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.
Additional immunosuppressive agents
Although glucocorticoids are considered the mainstay of treatment, additional immunosuppressive agents such as azathioprine and methotrexate are often required, both as glucocorticoid-sparing agents and to achieve adequate disease control.10 Addition of such agents from the outset is particularly necessary in patients with profound muscle weakness or those who have concomitant symptomatic interstitial lung disease.
No randomized controlled trial comparing azathioprine and methotrexate has been conducted to date. Therefore, the choice is based on patient preference, presence of coexisting interstitial lung disease or liver disease, commitment to limit alcohol consumption, and thiopurine methyltransferase status. Most patients need prolonged therapy.
In a randomized clinical trial, concomitant therapy with prednisone and azathioprine resulted in better functional outcomes and a significantly lower prednisone dose requirement for maintenance therapy at 3 years than with prednisone alone.43,44 Although no such randomized study has been conducted using methotrexate, several retrospective studies have demonstrated 70% to 80% response rates, including those for whom monotherapy with glucocorticoids had failed.45,46 The combination of methotrexate and azathioprine may be beneficial in patients who previously had inadequate responses to either of these agents alone.47
For severe pulmonary involvement associated with antisynthetase syndrome, monthly intravenous infusion of cyclophosphamide has been shown to be effective.48,49
Some recent studies established the role of tacrolimus in the treatment of both interstitial lung disease and myositis associated with antisynthetase syndrome.29 Cyclosporine has also been successfully used in a case of interstitial lung disease associated with anti Jo-1 syndrome.30
Rituximab, a monoclonal antibody to Blymphocyte antigen CD20, can also be used successfully in refractory disease,31 including refractory interstitial lung disease.32
In an open-label prospective study, polymyositis refractory to glucocorticoids and multiple conventional immunosuppressive agents responded well to high-dose intravenous immune globulin in the short term.50 However, the antisynthetase antibody status in this cohort was unknown; therefore, no definite conclusion could be drawn about the efficacy of intravenous immune globulin specifically in antisynthetase syndrome.
General measures
In patients with profound muscle weakness, physical therapy and rehabilitation should begin early. The goal is to reduce further muscle wasting from disuse and prevent muscle contractures. Patients with oropharyngeal and esophageal dysmotility should be advised about aspiration precautions and may need a swallow evaluation by a speech therapist; some may need temporary parenteral hyper-alimentation or J-tube insertion.
PROGNOSIS
If skeletal muscle involvement is the sole manifestation of antisynthetase syndrome, patients usually respond to glucocorticoids and immunosuppressive therapy and do fairly well. However, the outcome is not so promising when patients also develop interstitial lung disease, and the severity and type of lung injury usually determine the prognosis. As expected, patients with a progressive course of interstitial lung disease fare poorly, whereas those with a nonprogressive course tend to do relatively better. Older age at onset (> 60 years), presence of a malignancy, and a negative antinuclear antibody test are associated with a poor prognosis.7
Acknowledgment: The authors are grateful to Dr. Stephen Hatem, MD, staff radiologist, musculoskeletal radiology, Cleveland Clinic Imaging Institute, for help in the preparation of the magnetic resonance images. We also thank Dr. Steven Shook, MD, staff neurologist, Cleveland Clinic Neurological Institute, for help in summarizing the EMG findings.
