NORD gratefully acknowledges Frederick W. Miller, MD, PhD, Chief, Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, for assistance in the preparation of this report.
Antisynthetase syndrome is a rare, chronic disorder that can affect multiple systems of the body. The disorder is immune-mediated, which means there is inflammation resulting from abnormal functioning of the immune system and the presence of specific autoantibodies that target a specific protein in the body. The symptoms and severity of the disorder can vary greatly among affected individuals. Common symptoms include inflammation of the muscles (myositis), inflammation of several joints (polyarthritis), interstitial lung disease, thickening and cracking of the skin of the hands, and a condition called Raynaud phenomenon, in which the fingers or toes are numb or have a prickly sensation in response to cold. Affected individuals also have nonspecific symptoms like fatigue, unexplained fevers, and unintended weight loss. The exact, underlying cause is not fully understood. Antisynthetase syndrome sometimes occurs along with other conditions such as uncommon inflammatory muscle diseases like dermatomyositis or polymyositis.
The signs and symptoms can vary greatly from one person to another. Every person is unique and how the disorder will affect them can be very different. Symptoms can develop rapidly. Affected individuals will usually not have all of the symptoms discussed below. For example, some affected individuals will have little muscle involvement, but prominent signs of lung disease. Muscle disease, interstitial lung disease, and arthritis are generally considered the three main symptoms of this disorder (classic triad), but they may not develop at the same time.
Antisynthetase syndrome can affect the muscles. Muscle inflammation (myositis), muscle pain (myalgia), and muscle stiffness is common. These abnormalities can lead to muscle weakness. Inflammation of several joints of the body (polyarthritis) may also occur. Polyarthritis is associated with pain and stiffness of the affected joints. The surrounding bone is not affected (non-erosive arthritis).
Some individuals develop interstitial lung disease, which is characterized by progressive inflammation and scarring of the lungs, particularly of the tissue and space around the tiny air sacs, or alveoli. This area is called the interstitium. This can lead to shortness of breath, coughing, and difficulty swallowing (dysphagia). In some instances, progressive damage to the lungs can lead to respiratory insufficiency (when the lungs cannot deliver sufficient levels of oxygen to the body) and, eventually, life-threatening respiratory failure.
Nonspecific symptoms can also occur including unexplained fevers, fatigue, loss of appetite, unintended weight loss, and skin rashes including a heliotropic rash, a distinctive reddish-purple rash on the upper eyelid or across the cheeks and bridge of the nose in a ‘butterfly’ pattern. Thickening and cracking (fissuring) and discoloration of the skin of the hands, called mechanic’s hands) can also occur. Some individuals develop pain and numbness or a prickly feeling in the fingers and toes in response to cold (Raynaud phenomenon). During a Raynaud episode, the fingers or toes may turn white or blue.
The exact cause of antisynthetase syndrome is not fully understood. Affected individuals have autoantibodies. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Autoantibodies are ones that mistakenly attack healthy tissue. In antisynthetase syndrome, affected individuals have autoantibodies that target certain enzymes in the body called aminoacyl-tRNA synthetases. Enzymes are specialized proteins that help to bring about specific biochemical reactions in the body and aminoacyl-tRNA synthetases help to regulate the production of other proteins and are important for the overall health and function of the body. Researches do not know why these autoantibodies targets aminoacyl-tRNA synthetase. Not every person who develops these autoantibodies will go on to develop symptoms of antisynthetase syndrome.
The exact role these autoantibodies play in the development of antisynthetase syndrome is not fully understood. The autoantibodies that have identified in this disorder include anti-Jo1, anti-EJ, anti-OJ, anti-PL7, anti-PL12, anti-SC, anti-KS, anti-JS, anti-HA, anti-YRS, anti-tryptophanyl, and anti-Zo. Anti-Jo1 is the most common autoantibody in individuals with antisynthetase syndrome.
Some autoantibodies are more likely to be associated with specific symptoms. Muscle disease occurs more often with anti-Jo1 or anti-PL7. Interstitial lung disease occurs more often with anti-PL7, anti-PL12, anti-KS, and anti-OJ autoantibodies. Some individuals with anti-OJ autoantibodies have developed severe muscle weakness.
These autoantibodies are believed to be produced after a ‘triggering’ event such as a viral infection or exposure to certain drugs. When the immune system responds to these triggering events, something goes wrong, and these autoantibodies are created that then damage healthy tissue.
Some affected individuals may have a genetic predisposition to developing antisynthetase syndrome. A genetic predisposition means that a person may carry a gene or genes for a particular condition, but the condition will not develop unless other factors help to trigger the disease. Most likely, antisynthetase syndrome is a multifactorial disease, in which multiple factors including immune, genetic and environmental ones are necessary for the development of the disorder.
Antisynthetase syndrome is a rare disorder that affects females twice as often as males. Age of onset can range from the late teens to the elderly, with a mean average of the 50s. The exact incidence or prevalence of the disorder is unknown. Because rare disorders often go undiagnosed or misdiagnosed, determining the true frequency of antisynthetase syndrome in the general population is difficult.
A diagnosis of antisynthetase syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and tests that confirm the presence of autoantibodies against the enzyme, aminoacyl-tRNA synthetase.
Clinical Testing and Workup
Blood tests can reveal the presence of autoantibodies against the enzyme, aminoacyl-tRNA synthetase. Every person who has one of these autoantibodies does not, necessarily, develop antisynthetase syndrome. There are published criteria that have been proposed to help with diagnosis. However, these criteria are not universally accepted, and some physicians feel people may have antisynthetase syndrome even if they do not meet the requirements for diagnosis under these guidelines. Based on the guidelines, affected individuals must also have two major criteria or one major criterion, or two minor criteria of the disorder. The two major criteria are interstitial lung disease and muscle disease. Minor criteria are arthritis, Raynaud phenomenon, or thickening and cracking of the skin of the hands (mechanic’s hands).
Blood tests can also reveal elevated levels creatine kinase or aldolase, which are muscle enzymes. When these muscle enzymes are elevated, it is a sign of muscle damage. This is not specific to antisynthetase syndrome, and is a sign of many different types of muscle disease.
A specialized imaging technique called high resolution computerized tomography (CT) scanning may be used to detect and evaluate lung disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. High resolution CT scanning involves specific techniques that enhance or improve the resolution of the images. Pulmonary function tests may be administered to determine how effectively or ineffectively the lungs are working.
Specialized testing that records electrical activity in skeletal muscle at rest and during muscle contraction (electromyography [EMG]) may be performed to determine the health and effectiveness of the muscles.
The treatment of antisynthetase syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. General internists, specialists in the diagnosis and treatment of lung diseases (pulmonologists), specialists in the diagnosis and treatment of skeletal and muscle diseases (orthopedists), specialists in the diagnosis and treatment of immunological diseases (immunologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with antisynthetase syndrome.
Affected individuals may be treated with drugs that help to reduce inflammation called corticosteroids or drugs that suppress the activity of the immune system (immunosuppressive drugs). The effectiveness of these treatments and the amount of time an individual must remain on these medications will vary.
A drug called hydroxychloroquine has been used to treat skin symptoms.
Physical therapy is recommended to help to treat muscle disease by increasing muscle strength and reducing muscle wasting.
Some of the drugs that have been used to treat affected individuals include azathioprine, methotrexate, cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, or rituximab. More research is necessary to determine the long-term safety and effectiveness of these medications for the treatment of antisynthetase syndrome.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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American Thoracic Society. Interstitial Lung Disease. Available at: https://www.thoracic.org/patients/patient-resources/breathing-in-america/resources/chapter-10-interstitial-lung-disease.pdf Accessed March 22, 2018.
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