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Clinical and Experimental Immunology
I N T E R L A K E N L E A D E R S H I P AWA R D S
doi:10.1111/cei.12538
7th International Immunoglobulin Conference: Interlaken Leadership Awards
M. C. Dalakas*† and W. N. Löscher‡ *University of Athens Medical School, Athens, Greece, †Thomas Jefferson University, Philadelphia, PA, USA, and ‡Innsbruck Medical University, Innsbruck, Austria
Correspondence: M. C. Dalakas. E-mail: [email protected]
Summary The Interlaken Leadership Awards (ILAs), established in 2010, are monetary grants pledged annually by CSL Behring to fund research into the use of immunoglobulin (Ig) therapy, especially into its use in neurological disorders. Five recipients of the 2011/2012 Awards were invited to present their research at the 7th International Immunoglobulin Conference. Dr Honnorat reports on paraneoplastic neurological syndromes (PNS). His multi-centre Phase II trial, currently under way, will assess the efficacy of IVIg therapy in treating PNS in the first 3 months of treatment. Dr Geis shows improved disease scores after IVIg treatment in a mouse model of neuromyelitis optica (NMO). It is hoped that these promising results will translate well into human NMO. Dr Schmidt studied IVIg therapy in an mdx mouse model for Duchenne muscular dystrophy (DMD). He reports that motor function improved and myopathic changes in skeletal muscles and creatine kinase release were decreased. Dr Gamez presents the design and rationale for a Phase II clinical trial investigating the preoperative use of IVIg therapy in myasthenia gravis patients to prevent post-operative myasthenic crisis. Dr Goebel reports results from studies elucidating the immune-mediated pathogenesis of complex regional pain syndrome (CRPS), the successful IVIg therapy in a proportion of CRPS patients, and the development of a model for predicting which patients are more likely to respond to Ig therapy. Keywords: complex regional pain syndrome, Duchenne muscular dystrophy, myasthenia gravis, neuromyelitis optica, paraneoplastic neurological
syndrome
Introduction The Interlaken Leadership Awards (ILAs) are research grants awarded annually by CSL Behring to scientists around the world committed to furthering knowledge of the use of immunoglobulin (Ig) therapy. Established in 2010, the programme’s mission is to ‘explore novel opportunities to enhance quality of life (QoL) for patients using polyvalent immunoglobulins’ [1]. The current focus of the programme is neurological disorders. The papers in this section have been written by recipients of the 2011/2012 ILAs, and detail research into the treatment of neurological disorders with Ig therapy which has been made possible by funding from the Awards. Findings are presented from research designed or conducted in five different disorders: paraneoplastic neurological syndromes (PNS), neuromyelitis optica (NMO), 124
Duchenne muscular dystrophy (DMD), myasthenia gravis (MG) and complex regional pain syndrome (CRPS). Our understanding of the causes, pathology and specific therapies of these diseases is varied; however, all are seriously debilitating conditions which can leave patients with a very poor QoL. PNS encompass immune-mediated neurological conditions associated with cancer that affect multiple parts of the central and peripheral nervous system [2]. Dr Honnorat presents an overview of the existing retrospective and prospective clinical studies in PNS [3–13], and the rationale for the current Phase II, multi-centre trial investigating the efficacy of intravenous immunoglobulin (IVIg) in their treatment. Dr Geis has used the Award to study the effects of IVIg therapy in a mouse model of NMO, a central nervous system disease affecting the spinal cord and optic nerve,
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 124–126
Interlaken Leadership Awards
related to autoantibodies against aquaporin 4 (AQP4) [14]. Currently, treatments for NMO focus on removal of the autoantibodies or suppression of their production, B cell depletion or high-dose corticosteroid treatment; data from Dr Geis’ study have shown that IVIg treatment ameliorated symptoms in the mouse model, suggesting that treatment with IVIg may be explored as potential therapy in NMO patients. Unlike the other diseases discussed in this section, DMD is an inherited disorder, caused by mutations in the dystrophin gene on the X chromosome [15], which results not only in degenerative but also reactive inflammatory changes within the muscle. DMD patients experience devastating muscle degeneration and death before their fourth decade. Dr Schmidt and his team tested IVIg therapy in a mouse model for DMD, finding that motor function and muscle contractility were improved and myopathic changes and cellular infiltration were reduced. Whether these results will have any potential applications for the treatment of human disease remains to be determined. Dr Gamez, the only 2012 Award recipient in this section, is currently recruiting patients to his Phase II clinical trial of IVIg treatment for MG patients undergoing surgery. Procedures such as thymectomies are often required in these patients [16], but the use of general anaesthetic may carry a risk of inducing life-threatening muscle weakness [17]. Dr Gamez’s study aims to ascertain whether pre-operative treatment with IVIg could be helpful in reducing the occurrence of these myasthenic deteriorations. Finally, Dr Goebel presents data from his ongoing work looking into the potential uses of IVIg treatment in CRPS. Despite having been a recognized condition for more than a century, CRPS is an extremely complex and previously poorly understood condition where patients experience chronic, ongoing pain with no apparent cause which does not respond to typical pain relief treatments. Data now show that the ongoing pain signal may, at least partially, have an autoimmune pathogenesis, and it has also been shown that a proportion of patients may respond to treatment with IVIg therapy. Dr Goebel’s current research focuses on methods that could potentially predict response to Ig or other immunotherapies [18–20].
Acknowledgements M. C. D. and W. N. L. would like to thank Meridian HealthComms Ltd for providing medical writing services.
Disclosure M. C. D. has received speaking honoraria or served as a consultant for Novartis, CSL, Genzyme, Baxter, Octapharma, Dysimmue Foundation and Grifols. W. N. L. received project funding, travel support or speaker fees from CSL Behring, Lilly, Astellas, Genzyme, Baxter and Pfizer.
References 1 CSL Behring. Interlaken Leadership Awards Mission Statement. 2014. Available at: http://www.interlakenleadershipawards.com/ about.aspx (accessed 22 August 2014). 2 Graus F, Delattre JY, Antoine JC et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135–40. 3 Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997; 41:789–96. 4 Graus F, Keime-Guibert F, Rene R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124:1138–48. 5 Keime-Guibert F, Graus F, Fleury A et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000; 68:479–82. 6 Orange D, Frank M, Tian S et al. Cellular immune suppression in paraneoplastic neurologic syndromes targeting intracellular antigens. Arch Neurol 2012; 69:1132–40. 7 Rojas I, Graus F, Keime-Guibert F et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000; 55:713–5. 8 Shams’ili S, de Beukelaar J, Gratama JW et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006; 253:16–20. 9 Shams’ili S, Grefkens J, de Leeuw B et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003; 126:1409–18. 10 Sillevis Smitt P, Grefkens J, de Leeuw B et al. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002; 249:745– 53. 11 Uchuya M, Graus F, Vega F, Rene R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry 1996; 60:388–92. 12 van Broekhoven F, de Graaf MT, Bromberg JE et al. Human chorionic gonadotropin treatment of anti-Hu-associated paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2010; 81:1341–4. 13 Vernino S, O’Neill BP, Marks RS, O’Fallon JR, Kimmel DW. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol 2004; 6:55–62. 14 Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005; 202:473–7. 15 Deconinck N, Dan B. Pathophysiology of Duchenne muscular dystrophy: current hypotheses. Pediatr Neurol 2007; 36:1–7. 16 Mantegazza R, Bonanno S, Camera G, Antozzi C. Current and emerging therapies for the treatment of myasthenia gravis. Neuropsychiatr Dis Treat 2011; 7:151–60. 17 Chaudhuri A, Behan PO. Myasthenic crisis. Q J Med 2009; 102:97–107. 18 Goebel A, Vogel H, Caneris O et al. Immune responses to Campylobacter and serum autoantibodies in patients with
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 124–126
125
M. C. Dalakas & W. N. Löscher complex regional pain syndrome. J Neuroimmunol 2005; 162:184–9. 19 Kohr D, Singh P, Tschernatsch M et al. Autoimmunity against the beta(2) adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain 2011; 152:2690–700.
126
20 Tekus V, Hajna Z, Borbely E et al. A CRPS–IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome. Pain 2014; 155:299– 308.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 124–126
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Clinical and Experimental Immunology
I N T E R L A K E N L E A D E R S H I P AWA R D S
doi:10.1111/cei.12538
7th International Immunoglobulin Conference: Interlaken Leadership Awards
M. C. Dalakas*† and W. N. Löscher‡ *University of Athens Medical School, Athens, Greece, †Thomas Jefferson University, Philadelphia, PA, USA, and ‡Innsbruck Medical University, Innsbruck, Austria
Correspondence: M. C. Dalakas. E-mail: [email protected]
Summary The Interlaken Leadership Awards (ILAs), established in 2010, are monetary grants pledged annually by CSL Behring to fund research into the use of immunoglobulin (Ig) therapy, especially into its use in neurological disorders. Five recipients of the 2011/2012 Awards were invited to present their research at the 7th International Immunoglobulin Conference. Dr Honnorat reports on paraneoplastic neurological syndromes (PNS). His multi-centre Phase II trial, currently under way, will assess the efficacy of IVIg therapy in treating PNS in the first 3 months of treatment. Dr Geis shows improved disease scores after IVIg treatment in a mouse model of neuromyelitis optica (NMO). It is hoped that these promising results will translate well into human NMO. Dr Schmidt studied IVIg therapy in an mdx mouse model for Duchenne muscular dystrophy (DMD). He reports that motor function improved and myopathic changes in skeletal muscles and creatine kinase release were decreased. Dr Gamez presents the design and rationale for a Phase II clinical trial investigating the preoperative use of IVIg therapy in myasthenia gravis patients to prevent post-operative myasthenic crisis. Dr Goebel reports results from studies elucidating the immune-mediated pathogenesis of complex regional pain syndrome (CRPS), the successful IVIg therapy in a proportion of CRPS patients, and the development of a model for predicting which patients are more likely to respond to Ig therapy. Keywords: complex regional pain syndrome, Duchenne muscular dystrophy, myasthenia gravis, neuromyelitis optica, paraneoplastic neurological
syndrome
Introduction The Interlaken Leadership Awards (ILAs) are research grants awarded annually by CSL Behring to scientists around the world committed to furthering knowledge of the use of immunoglobulin (Ig) therapy. Established in 2010, the programme’s mission is to ‘explore novel opportunities to enhance quality of life (QoL) for patients using polyvalent immunoglobulins’ [1]. The current focus of the programme is neurological disorders. The papers in this section have been written by recipients of the 2011/2012 ILAs, and detail research into the treatment of neurological disorders with Ig therapy which has been made possible by funding from the Awards. Findings are presented from research designed or conducted in five different disorders: paraneoplastic neurological syndromes (PNS), neuromyelitis optica (NMO), 124
Duchenne muscular dystrophy (DMD), myasthenia gravis (MG) and complex regional pain syndrome (CRPS). Our understanding of the causes, pathology and specific therapies of these diseases is varied; however, all are seriously debilitating conditions which can leave patients with a very poor QoL. PNS encompass immune-mediated neurological conditions associated with cancer that affect multiple parts of the central and peripheral nervous system [2]. Dr Honnorat presents an overview of the existing retrospective and prospective clinical studies in PNS [3–13], and the rationale for the current Phase II, multi-centre trial investigating the efficacy of intravenous immunoglobulin (IVIg) in their treatment. Dr Geis has used the Award to study the effects of IVIg therapy in a mouse model of NMO, a central nervous system disease affecting the spinal cord and optic nerve,
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 124–126
Interlaken Leadership Awards
related to autoantibodies against aquaporin 4 (AQP4) [14]. Currently, treatments for NMO focus on removal of the autoantibodies or suppression of their production, B cell depletion or high-dose corticosteroid treatment; data from Dr Geis’ study have shown that IVIg treatment ameliorated symptoms in the mouse model, suggesting that treatment with IVIg may be explored as potential therapy in NMO patients. Unlike the other diseases discussed in this section, DMD is an inherited disorder, caused by mutations in the dystrophin gene on the X chromosome [15], which results not only in degenerative but also reactive inflammatory changes within the muscle. DMD patients experience devastating muscle degeneration and death before their fourth decade. Dr Schmidt and his team tested IVIg therapy in a mouse model for DMD, finding that motor function and muscle contractility were improved and myopathic changes and cellular infiltration were reduced. Whether these results will have any potential applications for the treatment of human disease remains to be determined. Dr Gamez, the only 2012 Award recipient in this section, is currently recruiting patients to his Phase II clinical trial of IVIg treatment for MG patients undergoing surgery. Procedures such as thymectomies are often required in these patients [16], but the use of general anaesthetic may carry a risk of inducing life-threatening muscle weakness [17]. Dr Gamez’s study aims to ascertain whether pre-operative treatment with IVIg could be helpful in reducing the occurrence of these myasthenic deteriorations. Finally, Dr Goebel presents data from his ongoing work looking into the potential uses of IVIg treatment in CRPS. Despite having been a recognized condition for more than a century, CRPS is an extremely complex and previously poorly understood condition where patients experience chronic, ongoing pain with no apparent cause which does not respond to typical pain relief treatments. Data now show that the ongoing pain signal may, at least partially, have an autoimmune pathogenesis, and it has also been shown that a proportion of patients may respond to treatment with IVIg therapy. Dr Goebel’s current research focuses on methods that could potentially predict response to Ig or other immunotherapies [18–20].
Acknowledgements M. C. D. and W. N. L. would like to thank Meridian HealthComms Ltd for providing medical writing services.
Disclosure M. C. D. has received speaking honoraria or served as a consultant for Novartis, CSL, Genzyme, Baxter, Octapharma, Dysimmue Foundation and Grifols. W. N. L. received project funding, travel support or speaker fees from CSL Behring, Lilly, Astellas, Genzyme, Baxter and Pfizer.
References 1 CSL Behring. Interlaken Leadership Awards Mission Statement. 2014. Available at: http://www.interlakenleadershipawards.com/ about.aspx (accessed 22 August 2014). 2 Graus F, Delattre JY, Antoine JC et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135–40. 3 Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997; 41:789–96. 4 Graus F, Keime-Guibert F, Rene R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124:1138–48. 5 Keime-Guibert F, Graus F, Fleury A et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000; 68:479–82. 6 Orange D, Frank M, Tian S et al. Cellular immune suppression in paraneoplastic neurologic syndromes targeting intracellular antigens. Arch Neurol 2012; 69:1132–40. 7 Rojas I, Graus F, Keime-Guibert F et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000; 55:713–5. 8 Shams’ili S, de Beukelaar J, Gratama JW et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006; 253:16–20. 9 Shams’ili S, Grefkens J, de Leeuw B et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003; 126:1409–18. 10 Sillevis Smitt P, Grefkens J, de Leeuw B et al. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002; 249:745– 53. 11 Uchuya M, Graus F, Vega F, Rene R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry 1996; 60:388–92. 12 van Broekhoven F, de Graaf MT, Bromberg JE et al. Human chorionic gonadotropin treatment of anti-Hu-associated paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2010; 81:1341–4. 13 Vernino S, O’Neill BP, Marks RS, O’Fallon JR, Kimmel DW. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol 2004; 6:55–62. 14 Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005; 202:473–7. 15 Deconinck N, Dan B. Pathophysiology of Duchenne muscular dystrophy: current hypotheses. Pediatr Neurol 2007; 36:1–7. 16 Mantegazza R, Bonanno S, Camera G, Antozzi C. Current and emerging therapies for the treatment of myasthenia gravis. Neuropsychiatr Dis Treat 2011; 7:151–60. 17 Chaudhuri A, Behan PO. Myasthenic crisis. Q J Med 2009; 102:97–107. 18 Goebel A, Vogel H, Caneris O et al. Immune responses to Campylobacter and serum autoantibodies in patients with
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 124–126
125
M. C. Dalakas & W. N. Löscher complex regional pain syndrome. J Neuroimmunol 2005; 162:184–9. 19 Kohr D, Singh P, Tschernatsch M et al. Autoimmunity against the beta(2) adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain 2011; 152:2690–700.
126
20 Tekus V, Hajna Z, Borbely E et al. A CRPS–IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome. Pain 2014; 155:299– 308.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 124–126
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
