Inflammatory Myopathies

 

Inflammatory myopathies (also referred to collectively as myositis) are a heterogeneous group of chronic autoimmune disorders characterized by inflammation of muscles and diverse clinical manifestations, with variable risk for organ involvement and cancer and variable response to treatment.   The disorders can be categorized into the following main subtypes, namely, polymyositis (PM), which may also be referred to as antisynthetase syndrome; dermatomyositis (DM); necrotizing autoimmune myositis (NAM); overlap myositis (myositis associated with other connective tissue diseases); and inclusion-body myositis (IBM).   Accurate diagnosis is critical for appropriate treatment, to determine prognosis, and to prevent complications, but can be challenging because of the possible multisystem involvement as well as the varied and overlapping presentations among subtypes.  Diagnosis involves clinical examination (particularly of patterns of muscle weakness), evaluation of the muscles using imaging and electromyography, laboratory tests for specific autoantibodies, and often, histologic analysis of biopsied muscle tissue.  Identification of specific autoantibodies can help to determine the disease subtype.  Other laboratory tests used to evaluate patients include creatine kinase (CK), alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) tests. 

Quick Answers for Clinicians

What clinical manifestations are associated with the main types of inflammatory myopathies?

For most subtypes, the clinical manifestations in an individual patient will vary depending on the particular autoantibodies present. Polymyositis (PM) is marked by proximal symmetric muscle weakness and includes antisynthetase syndrome, which is associated with features such as interstitial lung disease (ILD), Raynaud syndrome, arthritis, or hyperkeratotic lesions on their fingers (mechanic’s hands).  Dermatomyositis (DM) is associated with proximal muscle weakness and skin manifestations, but muscles are unaffected in some patients. In addition, DM is associated with cancer risk, lung involvement, and variable response to treatment. Necrotizing autoimmune myositis (NAM) manifests with proximal muscle weakness of the arms and legs in conjunction with markedly high muscle enzyme concentrations and some level of necrosis; some patients may have lung involvement.  Overlap myositis is associated with other connective tissue diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), or Sjögren syndrome (SjS). Inclusion-body myositis (IBM) is typically seen in patients older than 50 years and presents with gradually progressive distal weakness, which can occur asymmetrically, and knee extensor weakness; some patients may have progressive dysphagia.  All myositis subtypes except IBM are associated with an increased risk for malignancy.  This risk is highest in DM, in association with anti-TIF-1 gamma or anti-NXP-2 antibodies, and in NAM, in association with anti-HMGCR antibodies.  Refer to the Inflammatory Myopathy Subtypes, Associated Antibodies, and Clinical Characteristics table for additional details about clinical characteristics of subtypes.

What risk factors are associated with inflammatory myopathies?

Various genetic and environmental factors are thought to increase risk for inflammatory myopathies. Implicated factors include ultraviolet [UV] light exposure,  previous infections (eg, pneumonia, gastrointestinal infections, and fungal infections), and respiratory tract disease (eg, chronic obstructive pulmonary disease, asthma, and interstitial lung disease [ILD]).   Statin exposure is associated with necrotizing autoimmune myositis (NAM).  Some genetic characteristics that seem to confer risk for inflammatory myopathies include the human leukocyte antigen (HLA) 8.1 haplotype (in several subtypes), TIF1 variants (in dermatomyositis [DM]), FYCO1 variants (in inclusion-body myositis [IBM]), HLA DRB1*08:03 and DRB1*11:01 (in NAM), and PTPN22 variants (in polymyositis [PM]). 

How do inflammatory myopathies differ in children, and do diagnostic approaches differ in pediatric versus adult patients?

Pediatric or juvenile inflammatory myopathies are those in which the first symptom thought to be associated with the disease occurs before 18 years of age.  Specific pediatric inflammatory myopathies are juvenile dermatomyositis (JDM), which is most common, and juvenile polymyositis (JPM); other more rare forms include necrotizing autoimmune myositis (NAM) and overlap myositis, among others.  Pediatric patients with inflammatory myopathies are less likely to have interstitial lung disease (ILD) or malignancy and generally have lower mortality rates.  Unlike in adults, muscle biopsy is performed infrequently to diagnose inflammatory myopathies in children, in part because JDM, the most common pediatric inflammatory myopathy, presents with characteristic skin manifestations and generally does not require biopsy.  Because biopsy is often not performed in children, the classification system for children and adults developed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) enables a score to be calculated with or without biopsy data. (Refer to the EULAR/ACR Classification Criteria for Adult and Pediatric Inflammatory Myopathies table.)

Indications for Testing

Laboratory testing for inflammatory myopathies is appropriate in individuals with progressive muscle weakness, particularly in patients with muscular, cutaneous, pulmonary, and articular manifestations,  after more common etiologies have been ruled out.

Criteria for Diagnosis

The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) published updated classification criteria for inflammatory myopathies in 2017.  These criteria, presented in the following table, were intended to improve on the sensitivity and specificity of the 1975 Bohan and Peter criteria, help differentiate inflammatory myopathies from conditions with similar presentations, and distinguish the primary inflammatory myopathy subtypes.  An online calculator  is available to aid in use of the criteria.

EULAR/ACR Classification Criteria for Adult and Pediatric Inflammatory Myopathies
Category Characteristic Score (with Data from Muscle Biopsy)a Score (without Data from Muscle Biopsy)b

Laboratory findings

Anti-Jo-1 autoantibody present

3.8

3.9

Increased serum concentrations (above ULN) of CK, LDH, AST, or ALT

1.4

1.3

Age of onset of first symptom thought to be disease related

18-<40 yrs

1.5

1.3

≥40 yrs

2.2

2.1

Pattern of muscle weakness

Symmetric, often progressive; affects upper proximal extremities

0.7

0.7

Symmetric, often progressive; affects lower proximal extremities

0.5

0.8

Greater weakness in neck flexors than in neck extensors

1.6

1.9

Greater weakness in proximal leg muscles than in distal leg muscles

1.2

0.9

Skin manifestations

Heliotrope rash

3.2

3.1

Gottron papules

2.7

2.1

Gottron sign

3.7

3.3

Other clinical features

Dysphagia, esophageal dysmotility

0.6

0.7

Muscle biopsy features

Endomysial infiltration of mononuclear cells that surrounds but does not invade myofibers

1.7

n/a

Perimysial or perivascular infiltration of mononuclear cells

1.2

n/a

Perifascicular atrophy

1.9

n/a

Rimmed vacuoles

3.1

n/a

aWith data from biopsy, a score of <6.5 excludes idiopathic inflammatory myopathy, a score of 6.7 to <8.7 suggests probable idiopathic inflammatory myopathy, and a score ≥8.7 indicates definite idiopathic inflammatory myopathy.

bWith no data from biopsy, a score of <5.3 excludes idiopathic inflammatory myopathy, a score of 5.5 to <7.5 suggests probable idiopathic inflammatory myopathy, and a score ≥7.5 indicates definite idiopathic inflammatory myopathy.

n/a, not applicable; ULN, upper limit of normal

Sources: Oldroyd, 2018 ; Lundberg, 2017 

Identification of the particular inflammatory myopathy subtype can be performed only in cases of a diagnostic probability of >55% (corresponding to a EULAR/ACR score of 5.5 without biopsy data or 6.7 with biopsy data), per the EULAR/ACR criteria.   Refer to the Inflammatory Myopathy Subtypes, Associated Antibodies, and Clinical Characteristics table for additional details about clinical features of subtypes.

Laboratory Testing

Diagnosis

Laboratory testing for inflammatory myopathies includes a variety of tests, such as tests for muscle enzymes, antinuclear antibodies (ANAs), and myositis-related antibodies.

Muscle Enzyme Tests

Creatine kinase (CK) concentrations are increased in most patients with inflammatory myopathies; in many cases, CK elevations will be 10- to 50-fold.  The highest CK levels are associated with NAM and can be >50 x ULN in early, active disease.  However, the concentration of CK in serum corresponds to the extent of muscle necrosis; therefore, CK concentrations may be within normal ranges for inflammatory myopathy subtypes associated with less necrosis and in patients with limited muscle mass, including those with advanced myositis that has already resulted in muscle wasting.  Patients with other signs of myositis but normal CK levels should undergo further evaluation.

Serum concentrations of other muscle enzymes above the ULN, including AST, ALT, and LDH, also may help support a diagnosis of inflammatory myopathies and are included in the EULAR/ACR classification criteria. 

Antinuclear Antibody Tests

Testing for antinuclear antibodies (ANAs) using HEp-2 substrate immunofluorescent antibody (IFA) testing can be helpful to identify individuals at risk for connective tissue diseases (CTDs) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren syndrome (SjS), mixed connective tissue disease (MCTD), or CTD overlap syndromes. The presence of a specific HEp-2 IFA pattern may help determine the type of confirmatory test(s) needed to aid in diagnosis. However, the performance of ANA tests in inflammatory myopathies is not well established due to variability in the interpretation and reporting of HEp-2 IFA ANA patterns. Refer to the Antinuclear Antibody Disease Testing Algorithm for more information about ANA testing.

Myositis-Related Antibody Tests

Although anti-Jo-1 antibodies are the only antibodies included in the 2017 EULAR/ACR classification criteria, a number of other antibodies have been found to be useful in the evaluation of inflammatory myopathies.  Particular subtypes, associated antibodies, and related clinical manifestations are presented in the following table.

Inflammatory Myopathy Subtypes, Associated Antibodies, and Clinical Characteristics
Disease CK Concentration Age of Onset Associated Autoantibodies Clinical-Antibody Associations

PM

High

Can affect adults and children

Anti-Jo-1a

Anti-PL7a

Anti-PL12a

EJ

OJ

Also includes antisynthetase syndrome

Mild/moderate muscle involvement, ILD, possible mild skin involvement (in ~50% of cases), mechanic’s hands, Raynaud syndrome

DM

Normal or high CK

Affects adults and children

Anti-Mi2

Mild/moderate muscle involvement, classical skin rash

Anti-NXP2

Mild/moderate muscle involvement, myalgia, classical skin rash, calcinosis, distal extensor weakness, edema, dysphagia, increased malignancy risk

Anti-TIF1 (p155/140)

Mild muscle involvement, notable skin involvement, occasionally presents as amyopathic DM; significant malignancy association

Anti-SAE

Mild/moderate muscle involvement, classical skin rash

Anti-MDA5

No muscle involvement, notable skin involvement (amyopathic DM or hypomyopathic DM), occasionally presents with severe and rapidly progressive ILD

Antibody negative

Mild/moderate muscle involvement, classical skin rash

NAM

Very high CK (can be >50 x ULN); elevations may persist despite treatment

More often seen in adults

Anti-HMGCR

Significant muscle involvement; associated with statin exposure; also associated with increased malignancy

Anti-SRP

Significant muscle involvement, dysphagia; 20% of patients have lung involvement without skin lesions

Antibody negative

Significant malignancy association

Overlap myositis other than PM or antisynthetase syndrome

High

Can affect adults and children

Anti-PM/Scl

Characteristics of mild myositis and SSc, muscle weakness, ILD, skin involvement

Anti-Ku

SLE, mild muscle involvement, ILD

Anti-U1RNP

Characteristics of mild myositis, SSc, and SLE; possible glomerulonephritis and pulmonary hypertension

IBM

Lower CK; normal CK concentrations are not uncommon

Adults, usually >50 yrs

Anti-CN1A (low specificity)

Marked distal and quadriceps involvement; muscle involvement can be asymmetric; disease progresses slowly and is treatment refractory

aOther antibodies associated with antisynthetase syndrome include anti-Ha, anti-Z0, and anti-Ks. 

ILD, interstitial lung disease

Source: Selva-O-Callaghan, 2018 ; Schmidt, 2018 ; Dalakas, 2015 ; Mammen, 2011 ; Huber, 2018 ; Meyer, 2019 

Other Testing

Muscle Biopsy

Other testing for inflammatory myopathies includes histopathologic anaylsis of biopsied muscle tissue (refer to the previous EULAR/ACR Classification Criteria for Adult and Pediatric Inflammatory Myopathies table). A muscle biopsy, although not always performed in cases of DM, is generally considered to improve diagnostic accuracy.  Biopsy results help to identify the form of myositis and can be useful for prognosis. 

Electroneuromyography

Electroneuromyography is not included in the current EULAR/ACR criteria and has limited usefulness in cases of severe muscle loss. However, electroneuromyography is suggested as a means of excluding motor neuron disease and other conditions that may affect the neuromuscular junction, such as myasthenia gravis. 

Imaging

Although imaging studies are not specifically included in the most recent EULAR/ACR criteria for diagnosis, findings from imaging, including magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography (CT) can be an adjunct to other diagnostic tools to help classify the disease, evaluate disease activity, and assess the amount of tissue damage. 

Assessment for Associated Complications

Adult patients with inflammatory myopathies should be evaluated for malignancy due to an increased risk associated with all inflammatory myopathies other than IBM.  Cancer is among the leading causes of death in patients with inflammatory myopathies.  Laboratory tests that may help in an initial assessment for malignancy may include urinalysis for utero/renal cancer, CA 125 for ovarian cancer, or stool testing for occult blood to screen for colorectal cancer.

In addition to cancer, lung disease and cardiac involvement are leading causes of death in patients with inflammatory myopathies, and patients should be evaluated for these complications.  Troponin I assays can help identify cardiac involvement, and troponin I levels also correspond to the degree of skeletal muscle involvement.  Refer to the ARUP Consult Acute Coronary Syndrome topic for more information about troponin I testing. The ARUP Consult Interstitial Lung Diseases topic provides additional information about this lung disease that is associated with autoimmune conditions.

Monitoring

The International Myositis Assessment and Clinical Studies Group and EULAR/ACR recommend that patients with inflammatory myopathies undergo monitoring of muscle enzyme levels, in addition to regular assessment of overall physical activity, muscle strength, functional impairment, and extramuscular disease activity.  A number of clinical and functional assessment tools, such as the Adult Myopathy Assessment Tool and the Cutaneous Dermatomyositis Disease Area and Severity Index, are available for use in monitoring patients with particular inflammatory myopathies. 

ARUP Laboratory Tests

Muscle Enzyme Tests
ANA Panel Tests

Preferred ANA screening test for connective tissue diseases

Positive nuclear patterns reported include homogeneous, speckled, centromere, nucleolar, or nuclear dots; positive cytoplasmic patterns reported include reticular/AMA, discrete/GW body-like, polar/golgi-like, rods and rings, or cytoplasmic speckled patterns

Aids in initial diagnosis of connective tissue disease

The ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, Smith/RNP, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

ANA ELISA assays have been reported to have lower sensitivities than ANA IFA for connective tissue diseases

Initial screen for autoimmune connective tissue diseases

One or more reflexive tests may be added, depending on the ANA pattern detected

Myositis-Related Antibody Panel Tests

May be useful for evaluation of patients with progressive proximal muscle weakness and/or cutaneous manifestations suggestive of DM and/or associated connective tissue disease

Components: Jo-1, PL-7, PL-12, EJ, SRP, OJ, Mi-2, P155/140, SAE1, MDA5, NXP-2, and TIF1-gamma (TIF1-γ) antibodies

May be useful for evaluation of patients with progressive proximal muscle weakness and antisynthetase syndrome

Components: Jo-1, PL-7, PL-12, EJ, SRP, and OJ antibodies

May be useful for evaluation of patients with characteristic cutaneous manifestations of DM with or without muscle weakness

Components: Mi-2, P155/140, SAE1, MDA5, NXP-2, and TIF1-γ antibodies

May be useful in the differential evaluation of PM, DM, NAM, or overlap syndromes associated with connective tissue disease

Components: SSA 52 and 60 (Ro), SM/RNP (U1) (ENA), Jo-1, Mi-2, PL-7, PL-12, P155/140, EJ, Ku, SRP, OJ, SAE1, MDA5, NXP-2, TIF1-γ, fibrillarin (U3 RNP), and PM/Scl-100 antibodies

May be useful for evaluation of interstitial lung disease in the context of connective tissue disease

Components: SSA 52 and 60 (Ro), Scl-70, Jo-1, PL-7, PL-12, EJ, Ku, SRP, OJ, PM/Scl-100, MDA5, NXP-2, rheumatoid factor, cyclic citrullinated peptide (CCP), ANA antibodies, and RNA polymerase III antibody, IgG

Individual Myositis-Related Antibody Tests

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