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Antisynthetase Syndrome: Autoimmune Enzyme Deficiency

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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.

Medically reviewed by

Dr. Arpit Varshney

Published At January 20, 2023
Reviewed AtFebruary 7, 2024

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.

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Dr. Arpit Varshney
Dr. Arpit Varshney

General Medicine

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