1. © 2012 American Academy of Neurology IV IMMUNOGLOBULIN IN THE TREATMENT OF NEUROMUSCULAR DISORDERS Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

2. ©2012 American Academy of Neurology Authors  Huned S. Patwa, MD  Vinay Chaudhry, MD  Hans Katzberg, MD  Alex D. Rae-Grant, MD  Yuen T. So, MD, PhD

3. ©2012 American Academy of Neurology Sharing this information  The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan.com to learn about options for sharing this content beyond your personal use. guidelines@aan.com

4. ©2012 American Academy of Neurology Guideline Endorsement  Endorsed by the American Association of Neuromuscular and Electrodiagnostic Medicine

5. ©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

6. ©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

7. ©2012 American Academy of Neurology Background  IVIg is used to treat a range of immune- mediated 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.

8. ©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.

9. ©2012 American Academy of Neurology AAN Guideline Process  Clinical Question  Evidence  Conclusions  Recommendations

10. ©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 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)?

11. ©2012 American Academy of Neurology Clinical Questions, cont.  Is IVIg effective in neuropathy associated with 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?

12. ©2012 American Academy of Neurology Literature Search/Review  Rigorous, Comprehensive, Transparent Review abstracts Search Review full text Select articles Relevant Search

13. ©2012 American Academy of Neurology 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

14. ©2012 American Academy of Neurology AAN Level of Recommendations  A = Established as effective, ineffective or harmful (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

15. ©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

16. ©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).

17. ©2012 American Academy of Neurology Applying the Process to the Issue  We will now turn our attention to the guidelines.

18. ©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

19. ©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

20. ©2012 American Academy of Neurology Literature Search/Review  Rigorous, Comprehensive, Transparent 32 articles 943 abstracts Inclusion criteria: - Therapeutic articles assessing the efficacy, safety, tolerability, or IVIg mode of use in humans Exclusion criteria: - Case reports

21. ©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.

22. ©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.

23. ©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.**

24. ©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).

25. ©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?

26. ©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.

27. ©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).

28. ©2012 American Academy of Neurology Clinical Question 2  Is IVIg effective in GBS in children?

29. ©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).

30. ©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.

31. ©2012 American Academy of Neurology Clinical Question 3  Is steroid an effective adjunctive treatment in patients with GBS treated with IVIg?

32. ©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).

33. ©2012 American Academy of Neurology Clinical Question 4  What is the optimal IVIg dosing for GBS?

34. ©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).

35. ©2012 American Academy of Neurology Clinical Question 5  IVIg effective in CIDP?

36. ©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).

37. ©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.

38. ©2012 American Academy of Neurology Clinical Question 6  Is IVIg effective in MG?

39. ©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).

40. ©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.

41. ©2012 American Academy of Neurology Clinical Question 7  Is IVIg effective in MMN?

42. ©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).

43. ©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.

44. ©2012 American Academy of Neurology Clinical Question 8  Is IVIg effective in neuropathy associated with IgM paraprotein?

45. ©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).

46. ©2012 American Academy of Neurology Clinical Question 9  Is IVIg effective in neuropathy associated with dermatomyositis?

47. ©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).

48. ©2012 American Academy of Neurology Clinical Question 10  Is IVIg effective in IBM?

49. ©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).

50. ©2012 American Academy of Neurology IBM: Clinical Context  There is presently no effective treatment for IBM.

51. ©2012 American Academy of Neurology Clinical Question 11  Is IVIg effective in postpolio syndrome?

52. ©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).

53. ©2012 American Academy of Neurology Postpolio Syndrome: Clinical Context  There is presently no effective treatment for postpolio syndrome.

54. ©2012 American Academy of Neurology Clinical Question 12  Is IVIg effective in other neuromuscular disorders?

55. ©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).

56. ©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.

57. ©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 well- tolerated 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.

58. ©2012 American Academy of Neurology Adverse Effects: Clinical Context  It is important to assess individual patient risk for AEs when considering IVIg therapy.

59. ©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.

60. ©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.

61. ©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 guidelines@aan.com. guidelines@aan.com

62. ©2012 American Academy of Neurology  Questions/comments? Question-and-Answer Period

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