Inflammatory Neuropathy Consortium: Report of a meeting held on July 4th-6th, 2008 Bâtiment Babinski, Hôpital de la Salpêtrière, Paris, France
The Inflammatory Neuropathy Consortium held its first scientific meeting on the historic neurological site of the Hôpital de la Salpêtrière in Paris. The Consortium is a special interest group of the Peripheral Nerve Society and was inaugurated at a meeting of 18 neurologists in Amsterdam from April 13th to 15th, 2007 (Lunn et al., 2008). The Consortium recognizes the need for:
The Inflammatory Neuropathy Consortium was endorsed by a meeting of 75 members of the Peripheral Nerve Society at the Peripheral Nerve Society meeting in Utah in July 2007 and subsequently its organising committee was appointed as a standing committee of the Peripheral Nerve Society.
This meeting in Paris attracted 130 delegates, and included ten invited plenary lectures and over 60 abstracts presented as platform presentations or posters.
Hans-Peter Hartung (Düsseldorf, Germany) set the scene for the plenary lectures with an explanation of the mechanisms involved in autoimmune neurological disease. He evoked the molecular mimicry hypothesis of induction of autoimmune disease and the role of both bacterial and human genetics in the development of Guillain-Barré syndrome (GBS). He used the experimental autoimmune neuritis model to illustrate points in the inflammatory pathway which are susceptible to inhibition by relatively specific immunosuppressive drugs which are already being used in multiple sclerosis (MS) and might be used in inflammatory neuropathy.
Hugh Willison (Glasgow, UK) demonstrated his recently published experiments in which antibodies to ganglioside GD1a induced neuromuscular paralysis causing respiratory failure. Paralysis was dramatically cured by the complement inhibiting monoclonal antibody eculizumab. This is already available for treatment trials because of its approval for the treatment of paroxysmal nocturnal haemoglobinuria. He stressed the critical dependence of ganglioside configuration in lipid rafts in the membrane for recognition by antibodies. These configurations are altered by adjacent interacting ganglioside molecules. Antibodies to ganglioside complexes (initially pairs) are now being detected in sera from some patients with GBS syndrome which lack antibodies to individual gangliosides. This opens up a new level of complexity in the pathogenesis of GBS and hope that an explanation for the mechanism of the common form of the disease will be discovered.
Alberto Priori (Milano, Italy) reviewed the physiological basis of conduction block in multifocal motor neuropathy with conduction block (MMN). He showed that the degree of partial motor conduction block can be altered by both depolarisation and hyperpolarisation. Furthermore, the axons distant from the conventionally detected point of conduction block are often abnormal and usually hyperpolarised. He postulated that the pathophysiological abnormalities at the site of conduction block in MMN may arise from depolarization or hyperpolarization, probably depending on the course of disease.
Jean-Michel Vallat (Limoges, France) reviewed the morphological abnormalities in different forms of inflammatory neuropathy, illustrated by beautiful electron micrographs depicting the widely spaced myelin in IgM paraproteinaemic demyelinating neuropathy (PDN) associated with antibodies to myelin associated glycoprotein (MAG), the non-compacted myelin in POEMS syndrome and abnormalities of myelin in some patients with PDN associated with IgG or IgA paraproteins. He emphasised that nerve biopsies may detect pathology of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) which had not necessarily been demonstrated by neurophysiological tests and thus lead to treatment not previously considered and that biopsies are particularly important in understanding the mechanisms of dysimmune neuropathies.
Srini Kaveri (Paris, France) reviewed the multiple mechanisms of action of intravenous immunoglobulin (IVIg) which may be responsible for its efficacy in inflammatory neuropathy. He noted that 8% of the Fc portion of immunoglobulin is sialylated and this portion may be responsible for its anti-inflammatory effect. For instance, recombinant sialylated Fc has been shown to upregulate the inhibitory Fc in the FCyRIIb gamma mouse model. It has been shown that IVIg includes antibodies to BAFF, CD40 and other cell surface molecules and that it blocks the maturation, differentiation and function of dendritic cells. It also expands the CD25 positive, CD4 positive cell population which includes the regulatory T cells. Mimicking all these actions with a laboratory manufactured molecule is going to be difficult.
Maria Leandro (London, UK) introduced a fascinating session on lessons from other auto-immune diseases by describing the experience of Jo Edwards’ laboratory at University College in treating rheumatoid arthritis (RhA). They argued that B cell autoreactivity is important in pathogenesis and showed that the use of the CD20 B cell depleting antibody, rituximab, is highly efficacious in treating RhA. It was rapidly licensed for use in RhA in combination with methotrexate. It is used for patients who have not responded to tumor necrosis factor inhibitors. The CD20 molecule is not present on pro-B cells or on plasma cells. Curiously, rituximab reduces autoantibodies more than immunoglobulin levels or protective antibodies. Rituximab is an obvious candidate for use in inflammatory neuropathy.
Giampaulo Merlini (Pavia, Italy) gave a brilliant review of the different forms of amyloidosis and their treatment (Merlini and Bellotti, 2003). Many proteins can form beta-pleated sheets and be deposited as amyloid fibroids. Most patients with amyloid neuropathy have AL amyloid but a substantial minority have hereditary amyloidosis, of which the commonest form is due to a transthyretin mutation. Among patients with AL amyloid, about 20% have peripheral nervous system and 18% autonomic nervous system involvement. Abdominal fat pad aspiration led to a diagnosis of AL amyloid in 89% of patients. Modern cytotoxic regimes now often achieve worthwhile results with long term remissions in 30% of patients. Useful treatment is also now available for hereditary amyloid disease with liver transplants, which need to be performed early enough in the course of the disease that irreversible cardiac damage has not occurred. These are more successful in some forms of hereditary amyloid than others, as cardiac involvement may continue to progress. If cardiac involvement is already present, there is the possibility of performing a double liver-heart transplant. Trials have started of the use of diflunisal and protease inhibitors to dissolve or prevent fibril deposition.
Alan Tyndall (Basel, Switzerland) described the international experience with adult stem cell transplants for autoimmune diseases. 944 procedures have now been performed on 922 patients, of whom 21 have had second transplants. Sustained remissions have been achieved in systemic lupus erythematosus in 54%, MS in 32% and RhA in 12%. The transplant related mortality has been about 7%. In addition, there is interest in mesenchymal stem cells which are multipotent mesenchymal prodromal cells which can be obtained from fat or placenta, cultured and stored. They produce immunomodulatory molecules and have been helpful in acute graft versus host disease. Trials are now on-going in MS. There is a need for careful investigation of their use in inflammatory neuropathy, preferably with randomised controlled trials.
Catherine Lubetzki (Paris, France) gave an extremely clear and extensive review of the different immunosuppressive and immunomodulatory treatments which have been tried and shown effective in MS. Many of these have already been tried in inflammatory neuropathy, but others such as mitoxantrone, alemtuzemab and fingolimod have not.
Finally, Michael Collins (Marshfield, Wisconsin, USA) gave a detailed account of the classification and treatment of the vasculitides, concluding with an account of non-systemic vasculitis. He and the PNS guideline working party on vasculitic neuropathy have accumulated a large database of information on this controversial topic and we look forward to the production of their report which is still in progress.
Over 60 abstracts published in the June issue of the Journal of the Peripheral Nervous System were presented as platform presentations. The platform presentations provided the opportunity to flag important research projects which the Inflammatory Neuropathy Consortium wishes to pursue. Thus, Bart Jacobs from Rotterdam, The Netherlands introduced his plan to construct a database of 1000 patients with GBS which can be used to validate and further develop the Erasmus GBS Outcome Score (EGOS) prognostic model (van Koningsfeld, 2007). Richard Lewis (Detroit, Michigan, USA) has obtained funding from the GBS/CIDP Foundation International and a private donor to establish a register of patients with multifocal motor neuropathy which can be used to learn more about the natural history, treatments and prognosis of the disease. Bart Jacobs also presented an ambitious plan to develop a DNA bank from patients with GBS, CIDP and MMN. Although hints have come from small studies of associations with candidate immune response genes of different types in GBS and CIDP, none of the studies have been large enough to reliably detect important associations. Modern DNA technology allows the rapid and inexpensive performance of whole genome scans. If these are to be successful, they require in the order of 1000 DNA samples per patient group. The collection of such samples from well documented patients is an organisational challenge which the Inflammatory Neuropathy Consortium is ideally situated to undertake. The organising committee have asked Bart Jacobs to take the lead in preparing a proposal to tackle this problem which the Inflammatory Neuropathy Consortium will support and members will be asked to contribute.
In a popular session at the end of the meeting, recent advances in GBS were summarised by Pieter van Doorn (Rotterdam, The Netherlands), in CIDP by Ivo van Schaik (Amsterdam, The Netherlands), in MMN by Eduardo Nobile-Orazio (Milano, Italy), and in PDN by Michael Lunn (London, UK).
One of the most important aims of the Inflammatory Neuropathy Consortium is to help pursue trials of treatments for inflammatory neuropathy. These depend critically on appropriate outcome measures. Ingemar Merkies (Rotterdam, The Netherlands) is leading the PERINOMS study to compare and validate existing outcome measures used on both sides of the Atlantic and to develop a new activity limitations (disability) scale with improved linear performance characteristics. Plans are being developed for trials of a second immunoglobulin dose in Guillain-Barré syndrome (Pieter van Doorn, Rotterdam, The Netherlands) and of IVIg versus intravenous methylprednisolone in CIDP (Eduardo Nobile-Orazio, Milano, Italy). It is hoped that there will also be trials of immunosuppressant agents in CIDP. Animal model studies are ongoing to clarify the safety of sodium channel inhibition in axonal protection in GBS (Michael Lunn, London, UK), but it is regrettable that there are currently no ongoing registered trials of any agent in GBS.
It was a very positive meeting with the discussions in the corridors and at the dining table as important as the proceedings in the excellent lecture theatre in the Bâtiment Babinski. During the next year, the organising committee and designated members of the Inflammatory Neuropathy Consortium will pursue the projects mentioned. The Inflammatory Neuropathy Consortium will meet at the Peripheral Nerve Society meeting in Würzburg, Germany from 4th-8th July 2009. Be there! Also put in your diaries for 2010 a joint meeting of the Inflammatory Neuropathy Consortium and the Charcot-Marie-Tooth Consortium in the Red Centre, Uluru, Alice Springs, Australia in the third week of May.
We thank Alexion Pharmaceuticals, Inc., GBS/CIDP Foundation International, Genzyme Corporation, Kedrion S.p.A., LFB Biopharmaceuticals, Octapharma PPG, and Talecris Biotherapeutics for unconditional grants to support the meeting.
Merlini G, Bellotti V (2003). Molecular mechanisms of amyloidosis. N Engl J Med 349:583-596.
van Koningsveld R, Steyerberg EW, Hughes RA, Swan AV, van Doorn PA, Jacobs BC (2007). A clinical prognostic scoring system for Guillain-Barré syndrome. Lancet Neurol 6:589-594.
Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S, Masters CL, Merlini G, Saraiva MJ, Sipe JD (2007). A primer of amyloid nomenclature. Amyloid 14:179-183.