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Dr Frederick Miller

• Conference Report printed in Newsletter 55, December 2003

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Conference Report printed in Newsletter 55, December 2003 based on the talk given by Dr Fred Miller at the Myositis Support Group Conference 2003.

News and Views on Myositis

Dr Frederick Miller is Chief of the Environmental Autoimmunity Group at the National Institutes of Health in America. He is also on the medical advisory panel of the Myositis Association (America).

Myositis is the collective name given to a group of systemic muscle diseases that are thankfully rare. The annual incidence is estimated to be between 5 and 10 new cases per million people and its frequency of incidence may be on the increase. In general, the prevalence of polymyositis and dermatomyositis peaks in childhood (between the ages of 5-15 years) and adult midlife (between 30-50 years of age), whereas, IBM peaks after 50 years of age. Females are preferentially affected (~3:1) in all forms except in IBM (female:male ~1:3).The prevalence, frequency of clinical forms, and risk factors (genetic and environmental) for developing myositis are likely to differ in different parts of the world. African-Americans may have an increased risk of developing a myositis and poorer outcomes compared to Caucasians. Genetic risk factor associations have been identified for certain types of myositis however anecdotal clusterings of myositis suggest strong environmental influences as well.

Myositis refers to a group of systemic diseases that can be defined by clinical presentation, pathology, genetics, and serology. Myositis is typically categorised by clinical-pathologic characteristics. This gives rise to four main groups [1] dermatomyositis, [2] polymyositis, [3] inclusion body myositis and [4] other forms. Group [4] other forms of myositis includes myositis associated with another connective tissue disease, cancer-associated myositis, focal/nodular myositis, ocular/orbital myositis, eosinophilic myositis, and granulomatous myositis.

It is necessary to group specific types of myositis as this facilitates prediction of problems that may arise and influence treatment regimens adopted. Classification of myositis by serological characteristics is one such way to group the diseases that may provide predictive factors. Serological classification refers to the detection of antibodies that can be found in the blood and provides an insight into how a sufferer’s immune system is responding. It is thought that the majority of polymyositis and dermatomyositis sufferers will have some autoantibodies (estimated ~90%) and inclusion body myositis sufferers (estimated ~70%). Serological groups of interest in myositis involve Myositis-Specific Autoantibodies (MSAs) and Myositis-Associated Autoantibodies (MAAs). MSAs are autoantibodies that are only detected in myositis and not in any other inflammatory disease, which include; anti-aminoacyl-tRNA synthetases (anti-synthetase), anti-signal recognition particle (anti-SRP) and anti-SNF2-superfamily nuclear helicase (anti-Mi-2). Myositis-Associated Autoantibodies (MAAs) are autoantibodies that may be detected in myositis but may also be present in other diseases. MAAs include anti-U-RNP (U1, U2, U5), anti-Ro52, anti-PM/Scl, anti-Ku, anti-155kD, anti-MJ, anti-PMS-1, PMS-2. It must be reiterated that myositis can be present without MSAs and MAAs present. This may be because MSAs and MAAs are present but have yet to be identified.

Interestingly, serological groups differ in clinical features and disease course. Thus defining a sufferer’s serological group at the time of diagnosis may provide the required ‘clues’ to predict disease course, problems likely to arise, and suitable treatments that the patient may respond to. Sufferers with anti-synthetase autoantibodies have a greater likelihood to also suffer with interstitial lung disease, arthritis, mechanic’s hands, and fever. Myositis sufferers who have anti-signal recognition particle autoantibodies generally have an acute severe muscle weakness often associated with cardiac involvement and myalgias. Whereas, myositis sufferers with anti-Mi-2 antibodies have a greater skin involvement typically a V-sign rash, shawl-sign rash (across the shoulders) and cuticular overgrowth.

Unlike inherited myopathies and muscular dystrophies, myositis is not a pure genetic disease. There is however likely to be genetic heterogeneity amongst myositis groups. Genetic studies can be used not to diagnose myositis but to look at candidate genes to help our understanding of how the disease may have come about. The table below highlights genetic mutations of two genes, HLA-DRB1 and HLA-DQ1 which have been identified as potential risk factors in certain types or serological groups of myositis.

Genetic risk factors alone can not explain why some people develop myositis and others do not. Additional factors are likely to play an important role. It is this convergence of a genetic risk (rather than a genetic certainty) and environment trigger(s) at a specific moment in time that leads to an individual developing myositis. The ethnogeography of disease conceptualises that many diseases vary in prevalence and clinical expression in different ethnic groups around the world. The reasons for these differences remain unknown but natural global variations in genetics and environmental factors may play roles. Developing an understanding of the causes of these differences may give insight into disease pathogenesis.

The International Myositis Collaborative Study Group was established in 1991 to utilise the natural genetic and environmental variations around the world to begin to define and understand differences in the clinical expression, risk factors and pathogeneses of the myositis syndromes. Currently, involving 39 investigators at 15 centres on four continents and over 1100 patients enrolled on various studies focusing on cluster analyses of phenotypes, genetics, immune responses and exposures. Genetic risk and protective factors for myositis are likely to differ in ethnogeographic populations. There are many possible environment triggers that can be investigated as potential risk factors for myositis syndromes. Possible environmental risk factors that have been suggested include; infectious agents (bacteria, parasites, viruses), non-infectious agents, drugs (e.g. D-penicillamine, statins), biologics (e.g. vaccines, cytokines), foods (e.g. L-tryptophan, adulterated rapeseed oil), medical devices (e.g. collagen and silicone implants), occupational exposures (e.g. silica, superglues), other exposures (e.g. stress, mercury, petrochemicals), and ultraviolet radiation (UVR).

The objectives of the first worldwide myositis study were to determine if differences in clinical and antibody expression of myositis occur at different global locations and to determine if geoclimatic factors may influence the nature and frequency of dermatomyositis, polymyositis, and associated autoantibodies around the world. The relationship of 13 geoclimatic variables that may modulate disease were assessed with the proportion of dermatomyositis and anti-Mi-2 autoantibodies in 919 patients in centres across the world.

An initial observation made was that the proportion of dermatomyositis patients in the total inflammatory myositis populations varied at the global centres, i.e. the frequency of dermatomyositis versus polymyositis sufferers varies throughout the world. Of the geoclimatic variables investigated very few associations were drawn with the exception of ultraviolet light. Global ultra violet light levels strongly correlated with the proportion of dermatomyositis (and also anti-Mi-2 autoantibodies) around the world. Where ultraviolet light exposure was less there were fewer cases of dermatomyositis and where ultraviolet light exposure was greater there were more cases of dermatomyositis.

The primary findings of this worldwide study demonstrates that global surface ultraviolet radiation intensity at many points on the earth appears to be able to predict the proportion of dermatomyositis and dermatomyositis-autoantibodies. This study highlights that environmental data is just as important as genetic data. The proportion of dermatomyositis and dermatomyositis-autoantibodies observed around the world are not the sole result of inherent global variations of known genetic risk factors (HLA DRB1*0701 and the linked DQA1*0201 in Caucasians, and DRB1*0401 and the linked DQA1*0301 in Mesoamericans for anti-Mi-2) but also an environmental trigger too. These findings suggest that ultraviolet radiation may induce dermatomyositis or shift some polymyositis to dermatomyositis. A simple message for dermatomyositis sufferers from this observation is that they should avoid ultraviolet radiation as this may induce a flare of disease.

Many diseases, including myositis, are likely to develop as a result of the combination of genes and environmental exposures. By understanding how environment factors and genes interact we may be able to prevent disease. If we knew what made us susceptible we may be able to avoid the environmental risk factors.

Other recent developments in our understanding of myositis include; confirmation of an increased risk of certain cancers in dermatomyositis (~3 fold increased risk) and polymyositis (~1.5 fold increased risk) which typically occur within two years of diagnosis and thereafter the likelihood decreases; despite different pathology, there are remarkable similar cytokine (IL-1a/ß, TNFa, TGFß, MIP-1a/ß and MCP-1) profiles observed in the muscle biopsies of dermatomyositis, polymyositis and inclusion body myositis sufferers; increased maternal-fetal microchimerism in the peripheral blood and in target organs in juvenile myositis.

Interest and growing expertise in myositis amongst professionals from many fields of science and medicine should improve its management. Management goals include assuring an accurate diagnosis, identification of all manifestations of myositis, identification and attempts to minimise risk factors that may lead to poor prognosis, define the extent of disease activity and disease damage (table below), develop with the patient’s input, a holistic individualised treatment plan taking into account expectations, manifestations, prognosis and risk factors for adverse events to therapies.

To help define the disease pattern of a sufferer it is important to attempt to define characteristics present that may lead to poor prognosis. Identification of poor prognosis factors helps the clinician and the patient define suitable treatment(s) and management. Poor prognostic factors in myositis based on demographic features include; age: older versus younger, gender (?): female versus male, race(?): black versus white. Poor prognostic factors based on sign-symptom-disease complex include; fever, dysphagia, cardiac, pulmonary, or gastrointestinal involvement, delay to diagnosis and treatment, and failure to induce remission. Poor prognosis features based on clinical groups include; polymyositis, cancer-associated, or inclusion body myositis (versus dermatomyositis) and based on serologic groups; anti-synthetase or anti-SRP autoantibodies (versus anti-Mi-2 or anti-MAS).

The treatment of myositis should encompass the whole disease and not just treating active disease. Rehabilitation and physical therapy are critical to maintain range of movement and to improve strength and endurance during disease remission. Drug treatment typically involves steroids as a central therapy, but methotrexate and azathioprine are frequently prescribed in corticosteroid-resistant patients and combination therapy is increasingly used. Photoprotection, topical steroids and hydroxychloroquine are important adjunct therapies in severe dermatomyositis. Some inclusion body myositis patients may benefit from corticosteroid and cytotoxic therapy through slowing the rate of disease progression. Cyclophosphamide, Chlorambucil, Cyclosporin A, FK 506, Mycophenolate (CellCept), Etanercept (Enbrel), Infliximab (Remicade) or Rituximab (Rituxan) may help some patients refractory to other agents.

There are potential new therapies for myositis for which there have been case reports demonstrating an improvement. These include; Mycophenolate (CellCept), anti-TNF agents (etanercept [Enbrel] infliximab [Remicade]), autologous stem cell transplantation, anti-B cell therapies (rituximab [Rituxan]).

The International Myositis Assessment and Clinical Studies Group (IMACS) formed three years ago is a collaboration that focuses on improving the management of myositis by developing a consensus on the conduct and reporting of myositis clinical studies. This multi-speciality group of over 100 experts in adult and juvenile myositis have set out to define core set outcome measures, develop new assessment tools and achieve consensus on many clinical trial design issues.

Interest and expertise in myositis is growing and the formation of multi-speciality groups hopes to address in the future many myositis questions, which include; what are all the prognostic predictors for poor outcomes? Which therapies work best in which patients? What mechanisms induce and sustain myositis? What new better therapies can block these mechanisms? How many "elemental disorders" - defined by the necessary and sufficient genetic and environmental risk factors that lead to myositis - comprise these syndromes? Can we prevent some forms of myositis?

Future approaches into researching and treating myositis should be multifaceted. To achieve this we should encourage, international collaborations among basic researchers to optimise the use of existing clinical databases, repositories and resources, international collaborations among clinical researchers to standardise the conduct and reporting of clinical trials, make better utilisation of registries, patient support groups and information technology, initiate and promote large simple trials with long term follow-up, provide more support of research into risks, pathogeneses, and treatment.
In summary, myositis syndromes are a clinically, pathologically, genetically and serologically heterogeneous group of systemic diseases. Primary genetic risk factors for myositis are HLA and immunoglobulin genes, some ethnic groups, serologic and environmental exposure groups differ in the specific alleles of these risk factors. Environmental triggers are poorly understood, but temporal associations have been noted with infectious agents and selected drugs, biologics, foods, devices, UVR and other exposures. Therapy needs to be individualised to the medical history, disease course and prognostic risks of each patient. Recent advances in immunology and molecular biology, as well as new international collaborations, promise more rapid progress in basic and clinical research in the future.

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