REVIEW URRENT C OPINION
Epidemiology of sporadic inclusion body myositis Øyvind Molberg a,b and Cecilie Dobloug a
Purpose of review In this review, we describe recent progress in the clinical epidemiology of sporadic inclusion body myositis (IBM). Recent findings In a population-based, retrospective study from Norway, performed with a denominator population of 2.6 million; and with cases defined by the 1997 and/or 2011 European Neuro-Muscular Centre Research Diagnostic criteria, the estimated point prevalence of IBM was 3.3/100 000. Mean time from symptom onset to diagnosis was 5.6 years, longer than in earlier studies. The male to female ratio was 3 : 2, and the mean age at diagnosis 67 years, very similar to figures reported this year from a nationwide, Dutch myopathy registry. Coexisting rheumatic diseases were recorded in 25% of Norwegian IBM cases, with Sjøgren’s syndrome as the most commonly encountered. Mortality was increased in IBM, with a standardized mortality rate of 1.7, but there was no indication of increased cancer risk. Summary Population-based data indicate that the prevalence of IBM in Europe is higher than expected from previous studies. Diagnostic delay appears to be a persisting problem in IBM; a major challenge with promising new therapies on the horizon. Keywords epidemiology, idiopathic inflammatory myopathies, inclusion body myositis, population-based studies, prevalence
INTRODUCTION Sporadic inclusion body myositis (IBM) is an agerelated, slowly progressive, and disabling muscle disease [1,2,3 ]. The onset is insidious, but over time, the majority of patients develop a highly characteristic clinical picture with asymmetric proximal and distal weakness, and predominant involvement of the quadriceps and finger flexor muscles [4]. Traditionally, IBM has been regarded as one of the three idiopathic inflammatory myopathies (IIM) along with polymyositis and dermatomyositis, but there is growing evidence that the disease mechanisms in IBM differ from dermatomyositis and polymyositis. [5–7]. Over the past few years, there have been significant advances in IBM. Genetic studies have extended the knowledge of risk factors beyond the Human Leukocyte Antigen-molecules [8]; and we have more data on the specificity of the novel IBMrelated anticytosolic 5-nucleotidase 1A autoantibodies [9 ]. Recent data have shown that a high frequency of IBM cases harbour peripheral blood monoclonal T-cell populations, indicating a role of neoplastic immune cells in disease pathogenesis [10]. Methods for tracking muscle changes by MRI have also been published [11], and a huge &
&
multicentre effort has been undertaken to assess the sensitivity and specificity of previous and current IBM criteria sets [12]. Finally, targeted treatments of IBM have been assessed in randomized clinical trials [13,14]. In this review, we will focus on recent advances in the epidemiology of IBM. The review is divided in two parts. Part one has a focus on key methodological challenges with population-based IBM studies, whereas in part two we describe and discuss recent findings.
Methodological challenges related to the study of inclusion body myositis epidemiology
a
Department of Rheumatology, Oslo University Hospital (OUH) and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
b
Correspondence to Øyvind Molberg, Department of Rheumatology, Oslo University Hospital, PB 4950, Nydalen, N-0424 Oslo, Norway. Tel: +47 23073324; e-mail: [email protected] Curr Opin Rheumatol 2016, 28:657–660 DOI:10.1097/BOR.0000000000000327
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KEY POINTS Recent work estimated the population prevalence of sporadic IBM in Northern Europe to 3.3/100 000, which is higher than in previous studies. IBM is a progressive myopathy of the elderly, and it has a male predominance. Autoimmune features and coexisting systemic inflammatory rheumatic disease are common in IBM. Mortality is moderately increased in IBM, but there is no indication of increased cancer risk.
Centre (ENMC) Research Diagnostic criteria [12,15,16]. All the three steps outlined above are challenging. In general, ‘step first’ will often involve searches across patient administrative databases in the study area to capture all patients with International Classification of Disease (ICD) codes compatible with your condition of interest. For IBM, this strategy is difficult as there is no defined ICD code for IBM (Fig. 1). Alternatively, IBM screening may be performed by searches through the disease databases in the study area [17], by case reporting undertaken by treating physicians [18] or self-reporting by patients [3 ], but we are afraid that the sensitivity of these methods could be low. The next challenge is clinical information (step second). Schematically, there are two ways to obtain relevant data. The first is to approach all the potential IBM cases in the study area, perform clinical examinations (by protocol), and determine if they fulfil the criteria. Protocol-based clinical examination could be done in a cross-sectional setting (prevalent cases) or prospectively (incident cases). These designs have, to our knowledge, never been applied in population-based IBM studies. Prospective inclusion of all incident IBM cases in a defined study area would obviously be the ‘gold standard’ for epidemiological purposes, but, because of the rarity of IBM, it would require a large catchment area or a very long inclusion period. The &
The ultimate setup of a population-based IBM epidemiology study would be a three-step procedure where you, first, capture all potential IBM cases resident in your defined study area within your defined study period, second, obtain detailed information about the disease history and clinical status of all these potential IBM cases, and, third, use the information from second step to establish a study cohort that includes all cases fulfilling a defined set of IBM diagnostic criteria. For an optimal study performance, you should obviously select the diagnostic criteria with the highest sensitivity and specificity for IBM. Available evidence indicates that this is currently the 2011 European Neuro-Muscular
Search through hospital databases in study area for patients encoded with ten different ICD-10 codes* compatiable with idiopathic inflammatory myopathy (N = 3160)
Diagnosis other than IIM or miscoded cases (N = 2832)
Patients fulfilling Targoffproposed criteria for myositis Polymyositis (n = 100) Dermatomyositis (n = 128)
Search through pathology databases for muscle biopsies encoded with ‘inflammation’ (N = 500)
Pathology supportive of sporadic IBM (N = 21)
Chart review data fitting clinical sporadic IBM (N = 89)
21
Definite or probable sporadic IBM by histology (N = 79)
68
11
Patients fulfilling 2011 and/or 1997 ENMC criteria for sporadic IBM (n = 100) Patients fulfilling Peter and Bohan diagnostic criteria for myositis Polymyositis (n = 91) Dermatomyositis (n = 115)
Patients fulfilling 2011 ENMC IBM diagnostic criteria (n = 95)
Patients fulfilling 1997 ENMC IBM diagnostic criteria (n = 92)
* M33.1,.2 and .9, M60.8 and .9, G72.4,.8 and .9, G73.7.
FIGURE 1. Flow chart describing the search strategies applied for case identification in the population-based Southeast Norway Idiopathic Inflammatory Myopathy project. The IBM part of the project is marked with stapled lines. 658
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Sporadic inclusion body myositis Molberg and Dobloug
second alternative is to perform a comprehensive retrospective chart review on all the potential IBM cases in the study area. With a chronic disease like IBM, there is typically data from repeated visits across a long period of time, but missing information is still a limitation. Additionally, different specialities will often emphasize different aspects of IBM, and this can translate into systematic differences in chart content between IBM patients followed by neurologists and rheumatologists, respectively.
Population-based epidemiology studies in inclusion body myositis Few studies on the epidemiology of IBM have been performed. Here, we briefly describe the studies from this millennium. The first, large chart review study was a nationwide collaborative cross-sectional study from the Netherlands published in 2000 [18]. The study applied the 1997 ENMC Diagnostic criteria for IBM [19], and case finding was done by approaching neurology and rheumatology centres in the study area. Clinical information on the individual cases was gathered from charts and muscle biopsy review. Estimated population point prevalence was 4.9 per million (16 per million in the age group >50 years). Three Australian surveys, all based on local histopathology criteria, reported IBM prevalence ranging from 9.3 to 50.5 per million [20,21]. In Olmstead County, Minnesota, nine IBM cases were identified by chart review, giving a prevalence of 70.6 per million [22]. Data from Japan indicated that the prevalence was less than 10 per million in 2003, but rising towards 2012 [23]. Finally, a biopsy-register study from Turkey reported only 1 IBM case per million [17]. Recently, a population-based, retrospective IBM study was performed with a denominator population of 2.6 million in Norway [24 ,25 ]. In this country, patients with IIM are referred to, and followed up, by specialists at public hospitals, where IBM patients are cared for by either by neurologists or rheumatologists. The IBM study was part of a larger epidemiology study aiming to identify all IIM patients in the study area, and the polymyositis/dermatomyositis part of the project was recently published [26]. Case finding was done by broad ICD10 code searches across the patient administrative databases of the hospitals in the study area. The electronic patient journals of all the potential IBM patients identified were manually reviewed. Additionally, all muscle histology reports encoded with inflammation by the disease classification system were retrieved and reviewed (Fig. 1). Patients were classified by two IBM criteria sets, the ENMC &&
&
criteria from 1997 and 2011 [15,19]. The study was primarily designed to capture items in the 1997 criteria. These criteria were chosen because they were applied in the 2000 study from the Netherlands, the only previous, population-based IBM study from Europe [18]. Interestingly, when the patients were scored against the 2011 criteria, it became evident that eight patients excluded by the 1997 criteria because of incomplete histology features, met the 2011 criteria [24 ]. By the end of the study period, the estimated point prevalence of IBM in Norway was 33 per million, and similar for the 1997 and 2011 ENMC criteria. This estimate was substantially higher than previous European estimates [18]. The study had a long (10-year) acquisition period, and the number of new cases recorded every year was quite stable. Therefore, we used these retrospective data to estimate annual incidence rates, and found that they ranged from 2 to 6 new cases per million per year. Mean time from symptom onset to diagnosis was 5.6 years. Disappointingly, this diagnostic delay was even longer than in earlier studies [2,20]. The male to female ratio was 3 : 2, and the mean age at diagnosis 67 years, very similar to figures reported this year from the nationwide Computer Registry of all Myopathies and Neuropathies (CRAMP) in the Netherlands. In CRAMP, they reported that the male to female ratio in the 277 IBM patients included was 3 : 2, whereas the age at diagnosis was 70 years [27 ]. As a corollary, it is evident from the number of IBM cases in CRAMP that the prevalence of IBM in the Netherlands must be higher than previously estimated [18]. Analyses of recorded clinical features showed that swallowing difficulties was very common, particularly in the women, where 94% reported this symptom. Most of the IBM patients (65%) in the cohort were primarily followed by rheumatologists. It is possible that this, at least partly explains why the frequencies of autoimmune features and coexisting rheumatic diseases were higher than in previous studies [28,29]. Altogether, 37% of the 79 patients tested for antinuclear antibodies had a positive test and anti-SSA was positive in 22%; with a female predominance. Coexisting rheumatic disease were recorded in 25% of the IBM cases, with Sjøgren’s syndrome as the most commonly encountered (10 cases). Analyses based on an exposed/ unexposed strategy, with 15 unexposed controls per patient, showed that the standardized mortality rate in IBM, at 1.7 (95% CI: 1.2–2.3), was moderately increased. Aspiration because of dysphagia was recorded as the cause of death in 7 of the 31 deceased patients, making this the most common, possibly disease-related cause of death [25 ]. Overall, the
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&&
&
&
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Myositis and myopathies
most common cause of death was ischemic heart disease (8/31 cases). Data on cancer occurrence in the IBM cases and the unexposed controls were retrieved from the Cancer Registry in Norway. Analyses of these data gave no indication of increased cancer risk in IBM [25 ]. &
CONCLUSION Recent findings suggest that IBM is more prevalent in Europe than previously anticipated. Populationbased work confirms that IBM is a myopathy of the elderly, with peak age of onset at nearly 70 years, and most common in men. Coexisting rheumatic diseases, and then particularly Sjøgren’s syndrome, are frequent in IBM. Mortality is slightly increased, but there is no signal for cancer. Even the most recent studies show that diagnostic delay is a major challenge in IBM, strongly suggesting that measures to increase disease awareness are warranted. Acknowledgements None. Financial support and sponsorship The work was supported by the University of Oslo and the Norwegian Women’s Public Health Association, Oslo, Norway. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Mastaglia FL, Needham M. Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches. J Clin Neurosci 2015; 22:6–13. 2. Benveniste O, Guiguet M, Freebody J, et al. Long-term observational study of sporadic inclusion body myositis. Brain 2011; 134:3176–3184. 3. Paltiel AD, Ingvarsson E, Lee DK, et al. Demographic and clinical features of & inclusion body myositis in North America. Muscle Nerve 2015; 52:527–533. First large study on patient reported outcomes in IBM. 4. Brady S, Squier W, Hilton-Jones D. Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features. J Neurol Neurosurg Psychiatry 2013; 84:1240–1246. 5. Benveniste O, Stenzel W, Hilton-Jones D, et al. Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken. Acta Neuropathol 2015; 129:611–624.
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6. Lahouti AH, Amato AA, Christopher-Stine L. Inclusion body myositis: update. Curr Opin Rheumatol 2014; 26:690–696. 7. Askanas V, Engel WK, Nogalska A. Sporadic inclusion-body myositis: a degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy. Biochim Biophys Acta 2015; 1852:633–643. 8. Gang Q, Bettencourt C, Houlden H, et al. Genetic advances in sporadic inclusion body myositis. Curr Opin Rheumatol 2015; 27:586–594. 9. Herbert MK, Stammen-Vogelzangs J, Verbeek MM, et al. Disease specificity of & autoantibodies to cytosolic 5’-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Ann Rheum Dis 2016; 75:696–701. A large study on anticN-1A auto-antibodies in IBM. Confirms that 1/3 of IBM cases in referral cohorts are anticN-1A positive. Frequency of anticN-1A in unselected IBM cohorts is not known. 10. Greenberg SA, Pinkus JL, Amato AA, et al. Association of inclusion body myositis with T cell large granular lymphocytic leukaemia. Brain 2016; 139:1348–1360. 11. Morrow JM, Sinclair CD, Fischmann A, et al. MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study. Lancet Neurol 2016; 15:65–77. 12. Lloyd TE, Mammen AL, Amato AA, et al. Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology 2014; 83:426–433. 13. Ahmed M, Machado PM, Miller A, et al. Targeting protein homeostasis in sporadic inclusion body myositis. Sci Transl Med 2016; 8:331ra41. 14. Amato AA, Sivakumar K, Goyal N, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 2014; 83:2239–2246. 15. Rose MR. 188th ENMC International Workshop: Inclusion Body Myositis, 2-4 December 2011, Naarden, The Netherlands. Neuromuscular Disord 2013; 23:1044–1055. 16. Hilton-Jones D, Brady S. Diagnostic criteria for inclusion body myositis. J Intern Med 2016; 280:52–62. 17. Oflazer PS, Deymeer F, Parman Y. Sporadic-inclusion body myositis (s-IBM) is not so prevalent in Istanbul/Turkey: a muscle biopsy based survey. Acta Myol 2011; 30:34–36. 18. Badrising UA, Maat-Schieman M, van Duinen SG, et al. Epidemiology of inclusion body myositis in the Netherlands: a nationwide study. Neurology 2000; 55:1385–1387. 19. Verschuuren JJ, Badrising UA, Wintzen AR, et al. Inclusion body myositis. In: Emery A, editor. Diagnostic criteria for neuromuscular disorders. London, UK: Royal Society of Medicine Press; 1997. pp. 81–84. 20. Needham M, Corbett A, Day T, et al. Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis. J Clin NeurosciV 15 2008; 1350–1353. 21. Tan JA, Roberts-Thomson PJ, Blumbergs P, et al. Incidence and prevalence of idiopathic inflammatory myopathies in South Australia: a 30-year epidemiologic study of histology-proven cases. Int J Rheum Dis 2013; 16:331–338. 22. Wilson FC, Ytterberg SR, St Sauver JL, Reed AM. Epidemiology of sporadic inclusion body myositis and polymyositis in Olmsted County, Minnesota. J Rheumatol 2008; 35:445–447. 23. Suzuki N, Aoki M, Mori-Yoshimura M, et al. Increase in number of sporadic inclusion body myositis (sIBM) in Japan. J Neurol 2012; 259:554–556. 24. Dobloug GC, Antal EA, Sveberg L, et al. High prevalence of inclusion body && myositis in Norway; a population-based clinical epidemiology study. Eur J Neurol 2015; 22:672–741. Largest population-based IBM study to date, and the first to assess the 2011 ENMC criteria retrospectively in an unselected cohort. 25. Dobloug GC, Garen T, Brunborg C, et al. Survival and cancer risk in an & unselected and complete Norwegian idiopathic inflammatory myopathy cohort. Semin Arthritis Rheum 2015; 45:301–308. First population-based study in IBM to assess mortality and cancer risk. 26. Dobloug C, Garen T, Bitter H, et al. Prevalence and clinical characteristics of adult polymyositis and dermatomyositis; data from a large and unselected Norwegian cohort. Ann Rheum Dis 2015; 74:1551–1556. 27. Deenen JC, van Doorn PA, Faber CG, et al. The epidemiology of neuromus& cular disorders: age at onset and gender in the Netherlands. Neuromuscul Disord 2016; 7:447–452. The first IBM results from a recently established nationwide Myopathy registry in the Netherlands. 28. Badrising UA, Schreuder GM, Giphart MJ, et al. Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis. Neurology 2004; 63:2396–2398. 29. Rojana-udomsart A, Needham M, Luo YB, et al. The association of sporadic inclusion body myositis and Sjogren’s syndrome in carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype. Clin Neurol Neurosurg 2011; 113:559–563.
Volume 28 Number 6 November 2016
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Epidemiology of sporadic inclusion body myositis Øyvind Molberg a,b and Cecilie Dobloug a
Purpose of review In this review, we describe recent progress in the clinical epidemiology of sporadic inclusion body myositis (IBM). Recent findings In a population-based, retrospective study from Norway, performed with a denominator population of 2.6 million; and with cases defined by the 1997 and/or 2011 European Neuro-Muscular Centre Research Diagnostic criteria, the estimated point prevalence of IBM was 3.3/100 000. Mean time from symptom onset to diagnosis was 5.6 years, longer than in earlier studies. The male to female ratio was 3 : 2, and the mean age at diagnosis 67 years, very similar to figures reported this year from a nationwide, Dutch myopathy registry. Coexisting rheumatic diseases were recorded in 25% of Norwegian IBM cases, with Sjøgren’s syndrome as the most commonly encountered. Mortality was increased in IBM, with a standardized mortality rate of 1.7, but there was no indication of increased cancer risk. Summary Population-based data indicate that the prevalence of IBM in Europe is higher than expected from previous studies. Diagnostic delay appears to be a persisting problem in IBM; a major challenge with promising new therapies on the horizon. Keywords epidemiology, idiopathic inflammatory myopathies, inclusion body myositis, population-based studies, prevalence
INTRODUCTION Sporadic inclusion body myositis (IBM) is an agerelated, slowly progressive, and disabling muscle disease [1,2,3 ]. The onset is insidious, but over time, the majority of patients develop a highly characteristic clinical picture with asymmetric proximal and distal weakness, and predominant involvement of the quadriceps and finger flexor muscles [4]. Traditionally, IBM has been regarded as one of the three idiopathic inflammatory myopathies (IIM) along with polymyositis and dermatomyositis, but there is growing evidence that the disease mechanisms in IBM differ from dermatomyositis and polymyositis. [5–7]. Over the past few years, there have been significant advances in IBM. Genetic studies have extended the knowledge of risk factors beyond the Human Leukocyte Antigen-molecules [8]; and we have more data on the specificity of the novel IBMrelated anticytosolic 5-nucleotidase 1A autoantibodies [9 ]. Recent data have shown that a high frequency of IBM cases harbour peripheral blood monoclonal T-cell populations, indicating a role of neoplastic immune cells in disease pathogenesis [10]. Methods for tracking muscle changes by MRI have also been published [11], and a huge &
&
multicentre effort has been undertaken to assess the sensitivity and specificity of previous and current IBM criteria sets [12]. Finally, targeted treatments of IBM have been assessed in randomized clinical trials [13,14]. In this review, we will focus on recent advances in the epidemiology of IBM. The review is divided in two parts. Part one has a focus on key methodological challenges with population-based IBM studies, whereas in part two we describe and discuss recent findings.
Methodological challenges related to the study of inclusion body myositis epidemiology
a
Department of Rheumatology, Oslo University Hospital (OUH) and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
b
Correspondence to Øyvind Molberg, Department of Rheumatology, Oslo University Hospital, PB 4950, Nydalen, N-0424 Oslo, Norway. Tel: +47 23073324; e-mail: [email protected] Curr Opin Rheumatol 2016, 28:657–660 DOI:10.1097/BOR.0000000000000327
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www.co-rheumatology.com
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Myositis and myopathies
KEY POINTS Recent work estimated the population prevalence of sporadic IBM in Northern Europe to 3.3/100 000, which is higher than in previous studies. IBM is a progressive myopathy of the elderly, and it has a male predominance. Autoimmune features and coexisting systemic inflammatory rheumatic disease are common in IBM. Mortality is moderately increased in IBM, but there is no indication of increased cancer risk.
Centre (ENMC) Research Diagnostic criteria [12,15,16]. All the three steps outlined above are challenging. In general, ‘step first’ will often involve searches across patient administrative databases in the study area to capture all patients with International Classification of Disease (ICD) codes compatible with your condition of interest. For IBM, this strategy is difficult as there is no defined ICD code for IBM (Fig. 1). Alternatively, IBM screening may be performed by searches through the disease databases in the study area [17], by case reporting undertaken by treating physicians [18] or self-reporting by patients [3 ], but we are afraid that the sensitivity of these methods could be low. The next challenge is clinical information (step second). Schematically, there are two ways to obtain relevant data. The first is to approach all the potential IBM cases in the study area, perform clinical examinations (by protocol), and determine if they fulfil the criteria. Protocol-based clinical examination could be done in a cross-sectional setting (prevalent cases) or prospectively (incident cases). These designs have, to our knowledge, never been applied in population-based IBM studies. Prospective inclusion of all incident IBM cases in a defined study area would obviously be the ‘gold standard’ for epidemiological purposes, but, because of the rarity of IBM, it would require a large catchment area or a very long inclusion period. The &
The ultimate setup of a population-based IBM epidemiology study would be a three-step procedure where you, first, capture all potential IBM cases resident in your defined study area within your defined study period, second, obtain detailed information about the disease history and clinical status of all these potential IBM cases, and, third, use the information from second step to establish a study cohort that includes all cases fulfilling a defined set of IBM diagnostic criteria. For an optimal study performance, you should obviously select the diagnostic criteria with the highest sensitivity and specificity for IBM. Available evidence indicates that this is currently the 2011 European Neuro-Muscular
Search through hospital databases in study area for patients encoded with ten different ICD-10 codes* compatiable with idiopathic inflammatory myopathy (N = 3160)
Diagnosis other than IIM or miscoded cases (N = 2832)
Patients fulfilling Targoffproposed criteria for myositis Polymyositis (n = 100) Dermatomyositis (n = 128)
Search through pathology databases for muscle biopsies encoded with ‘inflammation’ (N = 500)
Pathology supportive of sporadic IBM (N = 21)
Chart review data fitting clinical sporadic IBM (N = 89)
21
Definite or probable sporadic IBM by histology (N = 79)
68
11
Patients fulfilling 2011 and/or 1997 ENMC criteria for sporadic IBM (n = 100) Patients fulfilling Peter and Bohan diagnostic criteria for myositis Polymyositis (n = 91) Dermatomyositis (n = 115)
Patients fulfilling 2011 ENMC IBM diagnostic criteria (n = 95)
Patients fulfilling 1997 ENMC IBM diagnostic criteria (n = 92)
* M33.1,.2 and .9, M60.8 and .9, G72.4,.8 and .9, G73.7.
FIGURE 1. Flow chart describing the search strategies applied for case identification in the population-based Southeast Norway Idiopathic Inflammatory Myopathy project. The IBM part of the project is marked with stapled lines. 658
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Volume 28 Number 6 November 2016
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Sporadic inclusion body myositis Molberg and Dobloug
second alternative is to perform a comprehensive retrospective chart review on all the potential IBM cases in the study area. With a chronic disease like IBM, there is typically data from repeated visits across a long period of time, but missing information is still a limitation. Additionally, different specialities will often emphasize different aspects of IBM, and this can translate into systematic differences in chart content between IBM patients followed by neurologists and rheumatologists, respectively.
Population-based epidemiology studies in inclusion body myositis Few studies on the epidemiology of IBM have been performed. Here, we briefly describe the studies from this millennium. The first, large chart review study was a nationwide collaborative cross-sectional study from the Netherlands published in 2000 [18]. The study applied the 1997 ENMC Diagnostic criteria for IBM [19], and case finding was done by approaching neurology and rheumatology centres in the study area. Clinical information on the individual cases was gathered from charts and muscle biopsy review. Estimated population point prevalence was 4.9 per million (16 per million in the age group >50 years). Three Australian surveys, all based on local histopathology criteria, reported IBM prevalence ranging from 9.3 to 50.5 per million [20,21]. In Olmstead County, Minnesota, nine IBM cases were identified by chart review, giving a prevalence of 70.6 per million [22]. Data from Japan indicated that the prevalence was less than 10 per million in 2003, but rising towards 2012 [23]. Finally, a biopsy-register study from Turkey reported only 1 IBM case per million [17]. Recently, a population-based, retrospective IBM study was performed with a denominator population of 2.6 million in Norway [24 ,25 ]. In this country, patients with IIM are referred to, and followed up, by specialists at public hospitals, where IBM patients are cared for by either by neurologists or rheumatologists. The IBM study was part of a larger epidemiology study aiming to identify all IIM patients in the study area, and the polymyositis/dermatomyositis part of the project was recently published [26]. Case finding was done by broad ICD10 code searches across the patient administrative databases of the hospitals in the study area. The electronic patient journals of all the potential IBM patients identified were manually reviewed. Additionally, all muscle histology reports encoded with inflammation by the disease classification system were retrieved and reviewed (Fig. 1). Patients were classified by two IBM criteria sets, the ENMC &&
&
criteria from 1997 and 2011 [15,19]. The study was primarily designed to capture items in the 1997 criteria. These criteria were chosen because they were applied in the 2000 study from the Netherlands, the only previous, population-based IBM study from Europe [18]. Interestingly, when the patients were scored against the 2011 criteria, it became evident that eight patients excluded by the 1997 criteria because of incomplete histology features, met the 2011 criteria [24 ]. By the end of the study period, the estimated point prevalence of IBM in Norway was 33 per million, and similar for the 1997 and 2011 ENMC criteria. This estimate was substantially higher than previous European estimates [18]. The study had a long (10-year) acquisition period, and the number of new cases recorded every year was quite stable. Therefore, we used these retrospective data to estimate annual incidence rates, and found that they ranged from 2 to 6 new cases per million per year. Mean time from symptom onset to diagnosis was 5.6 years. Disappointingly, this diagnostic delay was even longer than in earlier studies [2,20]. The male to female ratio was 3 : 2, and the mean age at diagnosis 67 years, very similar to figures reported this year from the nationwide Computer Registry of all Myopathies and Neuropathies (CRAMP) in the Netherlands. In CRAMP, they reported that the male to female ratio in the 277 IBM patients included was 3 : 2, whereas the age at diagnosis was 70 years [27 ]. As a corollary, it is evident from the number of IBM cases in CRAMP that the prevalence of IBM in the Netherlands must be higher than previously estimated [18]. Analyses of recorded clinical features showed that swallowing difficulties was very common, particularly in the women, where 94% reported this symptom. Most of the IBM patients (65%) in the cohort were primarily followed by rheumatologists. It is possible that this, at least partly explains why the frequencies of autoimmune features and coexisting rheumatic diseases were higher than in previous studies [28,29]. Altogether, 37% of the 79 patients tested for antinuclear antibodies had a positive test and anti-SSA was positive in 22%; with a female predominance. Coexisting rheumatic disease were recorded in 25% of the IBM cases, with Sjøgren’s syndrome as the most commonly encountered (10 cases). Analyses based on an exposed/ unexposed strategy, with 15 unexposed controls per patient, showed that the standardized mortality rate in IBM, at 1.7 (95% CI: 1.2–2.3), was moderately increased. Aspiration because of dysphagia was recorded as the cause of death in 7 of the 31 deceased patients, making this the most common, possibly disease-related cause of death [25 ]. Overall, the
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&&
&
&
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659
Myositis and myopathies
most common cause of death was ischemic heart disease (8/31 cases). Data on cancer occurrence in the IBM cases and the unexposed controls were retrieved from the Cancer Registry in Norway. Analyses of these data gave no indication of increased cancer risk in IBM [25 ]. &
CONCLUSION Recent findings suggest that IBM is more prevalent in Europe than previously anticipated. Populationbased work confirms that IBM is a myopathy of the elderly, with peak age of onset at nearly 70 years, and most common in men. Coexisting rheumatic diseases, and then particularly Sjøgren’s syndrome, are frequent in IBM. Mortality is slightly increased, but there is no signal for cancer. Even the most recent studies show that diagnostic delay is a major challenge in IBM, strongly suggesting that measures to increase disease awareness are warranted. Acknowledgements None. Financial support and sponsorship The work was supported by the University of Oslo and the Norwegian Women’s Public Health Association, Oslo, Norway. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Mastaglia FL, Needham M. Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches. J Clin Neurosci 2015; 22:6–13. 2. Benveniste O, Guiguet M, Freebody J, et al. Long-term observational study of sporadic inclusion body myositis. Brain 2011; 134:3176–3184. 3. Paltiel AD, Ingvarsson E, Lee DK, et al. Demographic and clinical features of & inclusion body myositis in North America. Muscle Nerve 2015; 52:527–533. First large study on patient reported outcomes in IBM. 4. Brady S, Squier W, Hilton-Jones D. Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features. J Neurol Neurosurg Psychiatry 2013; 84:1240–1246. 5. Benveniste O, Stenzel W, Hilton-Jones D, et al. Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken. Acta Neuropathol 2015; 129:611–624.
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Volume 28 Number 6 November 2016
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