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IV IMMUNOGLOBULIN IN THE
TREATMENT OF NEUROMUSCULAR
DISORDERS
Report of the Therapeutics and Technology
Assessment Subcommittee
of the American Academy of Neurology
©2012 American Academy of Neurology
Authors
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Huned S. Patwa, MD
Vinay Chaudhry, MD
Hans Katzberg, MD
Alex D. Rae-Grant, MD
Yuen T. So, MD, PhD
©2012 American Academy of Neurology
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©2012 American Academy of Neurology
Guideline Endorsement
 Endorsed by the American Association of
Neuromuscular and Electrodiagnostic
Medicine
©2012 American Academy of Neurology
Presentation Objectives
 To present analysis of the evidence regarding
efficacy of intravenous immunoglobulin (IVIg)
to treat neuromuscular disorders
 To present evidence-based recommendations
©2012 American Academy of Neurology
Overview
 Background
 Gaps in care
 American Academy of Neurology (AAN)
guideline process
 Analysis of evidence, conclusions,
recommendations
 Recommendations for future research
©2012 American Academy of Neurology
Background
 IVIg is used to treat a range of immunemediated neurologic diseases.
 The US Food and Drug Administration (FDA)
approved IVIg for use in Guillain-Barré
syndrome (GBS) and chronic inflammatory
demyelinating polyneuropathy (CIDP), but
IVIg use for non–FDA-approved indications is
common.
 Although IVIg appears to be well tolerated in
many patients, hypercoagulability and renal
failure are of concern.
©2012 American Academy of Neurology
Gaps in Care
 Given the FDA approved IVIg for use only in
GBS and CIDP, understanding what the
existing evidence says for IVIg use more
broadly would be helpful.
 Neurologists are familiar with the use of IVIg
for a variety of diseases; this guideline
presents the evidence supporting its use in a
broad range of neuromuscular diseases.
©2012 American Academy of Neurology
AAN Guideline Process
 Clinical Question
 Evidence
 Conclusions
 Recommendations
©2012 American Academy of Neurology
Clinical Questions
 Is IVIg effective in GBS in adults?
 Is IVIg effective in GBS in children?
 Is IVIg as effective as plasmapheresis in GBS in
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adults?
Is steroid an effective adjunctive treatment in
patients with GBS treated with IVIg?
What is the optimal IVIg dosing for GBS?
Is IVIg effective in CIDP?
Is IVIg effective in myasthenia gravis (MG)?
Is IVIg effective in multifocal motor neuropathy
(MMN)?
©2012 American Academy of Neurology
Clinical Questions, cont.
 Is IVIg effective in neuropathy associated with
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immunoglobulin M (IgM) paraprotein?
Is IVIg effective in neuropathy associated with
dermatomyositis?
Is IVIg effective in inclusion body myositis (IBM)?
Is IVIg effective in postpolio syndrome?
Is IVIg effective in other neuromuscular disorders?
©2012 American Academy of Neurology
Literature Search/Review
 Rigorous, Comprehensive, Transparent
Search
Search
Review abstracts
Review full text
Relevant
©2012 American Academy of Neurology
Select articles
AAN Classification of Evidence
 All studies rated Class I, II, III, or IV
 Five different classification systems
• Therapeutic
Randomization, control, blinding
• Diagnostic
Comparison with gold standard
• Prognostic
• Screening
• Causation
©2012 American Academy of Neurology
AAN Level of Recommendations
 A = Established as effective, ineffective or harmful
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(or established as useful/predictive or not
useful/predictive) for the given condition in the
specified population
B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive)
for the given condition in the specified population
C = Possibly effective, ineffective or harmful (or
possibly useful/predictive or not useful/predictive)
for the given condition in the specified population
U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven
• Note that recommendations can be positive or negative
©2012 American Academy of Neurology
Translating Class to
Recommendations
 A = Requires at least two consistent Class I
studies*
 B = Requires at least one Class I study or two
consistent Class II studies
 C = Requires at least one Class II study or two
consistent Class III studies
 U = Studies not meeting criteria for Class I
through Class III
©2012 American Academy of Neurology
Translating Class to
Recommendations, cont.
* In exceptional cases, one convincing Class I
study may suffice for an “A” recommendation
if 1) all criteria are met, 2) the magnitude of
effect is large (relative rate improved outcome
>5 and the lower limit of the confidence
interval is >2).
©2012 American Academy of Neurology
Applying the Process to the Issue
 We will now turn our attention to the
guidelines.
©2012 American Academy of Neurology
Methods
 MEDLINE, Web of Science, and EMBASE were
searched (1966–2009)
• Used search term “immunoglobulin” and one of
the following: myasthenia gravis, GBS,
neuropathy, CIDP, multifocal motor neuropathy,
polymyositis, dermatomyositis, diabetic
neuropathy, diabetic radiculoplexoneuropathy,
postpolio syndrome, paraproteinemic
neuropathy, Lambert-Eaton myasthenic
syndrome, Miller Fisher syndrome, inclusion body
myositis
• Relevant, fully published, peer-reviewed articles
©2012 American Academy of Neurology
Methods, cont.
 At least two authors reviewed each article for
inclusion
 Risk of bias was determined using the
classification of evidence scheme for
therapeutic articles
 Strength of recommendations were linked
directly to levels of evidence
 Conflicts of interest were disclosed
©2012 American Academy of Neurology
Literature Search/Review
 Rigorous, Comprehensive, Transparent
943
abstracts
Inclusion criteria:
- Therapeutic articles
assessing the efficacy, safety,
tolerability, or IVIg mode of
use in humans
Exclusion criteria:
- Case reports
32 articles
©2012 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Interventions
 Class I: Class I: A randomized, controlled clinical trial of the
intervention of interest with masked or objective outcome
assessment, in a representative population. Relevant baseline
characteristics are presented and substantially equivalent
among treatment groups or there is appropriate statistical
adjustment for differences. The following are also required:
•
•
•
•
Concealed allocation
Primary outcome(s) clearly defined
Exclusion/inclusion criteria clearly defined
Adequate accounting for dropouts (with at least 80% of enrolled
subjects completing the study) and crossovers with numbers
sufficiently low to have minimal potential for bias.
©2012 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Interventions, cont.
• For noninferiority or equivalence trials claiming to prove efficacy for
one or both drugs, the following are also required*:
The authors explicitly state the clinically meaningful difference to be
excluded by defining the threshold for equivalence or noninferiority.
The standard treatment used in the study is substantially similar to that
used in previous studies establishing efficacy of the standard treatment
(e.g., for a drug, the mode of administration, dose and dosage adjustments
are similar to those previously shown to be effective).
The inclusion and exclusion criteria for patient selection and the outcomes
of patients on the standard treatment are comparable to those of previous
studies establishing efficacy of the standard treatment.
The interpretation of the results of the study is based upon a per protocol
analysis that takes into account dropouts or crossovers.
©2012 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Interventions, cont.
 Class II: A randomized controlled clinical trial of the
intervention of interest in a representative population with
masked or objective outcome assessment that lacks one
criteria ae above or a prospective matched cohort study with
masked or objective outcome assessment in a representative
population that meets be above. Relevant baseline
characteristics are presented and substantially equivalent
among treatment groups or there is appropriate statistical
adjustment for differences.
 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.**
©2012 American Academy of Neurology
AAN Classification of Evidence
for Therapeutic Interventions, cont.
 Class IV: Studies not meeting Class I, II or III criteria including
consensus or expert opinion.
*Note that numbers 13 in Class I, item 5 are required for Class II in equivalence trials. If
any one of the three is missing, the class is automatically downgraded to Class III.
**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).
©2012 American Academy of Neurology
Clinical Question 1a and 1b
 Is IVIg effective in GBS in adults?
 Is IVIg as effective as plasmapheresis in GBS in
adults?
©2012 American Academy of Neurology
GBS in Adults: Conclusions
 Based on 2 Class I studies, IVIg is as efficacious
as plasmapheresis for treating GBS in adults.
Because plasmapheresis is established as
effective GBS treatment,1 we conclude that
IVIg also has established effectiveness.
 Based on one adequately powered Class I
study, the combination of plasmapheresis and
IVIg is probably not better than either
treatment alone.
©2012 American Academy of Neurology
GBS in Adults:
Recommendations
 IVIg should be offered to treat GBS in adults
(Level A).
 IVIg combined with plasmapheresis should
not be considered for treating GBS (Level B).
©2012 American Academy of Neurology
Clinical Question 2
 Is IVIg effective in GBS in children?
©2012 American Academy of Neurology
GBS in Children: Conclusion and
Recommendation
 Based on conflicting primary outcome
measures, IVIg benefit is uncertain in children
with GBS.
 There is insufficient evidence to support or
refute the effectiveness of IVIg in children
with GBS (Level U).
©2012 American Academy of Neurology
GBS in Children: Clinical Context
 Many experts consider it reasonable
treatment to use IVIg for GBS in children given
its effectiveness in the same disease in adults.
©2012 American Academy of Neurology
Clinical Question 3
 Is steroid an effective adjunctive treatment in
patients with GBS treated with IVIg?
©2012 American Academy of Neurology
GBS and Adjunctive Steroid Use:
Conclusion and
Recommendation
 Based on one underpowered Class I study,
evidence is insufficient to support or exclude
a benefit of adding methylprednisolone (MP)
to IVIg in GBS.
 Evidence is insufficient to recommend MP in
combination with IVIg (Level U).
©2012 American Academy of Neurology
Clinical Question 4
 What is the optimal IVIg dosing for GBS?
©2012 American Academy of Neurology
GBS and Optimal IVIg Dose:
Conclusion and
Recommendation
 Data are insufficient to make a
recommendation on optimal IGIV dosing
(Level U).
©2012 American Academy of Neurology
Clinical Question 5
 IVIg effective in CIDP?
©2012 American Academy of Neurology
CIDP: Conclusions and
Recommendation
 Based on 2 Class I studies, IVIg is effective for
the long-term treatment of CIDP.
 Data are insufficient to address the
comparative efficacy of prednisolone and IVIg
in treating CIDP.
 IVIg should be offered for the long-term
treatment of CIDP (Level A).
©2012 American Academy of Neurology
CIDP: Clinical Context
 Dosing, frequency, and duration of IVIg for
CIDP may vary depending on the clinical
assessment.
 Data are insufficient to address the
comparative efficacy of other CIDP treatments
(e.g., steroids, plasmapheresis,
immunosuppressants).
 Experts have identified that there may be
overuse of IVIg in long-term care of CIDP. We
were unable to evaluate this question using
available randomized trial data.
©2012 American Academy of Neurology
Clinical Question 6
 Is IVIg effective in MG?
©2012 American Academy of Neurology
MG: Conclusions and
Recommendation
 Based on one Class I study, IVIg is probably
effective in treating patients with MG.
 Evidence is insufficient to compare the
efficacy of IVIg and plasmapheresis in treating
MG.
 IVIg should be considered in the treatment of
MG (Level B).
©2012 American Academy of Neurology
MG: Clinical Context
 This recommendation was based on studies
involving primarily moderately or severely
affected patients.
 The benefits and risks of this medication
should be weighed carefully in patients with
mild MG.
 Further studies of IVIg efficacy in MG are
warranted due to the few randomized trials
and small study size to date.
©2012 American Academy of Neurology
Clinical Question 7
 Is IVIg effective in MMN?
©2012 American Academy of Neurology
MMN: Conclusion and
Recommendation
 Based on consistent results from 3 Class II
studies, IVIg is probably effective for MMN
treatment.
 IVIg should be considered for the treatment
of MMN (Level B).
©2012 American Academy of Neurology
MMN: Clinical Context
 MMN is a chronic disease requiring ongoing
treatment.
 No data are available to address optimal
treatment dosing, interval, and duration.
©2012 American Academy of Neurology
Clinical Question 8
 Is IVIg effective in neuropathy associated with
IgM paraprotein?
©2012 American Academy of Neurology
IgM Paraprotein‒associated
Neuropathy: Conclusion and
Recommendation
 Based on 1 Class I study and 1 Class II study,
IVIg is possibly ineffective for the treatment of
IgM paraprotein–associated neuropathy. A
modest benefit cannot be excluded due to
each study’s small sample size.
 Evidence is insufficient to assess the role of
IVIg in treating neuropathy associated with
IgM paraprotein (Level U).
©2012 American Academy of Neurology
Clinical Question 9
 Is IVIg effective in neuropathy associated with
dermatomyositis?
©2012 American Academy of Neurology
Dermatomyositis: Conclusion
and Recommendation
 Based on 1 Class II study, IVIg is possibly
effective for the treatment of nonresponsive
dermatomyositis in adults.
 IVIg may be considered for the treatment of
nonresponsive dermatomyositis in adults
(Level C).
©2012 American Academy of Neurology
Clinical Question 10
 Is IVIg effective in IBM?
©2012 American Academy of Neurology
IBM: Conclusion and
Recommendation
 Two Class I studies and 1 Class II study failed
to demonstrate a consistent or significant
clinical benefit of IVIg in treating IBM.
 Evidence is insufficient to support or refute
the use of IVIg in treating IBM (Level U).
©2012 American Academy of Neurology
IBM: Clinical Context
 There is presently no effective treatment for
IBM.
©2012 American Academy of Neurology
Clinical Question 11
 Is IVIg effective in postpolio syndrome?
©2012 American Academy of Neurology
Postpolio Syndrome: Conclusion
and Recommendation
 One Class I study showed a significant
difference, but the difference was not
clinically important for IVIg use on the most
affected muscle in postpolio syndrome. One
underpowered Class I study showed an effect
of IVIg for pain in postpolio syndrome but no
effect on strength or fatigue.
 Evidence is insufficient to support or refute
IVIg use in the routine treatment of postpolio
syndrome (Level U).
©2012 American Academy of Neurology
Postpolio Syndrome: Clinical
Context
 There is presently no effective treatment for
postpolio syndrome.
©2012 American Academy of Neurology
Clinical Question 12
 Is IVIg effective in other neuromuscular
disorders?
©2012 American Academy of Neurology
Lambert-Eaton Syndrome:
Conclusion and
Recommendation
 Based on 1 Class II study, IVIg is possibly
effective in Lambert-Eaton syndrome (LEMS).
 IVIg may be considered in the treatment of
LEMS (Level C).
©2012 American Academy of Neurology
Other Disorders: Conclusion and
Recommendation
 There are no controlled studies evaluating the
effects of IVIg on polymyositis, diabetic
polyradiculoplexoneuropathy, or Miller Fisher
syndrome.
©2012 American Academy of Neurology
Adverse Effects of IVIg
 Eighteen of the 22 prospective studies reviewed
recorded the number of serious and minor
adverse effects (AEs).
 There were no IVIg-related deaths in these
studies.
 Most studies concluded that IVIg was welltolerated and AEs were either transient or
manageable.
 Serious AEs related to IVIg were rare and
included aseptic meningitis, urticaria, heart
failure, myocardial infarction, and renal failure.
©2012 American Academy of Neurology
Adverse Effects: Clinical Context
 It is important to assess individual
patient risk for AEs when considering
IVIg therapy.
©2012 American Academy of Neurology
Future Research
Recommendations
 For most of the diseases examined here,
alternative treatment modalities are available.
Comparative studies may be helpful.
 IVIg benefit is generally short lived; further,
long-term studies might be useful.
 Studies are needed to explore possible
synergistic effects of adjunctive treatments
such as immunosuppressants or
plasmapheresis.
©2012 American Academy of Neurology
Future Research
Recommendations, cont.
 Few data are available on the optimal IVIg
infusion frequency and cumulative dose.
 A larger study of IVIg in patients with mild MG
may be useful.
 The issue of overtreatment of CIDP with IVIg,
which may be a clinically significant issue,
could be assessed with further observational
studies.
©2012 American Academy of Neurology
Reference
1. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A.
Evidence-based guideline update: plasmapheresis in neurological
disorders: report of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology. Neurology
2011;76:294–300.
For a complete list of references, please
access the full guideline at
[email protected].
©2012 American Academy of Neurology
Question-and-Answer Period
 Questions/comments?
©2012 American Academy of Neurology
Closing
 To access the complete guideline and related
guideline summary tools, visit
www.aan.com/guidelines.
 Thank you for your participation!
©2012 American Academy of Neurology