European Neurological Review, 2017;12(Suppl. 1):2–7
This article reports the proceedings of a satellite symposium held on 7 July 2016 at the 14th International Congress on Neuromuscular Diseases (ICNMD) symposium, Toronto, Canada. Therapeutic plasma exchange (TPE) removes pathogenic antibodies and immune complexes from the plasma. However, TPE may also impact a number of other immune-modulatory pathways that mediate cellular immunity. Data from clinical trials support the effectiveness of TPE in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, to date, the use of TPE for the treatment of chronic myasthenia gravis (MG) is not supported by large clinical studies and there are discrepancies between guidelines and clinical practice. More clinical trials are needed to understand the role of TPE in MG, GBS, and CIDP, as well as other neuromuscular diseases in which it is used, or which may represent potential targets for TPE.
Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, plasma exchange
Luis Querol received a scientific award from Grifols. Mazen M Dimachkie is on the speaker’s bureau or is a consultant for Alnylam, Baxalta, Catalyst, CSL-Behring, Mallinckrodt, Novartis NuFactor and Terumo BCT. He has also received grants from Alexion, Biomarin, Catalyst, CSL-Behring, FDA/OPD, GSK, Grifols, MDA, NIH, Novartis & TMA. Jean-Marc Leger acted as a consultant or received departmental research grants from Baxalta, CSL-Behring, LFB, Novartis, Terumo BCT and UCB. This article reports the proceedings of a sponsored satellite symposium held at the 14th International Congress on Neuromuscular Diseases symposium, Toronto, Canada, 7 July 2016 and, as such, has not been subject to this journal’s usual peer-review process. A member of the editorial board reviewed the report before publication.
Writing assistance was provided by Katrina Mountfort, Touch Medical Media, funded by Terumo BCT.
December 15, 2016 Published Online:
February 01, 2017
Mazen M Dimachkie, The University of Kansas Medical Center, Kansas City, Kansas, US. E: firstname.lastname@example.org
The publication of this article was funded by Terumo BCT.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Therapeutic plasma exchange (TPE) is a valuable technique in peripheral nervous system and neuromuscular diseases: the removal of autoantibodies and immune complexes ensures a rapid onset of action, and the treatment is safe and effective for long-term use. However, the mechanism of action of TPE involves more than the removal of large molecules; studies have shown that TPE has numerous immunomodulatory effects. Despite the fact that TPE is widely used in the treatment of neurological diseases, its effectiveness has only been formally demonstrated in a limited number of conditions: myasthenia gravis (MG), Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). This article describes the proceedings of a symposium convened at the 14th International Congress on Neuromuscular Diseases (ICNMD) symposium, in Toronto, Canada on 7 July 2016. The symposium aimed to further explore the immunomodulatory role of TPE, and to discuss current clinical evidence and unmet needs.
Luis Querol began his presentation by defining several terms that are often used interchangeably in the literature. Apheresis is derived from the Greek term aphaeresis, meaning to take away by force. Plasmapheresis refers to the removal of small volumes of plasma, not more than 15% of total blood volume (TBV), without necessarily replacing the volume. Therapeutic plasma exchange (the abbreviation TPE will be used in this report though PLEX, PE and PEX are also used to mean TPE) is the removal of large volumes of plasma (1 to 1.5 of patients’ TBV) with appropriate volume replacement using either albumin or fresh frozen plasma (FFP).1
Separation of blood components by TPE may employ a centrifuge or membrane filtration. The major differences between the two techniques are the plasma volumes required: centrifuge techniques require lower volumes than membrane and allow a higher plasma extraction rate, which affects the procedural time and the effectiveness of the procedure. Centrifuge TPE usually employs citrate as anticoagulation factor while membrane TPE employs heparin. In addition, centrifuge-based TPE requires a lower blood flow than membrane-based TPE (<150 ml/min versus >150 ml/min). As a result, centrifuge-based TPE can be performed successfully using peripheral venous access.2
The World Apheresis Association (WAA) apheresis registry now comprises data from 50,846 procedures performed in 7,142 patients, of which 16,942 were TPE.3 Most adverse events (AEs) associated with the procedure were reversible and mild in 2.4% of procedures, and included: vascular access problems (54%), device issues (7%), hypotension (15%) and tingling (8%). Moderate AEs were reported in in 3% of procedures and included: tingling (58%), urticaria (15%), hypotension (10%) and nausea (3%). In this registry, severe AEs occurred in only 0.4% of procedures: syncope/hypotension (32%), urticaria (17%), chills/fever (8%), arrhythmia/ asystole (4.5%), nausea/vomiting (4%). Centrifuge-based techniques are much more commonly used than membrane filtration (16:1) and are associated with fewer AEs (6% versus 11%). Procedures performed with central venous access are associated with more severe AEs compared with peripheral access.3
Despite its use in a variety of diseases, and the fact that the use of TPE dates back to the 1950s, its mechanism of action has only been evaluated in a limited number of small studies. While the early use of TPE involved the bulk removal of pathological substances, this action does not explain all of its therapeutic effects, particularly in neuromuscular conditions.4 Plasma exchange has the ability to modulate several immune mechanisms on which other drugs act individually. These are complementary to each other and include the removal of autoantibodies, immune complexes, cytokines etc. that control homeostasis and help to restore the patient’s immune function to normal (see Figure 1).5 In addition to the removal of pathogenic antibodies and circulating immune complexes, TPE also involves modification of immune complex structure and processing by changing the antigen/antibody ratio; modulation of immune complex solubility via complement activation; and modification of cellular components such as lymphocyte subsets.6
1. McLeod BC, Apheresis: Principles and Practice, 2nd edition, Bethesda: American Association of Blood Banks (AABB), 2003.
2. Williams ME, Balogun RA, Principles of separation: indications and therapeutic targets for plasma exchange, Clin J Am Soc Nephrol, 2014;9:181–90.
3. Mortzell Henriksson M, Newman E, Witt V, et al., Adverse events in apheresis: An update of the WAA registry data, Transfus Apher Sci, 2016;54:2–15.
4. Reeves HM, Winters JL, The mechanisms of action of plasma exchange, Br J Haematol, 2014;164:342–51.
5. Burmester GR, Feist E, Dorner T, Emerging cell and cytokine targets in rheumatoid arthritis, Nat Rev Rheumatol, 2014;10:77–88.
6. Bosch T, Current status in extracorporeal immunomodulation: immune disorders, Artif Organs, 1996;20:902–5.
7. De Luca G, Lugaresi A, Iarlori C, et al., Prednisone and plasma exchange improve suppressor cell function in chronic inflammatory demyelinating polyneuropathy, J Neuroimmunol, 1999;95:190–4.
8. Goto H, Matsuo H, Nakane S, et al., Plasmapheresis affects T helper type-1/T helper type-2 balance of circulating peripheral lymphocytes, Ther Apher, 2001;5:494–6.
9. Kambara C, Matsuo H, Fukudome T, et al., Miller Fisher syndrome and plasmapheresis, Ther Apher, 2002;6:450–3.
10. Clark WF, Dau PC, Euler HH, et al., Plasmapheresis and subsequent pulse cyclophosphamide versus pulse cyclophosphamide alone in severe lupus: design of the LPSG trial. Lupus Plasmapheresis Study Group (LPSG), J Clin Apher, 1991;6:40–7.
11. Glassman AB, Bennett CE, Alterations of lymphocyte responsiveness in Guillain-Barre syndrome. Effects of plasma exchange, Transfusion, 1983;23:369–72.
12. Dau PC, Increased proliferation of blood mononuclear cells after plasmapheresis treatment of patients with demyelinating disease, J Neuroimmunol, 1990;30:15–21.
13. Yeh JH, Wang SH, Chien PJ, et al., Changes in serum cytokine levels during plasmapheresis in patients with myasthenia gravis, Eur J Neurol, 2009;16:1318–22.
14. Tesar V, Jelinkova E, Jirsa M, Jr., et al., Soluble adhesion molecules and cytokines in patients with myasthenia gravis treated by plasma exchange, Blood Purif, 2000;18:115–20.
15. Yoshii F, Shinohara Y, Natural killer cells in patients with Guillain- Barre syndrome, J Neurol Sci, 1998;157:175–8.
16. Cortese I, Chaudhry V, So YT, et al., Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, Neurology, 2011;76:294–300.
17. Raphael JC, Chevret S, Hughes RA, et al., Plasma exchange for Guillain-Barre syndrome, Cochrane Database Syst Rev, 2012;CD001798.
18. Schwartz J, Winters JL, Padmanabhan A, et al., Guidelines on the use of therapeutic apheresis in clinical practice-evidencebased approach from the Writing Committee of the American Society for Apheresis: the sixth special issue, J Clin Apher, 2013;28:145–284.
19. Mehndiratta MM, Hughes RA, Agarwal P, Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy, Cochrane Database Syst Rev, 2004;CD003906.
20. Van den Bergh PY, Hadden RD, Bouche P, et al., European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision, Eur J Neurol, 2010;17:356–63.
21. Gajdos P, Chevret S, Toyka K, Plasma exchange for myasthenia gravis, Cochrane Database Syst Rev, 2002;CD002275.
22. Skeie GO, Apostolski S, Evoli A, et al., Guidelines for treatment of autoimmune neuromuscular transmission disorders, Eur J Neurol, 2010;17:893–902.
23. Pasnoor M, Wolfe GI, Nations S, et al., Clinical findings in MuSKantibody positive myasthenia gravis: a U.S. experience, Muscle Nerve, 2010;41:370–4.
24. Ahmed F, Vamanan, K., Dimachkie, M.M. et al. , Arteriovenous fistula for outpatient plasma exchange, J Clin Neuromuscular Dis, 2009;10:156–7; S–4.
25.Barth D, Nabavi Nouri M, Ng E, et al., Comparison of IVIg and PLEX in patients with myasthenia gravis, Neurology, 2011;76:2017–23.
26. Barnett C, Wilson G, Barth D, et al., Changes in quality of life scores with intravenous immunoglobulin or plasmapheresis in patients with myasthenia gravis, J Neurol Neurosurg Psychiatry, 2013;84:94–7.
27. Yuki N, Hartung HP, Guillain-Barre syndrome, N Engl J Med, 2012;366:2294–304.
28. Hughes RA, Wijdicks EF, Barohn R, et al., Practice parameter: immunotherapy for Guillain-Barre syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology, 2003;61:736–40.
29. Raphael JC, Chastang C, Masson C, et al., Guillain-Barre syndrome and plasma exchange, Lancet, 1985;2:45.
30. Efficiency of plasma exchange in Guillain-Barre syndrome: role of replacement fluids. French Cooperative Group on Plasma Exchange in Guillain-Barre syndrome, Ann Neurol, 1987;22:753–61.
31. van der Meche FG, Schmitz PI, A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain- Barre syndrome. Dutch Guillain-Barre Study Group, N Engl J Med, 1992;326:1123–9.
32. van Koningsveld R, Schmitz PI, Meche FG, et al., Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barre syndrome: randomised trial, Lancet, 2004;363:192–6.
33. Double-blind trial of intravenous methylprednisolone in Guillain-Barre syndrome. Guillain-Barre Syndrome Steroid Trial Group, Lancet, 1993;341:586–90.
34. Kleyweg RP, van der Meche FG, Schmitz PI, A randomized trial comparing intravenous immunoglobulin and plasma exchange in Guillain-Barre syndrome, Transfus Sci, 1994;15:389–92.
35. Appropriate number of plasma exchanges in Guillain-Barre syndrome. The French Cooperative Group on Plasma Exchange in Guillain-Barre Syndrome, Ann Neurol, 1997;41:298–306.
36. Hughes RA, Swan AV, van Doorn PA, Intravenous immunoglobulin for Guillain-Barre syndrome, Cochrane Database Syst Rev, 2014;CD002063.
37. Hughes RA, van Doorn PA, Corticosteroids for Guillain-Barre syndrome, Cochrane Database Syst Rev, 2012;CD001446.
38. Dyck PJ, O’Brien PC, Oviatt KF, et al., Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment, Ann Neurol, 1982;11:136–41.
39. van Schaik IN, Eftimov F, van Doorn PA, et al., Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial, Lancet Neurol, 2010;9:245–53.
40. Dyck PJ, Daube J, O’Brien P, et al., Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy, N Engl J Med, 1986;314:461–5.
41. Hahn AF, Bolton CF, Pillay N, et al., Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy. A double-blind, sham-controlled, cross-over study, Brain, 1996;119 ( Pt 4):1055–66.
42. Hahn AF, Bolton CF, Zochodne D, et al., Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebocontrolled, cross-over study, Brain, 1996;119 ( Pt 4):1067–77.
43. Hughes R, Bensa S, Willison H, et al., Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy, Ann Neurol, 2001;50:195–201.
44. Hughes RA, Donofrio P, Bril V, et al., Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebocontrolled trial, Lancet Neurol, 2008;7:136–44.
45. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al., Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy, Ann Neurol, 2013;73:370–80.
46. Miura Y, Devaux JJ, Fukami Y, et al., Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia, Brain, 2015;138:1484–91.
47. Ng JK, Malotka J, Kawakami N, et al., Neurofascin as a target for autoantibodies in peripheral neuropathies, Neurology, 2012;79:2241–8.
48. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al., Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg, Neurology, 2014;82:879–86.
49. Querol L, Rojas-Garcia R, Diaz-Manera J, et al., Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins, Neurol Neuroimmunol Neuroinflamm, 2015;2:e149
Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, plasma exchange