Epidemiology and Natural History of Inclusion Body Myositis

Abstract

Objectives

To determine the prevalence and natural history of sporadic inclusion body myositis (sIBM) and to test the hypothesis that patients with sIBM have higher cancer or mortality rates than the general population.

Methods

We sought patients with sIBM defined by the 2011 European Neuromuscular Centre (ENMC) diagnostic criteria among Olmsted County, Minnesota, residents in 40-year time period.

Results

We identified 20 patients (10 clinicopathologically defined, 9 clinically defined, and 1 probable) according to the ENMC criteria and 1 patient with all features of clinicopathologically defined sIBM except for symptom onset at <45 years of age. The prevalence of sIBM in 2010 was 18.20 per 100,000 people ≥50 years old. Ten patients developed cancers. The incidence of cancers in sIBM did not differ from that observed in the general population (odds ratio 1.89, 95% confidence interval [CI] 0.639–5.613, p = 0.24). Two-thirds of patients developed dysphagia, and half required a feeding tube. Nine patients required a wheelchair. The median time from symptom onset to wheelchair dependence was 10.5 (range 1–29) years. Overall life expectancy was shorter in the sIBM group compared to the general population (84.1 [95% CI 78–88.4] vs 87.5 [95% CI 85.2–89.5] years, p = 0.03). Thirteen patients died; 9 deaths were sIBM related (7 respiratory and 2 unspecified sIBM complications). Female sex (p = 0.03) and dysphagia (p = 0.05) were independent predictors of death.

Conclusion

Olmsted County has the highest prevalence of sIBM reported to date. Patients with sIBM have similar risk of cancer, but slightly shorter life expectancy compared to matched patients without sIBM.

Classification of Evidence

This study provides Class II evidence that patients with sIBM have similar risks of cancers and slightly shorter life expectancy compared to controls.

Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease in patients >50 years of age.¹ The prevalence of sIBM has varied from country to country, ranging from 0.1 to 13.93 per 100,000 people ≥50 years old.^2-8 This broad range of sIBM prevalence is thought to reflect the diverse genetic backgrounds, unrecognized environmental factors, or differences in case ascertainment methodology or diagnostic criteria applied.⁸

sIBM is classified as idiopathic inflammatory myopathy based on an autoaggressive inflammatory reaction noted on muscle biopsy.¹ The canonical histopathologic findings of myodegeneration (intracellular amyloid deposits, abnormal protein aggregates, and rimmed vacuoles) distinguish sIBM from other idiopathic inflammatory myopathies and may be responsible for its refractoriness to immunomodulatory therapy. Various autoimmune processes and chronic viral infections have been postulated to contribute to the pathogenesis of sIBM.^1,9-15

Associations between cancer and autoimmune myopathies are well established in dermatomyositis and immune-mediated necrotizing myopathy (IMNM)^16,17 but not in sIBM. Although chronic lymphoid leukemia and T-cell large granular lymphocytic leukemia (LGL) were reported in some patients with sIBM,^18,19 a Norwegian population-based study failed to identify an increased risk of cancers in patients with sIBM over a 10-year period.^20,21

In addition, functional outcome and survival data in sIBM are somewhat limited.^22-27 Conflicting data are available regarding mortality in patients with sIBM. Bulbar dysfunction and respiratory-related complications were thought to be common causes of death among patients with sIBM.²⁶

Here, we conducted a population-based epidemiology and natural history study of sIBM among Olmsted County, Minnesota, residents over a 40-year period.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline. The study was approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Board. Participants provided written informed consent.

Study Population

We conducted retrospective, case-control, population-based study in Olmsted County, Minnesota. Olmsted County is a relatively isolated, homogeneous community where health care to the local population is provided by a limited number of providers. We used the Rochester Epidemiology Project (REP) medical records linkage system to identify all individuals who were residents of Olmsted County and had a diagnosis of sIBM between January 1980 and December 2019. This was possible because essentially all Olmsted County residents seek care within the community including the 2 main providers, the Mayo Clinic and Olmsted Medical Center, and their affiliated hospitals and medical facilities. The REP has linked all the medical records from each provider using a unit medical record system whereby all outpatient, inpatient, emergency room, and nursing home information is kept in the same unit record.²⁸ The REP captures virtually all individuals who have resided in Olmsted County at some time from 1966 to the present, regardless of age, sex, ethnicity, disease status, socioeconomic status, or insurance status.^28,29 The REP ensures virtually complete ascertainment and follow-up of all patients with sIBM in this geographically defined community. Furthermore, the medical records are easily retrievable and available for review in both paper and electronic form.

Case Finding Strategy

The case ascertainment strategy is shown in figure. We identified all adults ≥18 years of age who were Olmsted County residents and seen at a primary care outpatient clinic, either at Mayo Clinic or Olmsted Medical Center, between January 1980 and December 2019. Initially, the database was screened with the following ICD-10 and ICD-9 codes for sIBM (359.71 or G72.41), other inflammatory and immune myopathies (359.7 or G72.49), other myopathies (359.8 or G72.89), myopathy unspecified (359.9), or symptomatic inflammatory myopathy in diseases classified elsewhere and other specified myopathies (359.6, G73.7 or G72.49). For cases predating 2010, medical record in Olmsted County containing 1 or more of the following terms alone or in combination were manually reviewed and crossed referenced to our muscle biopsy database to select only patients who underwent muscle biopsy: inclusion body myositis, myositis, myopathy not otherwise specified, polymyositis, inflammatory myopathy, or myopathy not otherwise specified . Two major acquisition routes were used to identify all the patients with sIBM: (1) chart review of all potential cases and (2) review of muscle biopsy reports when available. Information regarding medical history, malignancy, medications, electrophysiologic data (nerve conductions and EMG), muscle biopsies, mortality, and outcome status at last follow-up was gathered from the medical records linkage system from the REP. The functional outcome measures we recorded at the last visit were gait assistance with ankle-foot orthosis, cane, walker, or wheelchair.

Figure 1. Illustrative Representation of Case Selection and Ascertainment.

Case ascertainment and selection used to identify sporadic inclusion body myositis (sIBM) cases among Olmsted County residents. The importance of manually reviewing all cases is emphasized by 3 patients with diagnostic codes for sIBM who were excluded due to either lack of muscle biopsy (n = 2) or diagnostic codes given in error (n = 1). ENMC = European Neuromuscular Centre.

Identification of sIBM Cases

Patients were included if they fulfilled the 2011 European Neuromuscular Centre (ENMC) diagnostic criteria for sIBM and were further classified as clinicopathologically defined, clinically defined or probable sIBM accordingly.³⁰ We defined as having possible sIBM for those patients who fulfilled the 2011 ENMC criteria for clinicopathologically defined sIBM but had an age at onset <45 years. All muscle biopsy reports were reviewed by 2 authors (S.S. and T.L.). The following parameters were recorded: endomysial inflammatory infiltrates, lymphocyte invasion of nonnecrotic myofibers (autoaggression), rimmed vacuoles, cytochrome C oxidase–negative fibers, and the presence of intracellular congophilic deposits viewed under rhodamine optics. Congo red stain has been performed routinely in all muscle biopsies in our Muscle Laboratory since 1996.³¹ Major histocompatibility complex class I, TAR DNA-binding protein 43, and p-62 immunostains were not available in our laboratory during study period. Date of diagnosis was determined by the date of muscle biopsy. For those who had died since the initial assessment, the date and cause of death were retrieved from their medical records or death certificates.

Statistical Analyses

Incidence rates for sIBM were calculated assuming that individuals in Olmsted County ≥30 years of age were at risk. Age- and sex-specific person-years were denominators and estimated from decennial Census data for the county using projects between Census years. Only patients residing in Olmsted County at disease diagnosis were included in the incidence calculations. Incidence rates were age and sex adjusted, by decade, to the structure of the US population. The 1980 Census was used to estimates rates between 1980 and 1989; the 1990 Census for rates between 1990 and 1999; the 2000 Census for rates between 2000 and 2009; and the 2010 Census for rates between 2010 and 2019.³² The 95% confidence interval (CI) rates were estimated from the cumulative Poisson distribution. For comparison of cancer and mortality, each patient was matched with 10 age- and sex-matched controls who lived in Olmsted County on the date of their matched case’s diagnosis. Time to death as an outcome was obtained with Kaplan-Meier survival curves. For survival analysis data cutoff determined was time (months) from sIBM diagnosis to death in deceased patients or time (months) from sIBM diagnosis to last follow-up or December 2019 in the remaining patients. Univariate logistic regression analysis was used to investigate variables associated with death, including sex, age at diagnosis, age at onset, dysphagia with and without the need for feeding tube, or cricopharyngeal myotomy, dyspnea/orthopnea, concomitant autoimmune diseases, malignancies, and immunomodulatory treatment.

Data Availability

Deidentified data are available on reasonable request.

Results

Epidemiology

Twenty patients fulfilled the 2011 ENMC criteria for sIBM (10 clinicopathologically defined, 9 clinically defined, and1 probable). One patient with possible sIBM had symptom onset at age 43 years but had severe weakness of finger flexors and knee extensors with relatively mild involvement of shoulder abductors and hip flexors and all pathologic hallmarks of sIBM (autoaggressive inflammation, rimmed vacuoles, and congophilic deposits) (figure 1). Nine patients were described previously.³ All patients were White. Median age at symptom onset was 67 years (range 43–86 years). Median age at sIBM diagnosis was 68 years (range 51–87 years). Median time from symptom onset to diagnosis was 2 years (range <1–10 years). Of the 21 patients, there were 10 women and 11 men. Sex-specific incidence rates by decade are shown in table 1. The age- and sex-adjusted prevalence of sIBM among those ≥30 years of age was 12.78 per 100,000 (95% CI 2.50–23.06) in 1990, 10.43 per 100,000 (95% CI 2.69–18.16) in 2000, and 9.72 per 100,000 (95% CI 2.98–16.46) in 2010. To better compare our prevalence to other studies, we also calculated the prevalence among those ≥50 years of age, which resulted in the prevalence of 27.82 per 100,000 (95% CI 5.45–50.19) in 1990, 22.39 per 100,000 (95% CI 5.77–39.00) in 2000, and 18.20 per 100,000 (95% CI 5.58–30.83) in 2010.

Table 1.

Sex-Specific and Total Incidence of sIBM by Decade Among Olmsted County, Minnesota, Residents

Clinical Presentations

Presenting symptoms were quadriceps weakness (n = 18), handgrip weakness (n = 8), proximal arm weakness (n = 6), foot drop (n = 1), dyspnea (n = 1), and dysphagia (n = 1). Dysphagia was reported in 67% (14 of 21) of patients and was the presenting symptom in one of them. The median time from symptom onset to dysphagia was 72 months (range 0–236 months). Half of the patients with dysphagia eventually required feeding tube placement. Two patients also underwent cricopharyngeal myotomy with transient benefits. Median time from disease onset to feeding tube placement or cricopharyngeal myopathy was 10 years (range <1–29 years). Three patients had dyspnea; all were due to diaphragmatic weakness: 2 had abnormal needle EMG of the hemidiaphragm, and 1 had autopsy evidence of nonspecific myopathic changes of diaphragm. All 3 required noninvasive ventilation. Median time from symptom onset to dyspnea was 64 months (range 0–84 months).

Ancillary Tests

Detailed electrodiagnostic studies were available in 15 patients. In all but 1 patient, rapidly recruiting, short-duration, and low-amplitude motor unit potentials with mixed long-duration and high-amplitude motor unit potentials were observed. Fibrillation potentials were recorded in all patients except 1 who received several intra-articular steroid injections for arthritis before EMG. Finger/thumb flexors and quadriceps were the most severely affected muscles in 9 patients. Eight patients had concomitant length-dependent axonal peripheral neuropathy, for which the peripheral neuropathy could be explained by other etiologies (7 patients with diabetes mellitus and 1 patient with Sjogren syndrome).

Creatine kinase measurements were available in 12 patients with the median of 1 times the upper limit of normal (range <1–7 times the upper limit of normal). Only 3 patients in our cohort were diagnosed with sIBM in or after 2013 and underwent anti-cytosolic 5′-nucleotidase 1A (cN1A) antibodies evaluations, which were positive in 1 patient. Three of 14 patients had positive myositis-associated or -specific antibodies: 1 with Mi-2, MDA-5, SSA and SSB antibodies; 1 with SSA and SSB antibodies; and 1 with RNP antibodies. A patient with Mi-2 and MDA-5 antibodies had no cutaneous or pulmonary involvement and did not respond to immunomodulatory therapy but had positive anti-cN1A antibodies and all pathologic hallmarks of sIBM without perifascicular pathology.

Hepatitis C virus (HCV) antibodies were positive in 1 of 9 patients tested. HIV antibodies were negative in all 6 patients analyzed. Complete blood count at the time of diagnosis was normal in 13 patients. Only 2 patients in our cohort were diagnosed with sIBM after 2016, and both underwent T-cell LGL evaluations, both of which were negative. Monoclonal gammopathy was present in 3 of 20 patients (1 with IgG-λ, 1 with IgG-κ, and 1 with IgM-λ), none of whom had plasma cell neoplasm. All were evaluated by hematologists; 1 patient had a bone marrow biopsy, which showed no plasma cell dyscrasia.

Muscle biopsies showed all canonical findings of sIBM (autoaggressive inflammation, rimmed vacuoles, and intracellular congophilic deposits) in 11 patients. Ten patients had 1 or 2 of the canonical findings; 1 of these patients also had concomitant transthyretin amyloidosis-associated myopathy.

Associated Autoimmune Diseases and Malignancies

Autoimmune diseases were present in 10 of 21 (48%) patients as shown in table 2. Rheumatoid arthritis was the most common associated autoimmune disease (n = 4), followed by Sjogren syndrome (n = 2). Ten patients (53%) had malignancies as shown in table 2. Genitourinary (n = 3) and skin (n = 3) cancers are the most common associated malignancies. Median time from sIBM diagnosis to cancer diagnosis was 1.5 years after sIBM diagnosis (range 6 years before diagnosis–15 years after the diagnosis). Cancers occurred within 3 years of sIBM diagnosis in 5 patients. Six patients with sIBM and cancers received immunomodulatory therapy. Due to restricted consents in few patients, 17 sIBM patients were included for comparison of cancer rate to the age, sex and year matched controls. The cancer incidence did not significantly differ (odds ratio 1.89, 95% CI 0.639–5.613, p = 0.24).

Table 2.

Associated Autoimmune Diseases and Malignancies

Responsiveness to Immunomodulatory Therapies

Eleven patients received immunomodulatory therapies: 4 prednisone monotherapy and 7 prednisone and steroid-sparing agents (7 methotrexate, 3 azathioprine, 3 cyclophosphamide and 1 intravenous immunoglobulin). Three patients received more than 1 steroid-sparing agent. Eight patients were treated because of dysphagia. The median time from symptom onset-to-treatment initiation was 49 months (range 5 to 120 months). The median treatment time was 67 months (range 7–140 months). Compared to non-treated patients (table 3), treated patients required gait aids slightly later (7 vs 5 years after diagnosis, p = 0.05). The incidence of cancer did not differ by the use of immunomodulatory therapies or steroid-sparing agents. Muscle weakness and dysphagia progressed in all treated patients. No transient or objective improvement of muscle strength or dysphagia was observed.

Table 3.

Characteristics of Treated Versus Nontreated Patients With sIBM

Statin Use and Its Effect on Weakness

Eight patients were on statins while having weakness. The median time for statin exposure was 3 years (range 1–11 years). None of the patients reported muscle pain, rapid deterioration of weakness, or other adverse reactions to statin. We compared those who took statins to those who did not in several aspects, including time from symptoms onset to diagnosis, peak creatine kinase level, time for gait aids of any kind, and number of patients who required a wheelchair. However, there were no differences by statin use. The number of years of statin use and time for gait aid assistance did not correlate (R² = 0.12).

Survival and Outcomes

Outcome measures were available for all 21 patients. Ambulation aids were recorded and plotted against years from symptom onset as shown in figure. Up to the end of the study period (December 2019) or last follow-up, all patients needed walking assistances (walker [n = 9] and cane [n = 3]) or wheelchair (n = 9). The median time from symptom onset to the use of a cane or walker was 5 years (range 1–13 year) and to the use of a wheelchair was 10.5 years (range 1–29 years). Half of the patients required walking aids by 8 years after symptom onset.

Figure 2. Natural History, Outcome, and Survival in sIBM.

(A) Annual rate for ambulatory without walking aids after symptom onset showing that 50% of patients required walking aids at 8 years. (B) Life expectancy in sporadic inclusion body myositis (sIBM) vs our county age-, sex-, and year-matched controls. For graphical purposes, we determined age starting point at >60 years to be able to better graphically show difference in life expectancy.

During the follow-up time, 13 patients died, 10 of whom had dysphagia, and 1 was admitted to hospice care due to severe dementia with Lewy bodies and aspiration pneumonia as of December 31, 2019. Three other patients also had dementia (1 Alzheimer disease and 2 uncharacterized). Due to restricted consents in few patients, 17 patients with sIBM were included for comparison of life expectancy to the age, sex and year matched controls. Median age at death for patients with sIBM was 84 years (range 78–88.4 years), which was significantly shorter (p = 0.03) than that observed for age-, sex- and year-matched controls (88 years, range 85.2–89.5 years) (figure 2B). Of all variables investigated, dysphagia regardless of feeding tube or cricopharyngeal myotomy (p = 0.05) and female sex (p = 0.03) were found to be significantly associated with death among patients with sIBM. Respiratory involvement was not significant (p = 0.08). Receiver operating characteristic curve analysis with sIBM-related death as an outcome and age at onset as a predictor suggested an age >67 years as a best discriminant for a higher risk of death (area under the curve 0.64). This same cutoff point of age also remained significant when death from all causes were considered as outcome (area under the curve 0.78).

Causes of death were available for review in all patients. In 9 patients, death was associated with complications of sIBM, including aspiration pneumonia (n = 3), respiratory failure (n = 4), and progression of sIBM (n = 2), according to death certificates. The sIBM-unrelated death included sudden cardiac arrest (n = 1), acute gastrointestinal bleeding (n = 1), pulmonary embolism (n = 1), and terminal cancer (n = 1).

Discussion

There are geographic differences in the prevalence of sIBM, and only a few epidemiologic studies have been conducted in the United States.^3,8,22 The prevalence of sIBM in Olmsted County per 100,000 people ≥50 years of age in 2010 was 18.20, which is the highest prevalence of sIBM reported to date and greater than previously reported prevalence in studies in Ireland and Southern Australia of 11.7 per 100,000 and 13.93 per 100,000 for people ≥50 years of age.^5,7 The observed differences in sIBM prevalence could be due to a variety of factors. First, some epidemiologic studies identified cases strictly on the basis of the specific diagnostic codes of sIBM.⁷ In the present study, we show in figure 1 that only 30% of patients with sIBM in our cohort were assigned to specific diagnostic codes for sIBM, while the majority were given the nonspecific diagnostic codes. Thus, the use of only specific diagnostic codes will lead to a lower prevalence. Second, many studies were not population based, which could lead to underestimates or overestimates of prevalence.^{5,21,22,33-35} Third, there are several aspects to ascertaining an sIBM diagnosis that have changed over the last 40 years and could have affected the high prevalence of sIBM in Olmsted County, including (1) the early inclusion of Congo red stain in routine muscle histopathology in our laboratory since 1996, (2) the application of a more sensitive diagnostic criteria (ENMC), (3) general lifespan prolongation in Olmsted County as was seen worldwide, (4) longest study years reported (40 years) to date, (5) high disease awareness, and (6) a referral bias in the setting of tertiary care medical center. However, we cannot exclude environmental factors or genetic backgrounds that may lead to the high prevalence of sIBM in our area.

Although we reported the highest prevalence of sIBM to date, we observed a slight reduction of prevalence between decades, which could be due to the fluctuation of sIBM incidence over time. This observation differs from the South Australian and Japanese studies that showed trends for increased incidence or prevalence over time.^5,35 Median time from symptom onset to diagnosis in our cohort was 2 years, which is shorter than what was previously reported in United States (4.7 years), the Netherlands (5.6 years), or France and the United Kingdom (4.9 years).^27,36,37 This could be due to the unique setting of Olmsted County, in which the residents receive their medical care almost exclusively from a tertiary medical center.

Coexisting autoimmune disorders were frequent in our cohort and were noted in almost half of patients, which is higher than previously reported (33%).⁹ Unlike prior studies, rheumatoid arthritis, not Sjogren syndrome, is the most common associated autoimmune disease in our cohort.^10,38 This could be due to the increasing incidence of rheumatoid arthritis in Olmsted County over the years.^9,39 Abnormal HCV serology was identified in 28% of a Japanese sIBM cohort,¹⁴ but its frequency in Western countries is unknown. We identified HCV antibodies in only 1 of 9 patients with sIBM. A larger-scale study is necessary before any conclusion can be drawn regarding the association between sIBM and HCV.

The association between cancers and sIBM is controversial. Population-based studies identified the increased cancer risk in an Australian sIBM cohort but not in a Norwegian sIBM cohort.^20,40 Our results suggest that cancer is not more common in patients with sIBM compared to controls. This is important to prevent unnecessary imaging studies, radiation exposures, or procedures in patients with sIBM.

HMG-CoA reductase inhibitors (statins) are known for their myotoxicity and the association with IMNM. There is no consensus regarding the use of statins in patients with immune-mediated myopathies, apart from its contraindication in patients with HMGCR antibody–mediated IMNM. Our study shows that statins were well tolerated in our patients with sIBM and that statin use did not affect disease progression. This finding is similar to that in the recent retrospective study of statin use in patients with idiopathic inflammatory myopathies.⁴¹

sIBM is a slowly progressive myopathy, and few natural history studies have been conducted.^22,23,42,43 In our cohort, the median time from symptom onset to using a cane was 5 years and to first use of a wheelchair was 10.5 years, which are slightly shorter than previously reported (7.5–11 years for cane and 13–16 years for wheelchair).^23,27,42,44 Prior studies showed that faster progression occurred in patients with symptom onset after 60 years of age or in patients receiving immunosuppressive treatment.^27,45 However, in the current cohort, immunosuppressive-treated patients actually had slightly longer time of walking without any assisted device (7 vs 5 years, p = 0.05). Nevertheless, none of the treated patients reported any improvement of weakness or dysphagia. We do not have sufficient evidence to state that the treatment slows down progression because this requires a prospective study in a larger cohort of patients.

There are conflicting results regarding survival of sIBM. Life expectancy was normal in a French-British and a Dutch cohort,^23,27 but a Norwegian study identified a slightly higher mortality rate among patients with sIBM compared to controls.²⁰ In our cohort, the median age at death of patients with sIBM was 84 years, which is similar to that reported in the Netherlands. However, the lifespan among our patients with sIBM was slightly, but significantly, shorter compared to age-, year-, and sex-matched controls (figure 2B). Approximately 70% of deaths were sIBM related, especially respiratory complications from either aspiration pneumonia or diaphragmatic involvement. This is similar to previous reports.^45-48 Considering only sIBM-related death, dysphagia, female sex, and older age at diagnosis (>67 years) were predictors for shorter life expectancy. Dysphagia occurred in two-thirds of our patients, which is similar to previous reports (40%–80%).⁴⁹ Dysphagia typically occurs late in the course of the disease, but patients with sIBM may occasionally present with dysphagia at onset.⁵⁰ Our finding highlights the importance of future studies looking into the proper management of dysphagia among patients with sIBM.⁴⁹ Based on receiver operating characteristic curve analysis, an age of ≥67 years at diagnosis was a stronger predictor of all causes of mortality. In the French-British cohort of sIBM, older age at symptom onset was identified as the only poor prognostic factor similar to our finding.²⁷

Our study has few limitations. Because this is a population-based study, we could include only a small number of patients who are residents of this county. The small number may limit the generalizability of our findings. Compared to other cohort, the relatively shorter time from symptom onset to diagnosis in our cohort could be due to a referral bias. Given the retrospective nature of our study, serologic evaluation was not uniformly conducted in all the patients, especially those were diagnosed before the discovery of anti-cN1A antibodies or predate the report of the association between T-cell LGL and sIBM. Despite these limitations, our study provides valuable data on the epidemiology and natural history of sIBM.

The prevalence of sIBM in Olmsted County, Minnesota, in 2010 is the highest compared to the prevalence reported from other countries. Autoimmune diseases, especially rheumatoid arthritis, are common in our cohort. Statin therapy was well tolerated among our patients. The risk of cancer did not increase in sIBM. Patients with sIBM have a slightly shorter life expectancy compared to general population, especially in female patients, patients with dysphagia, or those with symptom onset after 67 years.

Glossary

CI

confidence interval

cN1A

cytosolic 5′-nucleotidase 1A

ENMC

European Neuromuscular Centre

HCV

hepatitis C virus

ICD

International Classification of Diseases

Ig

immunoglobulin

IMNM

immune-mediated necrotizing myopathy

LGL

large granular lymphocytic leukemia

REP

Rochester Epidemiology Project

sIBM

sporadic inclusion body myositis

Appendix. Authors

Study Funding

Discretionary fund, Department of Neurology, Mayo Clinic, Rochester, MN. This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosure

Drs. Shelly, Mandrekar, Naddaf, and Liewluck report no disclosures. Dr. Mielke receives funding from the NIH and an unrestricted research grant from Biogen and consults for Brain Protection Co. Dr. Milone receives research support from a Mayo Clinic benefactor and an honorarium to serve as associate editor of Neurology Genetics. Dr. Ernste has received support from Octapharma. Go to Neurology.org/N for full disclosures.