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## Complete Summary

#### GUIDELINE TITLE

Guidelines on use of anti-IFN-beta antibody measurements in multiple
sclerosis: report of an EFNS Task Force on IFN-beta antibodies in
multiple sclerosis.

#### BIBLIOGRAPHIC SOURCE(S)

Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J,
Polman C, Pozzilli C, Ross C, EFNS Task Force on Anti-IFN-beta
Antibodies in Multiple Sclerosis. Guidelines on use of anti-IFN-beta
antibody measurements in multiple sclerosis: report of an EFNS Task
Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005
Nov;12(11):817-27. \[85 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16241970)

#### GUIDELINE STATUS

This is the current release of the guideline.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Multiple sclerosis (MS)

#### GUIDELINE CATEGORY

Evaluation\
Prevention\
Screening\
Technology Assessment

#### CLINICAL SPECIALTY

Allergy and Immunology\
Family Practice\
Internal Medicine\
Neurology

#### INTENDED USERS

Clinical Laboratory Personnel\
Physicians

#### GUIDELINE OBJECTIVE(S)

-   To evaluate differences in immunogenicity of interferon-beta
    (IFN-beta) products

-   To evaluate the reliability and give recommendations on binding
    antibodies (BABs) and neutralizing antibodies (NABs) assays

-   To evaluate the impact of NABs on clinical efficacy and give
    recommendation on the clinical use of measurement of IFN-b
    antibodies

-   To review the evidence on prevention of NAB development and the
    management of patients with NABs

#### TARGET POPULATION

Patients with multiple sclerosis receiving interferon-beta therapy

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Interferon-beta (IFN-beta) antibody screening with binding antibody
    (BAB) assays (e.g., enzyme-linked immunosorbent assay \[ELISA\],
    Western blot \[WB\])

2.  IFN-beta antibody screening with neutralizing antibody (NAB) assays
    such as cytopathic effect (CPE) assay, MxA induction assay, and
    calculation of NAB titre using Kawade formula

3.  Discontinuing NAB measurements in NAB-negative patients and
    repeating NAB measurements in NAB-positive patients at intervals of
    3 to 6 months

4.  Discontinuing (IFN-beta) therapy in patients with high NAB titres

5.  Prevention and treatment of NABs with intravenous methylprednisolone

#### MAJOR OUTCOMES CONSIDERED

-   Influence of interferon-beta (IFN-beta) formulation, dosage, and
    route of administration on the immunogenicity of IFN-beta products

-   Sensitivity and specificity of binding antibody (BAB) and
    neutralizing antibody (NAB) assays

-   Correlation of NABs against IFN-beta with disease relapses, magnetic
    resonance imaging (MRI) outcomes, and disease progression

-   Effectiveness of steroid treatment

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

The task force systematically searched the Medline database for
available information published in English up to September 2004. Key
words included: interferon beta (IFN-beta), multiple sclerosis,
immunogenicity, antibodies, binding antibody assays, neutralizing
antibody assays. Articles related to this topic from the authors\'
personal literature databases were also included.

A PubMed search using \"binding antibodies assay interferon beta\" found
that 21 of the 55 articles were relevant for detection of binding
antibodies (BABs) with IFN-beta treatment.

PubMed was searched using the terms \"neutralizing antibodies interferon
beta assay.\" Thirty-four of 54 articles covered methods of neutralizing
antibody (NAB) detection and were included.

PubMed was searched for \"IFN-beta antibodies and multiple sclerosis\'\"
Of 236 articles, 103 were original articles or review articles on
antibodies against IFN-beta or controlled clinical trials of IFN-beta in
which measurements of antibodies were performed. For assessment of the
impact of NABs the task force selected randomized controlled trials of
IFN-beta in multiple sclerosis (MS) with blindly analysed NABs and
controlled non-randomized studies with blind evaluation of NABs of at
least 3-year duration (see Table 4 in the original guideline document).

#### NUMBER OF SOURCE DOCUMENTS

Binding antibodies -- 21 articles\
Neutralizing antibodies -- 34 articles\
Measurement of antibodies against interferon-beta in multiple sclerosis
-- 103 articles

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Evidence Classification Scheme for a Diagnostic Measure**

**Class I**: A prospective study in a broad spectrum of persons with the
suspected condition, using a \"gold standard\" for case definition,
where the test is applied in a blinded evaluation, and enabling the
assessment of appropriate tests of diagnostic accuracy

**Class II**: A prospective study of a narrow spectrum of persons with
the suspected condition, or a well-designed retrospective study of a
broad spectrum of persons with an established condition (by \"gold
standard\") compared to a broad spectrum of controls, where test is
applied in a blinded evaluation, and enabling the assessment of
appropriate tests of diagnostic accuracy

**Class III**: Evidence provided by a retrospective study where either
persons with the established condition or controls are of a narrow
spectrum, and where test is applied in a blinded evaluation

**Class IV**: Any design where test is not applied in blinded evaluation
OR evidence provided by expert opinion alone or in descriptive case
series (without controls)

**Evidence Classification Scheme for a Therapeutic Intervention**

**Class I**: An adequately powered prospective, randomized, controlled
clinical trial with masked outcome assessment in a representative
population or an adequately powered systematic review of prospective
randomized controlled clinical trials with masked outcome assessment in
representative populations. The following are required:

a.  Randomization concealment

b.  Primary outcome(s) is/are clearly defined

c.  Exclusion/inclusion criteria are clearly defined

d.  Adequate accounting for dropouts and crossovers with numbers
    sufficiently low to have minimal potential for bias

e.  Relevant baseline characteristics are presented and substantially
    equivalent among treatment groups or there is appropriate
    statistical adjustment for differences

**Class II**: Prospective matched-group cohort study in a representative
population with masked outcome assessment that meets a--e above or a
randomized, controlled trial in a representative population that lacks
one criteria a--e

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome assessment is independent of
patient treatment

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

For each specific issue at least one member of the task force assessed
all published papers and omitted those that did not fulfill given
criteria, read and rated the remaining articles according to the
guidance for preparation of neurological management guidelines by the
European Federation of Neurological Societies (EFNS) Scientific task
forces -- revised recommendations 2004 (see the \"Rating Scheme for the
Strength of the Evidence\" and the \"Rating Scheme for the Strength of
the Recommendations\" fields).

Only trials of sufficient duration ([\>]{.underline}3 years) and blind
evaluation of neutralizing antibody (NAB) status were graded as class I
evidence for effects of NABs. Trials of less sufficient duration (2--3
years) and blind evaluation of NAB status were graded as class II
evidence, and trials of inappropriate duration (\<2 years) and/or no
blind evaluation of NAB status were classified as class III evidence
regarding clinical effects of NABs.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Each paragraph of the guidelines was drafted by one member of the task
force and circulated to the other members. After appropriate revision
the guidelines were finalized and consensus was reached amongst all task
force members at meeting.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Rating of Recommendations for a Diagnostic Measure**

**Level A rating** (established as useful/predictive or not
useful/predictive) requires at least one convincing class I study or at
least two consistent, convincing class II studies.

**Level B rating** (established as probably useful/predictive or not
useful/predictive) requires at least one convincing class II study or
overwhelming class III evidence.

**Level C rating** (established as possibly useful/predictive or not
useful/predictive) requires at least two convincing class III studies.

**Rating of Recommendations for a Therapeutic Intervention**

**Level A rating** (established as effective, ineffective, or harmful)
requires at least one convincing class I study or at least two
consistent, convincing class II studies.

**Level B rating** (probably effective, ineffective, or harmful)
requires at least one convincing class II study or overwhelming class
III evidence.

**Level C rating** (possibly effective, ineffective, or harmful)
requires at least two convincing class III studies.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guidelines were validated according to the European Federation of
Neurological Societies (EFNS) criteria (Hughes RAC, Barnes MP, Baron J,
Brainin M \[2001\]. Guidance for the preparation of neurological
management guidelines by EFNS scientific task forces. *Eur J Neurol*
8:549-550).

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The levels of evidence (class I-IV) supporting the recommendations and
ratings of recommendations (A-C) are defined at the end of the \"Major
Recommendations\" field.

**Measurements of Binding and Neutralizing Antibodies**

*Binding Antibodies*

There are no existing recommendations on binding antibody (BAB) assays.
There is class I evidence that interferon-beta (IFN-beta) BAB assays
have a very high sensitivity and specificity, and can be reliably used
for IFN-beta antibody screening before performing a neutralizing
antibody (NAB) assay (**Level A recommendation**). Different BAB assays
should be evaluated and compared using a large number of serum samples
in order to identify the method with the best sensitivity and
specificity for NAB detection (**Level B recommendation**).

*Neutralizing Antibodies*

Measurements of binding and neutralizing antibodies against IFN-beta
should be performed in specialized laboratories (**Level A
recommendation**). Measurement of NABs with a validated cytopathic
effect (CPE) assay is still the gold standard. It is recommended that
A549 cells are used with a fixed amount of IFN-beta (the preparation
used by the patient) for stimulation and serial dilution of the test
sera. The stimulated cells can either be challenged with
encephalomyocarditis (EMC) viruses or MxA production determined.
Standard curves should be obtained using increasing amounts of IFN-beta
until saturation is reached. The NAB titre should be calculated using
the Kawade formula (Level A recommendation).

Titres above 20 to 60 (depending on the IFN-beta preparation used in the
assay) are associated with a loss of IFN-beta bioactivity (**class I
evidence**). As the European Medicines Association (EMEA) currently
validates a NAB assay based upon the MxA production of A549 cells (MxA
induction assay), it is recommended to use the EMEA protocol. (This
recommendation is only based on class IV evidence, but consensus was
reached to offer this advice as good practice.) Validation of simpler
NAB assay methods is strongly recommended such as the in vivo biological
response to IFN-beta administration (**Level A recommendation**).

**Clinical Use of Measurements of Antibodies against IFN-beta**

It is recommended that patients treated with IFN-beta are tested for the
presence of NABs at 12 and 24 months of therapy (**Level A
recommendation**). Measurements of NABs can be discontinued in those
patients remaining NAB-negative during this period but should be resumed
if disease activity increases (**Level B recommendation**). There is
class I evidence that the presence of NABs significantly hampers the
effect of IFN-beta on the relapse rate and on both active lesions and
burden of disease seen on magnetic resonance imaging (MRI). In patients
with NABs, NAB measurements should be repeated at intervals of 3 to 6
months and therapeutic options should be re-evaluated (**Level A
recommendation**). Therapy with IFN-beta should be discontinued in
patients with high titres of NABs (e.g., titres \>100 in patients using
IFN-beta-1b) sustained at repeated measurements with 3- to 6-month
intervals (**Level A recommendation**).

**Prevention and Treatment of NABs**

Limited evidence is available on managements that reduce NAB formation
to IFN-beta in multiple sclerosis (MS). Monthly 1 g intravenous (i.v.)
methylprednisolone (MP) administration has been revealed to be safe and
able to minimize the formation of NABs over time (**Level C
recommendation**). However, no effect has been observed in reducing the
amplitude of NABs titres once NABs have been formed. Further studies are
warranted to strengthen these results and to expand the knowledge in
such an intriguing matter.

**Principal Recommendations Regarding Measurements of Antibodies against
IFN-beta and the Clinical Use of NAB Measurements**

-   BAB assays can be reliably used for IFN-beta antibody screening
    before performing a NAB assay (**Level A recommendation**).

-   Measurements of binding and neutralizing antibodies against IFN-beta
    should be performed in specialized laboratories (**Level A
    recommendation**).

-   Measurement of NABs should be performed with a validated CPE assay
    or MxA production assay using serial dilution of the test sera. The
    NAB titre should be calculated using the Kawade formula (**Level A
    recommendation**).

-   Tests for the presence of NABs should be performed at 12 and 24
    months of therapy (**Level A recommendation**).

-   Measurements of NABs can be discontinued in those patients remaining
    NAB-negative during this period but should be resumed if disease
    activity increases (**Level B recommendation**).

-   In patient with NABs, measurements should be repeated after 3 to 6
    months (**Level A recommendation**).

-   Therapy with IFN-beta should be discontinued in patients with high
    titres of NABs sustained at repeated measurements with 3- to 6-month
    intervals (**Level A recommendation**).

**[Definitions]{.underline}**:

**Evidence Classification Scheme for a Diagnostic Measure**

**Class I**: A prospective study in a broad spectrum of persons with the
suspected condition, using a \"gold standard\" for case definition,
where the test is applied in a blinded evaluation, and enabling the
assessment of appropriate tests of diagnostic accuracy

**Class II**: A prospective study of a narrow spectrum of persons with
the suspected condition, or a well-designed retrospective study of a
broad spectrum of persons with an established condition (by \"gold
standard\") compared to a broad spectrum of controls, where test is
applied in a blinded evaluation, and enabling the assessment of
appropriate tests of diagnostic accuracy

**Class III**: Evidence provided by a retrospective study where either
persons with the established condition or controls are of a narrow
spectrum, and where test is applied in a blinded evaluation

**Class IV**: Any design where test is not applied in blinded evaluation
OR evidence provided by expert opinion alone or in descriptive case
series (without controls)

**Evidence Classification Scheme for a Therapeutic Intervention**

**Class I**: An adequately powered prospective, randomized, controlled
clinical trial with masked outcome assessment in a representative
population or an adequately powered systematic review of prospective
randomized controlled clinical trials with masked outcome assessment in
representative populations. The following are required:

a.  Randomization concealment

b.  Primary outcome(s) is/are clearly defined

c.  Exclusion/inclusion criteria are clearly defined

d.  Adequate accounting for dropouts and crossovers with numbers
    sufficiently low to have minimal potential for bias

e.  Relevant baseline characteristics are presented and substantially
    equivalent among treatment groups or there is appropriate
    statistical adjustment for differences

**Class II**: Prospective matched-group cohort study in a representative
population with masked outcome assessment that meets a--e above or a
randomized, controlled trial in a representative population that lacks
one criteria a--e

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome assessment is independent of
patient treatment

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion

**Rating of Recommendations for a Diagnostic Measure**

**Level A rating** (established as useful/predictive or not
useful/predictive) requires at least one convincing class I study or at
least two consistent, convincing class II studies.

**Level B rating** (established as probably useful/predictive or not
useful/predictive) requires at least one convincing class II study or
overwhelming class III evidence.

**Level C rating** (established as possibly useful/predictive or not
useful/predictive) requires at least two convincing class III studies.

**Rating of Recommendations for a Therapeutic Intervention**

**Level A rating** (established as effective, ineffective, or harmful)
requires at least one convincing class I study or at least two
consistent, convincing class II studies.

**Level B rating** (probably effective, ineffective, or harmful)
requires at least one convincing class II study or overwhelming class
III evidence.

**Level C rating** (possibly effective, ineffective, or harmful)
requires at least two convincing class III studies.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for selected
recommendations (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Appropriate measurement of binding antibodies (BABs) and neutralizing
antibodies (NABs) against interferon-beta (IFN-beta) and the clinical
use of measurement of INF-beta antibodies

#### POTENTIAL HARMS

Western blot method had a low false-negative rate when screening for
neutralizing antibody (NAB)-positivity.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

This guideline provides the view of an expert task force appointed by
the Scientific Committee of the European Federation of Neurological
Societies (EFNS). It represents a peer-reviewed statement of minimum
desirable standards for the guidance of practice based on the best
available evidence. It is not intended to have legally binding
implications in individual cases.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

The European Federation of Neurological Societies has a mailing list and
all guideline papers go to national societies, national ministries of
health, World Health Organisation, European Union, and a number of other
destinations. Corporate support is recruited to buy large numbers of
reprints of the guideline papers and permission is given to sponsoring
companies to distribute the guideline papers from their commercial
channels, provided there is no advertising attached.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J,
Polman C, Pozzilli C, Ross C, EFNS Task Force on Anti-IFN-beta
Antibodies in Multiple Sclerosis. Guidelines on use of anti-IFN-beta
antibody measurements in multiple sclerosis: report of an EFNS Task
Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005
Nov;12(11):817-27. \[85 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16241970)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2005 Nov

#### GUIDELINE DEVELOPER(S)

European Federation of Neurological Societies - Medical Specialty
Society

#### SOURCE(S) OF FUNDING

European Federation of Neurological Societies

#### GUIDELINE COMMITTEE

European Federation of Neurological Societies Task Force on IFN-beta
antibodies in multiple sclerosis

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Task Force Members*: P. S. Sørensen, Danish Multiple Sclerosis Research
Centre, Department of Neurology, Copenhagen University Hospital,
Rigshospitalet, Copenhagen, Denmark; F. Deisenhammer, Department of
Neurology, University of Innsbruck, Innsbruck, Austria; P. Duda,
Outpatient Clinic Neurology-Neurosurgery, University Hospitals, Basel,
Switzerland; R. Hohlfeld, Institute for Clinical Neuroimmunology,
University of Munich, Klinikum Grosshadern, Munich, Germany; K.-M. Myhr,
Department of Neurology, Haukeland University Hospital, Bergen, Norway;
J. Palace, Multiple Sclerosis Group, Radcliffe Infirmary, Oxford, UK; C.
Polman, Department of Neurology, VU University Medical Center,
Amsterdam, The Netherlands; C. Pozzilli, Department of Neurological
Sciences, II Faculty of Medicine, University \"La Sapienza\", Rome,
Italy; C. Rossi, Institute for Inflammation Research, Copenhagen
University Hospital, Rigshospitalet, Copenhagen, Denmark for the EFNS
Task Force on Anti-IFN-b Antibodies in Multiple Sclerosis

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available to registered users from the [European
Federation of Neurological Societies Web
site](http://www.efns.org/content.php?pid=142).

Print copies: Available from Prof. Per Soelberg Sorensen, MD, DMSci,
Department of Neurology 2082, Danish MS Research Center, Copenhagen
University Hospital, Rigshospitalet, DK 2100 Copenhagen, Denmark;
Phone: + 45 3545 2080; Fax: + 45 3545 2626; E-mail: <pss@rh.dk>

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Brainin M, Barnes M, Baron JC, Gilhus NE, Hughes R, Selmaj K,
    Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific
    Committee. Guidance for the preparation of neurological management
    guidelines by EFNS scientific task forces -- revised
    recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81.
    Electronic copies: Available in Portable Document Format (PDF) from
    the [European Federation of Neurological Societies Web
    site](http://www.efns.org/files/guideline_23.pdf).

-   Guideline papers. European Federation of Neurological Societies.
    Electronic copies: Available from the [European Federation of
    Neurological Societies Web
    site](http://www.efns.org/content.php?pid=141).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on December 6, 2006. The
information was verified by the guideline developer on January 2, 2007.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the Blackwell-Synergy copyright restrictions.

### DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008