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188th ENMC International Workshop: Inclusion Body Myositis, 2–4 December 2011, Naarden, The Netherlands

2013; Elsevier BV; Volume: 23; Issue: 12 Linguagem: Inglês

10.1016/j.nmd.2013.08.007

1873-2364

Michael R. Rose,

Systemic Sclerosis and Related Diseases

1. IntroductionThe 188th ENMC workshop titled “Inclusion Body Myositis” was held in Naarden, The Netherlands, 2–4 December 2011. The workshop received supplementary funding from the Myositis Support Group UK. This workshop aimed to build on the work of two previous IBM workshops held in the MRC Centre London 2008 and Paris 2009 [1Benveniste O. Hilton-Jones D. International workshop on inclusion body myositis held at the Institute of Myology, Paris, on 29 May 2009.Neuromuscul Disord. 2010; 20: 414-421Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 2Hilton-Jones D. Miller A. Parton M. Holton J. Sewry C. Hanna M.G. Inclusion body myositis: MRC centre for neuromuscular diseases, IBM workshop, London, 13 June 2008.Neuromuscul Disord. 2010; 20: 142-147Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. Its aims were to (1) review the diagnostic criteria for IBM, (2) foster future collaborative working in immunological and genetic IBM research, (3) review natural history studies and clinical trial protocols, (4) review the current status of clinical trials outcome measures and map the processes required to improve these, (5) establish the requirements for a global IBM registry, and (6) to scope the work required for the establishment of standards of care for IBM.The workshop was attended by 24 representatives from UK, France, Germany, Belgium, Netherlands, Sweden, Denmark, Australia and USA. Participants included neurologists, rheumatologists, physiotherapists, industry representatives and patient representatives.2. Diagnostic criteriaDavid Hilton-Jones led review and discussion of the diagnostic criteria for IBM. As we do not know the cause or primary pathogenic mechanisms of IBM there is no “gold standard” for diagnosis. The original IBM diagnostic criteria proposed by Griggs et al. [[3]Griggs R.C. Askanas V. DiMauro S. Engel A.G. Kapati G. Mendell J.R. et al.Inclusion body myositis and myopathies.Annal Neurol. 1995; 38: 705-713Crossref PubMed Scopus (682) Google Scholar] were primarily a pathological definition. Indeed in the Griggs’ criteria “definite IBM” was defined on histological features with no reference to the clinical features. When all of the major pathological features (partial invasion, vacuoles, amyloid deposition and tubulofilaments) are present, the diagnosis of IBM is secure, but extensive clinical experience since 1995 indicates that often in cases in which long-term review supports the diagnosis of IBM one or more of these pathological features may be absent from the first and even subsequent biopsies [[4]Chahin N. Engel A.G. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM.Neurology. 2008; 70: 418-424Crossref PubMed Scopus (177) Google Scholar]. It is possible that some of the pathological features may only appear later in the course of the disease, and that adherence to them will exclude patients earlier in the course of the disease, when they may be more likely to respond to therapeutic intervention. Earlier ENMC diagnostic criteria addressed some of these issues, with respect to both clinical and pathological features [[5]Verschuuren JJB U.A. Wintzen A.R. van Engelen B.G. van der Hoeven H. Hoogendijk J. Inclusion body myositis.in: Emery A E H Diagnostic criteria for neuromuscular disorders. Royal Society of Medicine, ENMC, London1997: 81-84Google Scholar].Moreover, since 1995 there have been further pathological developments, notably (a) new methods for the identification of abnormal protein aggregates, and (b) the use of MHC 1 up-regulation as a surrogate marker of inflammation. Thus, even the purely pathological criteria for the diagnosis of IBM require revision. Furthermore, although the Griggs’ criteria did allow clinical features to make a diagnosis of “possible IBM”, this required weakness affecting both proximal and distal upper limb. In reality, as proximal upper limb weakness is a very late feature, this made a clinical diagnosis in the early stages of IBM problematic.As well as making practical diagnosis of early IBM difficult, the existing criteria were liable to disallow the recruitment of early cases of IBM into clinical trials potentially meaning that such trials might miss an optimal therapeutic window that might only exist in the early stages of IBM. Since the publication of the Griggs criteria we have acquired a very extensive clinical experience of the presentation and evolution of IBM that can now permit a switch to a new set of diagnostic criteria emphasising clinical phenotype rather than pathology.Clinical experience has shown that there is a highly characteristic pattern of weakness in IBM, with selective involvement of long finger flexors and quadriceps, and that this may occur in the absence of the original, “essential”, Griggs pathological criteria. The absence of certain pathological findings might be due to biopsy sampling error or because some of the pathological changes appear only late in the disease if at all. The latter certainly seems the case as demonstrated by the natural history studies (see below).We therefore discussed revision of the IBM diagnostic criteria and the following changes were highlighted.For “Clinico-pathologically defined IBM” it was agreed that, unlike the original Griggs criteria, there should be the additional stipulation of an acceptable clinical picture.The age at onset was increased to 45. All agreed that presentation could occur before that age, but was extremely rare and that raising the age would help to exclude wrong diagnoses without significantly limiting the number of patients eligible for clinical trials.With respect to the original proposal that knee extensors should be weaker than hip flexors, it was noted that not infrequently there was roughly equal weakness of both. It was felt that this pattern of weakness was still highly suggestive of IBM as in most other myopathies, including polymyositis, hip flexion was always weaker than knee extension.All agreed that EMG was not useful in confirming or excluding the diagnosis of IBM and it was therefore omitted from the diagnostic criteria.There was debate about the significance, or otherwise, of the serum CK activity. The issues discussed included the following;A CK >15 times the upper limit of normal (UNL) is rare in IBM and should prompt a search for an additional cause or an alternative diagnosis to IBM.While genuine cases of IBM with CK >15 times UNL may represent outliers that would confound a clinical trial equally it is possible that such patients have more aggressive disease that might be more sensitive to therapeutic intervention, and should not be excluded from trials.We therefore agreed that for the purposes of these research criteria to use a criterion of “no higher than 15 times the upper limit of normal” which would include the vast majority of patients with IBM and thus not limit numbers for entry into a clinical trial.The revised ENMC IBM diagnostic criteria proposed by this workshop are hereby presented and should be referred to as the “ENMC IBM Research Diagnostic Criteria 2011” (Table 1) (See addendum).Table 1The ENMC IBM research diagnostic criteria 2011.Clinical and laboratory featuresClassificationPathological featuresDuration >12 monthsClinico-pathologically defined IBMAll of the following:Endomysial inflammatory infiltrateAge at onset >45 yearsRimmed vacuolesProtein accumulation⁎Demonstration of amyloid or other protein accumulation by established methods (e.g. for amyloid Congo red, crystal violet, thioflavin T/S, for other proteins p62, SMI-31, TDP-43). Current evidence favors p62 in terms of sensitivity and specificity but the literature is limited and further work required. or 15–18 nm filamentsKnee extension weakness ⩾ hip flexion weaknessand/orFinger flexion weakness > shoulder abduction weaknesssCK no greater than 15×ULNDuration >12 monthsClinically defined IBMOne or more, but not all, of:Endomysial inflammatory infiltrateAge at onset >45 yearsUp-regulation of MHC class IRimmed vacuolesKnee extension weakness ⩾ hip flexion weaknessandFinger flexion weakness > shoulder abduction weaknessProtein accumulation⁎Demonstration of amyloid or other protein accumulation by established methods (e.g. for amyloid Congo red, crystal violet, thioflavin T/S, for other proteins p62, SMI-31, TDP-43). Current evidence favors p62 in terms of sensitivity and specificity but the literature is limited and further work required. or 15–18 nm filamentssCK no greater than 15×ULNDuration >12 monthsProbable IBMOne or more, but not all, of:Endomysial inflammatory infiltrateAge at onset >45 yearsUp-regulation of MHC class IRimmed vacuolesKnee extension weakness ⩾ hip flexion weakness or Finger flexion weakness > shoulder abduction weaknessProtein accumulation⁎Demonstration of amyloid or other protein accumulation by established methods (e.g. for amyloid Congo red, crystal violet, thioflavin T/S, for other proteins p62, SMI-31, TDP-43). Current evidence favors p62 in terms of sensitivity and specificity but the literature is limited and further work required. or 15–18 nm filamentssCK no greater than 15×ULN Demonstration of amyloid or other protein accumulation by established methods (e.g. for amyloid Congo red, crystal violet, thioflavin T/S, for other proteins p62, SMI-31, TDP-43). Current evidence favors p62 in terms of sensitivity and specificity but the literature is limited and further work required. Open table in a new tab 3. Immunological studiesOlivier Benveniste reviewed the evidence of amyloid and phosphorylated tau deposits in certain muscle fibres of IBM patients and the arguments for protein degradation dysfunctions (at both, proteasome and autophagy levels). From different experiments in mouse models, it appears that the forced over-expression of different kind of proteins, not only amyloids (APP42, gelsolin) but also MHC class I in muscle, leads to muscle weakness, appearance of vacuoles with, in parallel, increase of proteasome and autophagy markers. Occasionally, but not usually, these amyloid deposits are accompanied by inflammatory infiltrates. It seems that, when the protein degradation systems are overloaded, amyloids appear within muscle fibres, e.g. as misfolded and/or ubiquinated protein accumulations. This situation may also exist in patients with a hereditary inclusion body myopathy due to a p97/VCP mutation, i.e. in a complex involved in the regulation of protein degradation through the proteasome and autophagy [[6]Meyer H. Bug M. Bremer S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system.Nat Cell Biol. 2012; 14: 117-123Crossref PubMed Scopus (570) Google Scholar]. The second hallmark of IBM is the presence of inflammatory infiltrates. Evidence of immune reaction was reviewed. Effector cells can be clonally expanded and mostly consist of CD8+, CD28− T cells which can exert cytotoxic activity and are found surrounding or invading muscle fibres. The latter may present so far unknown auto-antigens to these effector cells in a MHC class I restricted manner. MHC class I overexpression at the surface of muscle fibres has become a surrogate marker of inflammation. Most of the immune abnormalities are not only observable in muscle but also in the peripheral blood. Apart from the cellular immune response, auto-antibodies are also described in IBM [7Benjamin Larman H, Salajegheh M, Nazareno R, Lam T, Sauld J, Steen H, et al. Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol 2013;73:408–18.Google Scholar, 8Pluk H. van Hoeve B.J. van Dooren S.H. Stammen-Vogelzangs J. van der Heijden A. Schelhaas H.J. et al.Autoantibodies to cytosolic 5′-nucleotidase 1A in inclusion body myositis.Ann Neurol. 2013; 73: 397-407Crossref PubMed Scopus (177) Google Scholar]. Regulation mechanisms are present in parallel, such as active regulatory T cells or activation of negative second signal pathways (e.g. the PD-1/PD-L axis). These may counteract, at least in part, the cytotoxic auto-reactivation. Crucial cytokines and chemokines were reviewed in this context, most importantly IFN and IL1 (see below).A key question still remaining is whether the amyloid deposits are the cause or consequence of inflammation? If amyloids are a consequence of a primary immune reaction including secretion of cytokines that increased MHC class I expression to such an extent that protein degradation capabilities are overloaded, then a targeted immune intervention (such as by biotherapies) may be useful. If, however, IBM is a degenerative disease, where the accumulation of unfolded proteins causes a secondary immune reaction, an immunointervention may be of limited if any benefit.Jens Schmidt reviewed recent evidence that supports a distinct interrelationship between inflammatory and degenerative molecules in IBM pathology. In IBM in contrast to other inflammatory myopathies, the precursor molecule of β-amyloid (APP) significantly correlates with the key inflammatory molecules IFN-γ and CXCL-9 [[9]Schmidt J.B.K. Wrede A. Salajegheh M. Bähr M. Dalakas M.C. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle.Brain. 2008; 131: 1228-1240Crossref PubMed Scopus (158) Google Scholar]. A similar relationship, possibly mediated by the GSK-3β kinase, has been demonstrated in an animal model of the disease [[10]Kitazawa M.T.D. LaFerla F.M. Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3beta.Ann Neurol. 2008; 64: 15-24Crossref PubMed Scopus (75) Google Scholar]. Apart from inflammation, an early cell stress response around αB-crystallin and nitric oxide is present in IBM muscle and may precede accumulation of β-amyloid [9Schmidt J.B.K. Wrede A. Salajegheh M. Bähr M. Dalakas M.C. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle.Brain. 2008; 131: 1228-1240Crossref PubMed Scopus (158) Google Scholar, 11Muth I.E.B.K. Bähr M. et al.Proinflammatory cell stress in sporadic inclusion body myositis muscle: overexpression of aB-crystallin is associated with amyloid precursor protein and accumulation of bamyloid..J Neurol Neurosurg Psychiatry. 2009; 80: 1344-1349Crossref PubMed Scopus (39) Google Scholar]. The cytokines IFN-γ and IL-1β have been demonstrated to be key inducers of accumulation of β-amyloid in muscle cells. Autophagy is present in IBM and serves as a mediator between inflammation and degeneration by contributing to the processing of APP/β-amyloid and, at the same time, by presenting antigens via the MHC class 2 pathway in IBM muscle [[12]Keller C.W. Fokken C. Turville S.G. Lünemann A. Schmidt J. Münz C. et al.TNF-alpha induces macroautophagy and regulates MHC class II expression in human skeletal muscle cells.J Biol Chem. 2011; 286: 3970-3980Crossref PubMed Scopus (94) Google Scholar]. Collectively, the pathology of IBM is very complex (see Fig. 1) and improvement of future treatment efforts will only be possible by a better understanding of key mechanisms and how to target these [[13]Schmidt J. Of amyloid and inflammation: causes of chronic muscle disease.e-Neuroforum. 2010; 1: 81-88Crossref Google Scholar].In attempt to answer this key question, e.g. by looking for the nature of auto-antigens, the ENMC workshop proposed a multicentre immunology association study, and an international IBM registry to include data collection for prospective natural history studies and sample collection.The aims of the immunology study would be to perform:1.A bank of IBM sera for confirmation/identification of new auto- autoantibodies (Abs).2.A MHC-I bound peptide elution from IBM muscle followed by mass spectrometry identification and functional test of T cell cytotoxicity.3.A bank of T cell clones from IBM patients, to test cytotoxicity against:a.Antigen identified as targets of auto-Abs.b.Autologous myotubes.c.Amyloids.4. Genetic studiesMerrilee Needham reviewed the genetic studies in IBM. Until recently, genetic studies in IBM have been limited to candidate gene studies due to the low incidence of IBM, (with estimates ranging from 1 per million to 14 per million) [14Needham M. Corbett A. Day T. Christiansen F. Fabian V. Mastaglia F.L. Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis.J Clin Neurosci. 2008; 15: 1350-1353Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 15Serdaroglu P. Deymeer F. Parman Y. Prevalence of sporadic inclusion body myositis (s-IBM) in Turkey: a muscle biopsy-based survey.Neuromuscul Disord. 2007; 17: 849Abstract Full Text Full Text PDF Google Scholar]. Using this approach, the immune features of IBM have prompted studies of the Major Histocompatibility Complex (MHC). These have discovered a susceptibility region in the 8.1 ancestral haplotype in a 172 Kb region near the HLA-DRB10301 (HLA-DR3) allele. This region contains 3 genes; BTNL2, HLA-DRA and HLA-DRB3 [[16]Scott A.P. Laing N.G. Mastaglia F. Needham M. Walter M.C. Dalakas M.C. et al.Recombination mapping of the susceptibility region for sporadic inclusion body myositis within the major histocompatibility complex.J Neuroimmunol. 2011; 235: 77-83Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. Further studies are ongoing to identify the susceptibility gene. However it is possible that epistatic interactions at this site are important in determining susceptibility, as it appears that the HLA-DR1/DR3 combination is a higher risk for developing disease than HLA-DR3 homozygotes [[17]Mastaglia F.L. Needham M. Scott A. James I. Ziko P. Day T. et al.Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype.Neuromuscul Disord. 2009; 19: 763-765Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. Other candidate gene studies investigating the genes encoding some of the proteins that are deposited in IBM muscle including Amyloid Precursor Protein [[18]Sivakumar K. Cervenakova L. Dalakas M.C. Leon-Monzon M. Isaacson S.H. Nagle J.W. et al.Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy.Ann Neurol. 1995; 38: 267-269Crossref PubMed Scopus (15) Google Scholar], prion protein, [[19]Orth M. Tabrizi S.J. Schapira A.H. Sporadic inclusion body myositis not linked to prion protein codon 129 methionine homozygosity.Neurology. 2000; 55: 1235Crossref PubMed Scopus (11) Google Scholar] TDP43, [[20]Salajegheh M. Pinkus J.L. Taylor P.J. Amato A.A. Nazareno R. Baloh R.H. et al.Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis.Muscle & Nerve. 2009; 40: 19-31Crossref PubMed Scopus (162) Google Scholar] alpha-1-antichymotrypsin [[21]Gossrau G. Gestrich B. Koch R. Wunderlich C. Schroder J.M. Schroeder S. et al.Apolipoprotein E and alpha-1-antichymotrypsin polymorphisms in sporadic inclusion body myositis.Eur Neurol. 2004; 51: 215-220Crossref PubMed Scopus (11) Google Scholar] and apolipoprotein E [21Gossrau G. Gestrich B. Koch R. Wunderlich C. Schroder J.M. Schroeder S. et al.Apolipoprotein E and alpha-1-antichymotrypsin polymorphisms in sporadic inclusion body myositis.Eur Neurol. 2004; 51: 215-220Crossref PubMed Scopus (11) Google Scholar, 22Needham M. Hooper A. James I. van Bockxmeer F. Corbett A. Day T. et al.Apolipoprotein epsilon alleles in sporadic inclusion body myositis: a reappraisal.Neuromuscul Disord. 2008; 18: 150-152Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 23Askanas V. Engel W.K. Mirabella M. Weisgraber K.H. Saunders A.M. Roses A.D. et al.Apolipoprotein E alleles in sporadic inclusion-body myositis and hereditary inclusion-body myopathy.Ann Neurol. 1996; 40: 264-265Crossref PubMed Scopus (25) Google Scholar, 24Harrington C.R. Anderson J.R. Chan K.K. Apolipoprotein E type epsilon 4 allele frequency is not increased in patients with sporadic inclusion-body myositis.Neurosci Lett. 1995; 183: 35-38Crossref PubMed Scopus (33) Google Scholar, 25Love S. Nicoll J.A. Lowe J. Sherriff F. Apolipoprotein E allele frequencies in sporadic inclusion body myositis.Muscle & Nerve. 1996; 19: 1605-1607Crossref PubMed Scopus (11) Google Scholar] have thus far been negative. In addition, screening of other genes that cause ‘inclusion body myopathies’ including GNE, [[26]Vasconcelos O.M. Raju R. Dalakas M. GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM.Neurology. 2002; 59: 1776-1779Crossref PubMed Scopus (38) Google Scholar] VCP and the known myofibrillar genes [[27]Machado P. Hudson J. Miller A. Morrow J. Parton M. Bushby K. et al.Valosin containing protein (VCP) and myofibrillar myopathies (MFM) genes’ mutations are not associated with sporadic inclusion body myositis (sIBM)..JNNP. 2012; 83: 3e1Google Scholar] have also been negative in IBM.Due to increasing collaboration between IBM investigators and improvements in technology, it has become possible to consider more robust genetic techniques such as whole exome/genome screening looking for other susceptibility or causative genes. Michael Hanna is currently recruiting for an exome screening project in IBM patients. This project will initially require DNA samples from around 200 individuals who are diagnosed with definite IBM.A suitable, preferably age and sex-matched control group, is also required. Any initial results of this study will need to be confirmed in a larger cohort of around 700 definite IBM patients, and gathering this number of subjects will require international collaboration. The possibility of clinicians with an interest and expertise in IBM contributing to both DNA and serum (for immunology studies) banks was discussed.It is possible that, as in the case of other neurodegenerative disorders such as, Alzheimer’s Disease and Parkinson’s Disease, susceptibility to IBM is polygenic with multiple HLA and non-HLA genes making small individual contributions. However, there are many questions that remain unanswered. For example, are there environmental risk factors that have not yet been identified, and how might these be identified? The European Myositis Network is aiming to help answer this question (http://www.eumyonet.org/). The prevalence of IBM in different populations and ethnic groups, may provide clues to the aetiopathogenesis and the relative importance of genetic vesus environmental factors. It is possible that there are some IBM cases with a monogenetic cause as there are a few reports of IBM occurring within families [28Ranque-Francois B. Maisonobe T. Dion E. Piette J.C. Chauveheid M.P. Amoura Z. et al.Familial inflammatory inclusion body myositis.AnnRheumDis. 2005; 64: 634-637Google Scholar, 29Amato A.A. Shebert R.T. Inclusion body myositis in twins.Neurology. 1998; 51: 598-600Crossref PubMed Scopus (31) Google Scholar, 30Naumann M. Toyka K.V. Amato A.A. Shebert R.T. Inclusion body myositis in twins; correspondence.Neurology. 1999; 53: 656Crossref Google Scholar, 31Sivakumar K. Semino-Mora C. Dalakas M.C. An inflammatory, familial, inclusion body myositis with autoimmune features and a phenotype identical to sporadic inclusion body myositis. Studies in three families.Brain. 1997; 120: 653-661Crossref PubMed Scopus (64) Google Scholar]. Therefore additional studies looking at families with more than one affected member would also be useful.5. RegistriesMaggie Walter led a discussion on patient registries. These have been already proven to be useful tools to overcome fragmentation and to facilitate research in disease epidemiology, genotype-phenotype correlation, and natural history studies. They are also valuable for monitoring standards of care and greatly facilitate feasibility studies for clinical trials and recruitment into clinical trials. Currently there are European and global effort to set up patient registries for Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Within the Network of Excellence TREAT-NMD, national registries for DMD and SMA collect data in a harmonized way and contribute them to a European meta-database. These databases provide a useful model for how an IBM global registry should be organised. Currently there are a number of local IBM registries but these collect differing types of data by a variety of means and are not generally available to the research community as a whole. Harmonisation of IBM registries as has been done for DMD and SMA would certainly be beneficial. In contrast to some muscle disease registries where eligibility for entry to the registry can be gene based the eligibility for IBM patients would have to be based on histopathology and specific clinical findings although in the future possible underlying genetic defects may be identified that can assist with eligibility.The workshop agreed the need for concerted action towards setting up an international registry for IBM and participants volunteered to help set up the registry. The elements required for a global registry for IBM were discussed and a steering committee consisting of Ingrid Lundberg, Umesh Badrising, Jan de Bleecker, and James Miller agreed to establish the requirements for a global IBM registry and work towards its implementation. We agreed upon harmonizing existing databases and decided for a web-based patient self-report system along with professional report. As a primary goal, we decided to focus the IBM registries for the tasks of trial readiness, along with natural history and epidemiology. It was felt that a future workshop dedicated solely to IBM registry planning would be the next step and discussions to set up such a workshop are on-going.6. Natural historyNatural history studies are important in helping with clinical trials planning and the selection of the best measures of disease progression of IBM. Michael Hanna and James Miller presented data from their on-going prospective observational natural history studies in IBM. At the time of this workshop Michael Hanna’s group had enrolled 51 participants and there was one year follow up data on 21 subjects. Entry criteria included Griggs criteria or MRC 2008 criteria [2Hilton-Jones D. Miller A. Parton M. Holton J. Sewry C. Hanna M.G. Inclusion body myositis: MRC centre for neuromuscular diseases, IBM workshop, London, 13 June 2008.Neuromuscul Disord. 2010; 20: 142-147Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 32Griggs R.C. Askanas V. DiMauro S. Engel A. Karpati G. Mendell J.R. et al.Inclusion body myositis and myopathies.Ann Neurol. 1995; 38: 705-713Crossref PubMed Scopus (462) Google Scholar]. Although there have been previous studies describing the clinical features and progression of the disease most have been undertaken retrospectively or at a single time point [33Lotz B.P. Engel A.G. Nishino H. Stevens J.C. Litchy W.J. Inclusion body myositis. Observations in 40 patients.Brain. 1989; 112: 727-747Crossref PubMed Scopus (376) Google Scholar, 34Lindberg C. Persson L.I. Bjorkander J. Oldfors A. Inclusion body myositis: clinical, morphological, physiological and laboratory findings in 18 cases.Acta Neurol Scand. 1994; 89: 123-131Crossref PubMed Scopus (108) Google Scholar, 35Amato A.A. Gronseth G.S. Jackson C.E. Wolfe G.I. Katz J.S. Bryan W.W. et al.Inclusion body myositis: clinical and pathological boundaries.Ann Neurol. 1996; 40: 581-586Crossref PubMed Scopus (175) Google Scholar, 36Badrising U.A. Maat-Schieman M.L. van Houwelingen J.C. van Doorn P.A. van Duinen S.G. van Engelen B.G. et al.Inclusion body myositis. Clinical features and clinical course of the disease in 64 patients.J Neurol. 2005; 252: 1448-1454Crossref PubMed Scopus (98) Google Scholar, 37Felice K.J. North W.A. Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period.Medicine (Baltimore). 2001; 80: 320-327Crossref PubMed Scopus (78) Google Scholar] and only a few have prospectively followed-up the progression of the disease [38Cox F.M. Titulaer M.J. Sont J.K. Wintzen A.R. Verschuuren J.J. Badrising U.A. A 12-year follow-up in sporadic inclusion body myositis: an end stage with major disabilities.Brain. 2011; 134: 3167-3175Crossref PubMed Scopus (126) Google Scholar, 39Rose M.R. McDermott M.P. Thornton C.A. Palenski C. Martens W.B. Griggs R.C. A prospective natural history study of inclusion body myositis: implications for clinical trials.Neurology. 2001; 57: 548-550Crossref PubMed Scopus (55) Google Scholar, 40Dalakas M.C. Rakocevic G. Schmidt J. Salajegheh M. McElroy B. Harris-Love M.O. et al.Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis.Brain. 2009; 132: 1536-1544Crossref PubMed Scopus (156) Google Scholar]. This study showed that most patients showed a typical onset but atypical presentations in this cohort included falls (25%), mild dysphagia (7%) and myalgia (7%). Mean delay to diagnosis was 4 years and almost 50% of cases were initially misdiagnosed with polymyositis, peripheral neuropathy and motor neuron disease. The latter two misdiagnoses are probably explained by seemingly neurogenic findings on electromyography (EMG) commonly found in IBM. The fact that a neuropathy can be found in over 20% of cases can also confound the diagnosis of IBM [[37]Felice K.J. North W.A. Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period.Medicine (Baltimore). 2001; 80: 320-327Crossref PubMed Scopus (78) Google Scholar]. Asymmetry of symptoms was common both at onset and during progression, but the difference of strength between the two sides, as detected by MMT, was within normal range for the general population [[41]Crosby C.A. Wehbe M.A. Mawr B. Hand strength: normative values.J Hand Surg Am. 1994; 19: 665-670Abstract Full Text PDF PubMed Scopus (348) Google Scholar]. Mild dysphagia was common and was pr