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An Overview of Intravenous and Subcutaneous Immunoglobulin (IVIG/SCIG) In Neurology

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The utility of intravenous and subcutaneous immunoglobulin has evolved significantly from being a therapy narrowly used in primary immunodeficiencies, to becoming an option for patients in a wide array of clinical categories, including neurology.1

The exact role of IVIG in neurologic disorders varies based on the amount of clinical research for its use in each indication and can be categorized as being FDA approved (highest level of evidence), used off-label per guideline recommendations, or used with clinical caution in indications with more limited data.

Indications with FDA approval for IVIG

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Indications with off-label use for IVIG

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Indications with limited clinical support for IVIG

  • Stiff person syndrome12,13
  • Multiple sclerosis14,15,16
  • Childhood encephalitis17

IVIG is reserved as a last line treatment option in these indications if other treatments fail or cannot be tolerated by the patient. Dosing guidelines have yet to be clinically decided, and dosing is typically determined by the clinical judgement of the prescriber and individual, institutional protocols.

Monitoring

Monitoring for IVIG patients typically includes:

  • Blood pressure before, during and after the infusion3
    • - IVIG may cause hypotension or hypertension
  • Renal function3
    • - Monitor before initiating therapy, and then at appropriate intervals.
    - IVIG has a US boxed warning for renal dysfunction.
  • IgG concentrations3,18,19
    • - Monitor before initiating therapy, and then every 4-6 months. Measure every 2-3 months if switching from IV to SC IG.
    - IgG reference level: 700-1600 mg/dL
    - Goal trough level: >600 mg/dL OR at least as high as the previous trough level from the previous IVIG dose.
  • IgA concentrations3,18
    • - Low levels of IgA may lead to the formation of IgA antibodies.
    - Patients with IgA antibodies are at a greater risk of infusion reactions from IVIG.
    - Use low IgA IVIG for patients with low IgA and monitor closely for infusion reactions.
    - IgA reference level: 70-400 mg/dL
  • Signs of thrombosis3
    • - IVIG has box warning for increased risk of thrombosis.
    - Patients who have difficulties ambulating may be at a greater risk of thrombosis events.
  • Clinical response

The role of subcutaneous immunoglobulin (SCIG)

SCIG offers several benefits for patients who receive immunoglobulin therapy. The primary benefit is convenience, as the patient may be trained to self-administer SCIG or be able to have a caregiver trained to administer at home. Patients who have a busy schedule, live far away from infusion centers, or who have transportation barriers may find great freedom in switching from IVIG to SCIG. SCIG produces a less dramatic spike in serum IgG levels which is beneficial in reducing systemic side effects. Additionally, more frequent dosing of SCIG has been shown to produce higher trough levels, and patients may experience less variations in clinical response.20

The main limitations of SCIG are increased infusion-site reactions, increased dosing frequency, and less opportunity for healthcare monitoring during infusions. For these reasons, SCIG should be reserved for patients whose disease states are well controlled. If patients experience a decrease in therapeutic response while on SCIG, they may need to be switched back to IVIG therapy.

SCIG therapy, Hizentra, is currently FDA approved for CIDP.3 Refer to each product’s prescribing information leaflet for dosing guidance.

Final considerations

The use of IVIG and SCIG in immunology is an evolving topic with new research conducted on a regular basis. Consult your institution’s clinical databases to stay up to date with the latest information regarding IVIG in specific indications.

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References

  1. Hartung HP, Mouthon L, Ahmed R, Jordan S, Laupland KB, Jolles S. Clinical applications of intravenous immunoglobulins (IVIg)--beyond immunodeficiencies and neurology. Clin Exp Immunol. 2009 Dec;158 Suppl 1(Suppl 1):23-33. doi: 10.1111/j.1365-2249.2009.04024.x. PMID: 19883421; PMCID: PMC2801038.

  2. Hughes RA, Donofrio P, Bril V, et al., for the ICE Study Group. Intravenous immune globulin (10 percent caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized, placebo-controlled trial. Lancet Neurol 2008 Feb;7(2):136–44.

  3. Lexi-Drugs. [cited 2020 June 23] In Lexicomp Online [Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc. Available from:Available from: http://online.lexi.com.

  4. Elovaara I, Apostolski S, van Doorn P, et al; EFNS. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS Task Force on the Use of Intravenous Immunoglobulin in Treatment of Neurological Diseases [published correction appears in Eur J Neurol. 2009;16(4):547]. Eur J Neurol. 2008;15(9):893-908.[PubMed 18796075]

  5. Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012;78(13):1009-1015.[PubMed 22454268]

  6. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Lancet. 1997;349(9047):225-230.[PubMed 9014908]

  7. Raphael JC, Chevret S, Harboun M, Jars-Guincestre MC; French Guillain-Barré Syndrome Cooperative Group. Intravenous immune globulins in patients with Guillain-Barré syndrome and contraindications to plasma exchange: 3 days versus 6 days. J Neurol Neurosurg Psychiatry. 2001;71(2):235-238.[PubMed 11459901]

  8. Bain PG, Motomura M, Newsom-Davis J, et al. Effects of Intravenous Immunoglobulin on Muscle Weakness and Calcium-Channel Autoantibodies in the Lambert-Eaton Myasthenic Syndrome. Neurology. 1996;47(3):678-683.[PubMed 8797464]

  9. Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011;76(23):2017-2023.[PubMed 21562253]

  10. Gajdos P, Tranchant C, Clair B, et al; Myasthenia Gravis Clinical Study Group. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol. 2005;62(11):1689-1693.[PubMed 16286541]

  11. Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007;68(11):837-841.[PubMed 17353471]

  12. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. 2001.

  13. Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology. 2000. 

  14. Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet. 1997.

  15. Achiron A, Kishner I, Dolev M, et al. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J Neurol. 2004.

  16. Sorensen PS, Haas J, Sellebjerg F, Olsson T, Ravnborg M, Group TS. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology. 2004.

  17. Iro MA, Martin NG, Absoud M, Pollard AJ. Intravenous immunoglobulin for the treatment of childhood encephalitis. Cochrane Database Syst Rev. 2017;10(10):CD011367. Published 2017 Oct 2. doi:10.1002/14651858.CD011367.pub2

  18. Dati F, Schumann G, Thomas L, et al. Consensus of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins in serum based on the standardization against the IFCC/BCR/CAP Reference Material (CRM 470) Eur J Clin Chem Clin Biochem. 1996;34:517–20. International Federation of Clinical Chemistry, Community Bureau of Reference of the Commission of the European Communities, College of American Pathologists.

  19. Agarwal S, Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG values. Ann Allergy Asthma Immunol. 2007;99(3):281–283

  20. Shrestha P, Karmacharya P, Wang Z, Donato A, Joshi AY. Impact of IVIG vs. SCIG on IgG trough level and infection incidence in primary immunodeficiency diseases: A systematic review and meta-analysis of clinical studies. World Allergy Organ J. 2019 Oct 9;12(10):100068. doi: 10.1016/j.waojou.2019.100068. PMID: 31641401; PMCID: PMC6796775.

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