What is the diagnosis and workup of antisynthetase syndrome?

Diagnosis and Workup of Antisynthetase Syndrome

Antisynthetase syndrome should be diagnosed through detection of anti-aminoacyl-tRNA synthetase antibodies combined with clinical manifestations from the classic triad of myositis, interstitial lung disease, and arthritis, along with supportive features including fever, mechanic's hands, and Raynaud phenomenon. 1

Clinical Presentation

The syndrome presents with six cardinal features that should be systematically assessed 1:

• Myositis: Symmetric proximal muscle weakness developing over weeks to months, manifesting as difficulty rising from chairs, climbing stairs, lifting objects overhead, and combing hair 1
• Interstitial lung disease (ILD): The most important feature and major determinant of morbidity and mortality 1
• Arthritis: Inflammatory polyarthritis affecting multiple joints, often seronegative 1
• Mechanic's hands: Roughened, cracked skin on the lateral and palmar aspects of fingers 2
• Raynaud phenomenon: Episodic vasospasm of digits 2
• Fever: Constitutional symptom often present at disease onset 2

Critical pitfall: Not all features need to be present simultaneously—the syndrome can begin with a single manifestation and evolve over time, with "ex-novo" occurrence of additional triad findings in approximately 30-70% of patients depending on antibody specificity 3

Serological Testing

Primary Antibody Panel

A complete myositis-specific antibody panel should be ordered in all suspected cases, as approximately 80% of patients will have at least one detectable antibody 1:

• Anti-Jo-1 (anti-histidyl-tRNA synthetase): Most common, found in approximately 20% of adult patients with idiopathic inflammatory myopathy 2, 1
• Anti-PL-7 (anti-threonyl-tRNA synthetase): Present in <5% of cases 2
• Anti-PL-12 (anti-alanyl-tRNA synthetase): Present in <5% of cases 2
• Anti-OJ (anti-isoleucyl-tRNA synthetase): Present in <5% of cases 2
• Anti-EJ (anti-glycyl-tRNA synthetase): Present in <5% of cases 2
• Anti-KS (anti-asparaginyl-tRNA synthetase): Present in <5% of cases 2
• Anti-Ha, Anti-Zo: Rare variants, each <1% 2

Additional Autoantibody Screening

To exclude other connective tissue diseases that can mimic antisynthetase syndrome, the following should be tested 2:

• Antinuclear antibodies (by immunofluorescence) 2
• Rheumatoid factor 2
• Anti-citrullinated cyclic peptide antibodies 2
• Anti-SSA/Ro and anti-SSB/La (if Sjögren syndrome suspected) 2
• Anti-Scl-70/topoisomerase-1, anti-centromere, anti-RNA polymerase III (if systemic sclerosis suspected) 2

Muscle Assessment

Biochemical Markers

• Creatine phosphokinase (CPK): Elevated levels are characteristic and reflect active muscle inflammation 1
• CPK elevation distinguishes myositis from polymyalgia rheumatica-like syndromes, where CK should be within normal limits 1
• Aldolase and myoglobin: Additional markers of muscle damage 2

Electromyography (EMG)

EMG should demonstrate characteristic myopathic changes with increased spontaneous activity, distinguishing true myositis from polymyalgia-like syndromes 1

Muscle Biopsy

When diagnosis remains uncertain after serological and EMG testing, muscle biopsy shows endomysial mononuclear cell infiltrate surrounding and invading nonnecrotic muscle fibers, causing muscle fiber necrosis and regeneration 2

Pulmonary Evaluation

High-Resolution Chest CT (HRCT)

HRCT should be performed to assess for interstitial lung disease patterns, which may show 2:

• Reticular abnormalities
• Ground-glass opacities
• Subpleural and basal predominance
• Honeycombing in advanced cases

Pulmonary Function Tests

Testing typically reveals a restrictive pattern with low diffusing capacity 2

Inflammatory Markers

Basic laboratory assessment should include 2:

• Differential blood cell count
• C-reactive protein
• Erythrocyte sedimentation rate
• Serum creatinine
• Transaminases, γ-glutamyltransferase, and alkaline phosphatases

Diagnostic Algorithm

1. Clinical suspicion: Identify presence of myositis, ILD, arthritis, or other cardinal features 1
2. Serological confirmation: Order complete antisynthetase antibody panel 1
3. Muscle involvement documentation: Obtain CPK levels and EMG 1
4. Pulmonary assessment: Perform HRCT and pulmonary function tests if ILD suspected 2
5. Exclusion of mimics: Test for other connective tissue disease antibodies 2
6. Tissue confirmation: Consider muscle biopsy if diagnosis remains uncertain despite positive antibodies 2

Important caveat: Antibody specificity only partially influences clinical presentation and evolution—anti-Jo-1 is most likely to present with the classic triad and includes more muscle and joint involvement than other antisynthetase antibodies, but all antibody types can present with variable manifestations 4, 3