This is the current release of the guideline.

Multiple sclerosis

Management
Technology Assessment
Treatment

Neurology

Physicians

To evaluate the clinical and radiographic impact of neutralizing antibodies to interferon-beta in the treatment of multiple sclerosis

Individuals being treated for multiple sclerosis with interferon beta (IFN beta)

1. Treatment with interferon beta (IFN beta): IFN beta-1a, IFN beta-1b
2. Measurement of seroprevalence and titers of neutralizing antibodies (NAbs) to interferon beta
3. Clinical and radiologic assessment of multiple sclerosis activity

• Persistence of neutralizing antibodies (NAb) to interferon beta (IFN beta)
• Clinical impact of NAb to IFN beta on severity of multiple sclerosis (MS)
• Radiographic impact of Nab to IFN beta on severity of MS
• Rate of NAb production

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

A panel of neurologists analyzed the evidence relating to neutralizing antibodies (NAbs) using a literature search with the key words antibodies and interferon beta. The MEDLINE database was searched from 1966 to 2005. In addition, the reference lists of the articles identified were reviewed to identify articles not found by the computer search. Using these methods 627 articles were identified.

Twenty-seven articles in the English language reporting clinical or radiographic outcomes in both antibody positive and antibody negative patients were reviewed.

Weighting According to a Rating Scheme (Scheme Given)

Classification of Evidence for Therapeutic Intervention

Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) clearly defined; b) exclusion/inclusion criteria clearly defined; c) adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias; and d) 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–d above OR a randomized controlled trial in a representative population that lacks one criteria a–d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*

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

* Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Systematic Review with Evidence Tables

The entire panel classified the level of evidence provided by each article. Several studies were classified as providing Class II evidence, despite a randomized placebo-controlled trial design. This is because evidence associated with NAb status is always post hoc and because patients can never be randomized with respect to their ultimate Nab status. Therefore, one can never exclude the possibility that there are patient-specific factors, which both predispose certain patients to the development of Nabs and, in an unrelated manner, make them more or less susceptible to multiple sclerosis (MS) attacks. If so, this will make Nabs artificially appear to increase or decrease the MS attack rate, underscoring the fact that evidence of an association cannot prove causation.

Expert Consensus

Not stated

Classification of Recommendations

A = Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)

B = Probably effective, ineffective, or harmful for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)

C = Possibly effective, ineffective, or harmful for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

U = Data inadequate or conflicting; given current knowledge, treatment is unproven.

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

External Peer Review
Internal Peer Review

Draft guidelines were reviewed for accuracy, quality, and thoroughness by the American Academy of Neurology (AAN) members, topic experts, and pertinent physician organizations.

Final guidelines were approved by the Therapeutics and Technology Subcommittee on July 28, 2006; by the Practice Committee on November 11, 2006; and by the AAN Board of Directors on January 4, 2007.

Definitions of the strength of the recommendations (A, B, C, U) and classification of the evidence (Class I through Class IV) are provided at the end of the "Major Recommendations" field.

1. Treatment of multiple sclerosis (MS) with interferon beta (IFN beta) (Avonex, Betaseron, or Rebif) is associated with the production of neutralizing antibodies (Nabs) to the IFN beta molecule (Level A).
2. It is probable that the presence of NAbs, especially in persistently high titers, is associated with a reduction in the radiographic and clinical effectiveness of IFN beta treatment (Level B).
3. It is probable that the rate of NAb production is less with IFN beta-1a treatment compared to IFN beta-1b treatment (Level B). However, because of the variability of the prevalence data, and because Nabs disappear in the majority of patients even with continued treatment (especially in those with low-titer NAbs), the magnitude and persistence of any difference in seroprevalence between these forms of IFN beta is difficult to determine.
4. It is probable that the seroprevalence of Nabs to IFN beta is affected by one or more of the following: its formulation, dose, route of administration, or frequency of administration (Level B). Regardless of the explanation, it seems clear that IFN beta-1a (as it is currently formulated for intramuscular injection) is less immunogenic than the current IFN beta preparations (either IFN beta-1a or IFN beta-1b) given multiple times per week subcutaneously (Level A). Because NAbs may disappear in many patients with continued therapy, the persistence of this difference is difficult to determine (Level B).
5. Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) has been associated with a reduction in the therapeutic effects of IFN beta on radiographic and clinical measures of multiple sclerosis disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply (Level U).

Definitions:

Classification of Evidence for Therapeutic Intervention

Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) clearly defined; b) exclusion/inclusion criteria clearly defined; c) adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias; and d) 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–d above OR a randomized controlled trial in a representative population that lacks one criteria a–d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*

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

* Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

A = Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)

B = Probably effective, ineffective, or harmful for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)

C = Possibly effective, ineffective, or harmful for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

U = Data inadequate or conflicting; given current knowledge, treatment is unproven.

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

A better understanding of the impact of the development of neutralizing antibodies (NAbs) in patients treated with interferon beta (IFN beta) for multiple sclerosis on:

• Reduction in biologic action and effectiveness of IFN beta
• Persistence of NAB positivity
• Differences in seroprevalence between different IFN beta agents

Not stated

This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.

An implementation strategy was not provided.

Living with Illness

Effectiveness

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

2007 Mar 27

American Academy of Neurology - Medical Specialty Society

American Academy of Neurology (AAN)

Therapeutics and Technology Assessment Subcommittee

Primary Authors: D.S. Goodin, MD; E.M. Frohman, MD, FAAN; B. Hurwitz, MD; P.W. O'Connor, MD; J.J. Oger, MD, FRCPC, FAAN; A.T. Reder, MD; and J.C. Stevens, MD, FAAN

Therapeutics and Technology Assessment Subcommittee Members: Janis Miyasaki, MD, FAAN (Co-Chair); Yuen T. So, MD, PhD (Co-Chair); Carmel Armon, MD, MHS, FAAN (ex-officio); Vinay Chaudhry, MD, FAAN; Richard M. Dubinsky, MD, MPH, FAAN; Douglas S. Goodin, MD (ex-officio, facilitator); Mark Hallett, MD, FAAN; Cynthia L. Harden, MD; Kenneth J. Mack, MD, PhD; Fenwick T. Nichols III, MD; Michael A. Sloan, MD, MS, FAAN; James C. Stevens, MD; Paul W. O'Connor, MD, FAAN

This is the current release of the guideline.

None available

This summary was completed by ECRI Institute on May 14, 2007.

This NGC summary is based on the original guideline, which is copyrighted by the American Academy of Neurology.