Antisynthetase Syndrome: Autoimmune Enzyme Deficiency

Creator: Dr. Samarth Mishra
Published: 2023-01-20T16:26:04

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Antisynthetase syndrome is a chronic inflammatory autoimmune disorder that primarily affects the muscles along with other organs. Read on to know more.

Written by

Dr. Samarth Mishra

Medically reviewed by

Dr. Arpit Varshney

January 20, 2023

February 7, 2024

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Contents

What Is Antisynthetase Syndrome?
What Is the Cause of Antisynthetase Syndrome?
What Is the Pathophysiology of Antisynthetase Syndrome?
What Are the Signs and Symptoms of Antisynthetase Syndrome?
How to Diagnose Antisynthetase Syndrome?
How to Treat or Manage Antisynthetase Syndrome?
What Is the Differential Diagnosis of Antisynthetase Syndrome?
What Are the Complications of Antisynthetase Syndrome?
Who Is Susceptible to Antisynthetase Syndrome?

What Is Antisynthetase Syndrome?

Antisynthetase syndrome (ASSD) is a rare autoimmune disorder that affects multiple organs and usually presents as a triad of polymyositis (inflammatory muscle disease), interstitial lung disease, and host-derived autoantibodies against aminoacyl transfer RNA synthetase enzyme.

Who Is Susceptible to Antisynthetase Syndrome?

Antisynthetase syndrome is often seen in the adult population, with an average age of onset in the 50s. The condition is mostly seen in the female population twice as frequently as in males. An estimation suggests a prevalence of 3,000 to 30,000 cases in the United States.

What Is the Cause of Antisynthetase Syndrome?

Antisynthetase syndrome is an autoimmune disorder that means that the body creates antibodies against its own cell, which leads to the misrecognition of normal cells as antigenic. In antisynthetase syndrome, autoantibodies are generated against the aminoacyl transfer RNA synthetase enzyme, also known as the tRNA-ligase enzyme. This enzyme plays an essential role in protein synthesis.

The development of these autoantibodies is believed to have been triggered by external stimuli from certain bacterial or viral induction, environmental triggers, or a genetic predisposition. A genetically predisposed individual does not show any symptoms unless triggered by some external factor. Hence, antisynthetase syndrome is regarded as a multifactorial disorder with various genetic, environmental, pathogenic, and immunological etiology.

What Is the Pathophysiology of Antisynthetase Syndrome?

The pathophysiology of antisynthetase syndrome is mediated by autoantibodies against the tRNA-ligase enzyme. The function of tRNA is to carry the required amino acids to the ribosome. The tRNA-ligase enzyme is required in the charging or loading of amino acids onto the tRNA. The enzyme catalyzes the transesterification of amino acid or its precursor to its compatible tRNA to form an aminoacyl-tRNA (aa-tRNA). The tRNA-ligase enzyme is responsible for the creation of over 20 different types of aa-tRNA. After loading, the tRNA carries the amino acid to the ribosome, where it is offloaded and added to the growing polypeptide chain. Hence, the tRNA-ligase enzyme plays an important role in RNA translation gene expression during protein synthesis.

Due to the presence of autoantibodies against the enzyme, there is a decrease or complete absence of the tRNA-ligase enzyme, which leads to improper protein synthesis, which is an essential and continuous process in the muscle tissues.

The identified antibodies of the antisynthetase syndrome are 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 antibody, out of which anti-Jo1 is the most common autoantibody found in antisynthetase syndrome patients.

Some antibodies phenotypically reflect a specific symptom or affect a specific organ. Anti-Jo 1 or anti-PL7 usually causes muscle disorders, while anti-PL7, anti-PL12, anti-KS, and anti-OJ antibodies are associated with interstitial lung disease. Anti-SRP, anti-MDA-5, and anti-Mi-2 antibodies are specific to myositis, while ANA, anti-Ro or anti-SSA, anti-PM-Scl, anti-KU, and anti-U2 snRNP antibodies are non-specifically associated with myositis.

Incidentally, some patients with anti-OJ autoantibodies have also shown muscle weakness.

What Are the Signs and Symptoms of Antisynthetase Syndrome?

The various signs and symptoms of antisynthetase syndrome are:

Interstitial pulmonary disease.
Chest pain.
Cough
Muscle weakness.
Myalgias (muscle pain).
Myositis (inflammation of the muscle tissues).
Pulmonary fibrosis.
Respiratory insufficiency.
Hypotonia (low muscle tone).
Keratoconjunctivitis sicca (dry eyes).
Xerostomia (dry mouth).
Lack of skin elasticity.
Abnormality of the voice.
Aortic regurgitation(backflow of blood from the aorta into the right ventricle).
Dysphagia (difficulty in swallowing).
Joint dislocation.
Myocarditis (inflammation of the heart muscle).
Neoplasm.
Pruritus (itchy skin).
Pulmonary arterial hypertension.
Recurrent respiratory infections.
Skin rash.
Telangiectasia of the skin.
Non-erosive arthritis.
Raynaud’s phenomenon (pain and numbness in extremities due to cold).
Mechanic’s hands (painful, thickened, dry, cracked skin on hands).

How to Diagnose Antisynthetase Syndrome?

The diagnosis of antisynthetase syndrome begins with the recognition of characteristic symptoms and physical examination by the primary physician, which warrants further investigation.

According to the diagnostic criteria proposed by Connors et al.in 2010, the fulfillment of which results in an accurate diagnosis of the antisynthetase syndrome:

1. Essential Criteria: Detection of anti-aminoacyl tRNA synthetase antibodies in the serum.

2. Optional Criteria (Fulfillment of one or more of the criteria):

Raynaud’s phenomenon.
Arthritis.
Interstitial lung disease.
Fever.
Mechanic’s hands.

Another diagnostic criterion suggested by Solomon et al. in 2011 iterates:

1. Essential Criteria: Detection of anti-aminoacyl tRNA synthetase antibodies in the serum.

2. Optional Criteria: (Fulfillment of two major or one major and two minor criteria):

Major Criteria:

Interstitial lung disease.
Polymyositis or dermatomyositis.

Minor Criteria:

Arthritis.
Raynaud’s phenomenon.
Mechanic’s hands.

Blood tests can also reveal elevated levels of creatine kinase or aldolase, which indicates muscle dystrophy but is not diagnostic of the antisynthetase syndrome.

CT (computed tomography) of the lungs might be diagnostic of lung disease. Additionally, pulmonary function tests can be performed to assess the effectiveness of remaining lung function. Electromyography or EMG may be performed to determine the health of the muscles. Other supplemental tests that can be added to the diagnostic regimen are MRI, muscle biopsy, and swallowing function tests.

How to Treat or Manage Antisynthetase Syndrome?

The management protocol of antisynthetase syndrome is similar to other inflammatory autoimmune disorders. Corticosteroid is the first line of treatment, but post-remission tapering of corticosteroid may result in the recurrence of pulmonary symptoms. Azathioprine, Mycophenolate mofetil, Tacrolimus, Rituximab, and Cyclophosphamide are used in adjunct with corticosteroid therapy. IVIG (intravenous immunoglobulin) can also be included in pharmacotherapy. Pneumocystis jiroveci prophylaxis should be administered accordingly.

Anti-TNF inhibitors such as Etanercept and Adalimumab can be prescribed with caution to counter rheumatic symptoms.

Hepatitis-B vaccination is recommended for patients who present with hepatitis B surface antigen positive prior to Prednisone or other immunosuppressive therapy. Hydroxychloroquine is prescribed against skin symptoms. Physical therapy is necessary to improve muscle strength and reduce muscle wasting.

What Is the Differential Diagnosis of Antisynthetase Syndrome?

Rheumatoid arthritis.
Inflammatory myopathies.
Polymyositis.
Dermatomyositis.
Inclusion of body myositis.
Necrotizing autoimmune myopathy.
Interstitial lung disease.
Hypersensitivity pneumonitis

What Is the Prognosis of Antisynthetase Syndrome?

Patients with just muscle involvement mostly respond positively to corticosteroid and immunosuppressive therapy. The prognosis worsens with the involvement of lung abnormalities and is determined by the severity and type of lung injury. Old age, malignancy, and negative ANA antibody tests present a worse prognosis.

What Are the Complications of Antisynthetase Syndrome?

Respiratory failure.
Dysphagia (swallowing difficulties).
Malignancy (spread or transformation to cancer).

Conclusion

Due to the rarity of the condition and lack of proper research, the exact protocol for management is not established, and the current regime follows a symptomatic approach keeping side effects in consideration. Nevertheless, early diagnosis can prevent pulmonary manifestations, and along with physical therapy, remission can be achieved, and the patient can live an uneventful life.

Frequently Asked Questions

1. How Long Can Individuals With Antisynthetase Syndrome Expect to Live?

People with anti-synthetase syndrome often face severe and quickly worsening lung problems, known as Interstitial Lung Disease (ILD). Sadly, their life expectancy is shortened, mainly due to ILD and pulmonary hypertension. The survival rate over five years is around 90 percent for those with the anti-Jo-1 antibody and 75 percent for those without it. However, in some cases, the five-year survival can be as low as 31 percent.

2. What Factors Initiate the Onset of Antisynthetase Syndrome?

The exact reason for the antisynthetase syndrome is not entirely known. People with this condition have autoantibodies, special proteins in the immune system that usually target harmful invaders. However, these autoantibodies mistakenly attack healthy tissues in antisynthetase syndrome; specifically enzymes called aminoacyl-tRNA synthetases. These autoantibodies are thought to be created after a viral infection or exposure to certain drugs. There might be a genetic tendency to develop antisynthetase syndrome in some cases, but having the gene alone is not enough. It usually requires other factors like immune responses, genetics, and environmental influences for the syndrome to develop.

3. When Does Antisynthetase Syndrome Usually First Appear?

Antisynthetase syndrome, a rare condition, affects females twice as frequently as males. The age of onset ranges from the late teens to the elderly, with an average of around the 50s. The exact incidence or prevalence of the disorder remains unknown. Identifying how common antisynthetase syndrome is in the general population is hard because rare disorders like this one are frequently not recognized or diagnosed correctly.

4. What Is the Severity Level of Antisynthetase Syndrome?

Depending on the organs and systems affected, antisynthetase syndrome can have varying degrees of severity. Interstitial lung disease, which can have major effects on respiratory function, is a common outcome of the syndrome that can affect the lungs. Joint and cardiac involvement may also influence the degree of the condition's overall severity. The prognosis for people with this syndrome is often not good, mainly because the lungs get worse over time and are difficult to treat. The damage to the lung tissue is crucial for predicting how well someone might do. The illness usually lasts a long time, and it is likely linked to a lower chance of living longer.

5. Which Treatment Is Considered Most Effective for Antisynthetase Syndrome?

People with this condition might get corticosteroids or immunosuppressive drugs to lower inflammation. The effectiveness of these treatments and how long someone needs to take them can vary. For skin symptoms, a drug called Hydroxychloroquine may be used. Physical therapy is also suggested to improve muscle strength and prevent muscle loss in muscle disease.

6. Is Antisynthetase Syndrome Considered a Genetic Condition?

Antisynthetase syndrome is not solely a genetic condition, although autoimmune diseases do have a genetic component. Genetic factors may influence a person's susceptibility to the syndrome, but environmental triggers like infections or other outside factors also have a significant impact. To learn more about how genetic and environmental factors interact to cause antisynthetase syndrome, research is still being done.

7. How Does Antisynthetase Syndrome Manifest in the Lungs?

In people with ASS, the lungs are often affected, and this has a big impact on how well someone might do. The main lung problem in ASS is called Interstitial Lung Disease (ILD), but some patients also develop other issues like high blood pressure in the lungs or, less commonly, problems with the small airways or sudden respiratory failure. The reasons for these issues are not fully understood, but they are likely linked to the specific autoantibodies in the body. Lung problems in ASS can show up in different ways, from milder issues to more severe ones that can cause long-term damage if not diagnosed and treated correctly.

8. What Is the Alternative Term for Anti-synthetase Syndrome?

Anti-synthetase syndrome is also known as antisynthetase antibody syndrome or antisynthetase syndrome complex. The name reflects the presence of specific antibodies, such as anti-Jo-1, which are often associated with the syndrome. These antibodies target aminoacyl tRNA synthetases, contributing to the autoimmune response and the diverse clinical manifestations observed in individuals with this syndrome.

9. What Are the Characteristics of Antisynthetase Syndrome in the Fingers?

The antisynthetase syndrome is a diverse illness, and its symptoms depend on the specific antisynthetase antibody present. A condition known as ‘mechanic's hands’ is characterized by thickened skin on the palms, especially on the outer and lower parts of the fingers. Approximately 90 percent of cases show similar skin changes on the soles, often called ‘hiker's feet.’ A careful history can help distinguish between abnormal skin thickening and normal skin changes.

10. How Does Anti-Jo-1 Positivity Relate to Antisynthetase Syndrome?

When someone tests positive for antibodies against histidyl-tRNA synthetase (anti-Jo-1), they are said to have anti-Jo-1 positive antisynthetase syndrome, a subtype of antisynthetase syndrome. A unique combination of clinical manifestations, such as arthritis, Raynaud's phenomenon, interstitial lung disease, and myositis (inflammation of the muscles), are linked to this particular antibody. Antisynthetase syndrome is diagnosed and classified more easily when anti-Jo-1 antibodies are present.

11. What Are the Established Criteria for Diagnosing Antisynthetase Syndrome?

Diagnostic criteria for antisynthetase syndrome, as outlined by Connors et al. and Solomon et al., emphasize the significance of aminoacyl-tRNA synthetase autoantibodies (ARS).

- In Connors et al.'s criteria, definitive diagnosis requires the presence of ARS autoantibody along with at least one of the following: interstitial lung disease, arthritis, Raynaud’s phenomena, fever, or mechanic’s hands.

- Solomon et al.'s criteria demand a definitive diagnosis with the presence of ARS autoantibody plus two primary criteria or one major and two minor criteria. Major criteria include interstitial lung disease, dermatomyositis, or polymyositis by Bohan and Peter criteria, while minor criteria encompass arthritis, fever, and mechanic’s hands.

12. What Are the Observable Clinical Characteristics of Antisynthetase Syndrome?

Muscle disease, Interstitial lung disease, and arthritis are considered the main symptoms of antisynthetase syndrome (referred to as the classic triad). However, these symptoms may not appear simultaneously. In antisynthetase syndrome, muscles can be affected, leading to inflammation, muscle pain (myalgia), and stiffness, ultimately causing muscle weakness. Some individuals may also experience inflammation in multiple joints (polyarthritis).

Another common feature is interstitial lung disease (progressive inflammation and lung scarring). This primarily affects the tissue and space around tiny air sacs (alveoli) in the interstitium, causing shortness of breath and coughing. In severe cases, ongoing lung damage can result in respiratory insufficiency, where the lungs struggle to provide enough oxygen to the body. This may require oxygen therapy and, in extreme cases, lead to life-threatening respiratory failure.

Sources

Dr. Arpit Varshney

General Medicine

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