Epidemiology of Myositis

Abstract

Purpose of Review:

This review aims to synthesize recent developments in the epidemiology of idiopathic inflammatory myopathies (IIM), focusing on incidence, prevalence, disease classification, and clinical outcomes.

Recent Findings:

IIM is a rare group of autoimmune diseases characterized by muscle weakness and systemic involvement, with incidence rates ranging from 0.2 to 2 cases per 100,000 person-years. The role of myositis-specific autoantibodies (MSAs) in stratifying disease risk and prognosis is increasingly recognized, such as in anti-MDA5 positive DM, which is associated with a high risk of rapidly progressive interstitial lung disease. Furthermore, patients with IIM exhibit elevated risks of comorbidities, including cardiovascular disease and malignancy.

Summary:

IIM diseases are complex disorders with significant health impacts, necessitating enhanced awareness and research. Improved classification and understanding of MSAs are crucial for earlier diagnosis and tailored therapeutic strategies. Continued epidemiological research is essential to elucidate underlying mechanisms and inform future interventions, ultimately aiming to enhance the quality of life and clinical outcomes for affected patients.

1. Introduction

Idiopathic inflammatory myopathies (IIM), or autoimmune inflammatory myopathies, are a diverse group of rare autoimmune diseases primarily affecting skeletal muscle but also involving other organ systems such as the skin, joints, lungs, heart, and gastrointestinal tract. IIM most often presents with sub-acute or chronically progressive, symmetric proximal muscle weakness, pain, and fatigue. But patients can develop a wide range of extra-muscular manifestations, making diagnosis challenging in some cases. IIM is rare, with an incidence rate of 0.2 to 2 cases per 100,000 person-years and a prevalence of 2 to 25 cases per 100,000 people (1–3). In comparison, rheumatoid arthritis (RA) has an incidence of 13 to 37 per 100,000 person-years and a prevalence of 0.2% to 0.5% (4), while systemic lupus erythematosus (SLE) has an incidence of 23.2 per 100,000 person-years and a prevalence of 241 per 100,000 people (5). Despite its rarity, IIM is associated with a significant negative impact on patients’ mortality, morbidity, and healthcare utilization. Therefore, there is a pressing need for novel strategies and interventions to improve clinical outcomes for these patients.

Adult IIM can be divided into five main clinicopathologically distinct subtypes: dermatomyositis (DM), polymyositis (PM), immune mediated necrotizing myositis (IMNM), inclusion body myositis (IBM), and anti-synthetase syndrome (ASyS) (2). It is beyond the scope of this review to address pediatric IIM, like juvenile dermatomyositis (JDM). Additional work on this important patient population is urgently needed. The 2017 EULAR/ACR IIM classification criteria incorporate serological, clinical, and histopathologic data, reflecting newer understanding of IIM sub-types compared to prior IIM classification criteria, such as the Bohan and Peter criteria (6–8). Myositis Specific Antibodies (MSAs), for example, have become increasingly critical in establishing the diagnosis of IIM, identifying clinically important disease sub-types, and determining risk of particular extra-muscular manifestations and probable outcomes (1, 6).

This review aims to provide a rigorous and focused synthesis of recent developments in the understanding of IIM epidemiology, with particular emphasis on incidence and prevalence, disease classification, and clinical outcomes.

1.a. Dermatomyositis (DM)

DM is characterized by unique skin lesions alongside a diverse array of systemic manifestations, including muscular, joint, and pulmonary involvement. The subset of DM without muscle involvement is referred to as clinically amyopathic dermatomyositis (CADM). The distinct pathognomonic cutaneous findings of DM include violaceous papules and macules overlying the extensor surfaces of joints (Gottron’s papules and sign), heliotrope rash, V-sign and shawl sign (1, 9).

The age- and sex-adjusted overall incidence of DM from a population-based study of Olmsted County, Minnesota, USA is 1.1 per 100,000 person-years, translating to 2,858 new cases annually in the U.S (10**). The incidence of DM increases with age, peaking at 3.2 per 100,000 person-years in individuals aged 80 and older, and is higher among females 1.9 per 100,000 person-years than males. The overall prevalence of DM in the same cohort was found to be 13 per 100,000 person-years and 20 per 100,000 person-years among females. CADM had an incidence and prevalence of 0.5 and 7.0 per 100,000 person-years respectively (10**). The mean (SD) yearly age- and sex-adjusted incidence for DM in a retrospective nationwide cohort study of US veterans was 1.0 (0.4) per 100,000 persons (11). The age-adjusted incidence of DM was estimated as 1.2 per 1,000,000 person-years in the first systemic review of IIM epidemiology in Africa (12), and DM was the most prevalent (41%) IIM subtype in a cohort study from Oman with prevalence rate of 2.2 per 100,000 people (13).

MSAs are instrumental to diagnosis, risk stratification, and prediction of disease related complications (14). DM-associated MSAs, in the order of decreasing prevalence in the MYONET registry, include anti-Mi-2, anti-TIF1γ, anti-MDA5, anti-SAE and anti-NXP2 (3, 15). Of MSAs, the anti-TIF1γ-antibody, followed by the anti-NXP-antibody, has the strongest association with increased cancer risk (16**). Autoantibodies against cell division cycle and apoptosis regulator 1(CCAR1-antibodies) may be associated with lower cancer risk in anti-TIF1γ-Ab-positive DM (17*, 18). Anti-MDA5 Ab-positive DM is typically amyopathic and is often complicated by rapidly progressive interstitial lung disease (RP-ILD). This form of DM is more common in East-Asian populations, especially among women (14, 15, 19*, 20). Anti-NXP2-Ab-positive DM is a less common subtype of DM that is often characterized by prominent muscle disease, calcinosis, and dysphagia (1).

1.b. Polymyositis (PM)

PM is characterized by proximal, symmetric muscle weakness without any cutaneous involvement. PM was historically regarded as a common form of IIM, however, its prevalence in more recent studies has declined as many patients previously diagnosed with PM are now diagnosed instead with other conditions, such as IBM, IMNM or ASyS (21). There are no autoantibodies specific to PM, and a thorough evaluation to rule out other mimicking diagnoses is crucial. Further research is needed to help clarify the true prevalence and incidence of PM using newer classification criteria, such as the 2017 EULAR/ACR criteria.

1.c. Inclusion Body Myositis (IBM)

IBM is the most common IIM subtype among individuals over age 50 years (2). IBM typically presents with gradually-progressive, asymmetric proximal muscle weakness particularly involving the quadriceps and/or finger flexors, and it may go to cause dysphagia or respiratory compromise (22, 23). While IBM has often been considered a disease that predominantly affects older, White males (2, 3, 24*), a recent analysis of IBM patients in the Johns Hopkins Myositis Center Registry noted a significant number of females, Black, and younger individuals (24*). Black, compared to non-Black, patients experienced significant proximal muscle weakness but less dysphagia. Females and those with onset before age 50 were more likely initially to be misdiagnosed with PM. Additionally, females, compared to males, were more likely to develop dysphagia (24*). Autoantibodies to cytosolic 5’-nucleotidase (cN1a) are often observed in IBM and can aid in making the diagnosis (24*, 25*).

In a recent population-based study in Olmsted County, Minnesota, USA, the incidence of IBM, based on the European Neuromuscular Center (ENMC) 2013 criteria, was 0.32 to 1.22 per 100,000 person-years, with a prevalence of 182 per million in individuals aged 50 years or older (26). In a population-based study of western Sweden, IBM prevalence was 0.12 per 100,000 people and incidence was 0.012 per 100,000 person-years (25*). Key revisions to the 2024 ENMC IBM diagnostic criteria include decreasing the age cutoff for a common presentation of IBM from 50 to 45 years old and anti-cN1a Ab positivity as supporting evidence of IBM (23). These revised criteria will likely lead to higher estimates of IBM prevalence and incidence than have been previously observed.

1.d. Antisynthetase Syndrome (ASyS)

This IIM subtype is characterized by the serologic presence of anti-aminoacyl transfer RNA synthetase (ARS) antibodies, inflammatory myopathy, interstitial lung disease (ILD), arthritis, Raynaud’s phenomenon, and “mechanic’s hands” (9*). ARS antibodies account for 25–35% of all myositis specific antibodies and include anti-Jo1 (the most commonly reported ARS antibody), -PL7, -PL12, -EJ, -OJ, -KS, -Zo, and -Ha (27).

The prevalence and incidence of ASyS remains poorly characterized. Among MYONET registry participants, ASyS was one of the most common IIM, accounting for 17% of cases, following DM (31%) and PM (27%)(28). Data on ASyS incidence and prevalence from non-European and North American populations are more limited. In a systemic review of IIM in Africa, the frequency of ASyS was 2.9% (12). The mean (± SD) age of onset of ASyS is approximately 45 to 55 ±15 years, and ASyS is more common among females than males(9, 27, 29–31**).

Individual ARS antibodies are associated with increased risk of particular ASyS clinical manifestations. Isolated arthritis is associated with anti-Jo1 Ab positivity, isolated ILD with anti-EJ, myositis with anti-OJ, and Gottron’s sign with anti-PL7 (27). Anti-Ro52 positivity is associated with ILD, which can be rapidly progressing and confer an increased mortality (27). Cutaneous manifestations in ASyS can overlap with those of DM, but the presence of mechanic’s hands, ILD, and rarely cardiac involvement can help differentiate ASyS with DM-like cutaneous feature from true DM (9*). A recent large retrospective cohort study identified three distinct endotypes in ASyS patients using unsupervised clustering analysis based on clinical presentation and laboratory parameters: the rapidly-progressing (RP) RP-ILD cluster, the DM-like cluster, and the arthritis cluster (31**). The RP-ILD cluster (23.7%) was characterized by severe lung disease, with 93% in this cluster developing RP-ILD and 70% experiencing acute respiratory failure. Other symptoms more commonly seen in the RP-ILD compared to other clusters were fever, dyspnea, and elevated CRP and ESR. The DM-like cluster (14.5%) experienced heliotrope and Gottron’s rashes, prominent muscle weakness, and increased prevalence of anti-PL7 antibodies positivity. The arthritis cluster (61.8%) primarily displayed arthritis/arthralgia and mechanic’s hands and experienced the lowest risk of RP-ILD (31**). Interestingly, ARS profile was not a statistically significant factor identified by the machine learning algorithm used in generating these 3 unique ASyS endotypes.

1.e. Immune Mediated Necrotizing Myositis (IMNM)

IMNM is a rarer IIM subtype characterized by subacute, severe proximal muscle weakness, and markedly elevated serum CK levels (32). IMNM can be further subclassified by anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) antibody positivity status, and a seronegative subclass also exists (32). Anti-HGCR myopathy has been linked to statin exposure but can also occur in individuals with no known statin exposure (33, 34). Patients with anti-SRP myopathy have increased risk of more severe muscle weakness and respiratory muscle involvement than anti-HMGCR or seronegative IMNM (32). Extra-muscular manifestations of IMNM are rare. But cardiac involvement and ILD have been reported in anti-SRP myopathy (32, 35); and cutaneous manifestations (DM-like rash) and Raynaud’s phenomenon anti-HMGCR myopathy (32, 34, 36–38). IMNM has a higher prevalence among females than males; and while the mean age of onset is between 40 and 65 years, it can occur at any age (3, 32, 39*–41).

The total incidence of anti-HMGCR myopathy in Olmsted County, Minnesota, USA was 0.83 per 100,000 person-years and prevalence was 1.85 per 100,000 people (40). Among statin-exposed Americans, Native Americans compared to other racial/ethnic groups, had an approximately 150-fold increased prevalence of anti-HMGCR IMNM (42). In recent UK, Spanish, and Australian cohorts, anti-HMGCR IMNM incidence ranged from 0.9 to 6.0 per million (34, 41). In New Zealand, the overall incidence of anti-HMGCR IMNM was 4.0 per 100,000 persons per year, with twice the incidence among those over 40 years old and five-fold increased incidence among those of Polynesian ancestry (39*).

2. Disease Outcomes

Though IIM diseases are rare, they have a profound impact on both quality of life and life expectancy. High mortality rates in IIM stem from its association with ILD, malignancy, and cardiovascular disease (CVD). Understanding these outcomes is crucial for improving care strategies and enhancing the quality of life for individuals living with IIM.

2.a. Health related quality of life (HRQoL)

Certain comorbidities are common in IIM and contribute significantly to adverse outcomes, including end-organ damage and reduced patient productivity and well-being. Individuals with IIM report poorer HRQoL and well-being compared to the general population (43**). IIM disease activity and well-being are inversely associated (44), but further research is needed to disentangle these complex and multifactorial relationships. For example, IIM patients with advanced age, multimorbidity, and mental health conditions are at particularly increased risk of worse physical function (43**, 45, 46). Patients with IIM may also face financial strain from medical expenses, caregiving, and/or physical disabilities (47, 48). Thus, physicians should seek out opportunities to personalize treatment plans and help mitigate adverse impacts of IIM on patients HRQoL.

2.b. Cardiovascular (CV)

IIM patients have significantly elevated CV risk compared to the general population, and CV disease is a significant cause of increased mortality in these patients (49, 50*). This increased CV risk in IIM patients is driven not only by traditional CV risk factors, such as older age, male sex, dyslipidemia, hypertension, and smoking; but also likely by the chronic inflammation of IIM disease activity (51*). In PM and DM, the risk of adverse CV events is increased during the first five years after diagnosis compared during years 5 to 10 (relative risk of 3.51), suggesting that systemic inflammation related to IIM-disease activity may be a key determinant of this increased CV risk (52). The risk of adverse CV events was approximately 2.5 times higher in PM and DM compared to other IIM subtypes, and males have 43% higher risk than females (52). The prevalence of myocardial involvement in a single-center retrospective cohort of anti-MDA5 DM/CADM patients was 16%, with ventricular wall dyskinesia being the most common manifestation (53). Cardiac involvement of IMNM is controversial and mostly reported in anti-SRP antibody myopathy (54). A Chinese retrospective cohort study reported 50% prevalence of cardiac involvement in anti-SRP antibody-positive IMNM, where arrhythmia and ECG evidence of myocardial ischemia were the most common manifestations (54). Cardiac involvement in anti-HMGCR and seronegative IMNM appears uncommon, but has been documented in case reports (54). Future research is needed to advance understanding of the relationships of racial and ethnic diversity, genetic ancestry, socioeconomic status, and sex and gender with CV risk in IIM.

2.c. Malignancy

Patients with IIM are at an increased risk of malignancy, and this risk is greatest in DM and specifically DM with anti-TIF1γ or anti-NXP2 antibody positivity (55). In a retrospective analysis of the Johns Hopkins Myositis Cohort, anti-TIF1γ antibodies were strongly associated with contemporaneous cancer, particularly breast and ovarian (56**). Cancers were also common in patients with anti-Mi2, -SAE, and -NXP2 antibodies. However, those with anti-HMGCR, anti-MDA5, and anti-synthetase antibodies had cancer rates similar to those of the general population (56**). In a single center study from China, the pooled prevalence of cancer in anti-TIF1γ DM patients was 41%, with lung (23%), breast (17%), and gastric cancer (9%) reported most commonly (18). In a retrospective analysis from Japan, the standard incidence rate (SIR) for early phase malignancy (malignancy diagnosis within 3 years of IIM onset) was highest among anti-TIF1γ compared to anti-ARS, anti-MDA5, and anti-Mi2 (55) positive patients. Anti-MDA5 DM was associated with higher SIR of late phase malignancy (malignancy diagnosis within 4 to 10 years of IIM onset), suggesting longer duration cancer screening may be appropriate in these patients (16, 55). The International Myositis Assessment and Clinical Studies Group (IMACS) recently published cancer screening guidelines for IIM patients (16**), which is an important step in improving outcomes for these patients. However, when these guideline were retrospectively applied to a DM cohort, 90% were identified as intermediate- or high-risk, and would thus be recommended to receive more comprehensive cancer screening evaluations (e.g. CT imaging) (57*). Thus, additional studies, including cost-effectiveness analyses, should continue to refine cancer screening practices in IIM and improve outcomes for these patients.

Clinical factors associated with heightened risk of malignancy in IIM patients include advanced age, male sex, smoking history, skin necrosis, dysphagia, rapid-onset myositis, low lymphocytic infiltration in muscle biopsies, elevated inflammatory markers, and obesity (18, 58). While anti-TIF1γ antibodies-positivity is associated with increased malignancy risk, recent data suggest certain anti-TIF1γ patients may have lower malignancy risk than others based on additional auto-antibody profiles. For example, autoantibodies against the cell division cycle and apoptosis regulator 1 (CCAR1) were found to be linked with decreased cancer prevalence in anti-TIF1γ-positive dermatomyositis (DM) patients (17*). Additionally, anti-TIF1γ DM patients with compared to those without anti-Sp4 antibody positivity have lower cancer rates (59).

2.d. Pulmonary manifestations

The subtypes of IIM that are strongly associated with ILD include PM, DM, and ASyS (60). ILD was the common manifestation (96.6%) in a Chinese cohort (31**) and frequently reported in patients with ant-Jo1, -PL12, -PL7, and -EJ antibody positive patients (9, 27, 30, 31**). Screening for ILD is warranted for patients with anti-MDA-5 DM, ASyS, or overlap antibodies (e.g., PM-Scl, Ku, Ro52) as the presence of these autoantibodies are associated with heightened ILD risk (61). RP-ILD is a severe and often fatal complication of anti-MDA5 DM, with over 60% mortality within six months (20, 62). In another Chinese cohort, around 40% of anti-MDA5 DM patients develop RP-ILD (62). Various clinical factors are likely associated with mortality from RP-ILD in anti-MDA5 DM, including older age, male sex, poorer baseline pulmonary function, lymphocytopenia, high serum ferritin or CRP levels, anti-Ro52 antibody positivity, and severity of ILD at the time of diagnosis (14, 20, 62). However, clinician’s ability to predict which anti-MDA5 DM patients will or will not develop RP-ILD remains very limited. In recent studies, elevated plasma levels of secreted phosphoprotein 1 (SPP1) (63) and specific polymorphisms in the WDFY4 gene (62) may be associated with RP-ILD risk in anti-MDA5-DM; and if these relationships are replicated in additional studies, these biomarkers may be useful in improving RP-ILD risk stratification efforts in these patients.

3. Conclusion

In summary, IIM encompasses a varied spectrum of clinical disease that leads to significant adverse health impacts for patients. Recent advancements in the understanding of IIM epidemiology, in particular the use of specific MSAs to help risk-stratify patients, has improved clinicians’ ability to identify important clinical phenotypes and in turn to improve patient outcomes. Future work should build on this recent progress to close key knowledge gaps concerning the complex relationships between environmental (e.g. comorbidities, social determinants of health) and genetic risk factors for IIM incidence and disease progression; and should continue to incorporate increasingly diverse (e.g. racial/ethnic, SES) patient populations. Multi-disciplinary approaches leveraging novel causal inference and genetic epidemiologic methods may be especially helpful in further disentangling these relationships and identifying opportunities for therapeutic intervention.

Key points:

• IIM is a rare group of autoimmune diseases characterized by muscle weakness and systemic involvement, with incidence rates ranging from 0.2 to 2 cases per 100,000 person-years.

• The role of myositis-specific autoantibodies (MSAs) in stratifying disease risk and prognosis is increasingly recognized.

• Patients with IIM exhibit elevated risks of comorbidities, including cardiovascular disease and malignancy.

• Continued epidemiological research is essential to elucidate underlying mechanisms and inform future interventions, ultimately aiming to enhance the quality of life and clinical outcomes for affected patients.

Abbreviations:

anti-HMGCR

anti-3-hydroxy-3-methylglutaryl-coA reductase

anti-MDA5

anti-melanoma differentiation-associated gene 5

anti-NXP2

anti-nuclear matrix protein 2

anti-SAE

anti-small ubiquitin like modifier activating enzyme

anti-SRP

anti-signal recognition particle

anti-TIF1γ

anti-transcription intermediary factory 1γ (anti-TIF1γ)