IV Immunoglobulin IN THE TREATMENT OF NEUROMUSCULAR DISORDERS

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

2. Authors • Huned S. Patwa, MD • Vinay Chaudhry, MD • Hans Katzberg, MD • Alex D. Rae-Grant, MD • Yuen T. So, MD, PhD

3. 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.

4. Guideline Endorsement • Endorsed by the American Association of Neuromuscular and Electrodiagnostic Medicine

5. Presentation Objectives • To present analysis of the evidence regarding efficacy of intravenous immunoglobulin (IVIg) to treat neuromuscular disorders • To present evidence-based recommendations

6. Overview • Background • Gaps in care • American Academy of Neurology (AAN) guideline process • Analysis of evidence, conclusions, recommendations • Recommendations for future research

7. 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. 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. AAN Guideline Process • Clinical Question • Evidence • Conclusions • Recommendations

10. 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. 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. Literature Search/Review • Rigorous, Comprehensive, Transparent Search Search Review abstracts Review full text Relevant Select articles

13. 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. 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. 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. 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. Applying the Process to the Issue • We will now turn our attention to the guidelines.

18. 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. 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. 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

21. AAN Classification of Evidencefor 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. AAN Classification of Evidencefor 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. AAN Classification of Evidencefor 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. AAN Classification of Evidencefor 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. Clinical Question 1a and 1b • Is IVIg effective in GBS in adults? • Is IVIg as effective as plasmapheresis in GBS in adults?

26. 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. 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. Clinical Question 2 • Is IVIg effective in GBS in children?

29. 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. 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. Clinical Question 3 • Is steroid an effective adjunctive treatment in patients with GBS treated with IVIg?

32. 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. Clinical Question 4 • What is the optimal IVIg dosing for GBS?

34. GBS and Optimal IVIg Dose: Conclusion and Recommendation • Data are insufficient to make a recommendation on optimal IGIV dosing (Level U).

35. Clinical Question 5 • IVIg effective in CIDP?

36. 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. 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. Clinical Question 6 • Is IVIg effective in MG?

39. 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. 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. Clinical Question 7 • Is IVIg effective in MMN?

42. 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. MMN: Clinical Context • MMN is a chronic disease requiring ongoing treatment. • No data are available to address optimal treatment dosing, interval, and duration.

44. Clinical Question 8 • Is IVIg effective in neuropathy associated with IgM paraprotein?

45. 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. Clinical Question 9 • Is IVIg effective in neuropathy associated with dermatomyositis?

47. 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. Clinical Question 10 • Is IVIg effective in IBM?

49. 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. IBM: Clinical Context • There is presently no effective treatment for IBM.