International Symposium

 

The 12^th International Conference on Myasthenia Gravis and Related Disorders was held May 21-23, 2012 in New York City at the New York Academy of Sciences (NYAS). Held every five years, the meeting helps to keep the myasthenia gravis (MG) scientific community abreast of the latest developments and fosters interactions, especially for younger investigators. As has been the case since the first conference was held in 1954, the meeting was co-sponsored by the NYAS and Myasthenia Gravis Foundation of America (MGFA). Support was provided by MGFA, the National Institutes of Health (NIH), the National Institute of Neurological Disorders and Stroke (NINDS),the National Center for Advancing Transitional Sciences (NCATS), the Office of Rare Diseases (ORD) and several corporate sponsors. The meeting was organized by Drs. Emma Ciafaloni, University of Rochester; Matthew Meriggioli, University of Illinois College of Medicine; Robert Ruff, Louis Stokes Cleveland VA Medical Center and Case Western Reserve University; and Gil Wolfe, State University of New York at Buffalo School of Medicine and Biomedical Sciences. All are members of MGFA’s Medical/Scientific Advisory Board (M/SAB)

Nearly 300 scientists and clinicians from around the world attended the meeting, a 30 percent increase over the 2007 conference. The plenary sessions included 50 presentations; more than 100 abstracts were presented during two poster sessions. The keynote address by Marinos Dalakas, MD, summarized the evolution of biologics and other novel approaches in the treatment of MG and other immune-mediated neuromuscular disorders. Other highlights included developments pertaining to the structure of the neuromuscular junction, defects in regulatory T-cells, the discovery of low-density lipoprotein receptor-related protein 4 as an autoimmune target in MG, stem-cell mediated immunomodulation of lymphocytes derived from MG patients, recent basic and clinical findings in MuSK MG, the creation of patient registries for MG, and updates on clinical trials including the international thymectomy trial, acute management of MG exacerbations, methotrexate in MG, and preliminary investigations using complement inhibitors. The 13^th International Conference is scheduled to be held in the spring to summer of 2017.

 

 

The meeting site was within a few blocks of “Ground Zero.” That area of Manhattan is undergoing a revival with a spirit of hope and renewal. What better place than to hold this MG International Conference on the 58^th anniversary of the first International Conference on MG? I have personally attended every MG International Symposium since 1980 and this was by far the most energetic, collegial and hopeful meeting that I have attended.

Day 1 was opened by Brooke Grindlinger, PhD, from the NYAS and our own Sam Schulhof, Chairman of MGFA. The first series of lectures dealt with structure and function of the neuromuscular junction. For most people with MG, the disease is caused by antibodies directed against the acetylcholine receptor (AChR). This session discussed new science related to people who have MG caused by antibodies directed against other components of the neuromuscular junction.   What impressed me most were the first two presentations by Dr. Takamori from Japan, and by Dr. Nishimune from the University of Kansas, that discussed how new information about the structure of the neuromuscular junction led to new animal models of MG and Lambert-Eaton Myasthenia Syndrome (LEMS). Not only did the talks present models, they also discussed new treatment strategies that could be tried in animal studies, and if proven successful could lead to new clinical strategies for treating MG. The third presentation was on DOK-7, which is a recently identified neuromuscular junction protein that is involved in the formation of neuromuscular junctions. This presentation by Dr. Yamanashi from Japan summarized prior data from his laboratory showing that DOK-7 activated muscle specific kinase (MuSK). Antibodies to MuSK account for a major fraction of “seronegative MG” (MG where there are no antibodies to acetylcholine receptors (AChR)). Dr. Yamanashi demonstrated that antibodies directed against DOK-7 are found in the second largest group of people with seronegative MG following MuSK-antibody MG. Consequently, the very first session was packed with new information on causes of MG and treatment strategies for forms of MG that were not even recognized as recently as a decade ago.

 

The second session dealt with recent advances in immunology that relate to MG. The first presentation by Dr. Bach from Paris discussed the causes of autoimmune diseases including genetic predisposition to autoimmune diseases. He also presented interesting data indicating that alteration in the bacterial flora of the gut could change a person’s susceptibility to immune disorders. Two talks given by Drs. Sonia Berrih-Aknin from Italy and Meriggioli the University of Illinois described important roles that a subset of T-lymphocytes called regulatory T-Cells (T-reg) play in the genesis and perpetuation of MG. Dr. Lisak from Wayne State University in Detroit talked about the role of B-cells in MG. Basically, the B-cells make the antibodies that cause MG and the T-cell, especially the Treg cells, regulate the B-cells; and the Treg function is deranged in MG. Dr. De-Baets of Maastrict University combined findings from his laboratory in the Netherlands with data from colleagues in Oxford University in England about the role of the thymus in MG. The term T-cell refers to thymus-derived lymphocytes. There will be more to come about the role of the thymus gland in MG.

 

The 3^rd session focused on clinical and laboratory developments in MG. Dr. Massey from Duke University talked about differences in the clinical manifestations of different forms of MG such as seronegative vs. seropositive MG. Dr. Amelia Evoli from the Catholic University in Rome described unique challenges in managing people with seronegative MG. Among several differences, people with seronegative MG are more likely to have severe difficulty swallowing, and some treatments that work in seropositive are less effective for seronegative MG. Angela Vincent from Oxford University in the United Kingdom (UK) described the development and perfection of the assays for different types of antibodies that can produce MG. The session ended with a Dr. Dan Drachman from Johns Hopkins University discussing a large study of the genetic makeup of people with MG. The collection of specimens from this study was funded by the MGFA. MGFA’s involvement not only helped to fund the research, but also contributed to 14 MG centers in North America participating in the study. DNA was collected from more than 1000 people with MG and about 2000 controls. The genetic data will be analyzed at the NIH.

 

The last session dealt with outcome measures and clinical trial development in presentations from multiple sites in the US and from the UK. This is an area of MG research that is blossoming, in part because more clinical data is emerging, driving the need for more  effective measures of MG that are sensitive enough to detect changes in the clinical state of a patient during the course of a trial. There was a great deal of communication between different clinical research groups to coordinate studies so that the same measures are used in all studies. In conjunction with the point of having common measurement tools among studies, the MGFA is a strong advocate of the NIH Common Data Elements Initiative that is designed to develop common outcome measures across studies so that data from different studies can be compared. 

Short presentations of posters that were identified to be of high interest followed the end of the session. The first talk by Dr. Belaya and a multinational group from Spain and the UK identified a new gene mutation causing a congenital form of non-immune MG. The mutated gene had never been associated with MG before. The second poster was presented by Dr. Alejandro Gomez of Maastricht University in the Netherlands. This poster described promising studies of the agent Bortezomib that in tissue culture studies is able to inhibit cultured thymus cells. The last highlighted poster was a presentation about a new autoimmune target that may be associated with some forms of seronegative MG.

 

In summary, Day 1 was a big hit and the audience left with enthusiasm for the rest of the conference.

Day 2 opened with a Keynote speech by Dr.Marinos Dalakas, formerly of the National Institutes of Health and the University of Athens School of Medicine in Greece. This talk discussed novel approaches to treating autoimmune disorders by attacking T-Cells, B-Cells and cytokines (a class of biological agent that modulates the immuneresponse), and was followed by an excellent talk by Dr. Linda Kushner of George Washington University about the role of complement in autoimmune models of MG. Complement is a chemical cascade that is activated by the immune system and is responsible for killing cells. Dr. Kushner demonstrated that selective inhibition of complement could suppress the development of experimental MG. Dr. Kushner is working with a company to develop clinical trials of complement suppression for treating people with MG. Dr. Souroujon from Paris in cooperation with researchers in Israel, presented information about the role of Tregs in animal models of MG – this presentation reflected back to the presentations on Day 1 related to Tregs. Drs. Richman from University of California Davis and Christadoss from the University of Texas presented findings of seropositive and seronegative MG on animal models.

 

Session VI on Day 2 dealt with MG treatments. Dr. Tzartos from Greece gave a very interesting talk about the development of filtering the blood for antibodies that are specific to MG or MG related conditions. This technology was explored about 10 years ago by researchers in Japan without a useful product emerging. Dr. Tzartos benefits from the knowledge of this prior work combined with newer information about the antibodies targets in MG. The specific form of blood filtering represents an advance over plasmapheresis. There were additional presentations about treatment trials in Mycophenolate and other immune suppressive medications and monoclonal antibodies such as Rituximab that attacks specific classes of immune cells (lymphocytes). Dr. Sanders of Duke University presented information from the MGFA Task force on MG Study Design.

 

Day 2 ended with short talks about specific posters. Dr. Huijbers from the Leiden Medical Center in the Netherlands addressed the parts of the MuSK molecule that are targets for antibodies for seronegative MG with anti-MuSK antibodies. Dr. Aricha presented interesting findings from an animal model of MG.  She found that reducing the presence of a specific molecule called Aire, which is involved with immune regulation, resulted in less severe MG. Perhaps Aire is a target for future pharmaceuticals. Dr. Meriney from the University of Pittsburgh presented data using a molecule that inserts itself into membranes and is able to replace calcium channels. This molecule was able to reduce the severity of an animal model of LEMS.

Day 3 began with several presentations on congenital myasthenic syndromes. The congenital myasthenias refer to a collection of disorders that are usually caused by mutations that alter the structure and function of molecular components of the neuromuscular junction. The mutations can occur in the nerve terminal or in proteins in the synaptic cleft such as the molecule that normally breaks up acetylcholine (acetylcholine esterase). These presentations were made by research groups in the US – Dr. Andrew Engel at the Mayo Clinic and Ricardo Maselli at the University of Illinois, and a large research group at Oxford University in the UK. Dr. Harper at the Mayo Clinic showed that the EMG can be used to distinguish different forms of congenital MG.

 

Session VIII of Day 3 focused on LEMS with talks by Dr. Maddison in the UK and Dr. Titulaer in the Netherlands. Section IX focused on thymectomy and the MGFA and NIH supported Thymectomy Trial. The Thymectomy Trial is a truly international study with subjects enrolled in North and South America, Europe, Asia, Australia and Africa. Dr. Wolfe stated that the trial is close to the target for subject enrollment and that enrollment will conclude in November 2012. Dr. Henry Kaminski of George Washington University spoke about biomarkers, which are proteins, nucleic acids or imaging studies that can be used as surrogate measures for the presence of MG or responsiveness of MG to specific treatments. Dr. Marx from the University of Heidelberg discussed the pathological findings of the thymus gland specimens from the Thymectomy Trial. He stated that the specimens were received in excellent condition. The specimen analysis is ongoing. There were also presentations about different forms of surgical thymectomy.

 

The short poster talks were interesting. Dr. Cossins from the large Oxford research group discussed finding where antibodies are directed in cases of seronegative MG where there are no antibodies to MuSK, DOK-7 or the AChR. Dr. Plomp showed that the antibodies directed against MuSK from patients with seronegative MG do cause MG when used in an animal model. Dr. Sine from the Mayo Clinic discussed how studies of different mutations responsible for congenital myasthenias provided useful insights into how the AChR actually changes its conformation to become an ion channel. Dr. Alessandro Serra from the Cleveland VA Hospital discussed why some types of extraocular muscle fibers would be more susceptible to loss of AChR and how the differential susceptibility can explain why specific types of eye movements are compromised in MG. Dr.Ben-Ami from Israel and colleagues in Paris are using stem cells to alter properties of the immune cells from patients with MG to reduce MG severity. Their approach is potentially applicable to a variety of immune mediated diseases such as multiple sclerosis and rheumatoid arthritis.

 

The International Conference on Myasthenia Gravis and Related Disorders sponsored by the Myasthenia Gravis Foundation of America (MGFA) and the New York Academy of Science comes around only once every five years. As an MGFA board member and myasthenia patient I have been to several of the smaller scientific conferences that MGFA holds in conjunction with the American Academy of Neurology (AAN) or the American Association of Neurological and Electrodiagnostic Medicine (AANEM); but the 2012 conference being held in New York City where I live presented a unique opportunity for me to attend and observe this larger conference up close. 

 

I truly had no idea what to expect from this conference. I only knew that it was three days long and there would be a lot of scientific information that I probably would not understand. The other conferences are usually just one-half day long and have an average of 7 scientific presentations from researchers active in the MG field. The audiences at the various general medical conferences are usually clinicians or researchers who might have an interest in MG. These sessions have been informative and improved my understanding of MG, but this International Conference proved to be something totally different.

 

This was not just a conference of people who might be interested in MG; this was a conference of researchers and clinicians from all over the world who are actively working specifically on myasthenia and related disorders who came to share their work and get and give feedback to each other. Moreover, there were almost 300 people in attendance, and the most exciting and heartwarming aspect of those 300 people was the number of young researchers and scientists in the room who were presenting abstracts on work they are doing on myasthenia. Five of those young scientists were awardees of MGFA Travel Scholarships enabling them to attend the meeting in New York, present their work and participate in the conference.