2006 Scientific Session
of the Myasthenia Gravis Foundation of America, Inc.
by Robert L. Ruff, MD, PhD
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The annual scientific session of the Myasthenia Gravis Foundation of America (MGFA) was held on October 6, 2006 in Chicago, IL at the Hyatt Regency Hotel. The session was organized by Dr. Gil Wolfe.
The MGFA supports two types of research and educational grants. The Henry R. Viets Fellowship is targeted to healthcare professionals in training. The Viets award provides monies to expose healthcare professionals to clinical or basic science research in MG via a short term research project. The MGFA fellowships provide support for post-doctoral training in basic science or clinical research in MG. The Viets awards and MGFA fellowships are designed to get promising healthcare professionals interested in MG so that these individuals will direct their future energies toward elucidating the cause, improving treatment and developing a cure for MG. The meeting demonstrated the success of the fellowships. Several presentations were given by former MGFA fellows.
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Sponsors
of the
2006
Scientific Session:
Athena Diagnostics
Tatsuji Nambra, MD
(in honor of
Dr. David Grob)
Myasthenia Gravis Foundation of Illinois
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The meeting included discussion of the ongoing international clinical trial on thymectomy. There were thirteen presentations from around the world, including 11 talks and 2 posters. Many of the presentations related to immunology, seronegative MG (clinical MG in individuals who do not have antibodies (Ab) against the acetylcholine receptor (AChR) and clinical observations in people with MG. Brief reviews of the role of the immune system in MG and seronegative MG are provided to enhance understanding of the presentations.
The Role of the Immune System in MG
MG is an auto-immune disease involving the site of communication between nerve and muscle, the neuromuscular junction. The lymphocyte class of immune cells are divided into two large groups: Thymus-derived lymphocytes (T-cells) and B-cell lymphocytes. T-cells are involved in cell-medicated immune responses in which cells attack immune targets. B-cells are responsible for producing antibodies that target specific parts of proteins called epitopes. Cells that process and present potential immune targets (also called antigens) to the immune system are called antigen presenting cells (APCs). T-cells can modulate the activity of B-cells. MG is T-cell dependent antibody mediated disease in which T-cells modulate the activity of B-cells that produce antibodies that are directed primarily against the AChR and secondarily against other sites (epitopes) at the neuromuscular junction. The antibodies binding to the AChR trigger a complement-mediated cellular immune attack against the neuromuscular junction. Complement is an immune-medicated chemical cascade that destroys proteins and injures or destroys cells. Cytokines are proteins produces by the body that modulate the immune system. Interleukins (IL) are a class of cytokines that are secreted by lymphocytes. IL regulate the activities of different classes of immune system cells. Interferons (IFN) are a different class of immune regulatory proteins. A recently recognized factor that can alter the immune response seen in different tissues is that cells have chemicals or factors bound to them that can alter the intensity of the immune response. A chemical called DAF is a local immune response modifying agent that is present on skeletal muscle cells. These cell specific immune modifying agents may partially explain why some tissues, such as extraocular muscle, are preferentially involved in MG. Extraocular muscles (EOM) move the eyes and control the eyelids. When these muscles are not working in concert a person can have double vision (diplopia) or ptosis (drooping eye lids).
Title: Novel complement inhibitor ameliorates the outcome of experimental myasthenia gravis: Preliminary results
Authors: Jindrich Soltys, Chelliah Richmonds, Bendi Gong, Denise Hatala, Shanmugavel Veithesh, Andrew Young and Henry Kaminski (past MGFA awardee). Department of Neurology, Case Western Reserve University and Neurology Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH
A large body of research on clinical MG and experimental MG (EAMG) has shown that the damage to the endplate is complement-mediated. This study evaluated the effect of inhibiting complement on two different types of experimentally acquired myasthenia gravis (EAMG). One form is produced by injecting rats with active antibody – this is called passive transfer MG. The second form is produced by injecting rats with AChR protein and allowing the rats to generate antibodies that react with their own antibodies to produce an “active” form of EAMG. Rats in the treated group showed 100% survival rate and a good clinical score. Actively immunized rats produced high amount of AChR autoantibodies and had significant weight loss during the 4 week time that the EAMG developed. Complement inhibition was started 33 days after the start of induction of EAMG. Treatment with the complement inhibitor improved strength and result in weight gain (presumably due to recovery of muscle mass that was lost during the development of EAMG). In both the passive transfer and active transfer EAMG, treatment with complement inhibitor reduced the deposition of complement at the neuromuscular junction and reduced the intensity of the immune attack at the neuromuscular junction. In summary, the preliminary data presented in this talk indicate that complement inhibition could prove to be useful in treating human MG. Additional work will be needed to evaluate for long term complications of using complement inhibitor treatement before this strategy can be applied to humans.
Title: Anti-DAF antibody treatment augments the incidence and severity of ocular MG in HLA-DQ8 mice immunized with H-AChR γ subunit.
Authors: Jing Li (past MGFA Awardee), Erdem Tuzun (past MGFA Awardee), Shamsher S. Saini , Andrey Bednov, B. Paul Morgan*, Premkumar Christadoss. Departments of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070. * Cardiff University, Cardiff, United Kingdom.
Decay-accelerating factor (DAF) is produced by a diverse number of different types of cells, including skeletal muscle and is present on the cell surface. DAF is an intrinsic complement-regulatory protein whose function is to limit local production of complement and activation of the complement cascade that leads to cell damage. In addition, DAF was recently found to modulate T cell immunity by controlling T cell interactions with the immune cells that present antigens to the T cells (an early step in T cell–mediated immune reactions). The effect of DAF is to suppress the immune response against cells that produce DAF with higher DAF production resulting in greater reduction of the immune reaction. In this investigation the authors compared the level of complement activation, IgG deposition, and ultrastructural alterations at extraocular muscle and diaphragm neuromuscular junctions. Animals were assessed for acetylcholine receptor antibody production and T cell activation. EAMG was induced by giving multiple administrations of purified AChR protein (active transfer EAMG) to 8-12 week old mice deficient in the gene that makes DAF (Daf1-/-) and also injecting AChR into littermates who had a normal DAF gene function (Daf1+/+, these served as controls). Daf1-/- mice were weaker than the Daf1+/+ mice. All animals produced acetylcholine receptor antibody. Evidence of complement activation was more prominent on the endplates of the Daf1-/- animals. In addtion, the neuromuscular junctions of EAMG Daf1-/- animals had more injury than the EAMG Daf1+/+ mice. T cell activity was elevated in Daf1-/- mice. This study supports the role of complement activation in modulating the severity of EAMG. This study also demonstrated that the level of DAF on a cell surface will modulate the intensity of immune reactions and that DAF can modulate the level of T cell activation. Another implication of this study is help understand why certain muscles are targeted more strongly in autoimmune disease such as MG. Prior work from Dr. Kaminski’s laboratory showed that extraocular muscle, which moves the eyes and eyelids, had low levels of DAF, which may help to explain why extraocular are more severely affected in MG.
Suppression of Experimental Autoimmune Myasthenia Gravis (EAMG) by GM-CSF is Associated With an Expansion of FoxP3+ Regulatory T Cells
Authors: Matthew N. Merigglioli, Jian Rong Sheng, Liangcheng Li, Balaji B. Ganesh, Chenthamarakshan Vasu, and Bellur S. Prabhakar. University of Illinois in Chicago, Chicago, IL.
Autoimmune myasthenia gravis (MG) is a T cell dependent, antibody-mediated, organ specific autoimmune disease. Autoantibodies to the skeletal muscle acetylcholine receptor (AChR) impair neuromuscular transmission resulting in muscle weakness. Current therapies for MG produce non-specific immune suppression, and are associated with significant chronic side effects and enhanced risk for infection and malignancy. This presentation focused on the possibility that MG develops in part because individuals have an imbalance between immune reactive cells that trigger immune reactions and suppressor cells that attenuate immune reactions. Dendritic cells (DCs) have the potential to activate or tolerize T-cells in an antigen-specific manner. Tolerance means that an immune reaction against a specific protein such as the AChR would be suppressed without shutting down the rest of the immune system. In this study, the authors investigated the effects of mobilization of specific DC subsets - using granulocyte-macrophage colony-stimulating factor (GM-CSF) on the severity of active transfer experimental autoimmune myasthenia gravis (EAMG). They administered GM-CSF to mice prior to immunization with AChR and observed the effect on the frequency and severity of EAMG development. GM-CSF administered prior to immunization exerted a sustained suppressive effect against the induction of EAMG. This suppression was associated with lowered serum anti-AChR antibody levels, reduced T-cell proliferative responses to AChR, and an expansion in the population of cells the suppress immune reactions (FoxP3+ regulatory T cells). They also found reduced deposition of IgG and complement at endplates. These results highlight the potential of manipulating DCs as a strategy to induce tolerance and suppress MG. Further studies are necessary to determine if enhancing suppressor cell function will be useful in animals with established MG, which more closely resembles the condition of people with MG.
Background for presentations on Seronegative MG
Antibodies are proteins produced by the immune system that bind to and target substances for destruction by the immune system. Antibodies are designed to target foreign substances such as bacteria. In patients with MG, antibody production is disturbed and antibodies are produced against self (i.e., antibodies target normal body proteins). The most common and the major pathogenic autoantibodies in MG are directed against the AChR on skeletal muscle. Patients with antibodies against the AChR are considered to have seropositive MG. A fraction of patients with MG, about 20% of patients with MG, do not have anti-AChR antibodies. The MG in these patients is referred to as seronegative. Many people with seronegative MG have autoantibodies against other components at the neuromuscular junction. The autoantibodies cause additional problems for patients with MG. Serum from patients with seronegative MG can be injected into animals and cause a MG-like condition. Immunoglobulins from seronegative patients bind to muscle cells, but not to AChR. The most common target for antibodies in patients with seronegative MG appears to be a muscle protein called MuSK (muscle-specific receptor tyrosine kinase). MuSK is a muscle-specific protein that regulates how AChRs are incorporated into the neuromuscular junction. About 30-50% of seronegative MG patients are have antibodies directed against MuSK. The seronegative patients who have antibodies against MuSK are sometimes referred to in studies as MuSK+ or MuSK-MG. For comparison, patients with antibodies against the AChR are sometimes referred to as having AChR-MG.
Title: Have we discovered a new type of AchRAb negative MG?
Authors: Gina Eom (Viets Award winner), Tariq Aziz, Joel Oger. Neuroimmunology Laboratory, The University of British Columbia, Vancouver, British Columbia.
This study compared the presence of antibodies in patients with MG depending upon whether the assay for antibody was conducted using AChR extracted from human muscle or AChR produced by directly producing AChR from the DNA for the human AChR subunits. The AChR produced from human muscle likely contains more immune-reactive proteins than just the AChR. The authors found that some patients had serum that reacted against the “unclean” AChR produced from human muscle and not to the pure human AChR. This study is consistent with the idea that in some patients MG is triggered against proteins at the endplate other than AChR.
Title: Antibodies to acetylcholine receptors in seronegative myasthenia.
Authors: Angela Vincent, Maria Isabel Leite, Judy Cossins, John Newsom-Davis, David Beeson, Nick Willcox. Oxford University, Weatherall Institute, John Radcliffe Hospital, Oxford OX3 9DS , United Kingdom .
A subset of patients with MG do not have antibodies to the acetylcholine receptor that can be detected with routine diagnostic testing (seronegative MG, SNMG). MuSK antibodies are only present in some of these patients, and the number varies worldwide. Patients who have seronegative MG and who have antibodies against MuSK can be referred to as having MuSK-MG to distinguish them from patients who have anti-AChR antibodies (AChR-MG). MuSK-MG can be associated with severe bulbar and facial weakness and tongue atrophy. This group’s previous research indicated that some SNMG plasmas contain factors that inhibit AChR function. The effect was acute and reversible with washing. This led the reseaarchers to hypothesize that there might be antibodies that did not bind tightly to the AChR and thus were not able to bind to single AChRs floating in solution. These weakly binding antibodies might be able to bind to AChR that are closely packed, as is true on the endplate membrane, because an antibody could weakly bind to two AChRs with twice the force of binding to one AChR. The investigators explored the possibility that studying antibody binding to tightly clustered AChRs would demonstrate antibody binding to AChRs for patients who were antibody negative by the traditional assay. The researchers expressed rapsyn along with AChRs in cultured cells. Rapsyn cross-links AChRs producing clusters of closely packed AChRs. They found that more than 50% of the sera from SNMG patients bound to AChR clusters. Thus about half of the patients who have SNMG when tested with traditional assay techniques may anti-AChR abs that bind weakly to AChRs.
Title: MuSK antibody positive MG (MMG): Response to treatment in 30 patients.
Authors: Donald B. Sanders, Janice M. Massey, Vern C. Juel. Duke University, Durham, NC
This presentation describes the clinical status of 30 patients with MG who did not have antibodies to AChR, but did have antibodies to MuSK. Sixteen patients presented with typical MG, 8 had MG restricted to the shoulder girdle region and 6 had predominantly facial and throat weakness. There patients were predominantly women and more likely to be African-American compared to traditional MG. The MuSK MG patients often have a strongly positive improvement with plasmapheresis, but do not respond well to cholinesterase inhibitors. Most patients with MuSK MG have normal appearing thymus glands on imaging studies and when thymectomy is done the pathology appears to be normal. It is not clear if thymectomy is appropriate for people with MuSK MG. Some patients responded well to immune suppressive therapy, but it is not clear that is uniformly effective.
Title: Clinical characteristics of MuSK-antibody positive MG: A U.S. experience.
Authors: Mamatha Pasnoor, R.J. Barohn, L Herbelin, A. McVey, G.I. Wolfe, S.P. Nations, J.R. Trivedi, J.T. Kissel, R. Walsh, G.C. Claussen, S.J. Oh
The findings of this study were consistent with the study presented by Dr. Sanders, with a few differences. In this study about half of the patients were white and patients with predominantly shoulder girdle weakness were less common. As was found by Dr. Sanders, more than half of the patients did not respond well to cholinesterase inhibiting agents. In this study only about 50% of MuSK patients responded to steroids or immune suppressing agents, although more than half responded to some treatment so that most improved to treatment.
Title: Esophageal adynamia in a patient with muscle specific tyrosine kinase (MuSK) antibody positive myasthenia gravis (MMG).
Author: Donald B. Sanders. Duke University, Durham, North Carolina.
This was a case presentation of woman with MMG who had severe difficulty swallowing. A detailed study of her food pipe (esophagus) demonstrated that her swallowing problems were due to lack of rhythmic contraction of the esophagus, likely due to impaired functioning of striated muscle in the esophagus.
Clinical Studies about MG
Title: Psychosocial aspects of myasthenia gravis.
Authors: Lindsay Knudsen (Viets Award winner), Deborah Renard, Sarah Wolf, Kathleen Steldt, Milwaukee, WI
This study’s aim was to obtain information about the psychosocial issues facing the myasthenia gravis (MG) population. This study was done by mailing 101 people a questionnaire. Seventy people responded and of that group sixty-seven people with MG, ages 21-81, completed both the Millon Behavioral Medicine Diagnostic (MBMD) and a demographic questionnaire. The MBMD evaluates how a person is reacting to a condition, such as having MG. Women compared to men with MG were more likely to be dejected. Men were less likely to turn to religion and women were less likely to feel discomfort associated with MG. The reactions to MG were similar to other diseases with two exceptions: 1) MG patients were more likely to have restriction to movement and activity and 2) MG patients were more at ease discussing their illness. People who had MG for more than 5 years were more likely to feel dejected. This research suggests that counseling may be most beneficial for those newly diagnosed, younger, and with more severe disease. Although people with MG have many similarities to other chronically ill people, unique aspects of the MG experience affect both coping and counseling needs.
Title: Do the sera of patients with myasthenia gravis have antibodies that recognize CoA, lipoic acid, or glutathione: a search for a potential trigger of autoimmune myasthenia gravis.
Authors: Chih-Te Wu (MGFA awardee – through the Chapter Challange), Robert H. Fairclough
A small fraction of patients develop MG from exposure to a drug D-penicillamine. D-penicillamine acts in part by interacting with specific amino acids containing sulfhydryl groups that are present on the AChR. The authors found that other agents that interact with sulfhydryl groups may also predispose to the development of MG, perhaps because AChR with altered sulfhydryl groups are not correctly recognized by the immune system as “self”.
Title: Myasthenia gravis (MG) as an autoimmune manifestation of Non-Hodgkin Lymphoma (NHL) and its favorable response to Rituximab.
Authors: Kourosh Rezania, Helen Lin, Koen Van Besien, Joseph Baron, Vikram Penumalli, Betty Soliven. University of Chicago, Chicago, IL
MG can appear in patients with lymphomas and some autoimmune disorders, perhaps because the damaged immune systems are not correctly recognizing AChRs as “self” proteins. The authors found that the patients they studied responded well to treatment with Rituximab, which suppresses immune responses involving B-cells. Rituximab has been used in small studies of MG with encouraging results; however, additional studies will be needed to determine the role of Rituximab in treating MG.
Title: A trial of Mycophenolate (MMF) MuSK antibody positive MG (MMG): Response to treatment in 30 patients.
Authors: Donald B. Sanders, Janice M. Massey, Vern C. Juel. Duke University, Durham, NC
The results of the study were that MMF combined with prednisone did not provide a benefit over prednisone. The three month study included 80 patients who were evaluated using indexes of muscle strength and ability to function independently. Patients received MMF or placebo plus 20mg of prednisone per day. Patients receiving MMF and placebo were not different for muscle strength or ability to function.
Title: Thymectomy trial (MGTX) and biomarker study (BioMG) in non-thymomatous myasthenia gravis (MG).
Authors: John Newsom-Davis, Gary Cutter, Henry J Kaminski (past MGFA awardee), Gil I. Wolfe, Alfred Jaretzki III, Chichi Aban, Greg Minisman, Robin Conwit. This is a multi-national study with study sites in the Americas, Europe, Asia.
Thymectomy is the most commonly employed surgical treatment for MG. There has been an ongoing debate for many years about whether the procedure is effective in inducing remission of MG or reducing disease severity. The purpose of this international research program is to determine if the universally accepted and available surgical technique for thymectomy, trans-sternal resection, is more effective in treating MG than medical treatment alone. The transternal surgical approach for thymectomy involves cutting through the breastbone to allow surgeons to have full direct visualization of the chest cavity to improve the likelihood that all thymus tissue will be removed. This project has been in development since 2000. Drs. Fred Jaretzki (current member of the MGFA Board of Directors and Medical Advisory Board), Henry Kaminski, Rick Barohn, Gil Wolfe (members of the MGFA Medical Advisory Board) were among the initial group of MG clinical researchers who initiated development of the thymectomy trial. They were joined by Dr. Gary Cutter from University of Alabama in Birmingham who assisted with study design and who oversees the data collection and analysis. The MGFA is supporting a section of this study to evaluate pathology in the thymus and to compare pathology pattern with clinical state. Most of the study work is being funded by the NIH. MGFA provided early support to permit the investigators to get together to work out the initial version of the protocol. The thymectomy trial is designed to determine the efficacy of thymectomy in people with MG who do not have a thymoma. Note that people who have a thymoma need to have a thymectomy to remove the thymus tumor, which can compromise heart function and breathing. Therefore, people who have a thymoma should be considered for thymectomy independent of whether they have MG. To carry out the thymectomy trial, there are 67 centers in the USA, UK, Canada, South America and around the world. These centers have all committed to participate and to collect information in a uniform manner. This is an important study that will evaluate the benefits and risks of thymectomy and help to determine when this surgery should and should not be done. Additional information that will be examined are: 1) are there biomarkers (specific forms of proteins that can be detected by simple tests) that correlate with clinical course or response to treatment – this could help to determine the best treatment for an individual and 2) are there patterns of pathology in the removed thymus that can be used to predict disease severity and response to treatment. The study has just started. An initial progress report of this extremely important clinical trial in MG treatment will likely be presented at the international conference MG that will be held in Chicago in May 14-16, 2007.
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