Clinical and Experimental Immunology



7th International Immunoglobulin Conference: Neurology

E. Nobile-Orazio* and R. A. Lewis† *Humanitas Clinical and Research Center, Milan University, Rozzano, Milan, Italy, and † Cedars-Sinai Medical Center, Los Angeles, CA, USA

Correspondence: E. Nobile-Orazio. E-mail: [email protected]

Summary Immunoglobulin (Ig) therapy has been used and studied as a treatment for a variety of neurological conditions for decades. In some of these disorders Ig therapy has a significant role as a first-line treatment. This session explores the use of Ig therapy in immune-mediated peripheral neuropathies and various central nervous system (CNS) diseases. Informative practice points relating to the management and treatment of these diseases are discussed. Potential future neurological indications for Ig therapy, as well as data on efficacy and possible mechanisms of action, are also presented. In peripheral immune-mediated neuropathies, data show good response rates to Ig therapy and it is often used as a first-line treatment. Intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) are both well tolerated, but dose and dosing frequency should be based on individual clinical responses. In Alzheimer’s disease, although clinical data show no significant differences between IVIg and placebo, biomarker studies indicate that plasma-derived antibodies may be involved in clearance of amyloid aggregates from the brain. Data suggest that the use of high IVIg doses in earlystage Alzheimer’s treatment may warrant further investigation. Ig therapy is considered a valuable option for autoimmune encephalitis, an antibodymediated CNS disease. Combination treatment with IVIg and corticosteroids shows promising results and is proposed as a first-line treatment in these disorders. Until recently, very little was understood about the pathogenesis of chronic pain disorders. Data now indicate that perpetuation of the pain response may be underpinned by central immune activation. Some data suggest that Ig therapy may mitigate this effect, with good response rates in a number of studies, but these data need confirmation. Keywords: immunoglobulin, intravenous immunoglobulin, subcutaneous immunoglobulin, neurological disorders, biomarker

Introduction The use of intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) are becoming increasingly well documented in autoimmune peripheral neuropathies. These conditions are thought to be caused by inflammation through autoantibody targeting of myelin or axonal antigens, leading to symptoms such as motor weakness and sensory abnormalities. The immune-mediated pathogenesis of these diseases means that they are a potential target for Ig therapy. 22

Three of the most well-characterized immune-mediated neuropathies are discussed by Dr Claudia Sommer, including Guillain-Barré syndrome (GBS), multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). GBS is treated typically with IVIg or plasmapheresis. Various add-on therapies have been studied, but did not show additional benefit. In MMN, IVIg is the first-line treatment, while corticosteroids and plasmapheresis may worsen the condition. Combining IVIg with mycophenalate mofetil or rituximab did not confer any additional benefit. CIDP patients can be treated with

© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 22–24

Immunoglobulin therapy in neurology

IVIg, corticosteroids and plasmapheresis [1–4]. Response rates to these treatments are between 60 and 82% of patients. However, there remains a considerable proportion of non-responders for whom alternative therapy options are needed. Despite the lack of good data, combinations of immunosuppressants for the treatment of CIDP are used in clinical practice in these patients. MMN is a condition characterized by progressive, asymmetric motor weakness and multifocal conduction blocks. Dr Jean-Marc Léger reviews data from studies investigating the use of IVIg and SCIg therapy in MMN, with encouragingly positive results [5,6]. Dr Min-Suk Yoon also discusses data evaluating IVIg versus SCIg administration in CIDP. Among the benefits of SCIg therapy is the use of smaller, more frequent doses compared to IVIg, leading to shorter infusion times and less fluctuation in Ig trough levels between Ig doses. Additionally, patients may be able to selfadminister SCIg in their own homes, rather than travelling to a clinic to receive an IVIg infusion. The data presented indicate that SCIg is well tolerated by peripheral neuropathy patients and may be a preferable option for some [6,7]. In Dr Huned Patwa’s presentation on individualizing Ig treatment for neurology patients, it is noted that Ig therapy is not a one-size-fits-all treatment, and as most of these conditions require ongoing therapy, factors such as dose and frequency must be tailored to clinical outcome in the individual patient. Dr Patwa reviews current treatment guidelines and new data informing best practice for Ig dosing in various neurological disorders, including the role of IVIg and SCIg. The potential use of IVIg in Alzheimer’s disease has been under investigation for almost a decade, and Dr Norman Relkin’s session provides insight into new data in this field. Promising results from clinical studies support the view that plasma-derived Ig includes conformation-selective anti-amyloid antibodies which target multiple toxic forms of amyloid, thus preventing their early assembly [8]. Dr Myrna Rosenfeld records that anti-N-methyl-Daspartate (NMDA) receptor autoimmune encephalitis is the second most frequent immune-mediated encephalitis in children. Data elucidating the pathogenesis of antibodymediated central nervous system (CNS) diseases has led to the use of IVIg therapy plus steroids or plasma exchange as the first-line treatment regimen and has shown favourable response rates [9]. A further potential new indication for Ig therapy was presented by Dr Andreas Goebel, who explored the use of Ig therapy in chronic pain disorders. He reports that we are now beginning to understand the pathogenesis of these previously little-understood conditions, which depend largely upon central immune activation. Results from recent trials with IVIg in these patients [10–12] point to autoantibodymediated autoimmunity as a cause of chronic pain syn-

dromes, and the need for randomized controlled trials to identify the key to a better quality of life with these difficultto-treat diseases.

Acknowledgements The authors would like to thank Meridian HealthComms Ltd for providing medical writing services.

Disclosures E. N.-O. received consultancy fees from Baxter, CSL Behring, Kedrion and Novartis, honoraria for educational talks from Baxter, CSL Behring and Kedrion and travel support from Baxter and Kedrion. R. A. L. received consultancy fees from CSL Behring, Novartis and Axelacare.

References 1 Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Cochrane Database Syst Rev 2013; 12: CD001797. doi: 10.1002/ 14651858.CD001797.pub3. 2 Mehndiratta MM, Hughes RAC. Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2012; 8:CD002062.pub2. 3 Mehndiratta MM, Hughes RAC. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2012; 9:CD003906.pub3. 4 Léger JM, De Bleecker JL, Sommer C et al. Efficacy and safety of Privigen((R)) in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, openlabel Phase III study (the PRIMA study). J Peripher Nerv Syst 2013; 18:130–40. 5 van Schaik IN, van den Berg LH, de Haan R, Vermeulem Ml. Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database Syst Rev 2005; 2:CD004429. 6 Harbo T, Andersen H, Jakobsen J. Long-term therapy with high doses of subcutaneous immunoglobulin in multifocal motor neuropathy. Neurology 2010; 75:1377–80. 7 Markvardsen LH, Debost JC, Harbo T et al. Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 2013; 20:836–42. 8 Relkin N, on behalf of the GAP Study Group. Results of GAP (160701): a Phase III study of intravenous gammaglobulin for the treatment of mild to moderate Alzheimer’s disease. Presented at the Alzheimer’s Association International Conference (AAIC), Boston 2013. 9 Titulaer MJ, McCracken L, Gabilondo I et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12:157–65. 10 Goebel A, Baranowski A, Maurer K, Ghiai A, McCabe C, Ambler G. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med 2010; 152:152–8.

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E. Nobile-Orazio 11 Goebel A, Misbah S, MacIver K et al. Immunoglobulin maintenance therapy in long-standing complex regional pain syndrome, an open study. Rheumatology (Oxf) 2013; 52: 2091–3.


12 Goebel A, Stock M, Deacon R, Sprotte G, Vincent A. Intravenous immunoglobulin response and evidence for pathogenic antibodies in a case of complex regional pain syndrome 1. Ann Neurol 2005; 57:463–4.

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7th International Immunoglobulin Conference: Neurology.

Immunoglobulin (Ig) therapy has been used and studied as a treatment for a variety of neurological conditions for decades. In some of these disorders ...
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