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Myositis: Laboratory Support for Classification and Diagnosis

Myositis: Laboratory Support for Classification and Diagnosis

Clinical Focus

Myositis

Laboratory Support for Classification and Diagnosis

    

Contents

Clinical Background

Individuals Suitable for Testing

Test Availability

Table 1: Laboratory Tests for Classification and Diagnosis of Myositis

Test Selection and Interpretation

Table 2: Diagnostic Criteria for Polymyositis and Dermatomyositis

Figure 1: Idiopathic Inflammatory Myopathy: Selecting the Appropriate Laboratory Tests

Figure 2: Interpretation of Myositis Specific Antibodies Panel (Test Code 94777)

References
 

Clinical Background [return to contents]

Myositis is a general inflammation of the muscles caused by muscle injury, cancer, drugs, infection, genetic defects, or autoimmune disease. The most severe forms of myositis are autoimmune diseases called the idiopathic inflammatory myopathies (IIMs), which include polymyositis, dermatomyositis, inclusion body myositis (IBM), and necrotizing myopathy (NM). Because these are systemic diseases, affected individuals may exhibit extramuscular symptoms such as skin rashes, lung disease, joint pain, arthritis, Raynaud phenomenon, and "mechanic's hands."1

Idiopathic inflammatory myopathies are relatively rare causes of myositis, with a prevalence of fewer than 33 cases per 100,000 individuals in the United States.2 Polymyositis is the predominant type of IIM in adults, whereas dermatomyositis is predominant in children (juvenile dermatomyositis). Polymyositis and dermatomyositis are more often observed in women, whereas IBM is more often diagnosed in middle-aged men. NM is mostly associated with use of statin drugs, but is also observed in statin-naïve patients.3,4

Polymyositis and dermatomyositis commonly overlap with other autoimmune connective tissue diseases, such as systemic lupus erythematosus (SLE), Sjögren syndrome, systemic sclerosis, and rheumatoid arthritis.5 Although generally thought to be less severe in these overlap syndromes, myositis symptoms may be similar in intensity to, or worse than, those of primary myositis.6

The differential diagnosis of IIMs and overlap myositis begins with the exclusion of muscular dystrophy and myopathies of known cause (eg, infectious, metabolic, drug-induced, or neurologic). Diagnosis is aided by imaging, electromyography, biopsy, testing levels of muscle enzymes in serum, and the detection of myositis-specific and myositis-associated antibodies. In addition, the detection of certain antibodies may have prognostic value. This Clinical Focus provides information on the available laboratory tests and their use.

Owing to overlapping features and phenotypes associated with a given antibody, test results should be interpreted carefully in light of clinical and other laboratory data.

Individuals Suitable for Testing [return to contents]

  • Individuals with symptoms of IIM (eg, unexplained muscle weakness, rash, evidence of systemic disease)

Test Availability [return to contents]

Quest Diagnostics offers tests and panels that may be useful for classifying or diagnosing myositis. Table 1 is provided for informational purposes only and is not intended as medical advice. A physician's test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

Table 1. Laboratory Tests for Classification and Diagnosis of Myositis

Test Code

Test Name

Clinical Use

227

Aldolase

Diagnose PM/DM

374

Creatine Kinase (CK), Total

Diagnose PM/DM

5810(X)

Jo-1 Antibody

Diagnose PM/DM

593

Lactate Dehydrogenase (LD) 

Diagnose PM/DM

90995a

Myositis AssessRTM

Includes PL-7 (test code 90996), PL-12 (test code 90997), Mi-2 (test code 17172), Ku (test code 18855), EJ (test code 90998), OJ (test code 90999), and SRP (test code 16318)

Diagnose PM/DM

10185(X)a

Myositis AssessRTM plus Jo-1 Antibodies

Includes PL-7 (test code 90996), PL-12 (test code 90997), Mi-2 (test code 17172), Ku (test code 18855), EJ (test code 90998), OJ (test code 90999), SRP (test code 16318), and Jo-1 (test code 5810) antibodies

Diagnose PM/DM (Jo-1 provides a more definitive diagnosis)

94777b

Myositis Specific 11 Antibodies Panel

Includes autoantibodies for  EJ, Jo-1, MDA-5, Mi-2α, Mi-2β, NXP-2, OJ, PL-7, PL-12, SRP,  and TIF1-γ

Diagnose PM/DM (Jo-1 provides a more definitive diagnosis)
Diagnose NM
Diagnose cancer-associated DM
Diagnose juvenile DM
Diagnose amyopathic DM

94646

Anti-PM/Scl-100 Antibody, EIA

Diagnose overlap of PM/ DM with systemic sclerosis

18855

Ku Autoantibodies

Diagnose overlap of PM with SLE or systemic sclerosis

38568

Sjögren's Antibody (SS-A)

Diagnose overlap of PM/DM with Sjögren syndrome, SLE, or systemic sclerosis

38567

Sm/RNP Antibody

Diagnose overlap of PM with SLE or systemic sclerosis

DM, dermatomyositis; PM, polymyositis; NM, necrotizing myopathy; SLE, systemic lupus erythematosus

a

Panel components may be ordered separately.

b

This test was developed and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the U.S. Food and Drug Administration. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes.

Test Selection and Interpretation [return to contents]

Idiopathic Inflammatory Myopathies

Validated diagnostic criteria for IIM do not exist. However, the Bohan and Peter criteria7 (Table 2) are commonly used for diagnosis of polymyositis and dermatomyositis. These criteria are also supported by the International Myositis Assessment and Clinical Studies Group for enrollment of patients in clinical trials.8 Laboratory testing for muscle enzymes (creatine kinase, aldolase, transaminases, lactate dehydrogenase) can assist with diagnosis according to Bohan and Peter criteria. On initial evaluation, about 80% to 90% of myositis patients have elevated creatine kinase (CK) associated with muscle damage.9

Table 2. Diagnostic Criteria for Polymyositis and Dermatomyositis7

Classify patient as having definite dermatomyositis if ≥3 of the following criteria and rasha are present.b
Classify patient as having definite polymyositis if all 4 of the following criteria (without rasha) are present.b

Criteria

  1. Progressive proximal muscle weakness
  2. Elevated muscle enzyme levels in serum (creatine kinase, aldolase, transaminases, lactate dehydrogenase)
  3. Abnormal electrical activity on electromyography (polyphasic, short, and small action potentials; fibrillations, positive sharp waves, and insertional irritability; high-frequency repetitive discharges)
  4. Muscle biopsy findings consistent with polymyositis or dermatomyositis (necrosis, phagocytosis, regeneration, inflammation)

a

Heliotrope rash, Göttron sign, or Göttron papules.

b

Classify patient as having probable dermatomyositis if 2 of the criteria and rash are present; classify patient as having probable polymyositis if 3 of the criteria (without rash) are present.

Using elevated CK to diagnose IIMs has limitations, however. CK levels may be only slightly elevated, or normal, due to lack of muscle mass or the presence of circulating CK inhibitors or CK antibodies.10 Normal CK levels may also be observed in patients with IBM, as well as those with juvenile or amyopathic dermatomyositis (see below). Another limitation is that CK and other muscle enzymes are not specific markers of polymyositis/dermatomyositis. Serum elevations may be due to other types of muscle disease (muscular dystrophies, rhabdomyolysis), hypothyroidism, cardiac diesease, or liver disease. Consequently, tests employing antibody markers, rather than muscle enzymes, are used to specifically diagnose and classify IIMs.

Autoantibodies can be detected in approximately 50% of patients with polymyositis/dermatomyositis (Figures 1 and 2).1 The classical myositis-specific antibodies, which are often mutually exclusive, include the synthetase (Jo-1, EJ, OJ, PL-7, PL-12) antibodies and Mi-2 and SRP antibodies.1 Jo-1 antibody is observed in 21% of patients with polymyositis and in 11% of those with dermatomyositis.1 It is 100% specific for polymyositis/dermatomyositis.11,12 Thus, the International Myositis Classification Criteria Project includes Jo-1 positivity as a major contributor to a definitive IIM diagnosis.13 The remaining classical myositis-specific antibodies occur less frequently than Jo-11 but are also highly specific (97% to 100%) for polymyositis/dermatomyositis.11,14,15 Accordingly, a positive test result for any of the classical myositis-specific antibodies is highly suggestive of polymyositis or dermatomyositis (with rash, Table 2).  A negative test result does not rule out either polymyositis or dermatomyositis, however, as classical myositis-specific antibodies are not detected in 50% of patients with these IIMs.

Figure 1. Idiopathic Inflammatory Myopathy: Selecting the Appropriate Laboratory Tests

Figure 2. Interpretation of Myositis Specific Antibodies Panel (Test Code 94777)

The type of myositis-specific antibody detected correlates with clinical phenotype, disease severity, and treatment response. The presence of a synthetase antibody is associated with "antisynthetase syndrome," which is characterized by arthritis, mechanic's hand, fever, Raynaud phenomenon, myositis, and interstitial lung disease. The syndrome is commonly observed in both polymyositis and dermatomyositis patients.1 Mi-2 antibodies are associated with dermatomyositis rash, while SRP antibodies are associated with severe disease onset and a worse prognosis.6,8,9 In addition, SRP antibodies are also highly associated with NM.3 Detection of an SRP antibody thus suggests a need for more aggressive treatment.6,8,9 Detection of an Mi-2 antibody suggests that the patient may respond well to standard immunosuppressive therapy, whereas patients with antisynthetase syndrome typically have a moderate response.8

Myositis-associated antibodies (Ku, PM/Scl , Sjögren's antibody [SS-A], and Smith [Sm]/U1-RNP antibody) are less specific for polymyositis and dermatomyositis and are found in 1% to 13% of these patients.1 Ku and SS-A are found in 9% to 14% of IBM patients, who otherwise have low, or undetectable, myositis-specific or associated antibodies (≤3% of patients).1 Thus, a positive test result for a myositis-associated antibody in a symptomatic patient suggests the presence of either polymyositis, dermatomyositis (with rash), or IBM; overlap myositis is also a possibility (discussed below).

Cancer- and Juvenile-associated Dermatomyositis

Additional myositis-specific antibodies include TIF1-γ (p155) and NXP-2 (p140) antibodies, which are prevalent in adults with cancer-associated dermatomyositis and children with juvenile dermatomyositis.

In adults with dermatomyositis, TIF1-γ antibody has a sensitivity of 78% and a specificity of 89% for cancer.16 NXP-2 is detected in 31% of adults with cancer-associated adult dermatomyositis and, when combined with TIF1-γ measurement, improves the sensitivity for detecting cancer.17 Positive test results for either TIF1-γ or NXP-2 antibodies identify cancer in 83% of adults with dermatomyositis and are thus highly suggestive of malignancy.17

TIF1-γ can be detected in 35% of children with juvenile dermatomyositis, making it the most prevalent myositis-specific antibody among this group.18 NXP-2 is also prevalent, detected in 22% of these patients.18 Classical myositis-specific antibodies are generally far less prevalent in children, so including both TIF1-γ and NXP-2 in the panel improves sensitivity for juvenile dermatomyositis over the classical myositis-specific antibodies alone.18

Unlike in adults, TIF1-γ antibody is not associated with cancer in children.19 However, the presence of NXP-2 is highly associated with disease severity and calcinosis, which affects nearly one-third of patients with juvenile dermatomyositis and is a major cause of morbidity in this group.19

Amyopathic Dermatomyositis

MDA-5 antibody, another myositis-specific antibody, is prevalent in patients with clinically amyopathic dermatomyositis. These patients have rashes in the absence of clinical myositis. The presence of MDA-5 antibody is associated with a high likelihood of interstitial lung disease. Dermatomyositis patients with interstitial lung disease typically have a poorer prognosis because of rapid disease progression. A positive result for the MDA-5 antibody suggests that the patient is more than 18 times as likely to have interstitial lung disease as those who test negative.20 Early detection of interstitial lung disease by identifying the MDA-5 antibody may improve prognosis by prompting intensive immunosuppressive therapy early in the disease.21

Overlap Myositis

Myositis-associated autoantibodies are most often detected in patients with overlap myositis syndromes. Ku, PM/Scl, Sm/RNP, and SS-A antibodies are found in 13% to 32% of these patients.1 A positive result for the PM/Scl antibody suggests overlap of polymyositis (or dermatomyositis with rash) with systemic sclerosis. Ku or Sm/RNP antibodies suggest overlap with SLE or systemic sclerosis. The presence of Sjögren's antibody suggests overlap with SLE, Sjögren syndrome, or systemic sclerosis (Table 1).22

References [return to contents]

  1. Lega JC, Fabien N, Reynaud Q, et al. The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome. Autoimmun Rev. 2014;13:883-891.

  2. Meyer A, Meyer N, Schaeffer M, et al. Incidence and prevalence of inflammatory myopathies: a systematic review. Rheumatology (Oxford). 2015;54:50-63.

  3. Suzuki S, Nishikawa A, Kuwana M, et al. Inflammatory myopathy with anti-signal recognition particle antibodies: case series of 100 patients. Orphanet J Rare Dis. 2015;10:61. doi:10.1186/s13023-015-0277-y

  4. Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum. 2012;64:4087-4093.

  5. Iaccarino L, Gatto M, Bettio S, et al. Overlap connective tissue disease syndromes. Autoimmun Rev. 2013;12:363-373.

  6. Garton MJ, Isenberg DA. Clinical features of lupus myositis versus idiopathic myositis: a review of 30 cases. Br J Rheumatol. 1997;36:1067-1074.

  7. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292:344-347.

  8. Oddis CV, Rider LG, Reed AM, et al. International consensus guidelines for trials of therapies in the idiopathic inflammatory myopathies. Arthritis Rheum. 2005;52:2607-2615.

  9. Nagaraju K, Lundberg IE. Inflammatory diseases of muscle and other myopathies. In: Firestein GS, Budd RC, Gabriel SE, et al, eds. Kelley's Textbook of Rheumatology. Philadelphia, PA: Elsevier/Saunders; 2013:1404-1430.

  10. Volochayev R, Csako G, Wesley R, et al. Laboratory test abnormalities are common in polymyositis and dermatomyositis and differ among clinical and demographic groups. Open Rheumatol J. 2012;6:54-63.

  11. Hengstman GJ, van Brenk L, Vree Egberts WT, et al. High specificity of myositis specific autoantibodies for myositis compared with other neuromuscular disorders. J Neurol. 2005;252:534-537.

  12. Vazquez-Abad D, Rothfield NF. Sensitivity and specificity of anti-Jo-1 antibodies in autoimmune diseases with myositis. Arthritis Rheum. 1996;39:292-296.

  13. Pilkington C, Tjärnlund A, Bottai M, et al. Progress report on the development of new classification criteria for adult and juvenile idiopathic inflammatory myopathies [Pediatric Rheumatology Symposium abstract A47]. Arthritis Rheum. 2014;66:S70-S71.

  14. Aggarwal R, Oddis CV, Goudeau D, et al. Anti-signal recognition particle autoantibody ELISA validation and clinical associations. Rheumatology (Oxford). 2015;54:1194-1199.

  15. Nakashima R, Imura Y, Hosono Y, et al. The multicenter study of a new assay for simultaneous detection of multiple anti-aminoacyl-tRNA synthetases in myositis and interstitial pneumonia. PLoS One. 2014;9:e85062. doi.org/10.1371/journal.pone.0085062

  16. Trallero-Araguas E, Rodrigo-Pendas JA, Selva-O'Callaghan A, et al. Usefulness of anti-p155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis. Arthritis Rheum. 2012;64:523-532.

  17. Fiorentino DF, Chung LS, Christopher-Stine L, et al. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1gamma. Arthritis Rheum. 2013;65:2954-2962.

  18. Shah M, Mamyrova G, Targoff IN, et al. The clinical phenotypes of the juvenile idiopathic inflammatory myopathies. Medicine (Baltimore). 2013;92:25-41.

  19. Tansley S, Wedderburn LR. Comparing and contrasting clinical and serological features of juvenile and adult-onset myositis: implications for pathogenesis and outcomes. Curr Opin Rheumatol. 2015;27:601-607.

  20. Zhang L, Wu G, Gao D, et al. Factors associated with interstitial lung disease in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis. PLoS One. 2016;11:e0155381. doi.org/10.1371/journal.pone.0155381

  21. Nakashima R, Hosono Y, Mimori T. Clinical significance and new detection system of autoantibodies in myositis with interstitial lung disease. Lupus. 2016;25:925-933.

  22. Peng SL, Craft JE. Antinuclear antibodies. In: Firestein GS, Budd RC, Gabriel SE, et al, eds. Kelley's Textbook of Rheumatology. Philadelphia, PA: Elsevier/Saunders; 2013:789-803.
     

 

Content reviewed 07/2017

 
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* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.