abstract

Mean adherence rates have been determined (through the analysis of 24 studies reporting on this topic) for intramuscular interferon beta-1a, given once a week (69.4%); subcutaneous interferon beta-1b, given every other day (63.8%); subcutaneous interferon beta-1a, given 3 times a week (58.4%); and glatiramer acetate, given daily (56.8%), with better outcomes in adherent versus nonadherent individuals shown in a smaller number of studies

(128)

Narrative review of the literature on adherence to disease-modifying therapies among patients with multiple sclerosis.

Menzin J, Caon C, Nichols C, White L A, Friedman M, Pill MW

J Manag Care Pharm. 2013 Jan-Feb; 19(1 Suppl A):S24-40. PMID: 23383731. Abstract

Associated with a relative reduction of 10.5% (Betaferon) in the risk of ≥1 relapses during 2 years of treatment and is less cost effective than natalizumab, according to a pharmacoeconomic analysis that used pre-existing data

(91)

Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis.

Filippini G, Giovane C D, Vacchi L, D'Amico R, Di Pietrantonj C, Beecher D, Salanti G

Cochrane Database Syst Rev. 2013 Jun 6; 6:CD008933. PMID: 23744561. Abstract

and costs of treatment in the Russian healthcare system

(136)

[Pharmacoeconomic analysis of the efficacy of natalizumab in relapsing-remitting multiple sclerosis].

Zh Nevrol Psikhiatr Im S S Korsakova. 2014; 114(5):65-9. PMID: 24988963. Abstract

Unlike natalizumab, interferon beta was not observed to decrease the extent and severity of damage to white matter, as shown in a diffusion tensor imaging study

(200)

White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis.

Wiebenga OT, Schoonheim MM, Hulst HE, Nagtegaal GJA, Strijbis EMM, Steenwijk MD, Polman CH, Pouwels PJW, Barkhof F, Geurts JJG

AJNR Am J Neuroradiol. 2016 Mar 10. PMID: 26965463. Abstract

Interferon beta probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients

(73)

Fcγ receptors in Norwegian multiple sclerosis patients and healthy controls.

Gavasso S, Torkildsen Ø, Marøy TH, Ulvestad E, Myhr K-M, Vedeler CA

Acta Neurol Scand Suppl. 2012(195):84-9. PMID: 23278662. Abstract

Lack of response to interferon beta-1b treatment for 2 years is not correlated with an increase in serum levels of interleukin 17F (IL-17F), although levels of IL-17F above 200 pg/ml might forecast nonresponsiveness, based on analysis of samples from 239 RRMS patients

(90)

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

Hartung H-P, Steinman L, Goodin DS, Comi G, Cook S, Filippi M, O'Connor P, Jeffery DR, Kappos L, Axtell R, et al.

JAMA Neurol. 2013 Jun 3:1-5. PMID: 23732754. Abstract

Interferon beta does not affect the fraction of CD8+ T cells that produce interleukin-17 (IL-17) or IL-10, cell subsets that are elevated in RRMS patients in remission as compared with healthy people

(94)

Fraction of IL-10+ and IL-17+ CD8 T cells is increased in MS patients in remission and during a relapse, but is not influenced by immune modulators.

Peelen E, Thewissen M, Knippenberg S, Smolders J, Muris A-H, Menheere P, Tervaert CJW, Hupperts R, Damoiseaux J

J Neuroimmunol. 2013 May 15; 258(1-2):77-84. Epub 2013 Mar 19. PMID: 23517930. Abstract

Interferon beta does not affect an MS-associated pattern of peripheral oxidative stress markers (reduced blood levels of Coenzyme Q10 and increased blood levels of anti-oxidized-low-density lipoprotein antibodies)

(156)

Oxidative stress is differentially present in multiple sclerosis courses, early evident, and unrelated to treatment.

Gironi M, Borgiani B, Mariani E, Cursano C, Mendozzi L, Cavarretta R, Saresella M, Clerici M, Comi G, Rovaris M, et al.

J Immunol Res. 2014; 2014:961863. Epub 2014 Mar 26. PMID: 24741637. Abstract

Because specific disease-modifying therapies (DMTs) are effective in some individuals and not others, genetic biomarkers of treatment sensitivity could be useful in DMT selection; discriminative genetic markers (variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes) have been identified, with the CCR5*d+ IFNAR1*G combination indicating interferon beta rather than glatiramer acetate treatment, based on a study of responders and nonresponders among >500 individuals treated with interferon beta or glatiramer acetate

(129)

Comparative pharmacogenetics of multiple sclerosis: IFN-β versus glatiramer acetate.

Kulakova OG, Tsareva E Y, Lvovs D, Favorov AV, Boyko AN, Favorova OO

Pharmacogenomics. 2014 Apr; 15(5):679-85. PMID: 24798724. Abstract

Resumption of interferon beta treatment within two weeks after delivery (versus later in the postpartum year) does not decrease the risk of relapse in the first six months postpartum, but might decrease the risk later in the first year postpartum

(154)

Immunomodulatory agents and risk of postpartum multiple sclerosis relapses.

Beaber B E, Chi MD, Brara S M, Zhang J L, Langer-Gould AM

Perm J. 2014 Winter; 18(1):9-13. PMID: 24626066. Abstract

Potential interferon beta treatment response genetic markers have been identified in a genome-wide association study involving 151 individuals with MS and validated in an independent group of 479 individuals

(203)

Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study.

Mahurkar S, Moldovan M, Suppiah V, Sorosina M, Clarelli F, Liberatore G, Malhotra S, Montalban X, Antigüedad A, Krupa M, et al.

Pharmacogenomics J. 2016 Mar 22. PMID: 27001119. Abstract

Nonresponse to interferon beta therapy is associated with an intronic variant in the gene SLC9A9, which encodes an Na+ -H+ exchanger, as shown in a genome-wide association study and validated in 3 independent cohorts

(174)

A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity.

Esposito F, Sorosina M, Ottoboni L, Lim ET, Replogle JM, Raj T, Brambilla P, Liberatore G, Guaschino C, Romeo M, et al.

Ann Neurol. 2015 Apr 25. PMID: 25914168. Abstract

Animal:

Interferon beta (used experimentally rather than interferon beta-1b) affects myeloid antigen-presenting cells, which may be responsible for immune modulation mediated by interferon beta, as shown by experiments in mice

(12)

Bench to bedside: tempering antigen-presenting cells in multiple sclerosis.

Prod'homme T, Zamvil SS

Nat Med. 2008 Jun; 14(6):614-5. PMID: 18535577. Abstract

Appears to suppress the Nod-like receptor, pyrin domain-containing 3 inflammasome and thereby ameliorate experimental autoimmune encephalomyelitis in a mouse model

(66)

Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.

Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML

Sci Signal. 2012 May 22; 5(225):ra38. PMID: 22623753. Abstract

Supresses Nod-like receptor, pyrin domain-containing 3 inflammasome activity in a mechanism that is mediated by suppressor of cytokine signaling 1, Vav1, Rac1-GTP, and mitochondrial reactive oxygen species generation

(66)

Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.

Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML

Sci Signal. 2012 May 22; 5(225):ra38. PMID: 22623753. Abstract

Attenuates experimental autoimmune encephalomyelitis (EAE) pathogenicity, but only in Nod-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome-dependent, and not in NLRP3 inflammasome-independent, EAE

(66)

Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.

Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML

Sci Signal. 2012 May 22; 5(225):ra38. PMID: 22623753. Abstract

Combination therapy consisting of murine interferon beta (which is immunomodulatory) and dimethyl fumarate (which is neuroprotective) is more effective in treating experimental autoimmune encephalomyelitis (providing better axon protection) than either therapy alone

(126)

Neuroprotective dimethyl fumarate synergizes with immunomodulatory interferon beta to provide enhanced axon protection in autoimmune neuroinflammation.

Reick C, Ellrichmann G, Thöne J, Scannevin RH, Saft C, Linker RA, Gold R

Exp Neurol. 2014 Apr 13. PMID: 24731948. Abstract

Treatment with a combination of interferon beta-secreting mesenchymal stem cells and minocycline reduces the severity of experimental autoimmune encephalomyelitis, primarily by promoting blood-spinal cord barrier integrity

(137)

Interferon β-secreting mesenchymal stem cells combined with minocycline attenuate experimental autoimmune encephalomyelitis.

Hou Y, Ryu C H, Jun J A, Kim S M, Jeong C H, Jeun S-S

J Neuroimmunol. 2014 Jun 20. PMID: 25005115. Abstract

(Recombinant mouse) interferon beta expands the population of transitional and regulatory B cells, and increases secretion of interleukin-10 in the spleen, in experimental autoimmune encephalomyelitis mice

(162)

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity.

Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, et al.

J Immunol. 2015 Mar 1; 194(5):2110-2116. Epub 2015 Feb 02. PMID: 25646307. Abstract

(Recombinant mouse) interferon beta reduces the severity of experimental autoimmune encephalomyelitis in mice

(162)

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity.

Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, et al.

J Immunol. 2015 Mar 1; 194(5):2110-2116. Epub 2015 Feb 02. PMID: 25646307. Abstract

(Recombinant mouse) interferon beta increases the production of anti-myelin oligodendrocyte glycoprotein IgG, but not IgM, in experimental autoimmune encephalomyelitis mice; disease severity does not correlate with the increased IgG levels

(162)

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity.

Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, et al.

J Immunol. 2015 Mar 1; 194(5):2110-2116. Epub 2015 Feb 02. PMID: 25646307. Abstract

(Recombinant mouse) interferon beta does not provide a clinical or histopathological benefit in experimental autoimmune encephalomyelitis (EAE) mice that are deficient for B cells (muMT mice), although it does in wild-type EAE mice

(162)

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity.

Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, et al.

J Immunol. 2015 Mar 1; 194(5):2110-2116. Epub 2015 Feb 02. PMID: 25646307. Abstract

Regulatory and Commercial Status

Status for MS:

Approved in US, EU, and other countries for relapsing forms of MS

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

(5)

10 years of interferon beta-1b (Beta feron therapy.

Kappos L, Hartung H-P

J Neurol. 2005 Sep; 252 Suppl 3:iii1-iii2. PMID: 16170493. Abstract

(15)

Berlex continues legal challenge to FDA over MS drug.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

(38)

Glaser V

Nat Biotechnol. 1996 Jul; 14(7):811-2. PMID: 9630997. Abstract

Approved in EU for CIS, RRMS, and SPMS with active disease

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

First disease-modifying therapy approved by the US Food and Drug Administration for use in MS (July, 1993)

(30)

Interferon-beta1b for the treatment of multiple sclerosis.

Lam S, Wang S, Gottesman M

Expert Opin Drug Metab Toxicol. 2008 Aug; 4(8):1111-7. PMID: 18680445. Abstract

(38)

Berlex continues legal challenge to FDA over MS drug.

Glaser V

Nat Biotechnol. 1996 Jul; 14(7):811-2. PMID: 9630997. Abstract

Highest status achieved (for any condition):

Approved

(30)

Interferon-beta1b for the treatment of multiple sclerosis.

Lam S, Wang S, Gottesman M

Expert Opin Drug Metab Toxicol. 2008 Aug; 4(8):1111-7. PMID: 18680445. Abstract

Other uses:

Has been tested in pilot studies for use in chronic viral dilated cardiomyopathy

(41)

Interferon beta-1b therapy in chronic viral dilated cardiomyopathy--is there a role for specific therapy?

Zimmermann O, Rodewald C, Radermacher M, Vetter M, Wiehe JM, Bienek-Ziolkowski M, Hombach V, Torzewski J

J Card Fail. 2010 Apr; 16(4):348-56. Epub 2010 Feb 07. PMID: 20350703. Abstract

Has been tested but not found to be effective for use in neuromyelitis optica

(42)

Interferon-beta(1b) treatment in neuromyelitis optica.

Tanaka M, Tanaka K, Komori M

Eur Neurol. 2009; 62(3):167-70. Epub 2009 Jul 07. PMID: 19590215. Abstract

Administration:

For Betaseron, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer

(15)

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

For Extavia, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer

(40)

Patient Satisfaction with the New Interferon Beta-1b Autoinjector (BETACONNECT™).

Novartis, Aug 2009

Accessed on 28 Mar 2012 from http://www.pharma.us.novartis.com/product/pi/pdf/extavia.pdf.

The Betaconnect autoinjector was associated with a high level of patient satisfaction in an industry-funded study involving 118 individuals with MS

(195)

Ziemssen T, Sylvester L, Rametta M, Ross A P

Neurol Ther. 2015 Dec; 4(2):125-36. Epub 2015 Oct 27. PMID: 26662362. Abstract

Negative effects:

Anaphylaxis

(15)

Interferon-β-1b: a review of its use in multiple sclerosis.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Decreased neutrophil count

(2)

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Decreased white blood cell count

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Depression

(15)

Interferon-β-1b: a review of its use in multiple sclerosis.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Elevated liver enzymes

(2)

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

One case of severe liver dysfunction has been reported in a patient who received interferon beta-1b and who had taken a melilot (sweet clover) supplement containing coumarin for three years

(50)

Severe liver dysfunction possibly caused by the combination of interferon beta-1b therapy and melilot (sweet clover) supplement.

Tamura S, Warabi Y, Matsubara S

J Clin Pharm Ther. 2012 May 30. PMID: 22642738. Abstract

Flu-like symptoms (which generally decrease after the first year)

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Injection site necrosis

(15)

Interferon-β-1b: a review of its use in multiple sclerosis.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Injection site reactions (such as redness, swelling, pain, and hypersensitivity) (generally decrease after the first year)

(2)

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Associated with multiple cutaneous necrotic lesions after 3 months of treatment in an individual with RRMS

(172)

Multiple cutaneous necrotic lesions associated with Interferon beta-1b injection for multiple sclerosis treatment: A case report and literature review.

Faghihi G, Basiri A, Pourazizi M, Abtahi-Naeini B, Saffaei A

J Res Pharm Pract. 2015 Apr-Jun; 4(2):99-103. PMID: 25984549. Abstract

Associated with severe septal panniculitis at the injection site in an individual with MS

(160)

Severe septal panniculitis in a multiple sclerosis patient treated with interferon-beta.

Mazzon E, Guarneri C, Giacoppo S, Rifici C, Tchernev G, Polimeni G, Wollina U

Int J Immunopathol Pharmacol. 2014 Oct-Dec; 27(4):669-74. PMID: 25572749. Abstract

Long-term use (≥2 years) is associated with a high prevalence (75%) of individuals exhibiting ≥1 cutaneous adverse event at a given point in time, based on a cross-sectional study

(147)

Prevalence of cutaneous adverse events associated with long-term disease-modifying therapy and their impact on health-related quality of life in patients with multiple sclerosis: a cross-sectional study.

Balak D M, Hengstman G J, Hajdarbegovic E, van den Brule R J, Hupperts RMM, Thio H B

BMC Neurol. 2013 Oct 16; 13(1):146. Epub 2013 Oct 16. PMID: 24131589. Abstract

Lymphopenia

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Lymphadenopathy

(2)

Interferon-β-1b: a review of its use in multiple sclerosis.

Plosker GL

CNS Drugs. 2011 Jan; 25(1):67-88. PMID: 21128695. Abstract

Nephrotic syndrome, with membraneous nephropathy revealed by histology, has occurred in two MS patients after long-term therapy

(74)

Nephrotic syndrome in multiple sclerosis patients who had undergone long-term interferon β-1b therapy.

Ikeda K, Okamoto T, Yamamura T, Ohsawa I, Furutera R, Murata M

Rinsho Shinkeigaku. 2013; 53(1):19-23. PMID: 23328061. Abstract

Nephrotic syndrome (suggestive of lupus nephritis) has been observed in one patient (with no evidence of systemic lupus erythematosus) after long-term treatment, which partially subsided after the patient switched to glatiramer acetate

(78)

Nephrotic Syndrome in a Multiple Sclerosis Patient Receiving Long-term Interferon Beta Therapy.

Wallbach M, Gröne HJ, Kitze B, Müller GA, Koziolek MJ

Am J Kidney Dis. 2013 Jan 31. PMID: 23375818. Abstract

Associated with pulmonary and cutaneous sarcoidosis in one individual with MS

(113)

Cutaneous and pulmonary sarcoidosis following treatment of multiple sclerosis with interferon-beta-1b: a case report.

Sahraian M A, Naser Moghadasi A, Owji M, Maboudi M, Kosari F, McGee JC, Minagar A

J Med Case Rep. 2013 Dec 13; 7(1):270. Epub 2013 Dec 13. PMID: 24330713. Abstract

Seizures

(15)

Rare MEFV variants are not associated with risk to develop multiple sclerosis and severity of disease.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Interferon beta treatment has been associated with the development of severe systemic side effects in MS patients with rare variants in MEFV (Mediterranean fever gene) in a Belgian population

(75)

Pauwels I, Cosemans L, Boonen S, Dubois B, Goris A

Mult Scler. 2013 Jan 16. PMID: 23325590. Abstract

Suicide

(15)

Interferon beta-1b-induced Sweet's syndrome in a patient with multiple sclerosis.

Bayer HealthCare Pharmaceuticals Inc. , May 2010

Accessed on 27 Mar 2012 from http://berlex.bayerhealthcare.com/html/products/pi/Betaseron_PI.pdf..

Induced Sweet's syndrome in one MS patient

(95)

Kim Y J, Lee H Y, Lee J Y, Yoon T Y

Int J Dermatol. 2013 Jun 20. PMID: 23786157. Abstract

Interferon beta has been associated with thrombotic microangiopathy caused by acquired ADAMTS13 deficiency, which was in turn the result of anti-ADAMTS13 IgG antibodies that developed after interferon beta therapy in one MS patient

(81)

Thrombotic microangiopathy due to acquired ADAMTS13 deficiency in a patient receiving interferon-beta treatment for multiple sclerosis.

Orvain C, Augusto J-F, Besson V, Marc G, Coppo P, Subra J-F, Sayegh J

Int Urol Nephrol. 2013 Feb 24. Epub 2013 Feb 24. PMID: 23435773. Abstract

Association of interferon beta drugs with thrombotic microangiopathy and nephrotic syndrome has led the European Medicines Agency to require stronger label warnings for Betaferon and Extavia (August 2014)

(143)

EU regulator warns on possible MS drugs side effects

Reuters, 20 Aug 2014

Accessed on 25 Aug 2014 from http://www.reuters.com/article/2014/08/20/ms-drugs-sideeffects-idUSL5N0QQ3T620140820.

Warning about a risk of thrombotic microangiopathy has been added to the patient package insert of Betaseron and Extavia by the US Food and Drug Administration (December 2015)

(198)

Drug Safety Labeling Changes

US Food and Drug Administration, 13 Jan 2016

Accessed on 29 Jan 2016 from http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm480758.htm.

Interferon beta has been associated with an increased incidence of thyroid dysfunction and thyroid autoimmunity during the initial year of treatment in an Italian multicenter study

(122)

Thyroid autoimmunity and dysfunction in multiple sclerosis patients during long-term treatment with interferon beta or glatiramer acetate: an Italian multicenter study.

Frisullo G, Calabrese M, Tortorella C, Paolicelli D, Ragonese P, Annovazzi P, Radaelli M, Malucchi S, Gallo A, Tomassini V, et al.

Mult Scler. 2014 Feb 10. PMID: 24515732. Abstract

Has been associated with the development of tumefactive brain lesions in neuromyelitis optica

(157)

Harmel J, Ringelstein M, Ingwersen J, Mathys C, Goebels N, Hartung H-P, Jarius S, Aktas O

BMC Neurol. 2014 Dec 17; 14(1):247. Epub 2014 Dec 17. PMID: 25516429. Abstract

Associated with livedo reticularis and secondary Raynaud phenomenon in one individual with MS, which, along with complications seen in other individuals, suggest that the drug can have vasoconstrictive and procoagulant effects

(115)

Interferons beta have vasoconstrictive and procoagulant effects: A woman who developed livedo reticularis and Raynaud phenomenon in association with interferon beta treatment for multiple sclerosis.

Rot U, Ledinek A H

Clin Neurol Neurosurg. 2013 Dec; 115 Suppl 1:S79-81. PMID: 24321162. Abstract

Exposure to interferon beta during pregnancy does not seem to be a major teratogenic risk, based on an analysis of 78 pregnancies

(65)

Multiple sclerosis and pregnancy: experience from a nationwide database in Germany.

Hellwig K, Haghikia A, Rockhoff M, Gold R

Ther Adv Neurol Disord. 2012 Sep; 5(5):247-53. PMID: 22973421. Abstract

Not associated with increased rates of pregnancy-related adverse events or birth defects in a prospective observational study involving a registry of 99 pregnant women with MS

(132)

Final results from the Betaseron (interferon β-1b) Pregnancy Registry: a prospective observational study of birth defects and pregnancy-related adverse events.

Coyle PK, Sinclair SM, Scheuerle AE, Thorp JM, Albano JD, Rametta MJ

BMJ Open. 2014; 4(5):e004536. PMID: 24821713. Abstract

Exposure to Betaferon/Betaseron during pregnancy is not associated with an increased rate of birth defects or spontaneous abortion, according to data on 423 prospective pregnancies (pregnant at time of reporting) with known outcomes in a pharmacovigilance database

(144)

Pregnancy outcomes in patients exposed to interferon beta-1b.

Romero RS, Lünzmann C, Bugge J-P

J Neurol Neurosurg Psychiatry. 2014 Sep 2. PMID: 25185209. Abstract

Exposure in would-be fathers just before (within 64 days, the duration of spermatogenesis) or at the time of conception does not appear to be associated with lower birth weight or a change in gestational age of newborns, based on an analysis of 37 cases of exposure to interferon beta

(125)

Birth Outcomes in Newborns Fathered by Men with Multiple Sclerosis Exposed to Disease-Modifying Drugs.

Lu E, Zhu F, Zhao Y, van der Kop M, Synnes A, Dahlgren L, Sadovnick DA, Traboulsee A, Tremlett H

CNS Drugs. 2014 Mar 19. PMID: 24643915. Abstract

Paternal exposure was not associated with increased risk of spontaneous abortion, congenital malformations, or adverse fetal outcomes, based on a study of 39 pregnancies fathered by men with MS exposed to interferon beta at time of conception as compared with 33 pregnancies fathered by men with MS without disease-modifying therapy exposure at that time

(134)

Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study.

Pecori C, Giannini M, Portaccio E, Ghezzi A, Hakiki B, Pastò L, Razzolini L, Sturchio A, De Giglio L, Pozzilli C, et al.

BMC Neurol. 2014 May 26; 14(1):114. Epub 2014 May 26. PMID: 24884599. Abstract

Does not cause teratogenic effects at the macroscopic level in cultured rat embryos, but does retard embryonic growth

(196)

The potential teratogenic effects of interferon beta-1a (IFNβ-1a) and interferon beta-1b (IFNβ-1b) on in vitro embryonic development.

Uçar İ, Ertekin T, Nisari M, Ceylan D, Al Ö, Ülger H

Folia Morphol (Warsz). 2015 Dec 29. PMID: 26711647. Abstract

Interferon beta did not reduce the efficacy of vaccination against pandemic H1N1 (swine flu, in 2009) or seasonal influenza (in 2010)

(116)

Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.

Olberg HK, Cox RJ, Nostbakken JK, Aarseth JH, Vedeler CA, Myhr K-M

Mult Scler. 2014 Jan 16. PMID: 24436455. Abstract

Interferon beta was not found to be associated with an increased risk of cancer (overall or specifically breast, colorectal, lung, or prostate) over 12 years in a case-control study involving 5146 individuals with RRMS, but a non-significant trend toward an association with breast cancer was detected

(151)

Assessment of cancer risk with β-interferon treatment for multiple sclerosis.

Kingwell E, Evans C, Zhu F, Oger J, Hashimoto S, Tremlett H

J Neurol Neurosurg Psychiatry. 2014 Mar 4. PMID: 24594506. Abstract

Commercial:

Betaferon/Betaseron was developed by Schering AG (which operated as Berlex Laboratory in North America), a company that was taken over by Bayer HealthCare

(39)

PrescriptionDrug-Info.com, 26 Jan 2012

Accessed on 28 Mar 2012 from http://www.prescriptiondrug-info.com/drug_details.asp?title=Extavia&page=1008148&ad=true.

Betaferon/Betaseron is marketed by Bayer HealthCare

(39)

PrescriptionDrug-Info.com, 26 Jan 2012

Accessed on 28 Mar 2012 from http://www.prescriptiondrug-info.com/drug_details.asp?title=Extavia&page=1008148&ad=true.

Novartis introduced Extavia in 2009; Extavia is manufactured by Bayer HealthCare and distributed by Novartis

(39)

PrescriptionDrug-Info.com, 26 Jan 2012

Accessed on 28 Mar 2012 from http://www.prescriptiondrug-info.com/drug_details.asp?title=Extavia&page=1008148&ad=true.

(40)

Novartis, Aug 2009

Accessed on 28 Mar 2012 from http://www.pharma.us.novartis.com/product/pi/pdf/extavia.pdf.

Zist Daru Danesh Ltd (Iran) began producing ZIFERON in 2010

(36)