Antisynthetase syndrome: Not just an inflammatory myopathy
ABSTRACTIn recent years, antisynthetase syndrome has been recognized as an important cause of autoimmune inflammatory myopathy in a subset of patients with polymyositis and dermatomyositis. It is associated with serum antibodies to aminoacyl-transfer RNA synthetases and is characterized by a constellation of manifestations, including fever, myositis, interstitial lung disease, “mechanic’s hands,” Raynaud phenomenon, and polyarthritis. Physicians should be familiar with its variety of clinical presentations and should include it in the differential diagnosis in patients presenting with unexplained interstitial lung disease.
KEY POINTS
- Antisynthetase syndrome can present with a wide variety of clinical manifestations, including myositis and interstitial lung disease.
- The type and severity of interstitial lung disease usually determine the long-term outcome.
- In the appropriate clinical setting, the diagnosis is usually confirmed by the detection of antibodies to various aminoacyl-transfer RNA synthetases, anti-Jo-1 antibody being the most common.
- Although glucocorticoids are considered the mainstay of treatment, additional immunosuppressive agents such as azathioprine or methotrexate are often required as steroid-sparing agents and also to achieve disease control.
- In the case of severe pulmonary involvement, cyclophosphamide is recommended.
Pulmonary function testing
If antisynthetase syndrome is suspected or diagnosed, baseline pulmonary function testing (spirometry and carbon monoxide diffusion capacity) is indicated. It will often detect occult interstitial lung disease (reduced forced vital capacity and carbon monoxide diffusion capacity), and the diagnosis will be substantiated on thoracic high-resolution computed tomography. Respiratory muscle weakness can be detected with upright and supine spirometry.40 Weakness of these muscles contributes to shortness of breath, and patients may need ventilatory support.
Thoracic high-resolution computed tomography
Different patterns of lung injury can be seen in antisynthetase syndrome. Diffuse ground-glass opacification may suggest a nonspecific interstitial pneumonitis pattern, which is the most common form of interstitial lung disease (Figure 2), whereas coarse reticulation or honeycombing correlates with a usual interstitial pneumonitis pattern. Patchy consolidation or air-space disease can occur if cryptogenic organizing pneumonia is the predominant pattern of lung injury.
Swallowing evaluation
A comprehensive swallowing evaluation by a speech therapist may be necessary for evaluation of dysphagia (from oropharyngeal and striated esophageal muscle weakness) and determination of aspiration risk (Table 2).
Lung histopathology
If necessary, a surgical lung biopsy is needed to document the pathologic pattern of injury, including the amount of fibrosis in the lung. Historically, in idiopathic inflammatory myopathy patients in general, this has taken the form of usual interstitial pneumonia, organizing pneumonia, or diffuse alveolar damage.41 With the emergence of the definition of nonspecific interstitial pneumonitis and fibrosis as a documented and accepted pattern, more studies have found this to be the most common pattern of lung injury.16 It is characterized by diffuse involvement of the lung by an interstitial chronic inflammatory infiltrate, a cellular type of nonspecific interstitial pneumonitis that progresses in a uniform pattern to a fibrotic type (Figure 5). This form of fibrosis rarely results in significant remodeling, so-called honeycomb changes. In addition, anti-Jo-1 antibody patients may also have an increased incidence of acute lung injury, including acute diffuse alveolar damage that is often superimposed on the underlying chronic lung disease.42
In patients with pulmonary hypertension, histopathologic studies of the muscular pulmonary arteries often show moderate intimal fibroplasia, suggesting that a pulmonary arteriopathy with intimal thickening and luminal narrowing develops in some of these patients (Figure 5), independent of chronic hypoxic pulmonary vasoconstriction or vascular obstruction due to its entrapment within fibrotic lung tissue.17
TREATMENT
Glucocorticoids are the mainstay
Glucocorticoids are considered the mainstay of treatment. Patients should be advised that long-term use of glucocorticoids is necessary, though the response is variable. It is also important to discuss possible side effects of long-term glucocorticoid use.
Standard practice is to initiate treatment with high doses for the first 4 to 6 weeks to achieve disease control, followed by a slow taper over the next 9 to 12 months to the lowest effective dose to maintain remission. If the patient is profoundly weak, especially with respiratory muscle weakness or significant dysphagia and aspiration risk, hospital admission for intravenous methylprednisolone 1,000 mg daily for 3 to 5 days may be necessary. Otherwise, oral prednisone 1 mg/kg/day would be the usual starting dose.
If the patient’s muscle strength initially improves and then declines weeks to months later despite adequate therapy, glucocorticoid-induced myopathy should be suspected, especially if the muscle enzymes are within the reference range. This is more likely to occur if high-dose prednisone is continued for more than 6 to 8 weeks.
Improvement in muscle strength, which can take several weeks to several months, is a more reliable indicator of response to therapy than the serum creatine kinase level, which may take much longer to normalize. Relying on normalization of the creatine kinase level alone may lead to unnecessary prolongation of high-dose glucocorticoid therapy. It may take several months for the muscle enzymes to normalize, and there is usually a time lag between normalization of muscle enzymes and complete recovery of muscle strength.
Long-term use of high-dose prednisone leads to glucocorticoid-induced osteoporosis. Therefore, patients should receive osteoporosis prophylaxis including antiresorptive therapy with a bisphosphonate. In addition, prophylaxis against Pneumocystis jirovecii is indicated for patients treated with high-dose glucocorticoids.
