Myositis

Background

Unexplained inflammation in muscle, known as “myositis”, represents a difficult group of related disease, affecting about 10,000 people in the UK. Unlike other muscle diseases such as muscular dystrophy, myositis can be treated. Myositis can also affect internal organs including the heart, lungs and gut. Treatments for myositis can have a lot of side effects and are not always effective. Doctors may not be familiar with recognising the signs of myositis, especially in children. Delays in the diagnosis may lead to irreversible muscle damage; therefore sufferers often remain weak and disabled, leading to a significant burden for carers, parents and society.

Even between experts, there is lack of agreement how to diagnose and treat myositis. The diagnosis can be made by taking a muscle biopsy. The way these biopsies are interpreted varies widely between hospital laboratories and can lead to a wrong diagnosis being made. For example, an incorrect diagnosis of myositis can be made when the correct diagnosis is actually muscular dystrophy, where the potentially toxic treatments for myositis are inappropriate and will not help.

Current treatments are mostly borrowed from related musculoskeletal diseases. There is no national or even international guidance about which treatments to use and at what point in the disease. The fact that drugs for myositis work so poorly reflects our lack of understanding of what causes the disease, and this ignorance has slowed down the development of more effective new drugs. To improve future myositis treatments, a better understanding of what actually causes these diseases is urgently required so that new and more effective drugs can be developed.

Research aims

Objective

To improve the way we treat sufferers with unexplained inflammation in muscle (myositis), by bringing together UK experts, increasing awareness of myositis in the health-care community, improving the way we diagnose myositis, and enhancing health-care professionals training.

Background

Unexplained inflammation in muscle, known as "myositis", represents a difficult group of related disease, affecting about 10,000 people in the UK. Unlike other muscle diseases such as muscular dystrophy, myositis can be treated. Myositis can also affect internal organs including the heart, lungs and gut. Treatments for myositis can have a lot of side effects and are not always effective. Doctors may not be familiar with recognising the signs of myositis, especially in children. Delays in the diagnosis may lead to irreversible muscle damage; therefore sufferers often remain weak and disabled, leading to a significant burden for carers, parents and society. Even between experts, there is lack of agreement how to diagnose and treat myositis. The diagnosis can be made by taking a muscle biopsy. The way these biopsies are interpreted varies widely between hospital laboratories and can lead to a wrong diagnosis being made. For example, an incorrect diagnosis of myositis can be made when the correct diagnosis is actually muscular dystrophy, where the potentially toxic treatments for myositis are inappropriate and will not help. Current treatments are mostly borrowed from related musculoskeletal diseases. There is no national or even international guidance about which treatments to use and at what point in the disease. The fact that drugs for myositis work so poorly reflects our lack of understanding of what causes the disease, and this ignorance has slowed down the development of more effective new drugs. To improve future myositis treatments, a better understanding of what actually causes these diseases is urgently required so that new and more effective drugs can be developed.

Context

Careful research into what causes myositis, working out whether certain types of myositis respond or not to certain treatments, understanding which patients are most at risk of serious complications, and looking at how we can diagnose myositis more accurately is all vitally important, to improve the clinical care of sufferers with myositis. We must re-educate the health-care community that may encounter myositis, to further improve the outlook for sufferers. We need to improve the care given to myositis sufferers and the best way to achieve this improvement is by combining together collective expertise. We would like different medical disciplines such as adult and paediatric rheumatology, neurology and histopathology to work together and share knowledge. A non-funded organisation, UKMYONET, has been created, which aims to share expertise and generate ideas for future studies and drug trials to eventually produce new treatments. In addition, a UK network exists working on childhood myositis, the Juvenile Dermatomyositis Research Group, and needs to work closely with UKMYONET.

Hypothesis

The interaction of genetic and environmental susceptibility factors leading to distinct clinical patterns of disease in adult and juvenile myositis can be better studied by investigating those factors in well defined serological subsets of disease.

Overall purpose

To gain better mechanistic insights into Myositis aetiopathogenesis and clinical heterogeneity to ultimately facilitate downstream optimisation of currently available treatments and identification of new therapeutic targets.

Our aims are as follows

A) To investigate the prevalence, immunogenetic associations and clinical specificity of antibodies in European adult and juvenile Myositis populations.

B) To identify and characterise disease susceptibility genes in adult and juvenile myositis.

C) To assess the utility of a comprehensive autoAb profile and genetic status in determining clinical outcomes in adult and juvenile myositis.

Research projects

We form part of a programme of research run through The University of Manchester to study clinical and genetic risk factors in inflammatory myopathy. This has been part-funded by an Arthritis Research UK programme grant to advance understanding in myositis immunogenetics. Our ongoing research projects include:

1. Genomewide Association Study

Genetic risk factors for adult dermatomyositis (DM) and juvenile DM outside of the major histocompatibility complex (MHC) have been difficult to identify, although family studies have suggested that DM shares genetic risk factors with other autoimmune diseases. We performed a genome-wide association study on adult DM and juvenile DM subjects of European ancestry meeting probable or definite Bohan and Peter criteria using the Illumina platform.

2. Immunochip study

A further genetic study is underway utilising the custom Illumina "Immunochip" which contains over 150,000 genetic markers identified from other autoimmune diseases. We expect to report on about 3,000 adult and juvenile cases with myositis.

3. Novel antibody specificities in myositis

A number of novel antibody specificities have been identified in conjunction with our colleagues at the Royal National Hospital for Rheumatic Diseases, Bath, including anti-SAE1, EIF3, NXP-2, and TIF1gamma.

4. Gene-environment interactions in myositis

This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive myositis. Smoking appears to be associated with an increased risk of possession of anti-Jo-1 in HLA-DRB1*03-positive myositis cases. We hypothesise that an interaction between HLA-DRB1*03 and smoking may prime the development of anti-Jo-1 antibodies.

5. Inclusion Body Myositis (IBM) study

We are collaborating with Professor Michael Hanna at the MRC Centre for Neuromuscular Diseases (principal investigator on MRC project grant (MR/J004758/1)) on an exome sequencing study to evaluate rare variants associated with IBM. Patient DNA samples for this study will be provided through IBM-net and UKMYONET.

6. Statin study

Statin-induced necrotizing myostis is increasingly being recognised as part of the "statin-induced myopathy spectrum". As in other immune mediated necrotizing myopathies, statin-induced myositis is characterised by proximal muscle weakness with marked serum CK elevations and histological evidence of myonecrosis, and with little or no inflammatory cell infiltration. Unlike other necrotizing myopathies, statin-induced myopathy is associated with the presence of autoantibodies directed against 3-hydroxy-3-methylglutaryl- coenzyme A reductase (the enzyme target of statin therapies), and with HLA-DRB1*11. We are collecting such patients within the UK with a view to performing more detailed genetic studies.

People

Prof. William Ollier

Prof. Robert Cooper

Dr. Hector Chinoy

Dr. Janine Lamb

Mr. Paul New - Research Coordinator

Mrs. Fiona Marriage - Experimental Officer

Ms. Hazel Platt - Experimental Officer

Simon Rothwell - PhD Student

Jamie Ellingford - PhD Student (start, Sept 2013)

Selected publications

Miller F.W., Cooper R.G., Vencovsky J., Rider L.G., Danko K., Wedderburn L.R., Lundberg I.E., Pachman L.M., Reed A.M., Ytterberg S.R., Padyukov L., Selva-O’Callaghan A., Radstake T., Isenberg D.A., Chinoy H., Ollier W.E.R., O’Hanlon T.P., Peng B., Lee A., Lamb J.A., Chen W., Amos C.I., Gregersen P.K., Myositis Genetics Consortium. Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders. Arthritis Rheum 2013 (submitted)

Massey J., Rothwell S., Rusbridge C., Tauro A., Addicott D., Chinoy H., Cooper R.G., Ollier W.E.R., Kennedy L.J. Association of an MHC Class II haplotype with increased risk of polymyositis in Hungarian Vizsla dogs. PLoS One. 2013;8(2):e56490.

Chinoy H., Li, C., Platt H., Fertig N., Varsani H., Gunawardena H., Betteridge Z., Oddis C.V., McHugh N.J., Wedderburn L.R., Ollier W.E.R., Cooper R.G. Genetic Association Study of NF-κB genes in UK Caucasian Adult and Juvenile Onset Idiopathic Inflammatory Myopathy. Rheumatology 2012;51(5):794-799

Chinoy H., Adimulam, S., Marriage F., New P., Vincze M., Zilahi E., Kapitány A.., Gyetvai A., Ekholm L., Novota P., Remakova M., Charles P., McHugh N.J., Padyukov L., Alfredsson L., Vencovsky J., Lundberg I. E., Danko K., Ollier, W.E., Cooper, R.G. The interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann Rheum Dis 2012 Jun;71(6):961-5

Mercer L.K., Moore T.L., Chinoy H., Murray A.K., Vail A., Cooper R.G., Herrick A.L. Quantitative nailfold video capillaroscopy in patients with idiopathic inflammatory myopathy; Rheumatology 2010: 49(9):1699-705.

Betteridge Z., Gunawardena H., Chinoy H., North J., Ollier W.E.R., Cooper R.G., McHugh N.J. Clinical and HLA-class II haplotype associations of autoantibodies to small ubiquitin-like modifier enzyme, a dermatomyositis-specific autoantigen target, in UK adult-onset Caucasian myositis; Ann Rheum Dis 2009;68(10):1621-5

Chinoy H., Payne D., Poulton K.V., Fertig N., Betteridge Z., Gunawardena H., Davidson J.E., Oddis C.V., McHugh N.J., Wedderburn L.R., Ollier W.E., Cooper R.G. HLA-DPB1 associations differ between DRB1*03 positive anti-Jo-1 and anti-PM-Scl antibody positive idiopathic inflammatory myopathy. Rheumatology 2009;48(10):1213-7

Gunawardena H., Wedderburn L.R., Chinoy H., Betteridge Z., North J., Ollier W.E.R., Cooper R.G., Oddis C.V., Ramanan A.V., Davidson J.E., McHugh N.J. Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis; Arthritis Rheum 2009;60(6):1807-14

Chinoy H., Salway F., Fertig N., Ollier W.E.R., Cooper R.G. Clinical, serological and HLA profiles in non-Caucasian UK idiopathic inflammatory myopathy; Rheumatology 2009;48(5):591-2.

Chinoy H., Platt H., Lamb J.A., Betteridge Z., Gunawardena H., Fertig N., Varsani H., Davidson J., Oddis C.V., McHugh N.J., Wedderburn L.R., Ollier W.E.R., Cooper R.G. The PTPN22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients; Arthritis Rheum 2008;58(10):3247-3254.

Gunawardena H., North J., Wedderburn L.R., Davidson J.E., Betteridge Z., Dunphy J., Chinoy H., Cooper R.G., McHugh N.J. Clinical associations of autoantibodies to a p155/140 kDa doublet in adult and juvenile dermatomyositis; Rheumatology 2008;47(3):324-8.

Sultan SM, Allen E, Oddis CV, Keily P, Cooper RG, Lundberg IE, Vencovsky J, Isenburg DA. Reliability and validity of the myositis disease activity assessment tool. Arth Rheum 2008, 58: 3593-3599.

Thompson B, Corris P, Miller JAL, Cooper RG, Halsey JP, Isaacs JD. Alemtuzumab (Campath-1H) for treatment of refactory polymyositis. J Rheumatol 2008, 35: 2080-2082.

Wedderburn L.R., McHugh N.J., Chinoy H., Cooper R.G., Salway F., Ollier W.E.R., McCann L.J., Varsani H., Dunphy J., North J., Davidson J.E. HLA haplotype and autoantibody associations in children with juvenile dermatomyositis and scleroderma overlap; Rheumatology 2007;46(12):1786-91.

Chinoy H., Salway F., John S., Fertig N., Tait B.D., Oddis C.V., Ollier W.E.R., Cooper R.G. Tumour necrosis factor alpha single nucleotide polymorphisms are not independent of HLA class I and II in the idiopathic inflammatory myopathies; Rheumatology 2007;46(9):1411-6.

Chinoy H., Salway F., John S., Fertig N., Tait B.D., Oddis C.V., Ollier W.E.R., Cooper R.G. Interferon-gamma and interleukin-4 gene polymorphisms in UK Caucasian idiopathic inflammatory myopathy patients; Ann Rheum Dis 2007;66(7):970-3.

Chinoy H., Fertig N., Oddis C.V., Ollier W.E.R., Cooper R.G. The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis; Ann Rheum Dis 2007;66(10):1345-9.

Chinoy H., Salway F., Fertig N., Tait B.D., Oddis C.V., Ollier W.E.R., Cooper R.G. Monocyte chemotactic protein-1 single nucleotide polymorphisms do not confer susceptibility for the development of adult onset polymyositis/dermatomyositis in UK Caucasians; Rheumatology 2007;46(4):604-7.

Edge K., Chinoy H., Cooper R.G. Serum alanine aminotransferase elevations correlate with serum creatine phosphokinase levels in myositis. Rheumatology 2006;45(4):487-8.

Chinoy H., Salway F., Fertig N., Shephard N., Tait B.D., Thomson W., Isenberg D.A., Oddis C.V., Silman A.J., Ollier W.E.R., Cooper R.G. In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype; Arthritis Research & Therapy 2006;8:R13.

Molloy CB, Al-Omar AO, Edge KE, Cooper RG. Voluntary activation failure is detectable in some myositis patients with persisting quadriceps femoris weakness: an observational study. Arth Res Ther 2006, 6:R67, published online at hppt://arthritis-research.com/content/8/3/R67.

Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE, Oddis C, Pilkington C, Plotz P, Scott D, Vencovsky J, Cooper R, Rider L, Miller F. International consensus outcome measures for patients with idiopathic inflammatory myositis. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology 2004, 43:49-54.

Miller FM, Rider LG, Chung YL, Cooper R, Danko K, Farewell V, Lundberg I, Morrison C, Oakley L, Pilkington C, Vencovsky J, Scott DL, Isenberg DA. Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatology 2001, 40: 1262-1273

Collaborations

Some of our ongoing collaborations are highlighted below:

Profs Cooper, principal investigator, and Profs Ollier, Wedderburn, and McHugh, and Drs Chinoy and Lamb are co-applicants on a 5-year Arthritis Research UK funded Programme Grant. Prof Cooper is principal investigator on grants from the European Science Foundation (to provide EU-based IIM networking activity) and the Association Francaise contre les Myopathies (provide support for genotyping and serotyping). UKMYONET is adopted on the UKCRN portfolio (UKCRN ID 7996).
Dr Chinoy is chair of the Euromyositis Registry (www.euromyositis.eu), an EU-wide web-based consortium created to obtain uniform, longitudinal data of adult and juvenile IIM to achieve increased knowledge on disease course and prognosis of myositis. In addition, the registry can be used as a tool in clinic to assess patients. The registry can be used in the future by any interested party contributing UKMYONET data. The UK JDRG is currently working on a core minimal dataset, which is to be proposed as a juvenile component of the Euromyositis Registry. The dataset will be available and ready for the Arthritis Research UK INBANK initiative once the IIM arm of INBANK is launched.
Prof Michael Hanna is the principal investigator on an MRC project grant (MR/J004758/1) to undertake an exome sequencing study to evaluate rare variants associated with IBM. Patient DNA samples for this study will be provided through IBM-net and UKMYONET.
Prof Lucy Wedderburn is the chief investigator of the UK wide JDM Cohort and Biomarker Study, funded by a Wellcome Trust Biomedical Resources grant, which supports a Biobank manager/biopsy research fellow and Data manager. In addition, the UK JDM Cohort study is adopted onto the NIHR Medicine for Children Research Network portfolio (study ID-7723). The JDM Cohort study has been highly productive, with 19 publications from 2009-12. Key contributions have included to the GWAS (international effort), to serology and genetic studies, and in defining a key minimal core data set for collection on all JDM cases (in collaboration with the Euromyositis Registry).
Dr Patrick Gordon is co-applicant for ARTEMIS, an investigator led international study of Abatacept in IIM, funded by Bristol Myers Squibb and the Myositis Support Group UK. He is co-applicant on an MRC funded grant from the General Practitioner Research Database (now Clinical Practice Research Datalink) to assess incidence of cardiovascular disease in IIM.
UK MYONET activities and those of the UK JDRG tie in well with ongoing international activities. The European Science Foundation currently funds EuMyoNet, a European collaborative networking group (led by Professor Ingrid Lundberg) and the Euromyositis Registry, and has an initiative to part-fund a biopsy standardization study. The UKMYONET and EuMyoNet patient/sample collections have enabled an international collaboration, MYOGEN, with Profs Fred Miller (National Institute of Health, USA) and Peter Gregerson (Feinstein Institute, New York, US). All contributors to UK MYONET and JDRG are also contributing to international studies notably EuMyoNet, MYOGEN, and the International Myositis Assessment and Clinical Studies Group (IMACS).

Funding Bodies

2010-14: Arthritis Research UK Programme Grant.

"Integrated serological and genetic studies in idiopathic inflammatory myopathies (IIM) to investigate disease mechanisms and better define clinical outcomes" - three UK centres (Manchester, Bath and the Institute for Child Health, London) collaborating on programme of work correlating myositis genotype, serotype and phenotype, to investigate disease mechanisms. The work has fostered UK national, pan-European and now US collaboration, and also facilitated the execution of an international exploratory genome wide association scan (GWAS) in myositis.

2010-15: European Science Foundation (ESF) Grant.

Grant to 3 Co-PIs, Ingrid Lundberg (Sweden), Jiri Vencovsky (Prague) and Robert Cooper (Manchester), remit to set up a 5 year ESF-funded Research Networking Programme for myositis (EuMyoNet), to foster EU wide collaborative research into myositis. All 3 PIs are members of the EuMyoNet Steering Committee.

2010-12: Association Francaise contre les Myopathies (AFM).

"Development of Functional biomarkers in a European network for inflammatory myopathies, EuMyoNet". Grant to 4 Co-PIs, Ingrid Lundberg (Karolinska, Sweden), Robert Cooper (Manchester, UK), Peter Charles (London, UK), RA Zubarev (Karolinska, Sweden). Remit to elucidate important biomarkers for Myositis within a 1000 plus cohort of European Myositis cases, so as to better define and predict outcomes.

2000-2011: Commercial Trials Income.

In addition to attracting grant incomes, Prof Robert Cooper continues to attract multiple commercial pharmaceutical trials, acting as local PI. As a result of this activity, a steady commercial income stream has been generated, the funds being held in a trust-based endowment fund, and Robert Cooper is a member of the Trust Clinical Trials Unit steering committee. These commercially-generated funds have directly supported the following primary research activities: