Workshop on inflammatory myopathy Bethesda, 5–6 April 2000

Neuromuscular Disorders 11 (2001) 93±95

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Workshop report

Workshop on in¯ammatory myopathy Bethesda, 5±6 April 2000 1. Introduction The National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Neurological Diseases and Stroke, and the Of®ce of Rare Diseases of the National Institutes of Health brought together investigators of several disciplines from around the world to discuss in¯ammatory muscle disease in Bethesda during the ®rst week of April 2000. The purpose of the meeting ± the ®rst in a series to be sponsored by NIAMS and NINDS on various muscle diseases ± was to stimulate new research on this uncommon and understudied family of diseases by introducing a variety of investigators in disciplines relevant to in¯ammatory myopathy to the current state of knowledge, encouraging new cross-disciplinary collaborations, and suggesting new areas for research support. The current state of knowledge of in¯ammatory myopathy was presented by a group of clinicians and clinical and basic investigators (P. Plotz of NIH ± overview; R. Sontheimer of the University of Texas ± skin manifestations; L. Rider of FDA ± juvenile myositis; V. Askanas of USC and Z. Argov of Hadassah University Hospital ± inclusion body myopathy; I. Lundberg of the Karolinska Institute and Z. Howard of NCI ± the role of cytokines and chemokines; F. Miller of CBER, FDA and I. Targoff of the University of Oklahoma ± humoral autoimmunity; A. Rosen, L. CasciolaRosen of Johns Hopkins and R. Hohlfeld of the Max Planck Institute of Neurobiology in Munich ± apoptosis and the mechanisms of cell injury and death). Basic science overviews of apoptosis (P. Henkart of NCI), cytokines and chemokines (J. O'Shea of NIAMS), humoral autoimmunity (B. Diamond of Albert Einstein University), and the role of Fc receptors (J. Ravetch of Rockefeller University) were interspersed through the session. 2. Clinical disorders Among the clinical points of discussion were the need to: de®ne the borders between in¯ammatory myopathy, particularly treatment-resistant polymyositis, and genetic dystrophies which they mimic clinically; recognize the close relationship between dermatomyositis and a variant, `amyopathic dermatomyositis', in which the typical skin features 0960-8966/01/$ - see front matter Published by Elsevier Science B.V. PII: S 0960-896 6(00)00178-4

are unaccompanied by muscle involvement; understand the causes of the more prominent features of juvenile disease, including GI ulcerations, calcinosis, and lipodystrophy; and appreciate the possibility that sporadic inclusion body myositis (IBM) may primarily be a degenerative disease involving normal aging processes, oxidative stress, and dysregulation of b amyloid precursor protein and various transcription factors, with in¯ammation playing only a secondary role. In this and later discussions on IBM, the heterogeneity of the syndrome was discussed, in that some patients demonstrate much more in¯ammation in muscle and clinical immune abnormalities than others, and the possibility that IBM may encompass many disorders was considered. The poor response of all sporadic IBM patients to anti-in¯ammatory therapy was both emphasized (R. Barohn of the University of Texas and others) and disputed (V. Askanas, K. Engel, F. Miller and others). There was a sentiment among some at the meeting that IBM should no longer be grouped among the in¯ammatory myopathies. 3. Pathogenesis of myositis The mechanisms of cell injury in in¯ammatory myopathy are not yet fully clear. Apoptosis has not been recognized histologically in myositis biopsies, but there is considerable evidence that perforin and granzyme B play an important role, particularly in polymyositis. The still limited evidence on the cytokine milieu, presented by I. Lundberg, suggests that pro-in¯ammatory cytokines may be absent in biopsies even with highly sensitive assays. Muscle cells appear to have considerable resistance to apoptosis both in vitro and in vivo, but it was pointed out that in a multinucleate cell, limited forms of cell death (`a near-death experience' according to T. Partridge) may occur. L. Casciola-Rosen noted that the route to the development of some of the myositis-speci®c and other autoantibodies may involve the unique susceptibility of the targeted antigens to granzyme B cleavage. Z. Howard raised the possibility that one of the common target autoantigens, histidyl-tRNA synthetase (Jo-1), might contribute to the autoimmune response to itself because it appears to have chemokine-like properties after granzyme B cleavage. In her overview, B. Diamond pointed out that a number of central questions in myositis and related autoimmune

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diseases remain unanswered. Are autoantibody responses Tcell-dependent? Are there autoreactive T-cells? Are the autoantibodies pathogenic? Do the B-cells make them function as APC? In what ways are central and peripheral tolerance involved? It was recognized that the possible role of the activating (FcRIII) and inhibitory (FcRII) Fc receptors was completely unexplored in in¯ammatory myopathy. 4. Other in¯ammatory disorders Two closely related autoimmune in¯ammatory illnesses were also discussed: multiple sclerosis by H. McFarland of NINDS and myocarditis by B. Diamond and by L. Sweeney of the University of Pennsylvania. B. Diamond noted that the expression of autoimmunity may depend on genetic factors affecting antigen display in target tissues. L. Sweeney described the potential use of measures to block apoptosis, such as the provision of Bcl-2, to prevent the late ®brosis in a model of cardiomyopathy. 5. Animal models of myositis Dr K. Nagaraju of NIAMS and Johns Hopkins gave an overview of animal models of myositis in which he presented the features of a number of models. He pointed out that considering the known complexity of in¯ammation in human disease, we should not expect any single animal model to recapitulate all the features of any human disease. He presented his new murine model of in¯ammatory myopathy in which the controlled up-regulation of MHC class I leads to a self-sustaining myopathy with many features of the human disease, with the production of autoantibodies, including antibodies to histidyl-tRNA synthetase. P. Clemens of the University of Pittsburgh described a new viral model of myositis with chronic in¯ammation and calcinosis in mice given Theiler's virus at age 10±14 days. 6. Role of T-cells in in¯ammatory myopathies In the discussions concerning the role of T-cells in in¯ammatory myopathy led by L. Glimcher of Harvard, the importance of the cytokine milieu in determining the course of in¯ammation was emphasized, and the need to increase information about this aspect of the in¯ammatory myopathies was raised. It remains unclear to what extent muscle cells themselves play a role as antigen-presenting cells. 7. In¯ammation in the muscular dystrophies In a session devoted to the role of in¯ammation in the dystrophies, Z. Argov of Hadassah University Hospital presented an overview of the evidence that in¯ammatory cells are present in muscles in most human dystrophies, although their contribution to pathogenesis and clinical

expression remain uncertain. In some dystrophies, there is evidence of the clinical bene®t of some medications such as prednisone that affect in¯ammation, but it was noted that these medications have many other effects. J. Kissel of Ohio State University noted that the clinical expression of the known autosomal dominant dystrophy FSH, in which in¯ammation is a common histologic feature, is highly variable. The spectrum of in¯ammatory cells differs from that in in¯ammatory myopathy, and the disease is clinically unresponsive to prednisone although the creatine kinase level may fall. To what extent the in¯ammation is a secondary consequence of other events is unknown. The presence of in¯ammation in canine and murine dystrophy was noted by J. Tidball of UCLA, and M. Spencer of UCLA provided evidence that depletion of lymphocytes can ameliorate the expression of murine MDX dystrophy and of the more severe disease in utrophin knockout-MDX mice. T. Partridge of Hammersmith Hospital showed that the distribution of lesions and the histology of the vasculature in MDX mice strongly suggest that the microvasculature is involved in the pathogenesis, perhaps because of the failure of nNOS to counteract the vasoconstriction induced by cytokines released by myonecrosis. A. Koch of Northwestern University presented an overview of the role of the vascular endothelium in in¯ammatory processes. 8. Repair and regeneration of damaged muscle The process of the repair of damaged muscle was extensively discussed. J. Tidball described the role of ED2 macrophages and leukemia inhibitory factor in the repair of muscle injury in a rat model. C. Noguchi of NIDDK pointed out the presence of receptors for erythropoietin on satellite cells as well as vascular endothelium and noted that animals lacking this receptor die in utero with a failure of heart development. This work suggests a role for epo in muscle regeneration, which is to be explored. T. Partridge doubted the importance of circulating stem cells in repairing injured muscle since in his model of unilateral limb irradiation, muscle regeneration does not occur. L. Sweeney discussed the probable importance of IGF-1 signaling in the proliferation and differentiation of muscle. The receptors are widely present, and experiments show that the provision of IGF-1 in viral constructs may lead to muscle growth and cell fusion in normal mice and to the functional rescue in MDX mice. R. Bassel-Duby of the University of Texas Southwestern presented work on the effect of calcium concentration on muscle cell differentiation, presumably through effects on the calcineurin-NFAT pathway. 9. Oxidative stress In a session on muscle imaging and on the response to oxidative stress, M. Kushmerick of the University of Washington demonstrated the potential of magnetic reso-

P.H. Plotz et al. / Neuromuscular Disorders 11 (2001) 93±95

nance imaging and spectroscopy to provide evidence of the biochemical state of the muscle, including cross-sectional metabolic maps of limbs. T. Rando of Stanford presented studies on the role of oxidative stress and NOS (nitric oxide synthetase), catalase, and SOD (superoxide dysmutatase) in MDX mice. He noted that mice transgenic for overexpression of SOD develop a severe myopathy. 10. New technology In the session on new directions, the usefulness of AAV (adeno-associated virus) (L. Sweeney) and of high capacity adenoviral vectors under development (P. Clemens) as agents that deliver genes to muscle was discussed. Considerable discussion was devoted to the application of microarray technology. E. Hoffman of the Children's National Medical Center gave an overview of current technologies, including their relative strengths and their relative costs. He noted that expression pro®ling had already proved clinically useful, citing as an example the diagnosis of the genetic lesion in a child with infantile `myositis'. He is developing micro-arrays for human muscle gene expression, and R. Bassel-Duby has developed a micro-array for studying mouse muscle gene expression. Both are actively seeking collaborators to apply their techniques to human disease or to experimental models. 11. Diagnosis and classi®cation F. Miller, L. Pachman of Northwestern University, I. Targoff, C. Oddis of the University of Pittsburgh and others discussed the current imprecise diagnostic criteria and classi®cation schemes, the known and suspected immunogenetic risk factors for the clinical-pathologic, serologic and racial groups, and the availability of clinical databases and specimen repositories from myositis patients already in existence or under development. The observations on familial polymyositis, dermatomyositis and inclusion body myositis, the similarities among affected members of a given family, and the serologic and genetic differences between familial and sporadic disease were outlined. Our limited abilities to predict which patients will respond to which therapies, the relative lack of accurate tools to assess outcomes, and the wide variation in responses to therapeutic intervention and rehabilitation were reviewed. Furthermore, F. Miller strongly presented the case for the importance of clinical therapeutic studies now, even while new experimental information is being obtained. He stressed the limited support for such studies despite the substantial number of new cases each year and the limited therapeutic success with current approaches, particularly in adults. There was discussion of the need to set up a mechanism for collaborative clinical trials, perhaps through the establishment of a consortium involving both neurologists and rheumatologists, the two major medical specialties caring for myositis patients.

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12. Summing up and conclusions In a brief summing up, V. Dubowitz of Hammersmith Hospital noted that the different types of myositis clearly respond differently to therapy and therefore it is important to recognize the distinctions among types in planning trials of therapy. He emphasized the skepticism in including IBM among the in¯ammatory myopathies. D. Carson of the University of California at San Diego emphasized the need to understand how immune responses develop in injured and dystrophic muscle, how individual muscle cells respond to injury, how to prevent post-injury degeneration, what role angiogenesis, chemokines, cytokines, and stem cells play in the response to in¯ammatory injury, and how they can be harnessed in repair. T. Partridge noted that muscle as a tissue is unusual in that most of the genes expressed in the adult animal are not expressed during the development of immunological tolerance. He wondered if this fact was connected to the apparent active suppression of MHC Class I in muscle and its striking up-regulation in in¯ammatory myopathy. He and E. Hoffman both noted, referring to many of the observations presented at the meeting, that the structure of the connective tissue in muscle, including the basal lamina and the vasculature, needed to be studied in much greater depth. In summary, the panorama of approaches to studying in¯ammatory muscle disease was reviewed and the great lack of knowledge in these areas was emphasized. The presentations, taken together, suggest a number of research areas that might bene®t from directed support. ² Better understanding of basic muscle biology, responses to injury and repair mechanisms. ² Dissection of the processes by which muscle cells are damaged and repaired in the in¯ammatory myopathies. ² Deeper exploration of the role of in¯ammatory myopathy in dystrophies and possibly other muscle diseases. ² Establishment of a collaborative clinical group that would develop or adopt consensus criteria for the myositis syndromes and their subgroups, de®ne standard approaches to evaluate disease activity, disease damage and clinical outcomes, and perform multi-center clinical trials of promising therapeutics. Paul H. Plotz, Frederick Miller, Eric Hoffman, Livia Casciola-Rosen, Antony Rosen Correspondence: Paul Plotz, Chief, ARB, NIAMS, NIH, Clinical Center 9N244, MS1820, Bethesda, MD 20892-1820 Tel.: 1301-496-1474 Fax: 1301-402-0012 e-mail: [email protected]