Dr Ju Ann Tan, Department of Immunology, SA Pathology, Flinders Medical Centre, Bedford Park 5042, SA, Australia. Email: email@example.com
Aim: To describe the epidemiology of biopsy-proven idiopathic inflammatory myopathies (IIM) in South Australia (SA).
Methods: Cases of IIM were ascertained by review of all muscle biopsy reports from the Neuropathology Laboratory, Hanson Institute (wherein all adult muscle biopsies in SA are reported) from 1980 to 2009. Clinical correlation of these patients by review of medical records was undertaken. SA population denominator numbers were obtained from the Australian Bureau of Statistics.
Results: Three hundred and fifty-two biopsy-proven cases of IIM were identified between 1980 and 2009. The overall annual incidence of IIM appeared to be rising with a mean incidence of eight cases per million population (95% CI: 7.2–8.9). This corresponded with an increasing annual incidence of inclusion body myositis (IBM) (prevalence of 50.5 cases per million population in 2009, 95% CI: 40.2–62.7). A female preponderance was noted in both dermatomyositis (DM) (F : M = 2.75 : 1.00) and polymyositis (PM) (F : M = 1.55 : 1.00) but gender distribution was almost equal in IBM (F : M = 1.1 : 1.0). Mean age at diagnosis for IBM (67.5 years) was higher than for DM (55.1 years) and PM (59.0 years). A higher proportion of DM patients reported living in urban dwellings and DM patients tended to be predominantly professionals.
Conclusions: In SA there is an increasing incidence of IBM and the prevalence is one of the highest reported to date. This may reflect an increase in the number of biopsies performed, improved histological techniques or a genuine increase in incidence.
Idiopathic inflammatory myopathies (IIM) are a heterogenous group of autoimmune muscular disorders characterised by progressive proximal muscle weakness and inflammatory changes on muscle histology. IIM may be classified according to clinical features, presence of autoantibodies or muscle biopsy findings. Several classification schemes have been proposed, with the first proposed in 1958.1–4 The majority of studies in the myositis literature have utilised the Bohan and Peter5,6 classification criteria to define dermatomyositis (DM) and polymyositis (PM). With recognition of inclusion body myositis (IBM) as a separate IIM subset, newer classification criteria have been proposed,7,8 but none has been uniformly accepted to define homogenous populations of IIM patients.1 However, it is generally accepted that muscle biopsy is the definite diagnostic test and helps to accurately differentiate the three major subsets of disease, namely DM, PM and IBM.9
The rarity and heterogeneity of IIM contribute to the lack of sufficiently powered studies on epidemiology, histopathogenesis, diagnostic criteria, clinical features, therapeutic options and prognosis. Hitherto published epidemiological data showed variable incidence and prevalence mostly attributed to the heterogeneity of the populations studied and lack of uniform diagnostic criteria for inclusion into trials.1 Setting up large-scale registries and development of expert guidelines may be needed to address this conundrum. Here in South Australia (SA), a data registry was set up to include all biopsy-proven IIM, providing a homogenously defined population of IIM patients for subsequent studies. In the present study we sought to determine the epidemiology of PM, DM and IBM in South Australia over a 30-year period, from 1980 to 2009.
Patient selection by histopathological criteria
Idiopathic inflammatory myopathy cases were ascertained from a systematic review of muscle biopsies reported at the Neuropathology Laboratory, Institute of Medical and Veterinary Science, Adelaide, SA, wherein all adult muscle biopsies in SA are reported. Patient medical records were reviewed for clinical correlation. In the present study we selected only patients who fulfilled histological criteria for DM, PM or IBM from the database and included only adult patients aged 18 years and above, who were residents of SA. Further demographic features of this patient cohort, including gender, age, postcode of residence and occupation at the time of muscle biopsy were determined from medical records and patient-reported questionnaires. The histopathological criteria employed are listed in Table 1. This study was approved by the Ethics Committees of all participating hospitals in SA. Approval to access medical records of all patients was granted and informed consent was sought from all living patients for inclusion into the study.
Table 1. Histological criteria for diagnosis of DM, PM and IBM at the Neuropathology Laboratory, Institute of Medical and Veterinary Sciences, SA
Inclusion body myositis (IBM)
CD45 is used as a generic marker for all lymphocytes. EM, electron microscopy; MHC, major histocompatibility complex; TDP, TAR DNA binding protein.
Perifascicular atrophy Inflammatory infiltrate of CD4+ T lymphocytes and B lymphocytes in interstitial space with perivascular accentuation Polyfocal, polyphasic muscle fibre necrosis and regeneration MHC1 sarcolemmal positivity
Lymphocytic invasion of non-necrotic muscle fibres Inflammatory infiltrate of CD45+ lymphocytes and CD68+ macrophages in interstitial space Polyfocal polyphasic muscle fibre necrosis with regeneration MHC1 sarcolemmal positivity (strong)
Rimmed vacuoles Inflammatory infiltrate of CD45+ lymphocytes and CD68+ macrophages in interstitial space MHC1 sarcolemmal positivity (strong) EM findings: tubulofilamentous inclusions TDP-43, Tau, amyloid immunoabnormalities (not seen in all)
The data collected was analyzed for descriptive epidemiology. Binary data was tested for differences using Pearson’s chi-square test, whereas continuous data was tested with the t-test. Only associations with P < 0.05 were considered statistically significant. Statistical analyses were performed using Stata Statistical Software, Release 11 (StataCorp LP, College Station, TX, USA). SA population numbers were obtained from the Australian Bureau of Statistics. Occupational types were coded (with some adjustment) according to the 2006 Australian and New Zealand Standard Classification of Occupations (ANZSCO).
Incidence and prevalence
A total of 352 patients with IIM were identified from 1980 to 2009 (45 DM patients [12.8%], 181 PM [51.4%] and 126 IBM [35.8%]). The mean incidence of IIM was 8.0 × 10−6 (95% CI: 7.2–8.9). From subgroup analysis, the mean incidence of DM was 1.0 × 10−6 (95% CI: 0.8–1.4), PM 4.1 × 10−6 (95% CI 3.6–4.8) and IBM 2.9 × 10−6 (95% CI: 2.4–3.4). The incidence of IIM over the 30-year study period is shown in Figure 1. The overall annual incidence rate shows a rising trend since 1980 reaching a peak of 17.2 × 10−6 in 2006. Cases of IBM largely account for the significant increase in incidence subsequent to 2002 (P for trend = 0.02). DM incidence rates remained stable with no significant trends observed, whereas the annual number of new PM cases was variable.
The reported prevalence of IBM has varied considerably; in the present study we observed the prevalence of IBM was 50.5 × 10−6 (95% CI: 40.2–62.7) with adjusted prevalence of 139.3 × 10−6 (95% CI: 110.1–173.9) for age 50 years and above. Table 2 summarises our findings and previously reported numbers.
Table 2. Summary on studies of incidence and prevalence of IIM
Our population group comprised 209 females (59%) and 144 males (41%). Both DM and PM groups demonstrated a female preponderance with F : M ratio of 2.75 (33 females, 12 males) and 1.55 (110 females, 71 males), respectively. Gender distribution among the IBM group was almost equal with 66 females and 60 males.
Age distribution and age-adjusted incidence rates
Inclusion body myositis occurred almost exclusively in patients above the age of 50 years (97% of all IBM patients) reaching a peak in the 71–80-year age group. The youngest IBM patient was 35 years of age. No differential in age groups was observed for DM or PM; however, the peak incidence of PM was in the 51–60-year age group (Fig. 2).
The mean age of DM patients was 55.1 ± 15.8 years (range, 18–90 years) and PM patients 59.0 ± 13.9 years (range, 18–86 years). IBM patients were the oldest with a mean age of 67.5 ± 10.2 years (range, 35–92 years). Overall incidence rate was highest during the eighth decade (Fig. 3), and this is likely explained by the high incidence of IBM in this age group.
There was a trend that more patients with DM lived in an urban dwelling at the time of muscle biopsy (85.7%) compared with 73.8% of the general SA population (P = 0.06). There was no difference in the proportions of patients with IBM (76.4%) and PM (72.4%) living in an urban environment compared with the general SA population.
Occupational data were available for 149 patients. Although numbers were small and not statistically significant (P = 0.23), we noted that a majority (40%) of our DM patients were professionals, compared to 23.7% of PM patients and 22.9% of IBM patients (Fig. 4).
Epidemiological studies on inflammatory myopathies are, by far, lacking and limited by numerous factors, including the rarity of the condition. The impact of this disease on patient quality of life is significant, but the implications of its long-term effects are poorly understood.23,24 We sought to address some of the limitations presented by other authors, such as small patient numbers, diagnostic classification issues and incomplete case ascertainment; our study population is one of the largest published.
The mean incidence rate for IIM in our study was similar to that reported recently, with an overall worldwide average ranging from 2.18 × 10−6 to 7.6 × 10−6.25 Depending on the diagnostic criteria employed, some of these earlier studies do not distinguish IBM from PM and this is likely to account for the variability in disease incidence. The incidence rates for DM and PM in SA concurred with those in previously published Australian data.14,19 We observed a high prevalence of IBM in SA, which was significantly higher than reported earlier. One study from Western Australia reported a prevalence of 14.9 × 10−6 (age-adjusted > 50 years 51.3 × 10−6).21 However, our findings were comparable to a small population-based study (n = 9) in which the authors reported a prevalence of 70.6 × 10−6.20
The high prevalence of IBM in SA may be attributed to increased disease recognition as a result of increased physician awareness, improvements in disease diagnosis with the recent progress in histopathological understanding of the disease and diagnostic advances such as electron microscopy. A genuine increase in disease incidence should not be discounted. Approximately 32% of DM patients in SA have their disease confirmed with a muscle biopsy and therefore our numbers are almost certainly underestimations.19 Despite this, there are no prior reported data pertaining to the frequency of biopsies performed on suspected IIM cases for comparison and our high IBM rates may be reflective of the frequency of muscle biopsies in our practice.
The increasing annual incidence of IIM over time was also previously observed in studies on DM and PM by Oddis and Benbassat.10,11,25 However, our study has demonstrated that while the incidence of DM remained stable annually, new cases of IBM have contributed significantly to the overall increasing time trends subsequent to 2002. This emphasizes the importance of studying IBM as a separate diagnostic subset.
It is believed that IBM tends to occur more frequently in male patients,15,21,26 but this was not apparent from our study population; females and males were equally affected (66 females:60 males). This male preponderance was hypothesized to be due to hormonal factors with estrogen believed to be protective on skeletal muscle, and a possible unidentified activating or stimulatory gene preferentially expressed in males.26 Prior to the recognition of IBM as a separate entity, most patients would have been classified as PM based on the Bohan and Peter criteria27 and there has always been a strong female bias in PM.1,28,29 With increasing awareness and for reasons related to improved diagnosis of IBM discussed above, what would have been classified as ‘PM’ in the past, is now recognized as IBM. This may explain the higher proportion of IBM female patients in our study. A small study on nine IBM patients had also reported a female preponderance.30
Our data was in keeping with the suggestions that IBM is a disease of the elderly,25,26,29–31 with 97% of our affected patients above 50 years of age. IBM patients demonstrated the oldest mean age at 67.5 years compared to the other subsets. PM commonly occurs after the second decade of life and DM has been noted to occur not only in adults but in children in the form of juvenile DM which has a characteristic pattern distinct from the adult form.
It is interesting to note that DM is not the most common IIM across all age groups studied as otherwise suggested.29,32 However, our study excluded juvenile cases and DM is the most common form of IIM in children.33 PM was more frequent in our population with IBM the commonest form of IIM affecting patients in the eighth decade.
Postal codes and occupational types were used as a crude measure of socio-economic status and DM patients in this study had the highest proportion of urban dwellers (85.7%) and similarly, the highest proportion of professionals (40%), compared to the other subsets. Our results seem to suggest a possible association of DM with a higher socio-economic status. Environmental factors may play a role here. This observed trend will need to be validated by further studies, preferably with larger DM numbers. A recent Australian study investigating associations between IIM and environmental factors such as latitude, sun exposure, relative humidity and rainfall have not identified any significant risk factors,19 although UV radiation and latitude have been shown to be of pathogenetic importance elsewhere.34,35 The pathogenesis of IIM is still debated in the literature with most authors believing that the disease trigger lies in an interaction between environmental factors and infection, in a genetically susceptible individual with certain human leukocyte antigen (HLA) genes (such as HLA-DRB1*03, HLA-DR3, HLA-DR4).28,32,36–38
The strength of this study relies upon our patient selection method. Our cohort was selected based on muscle biopsy results, defining a homogenous population for IIM studies. We were privileged in this manner because all adult muscle biopsies in SA are reported in a single pathology institute under the purview of an expert neuromuscular histopathologist (author PB), therefore minimizing inter-laboratory or inter-pathologist variability. Medical records were then reviewed for diagnostic correlation so we were satisfied that the diagnosis of IIM in our patients fulfilled clinical, serological and histological criteria. We previously published the proportions of patients with biopsy-proven IIM who fulfilled definite or probable Bohan and Peter criteria for DM, PM and IBM (88%, 81% and 90% respectively).38 If any doubt arises, an independent review of past biopsy samples are readily performed. We do acknowledge that, at present, the process of defining histological features as part of the diagnostic criteria for IIM is an ongoing debate, or some would argue, may not be entirely possible given the heterogeneity of disease presentation and variable yield of muscle biopsy.4,7,8,25,28,32 The differing inclusion criteria adopted in previous studies would need to be taken into account when comparing our findings. Our numbers are also likely underestimates as we have not identified patients diagnosed with IIM on the basis of typical clinical or serological/biochemical features.
We found that the overall incidence of IIM is rising in South Australia, particularly for IBM. The prevalence of IBM in our population is among the highest reported and this is attributed to increased disease recognition, higher biopsy rates and improved histopathological criteria and techniques. A genuine increase in disease incidence remains a possibility. Our observation that DM is associated with urban dwellers and socio-economic factors, suggests a role for environmental factors in disease pathogenesis. With better understanding of the disease pathogenesis and validation of the many proposed diagnostic criteria, it is hoped that future studies would clear the uncertainties of inflammatory myopathies.
Data acquisition and collation: Vidya Limaye, Peter Roberts-Thomson, Cox SR; Muscle biopsy reporting: Peter Blumbergs; Statistical analysis: Tan JA, Hakendorf P; Manuscript preparation: all authors.