Antisynthetase syndrome is a rare, chronic, autoimmune disorder characterized by Interstitial Lung Disease (ILD), inflammatory myositis, fever, Raynaud’s phenomenon, mechanic’s hand, and inflammatory polyarthritis in the setting of antibodies against amino acyl-transfer RNA synthetases, with anti-Jo-1 antibody being the most common and 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 the 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.
It was described as a triad of polymyositis,diffuse interstitial lung disease and serum autoantibodies to aminoacyl transfer RNA synthetase (anti-ARS). The pathogenesis of antisynthetase syndrome involves autoantibodies to eight of the aminoacyl–transfer RNA synthetases. In ASS, 68-87% of the anti-ARS consists of anti-jo-1 antibody. Seven other anti-ARS identified are rarely seen. Anti SSA autoantibodies and anti-Ro 52 are frequently seen in anti–ARS positive patients [rx]. ASS is characterized by varying degrees of interstitial lung disease, myositis, arthropathy, fever, Raynaud’s phenomenon and mechanic’s hands [rx]. Key features for the diagnosis of ASS include the presence of an Anti-ARS antibody, accompanied by myositis, ILD or both [rx].
Causes
The exact cause of the 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. Research does not know why these autoantibodies targets aminoacyl-tRNA synthetase. Not every person who develops these autoantibodies will go on to develop symptoms of the antisynthetase syndrome.
The exact role these autoantibodies play in the development of antisynthetase syndrome is not fully understood. The autoantibodies that have been 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 the 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 the 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, the antisynthetase syndrome is a multifactorial disease, in which multiple factors including immune, genetic and environmental ones are necessary for the development of the disorder.
Diagnosis
A diagnosis of the antisynthetase syndrome is based upon the 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.
These may include the following depending on the clinical context:
- Muscle enzymes eg creatinine kinase (CK) and aldolase: these are often elevated
- Muscle antibodies
- Electromyography (EMG)
- Magnetic resonance imaging (MRI) of affected muscles
- Muscle biopsy
- Lung function tests
- High resolution computed tomography scan (CT) of the chest
- Evaluation of swallowing difficulties and aspiration risk
- Lung biopsy
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 the 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, the Raynaud phenomenon, or the thickening and cracking of the skin of the hands (mechanic’s hands).
Blood tests can also reveal elevated levels of 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 the 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.
Treatment
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 the antisynthetase syndrome.
Glucocorticosteroids are the mainstay of treatment for antisynthetase syndrome and are often required for several months or years. Prednisone is initially given at high doses (1 mg/kg/day) for 4–6 weeks to achieve disease control, then tapered slowly over 9–12 months to the lowest effective dose to maintain remission. In more severe cases, pulsed intravenous (IV) methylprednisolone for 3–5 days may be necessary.
Prednisone in the dose of 1mg/kg/day remains the drug of choice for the treatment of this disorder. High dose of steroid is used in the initial phase. Remission is achieved in 25-68% of cases when high dose of corticosteroids are given as part of initial therapy [rx]. Studies have found a better response to steroid therapy in patients with Non-Specific Interstitial Pneumonia (NSIP) and Cryptogenic Organizing Pneumonia (COP) when compared to those with Usual interstitial pneumonia (UIP) [rx]. Monthly IV pulse therapy with cyclophosphamide has shown to be effective when ILD is prominent. Steroid sparing agents azathioprine, methotrexate and cyclosporine have been used with low to moderate success [rx]. Mycophenolate mofetil has been used in anti-jo-1 positive patients with refractory ILD with improvement of ILD. In some series Rituximab has been used with moderate success in patients with worsening of the ILD despite aggressive conventional treatment. However, prospective studies are needed to assess the safety issues of Rituximab [rx]. The dermatologic manifestations are treated with hydroxychloroquine. ILD is the major determinant of morbidity and mortality in Antisynthetase syndrome.
Anti-TNF inhibitors, such as etanercept (Enbrel) and adalimumab (Humira), are medications typically used for rheumatoid arthritis. If arthritis symptoms are predominant in a patient with antisynthetase syndrome, these medications may be preferred. They should be used with caution, however, as these biologic drugs are sometimes associated with the development of myositis.
Intravenous immunoglobulin (IVIG), a blood product containing the pooled immunoglobulin G antibodies from donors, is used in the treatment of many immune deficiency and autoimmune disorders, though its exact mechanism of action is unknown. In a randomized, placebo controlled trial of IVIG treatment in 15 patients with dermatomyositis, patients randomized to receive IVIG had significant improvement in muscle strength and symptoms (rx). A recent case report suggested
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.
Investigational Therapies
Some of the drugs that have been used to treat affected individuals include azathioprine, methotrexate, cyclophosphamide, cyclosporine, tacrolimus, and mycophenolate mofetil, or rituximab. More research is necessary to determine the long-term safety and effectiveness of these medications for the treatment of the antisynthetase syndrome.
Therapies for Anti-synthetase Syndrome-ILD
| Drug | Suggested Starting Dose | Clinical Use | Monitoring | Adverse effects* |
|---|---|---|---|---|
| Corticosteroids | 1 mg/kg/day | First-line therapy | Glucose, weight, blood pressure | Hypertension, weight gain, hyperglycemia |
| Azathioprine | 1 mg/kg/day | Most common second-line agent | CBC, renal/liver function | Leukopenia, hepatic injury, pancreatitis |
| Mycophenolate mofetil | 500 mg twice daily | Second-line agent in addition to corticosteroids | CBC | Diarrhea, cytopenias |
| Tacrolimus | 1 mg twice daily | Add-on therapy | Renal function, blood pressure, electrolytes, CBC, drug level | Renal failure, hypertension, hyperglycemia |
| Rituximab | ** | Rescue therapy, added to standard immunosuppression | CBC | Infection, neutropenia, infusion reaction |
| Cyclophosphamide | 1–2 mg/kg/day by mouth or 500–1000 mg IV every 4 weeks** | Rescue therapy (e.g. ARDS) | CBC, urinalysis, renal function | Malignancy, cytopenias, hemorrhagic cystitis, sterility |
| IVIG | ** | Add-on therapy | Immunoglobulin G levels | Infusion reaction, infection from donor |
References
