Antisynthetase syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: M. Hassan, M.B.B.S

Synonyms and keywords:

Overview

Antisynthetase syndrome, an uncommon autoimmune disorder, is characterized by antibodies against aminoacyl-transfer ribonucleic acid synthetases, with various combinations of three cardinal manifestations of interstitial lung disease (ILD), polymyositis, and arthritis. Other features of antisynthetase syndrome may include pyrexia of unknown origin, mechanic's hand (hyperkeratotic skin changes along the lateral surfaces of the digits) and Raynaud's phenomenon.

Till date, nine different anti-aminoacyl t-RNA synthetase (ARS) antibodies have been identified to play a role in the development of antisynthetase syndrome.

Historical Perspective

In 1990, Marguerie et al and coworkers first described antisynthetase syndrome as a triad of polymyositis, interstitial lung disease (ILD), and the presence of myositis-specific autoantibodies to aminoacyl-transfer ribonucleic acid synthetases.

Pathophysiology

Antisynthetase syndrome is characterized by the presence of myositis-specific anti-synthetase antibodies.

Anti-ARS antibodies	Antigen	Clinical features
Anti-Jo-1	Histidyl-tRNA synthetase	Antisynthetase syndrome Arthritis Interstitial lung disease Fever Mechanic's hands Raynaud's phenomenon Flare up in spring Moderate response to treatment Poor prognosis Associated with epstein-Barr virus (EBV), adenovirus, and influenza infection
Anti PL-12	Alanyl-tRNA synthetase, Alanyl-tRNA
Anti-EJ	Glycyl-tRNA synthetase
Anti-OJ	Isoleucyl-tRNA synthetase
Anti-KS	Asparaginyl-tRNA synthetase
Anti-PL-7	Threonyl-tRNA synthetase
Anti-Ha	Tyrosyl-tRNA synthetase
Anti-Zo	Phenylalanyl-tRNA synthetase

Causes

The exact cause of antisynthetase syndrome is not fully understood.

Differentiating Antisynthetase syndrome from other Diseases

Antisynthetase syndrome may be misdiagnosed as idiopathic interstitial lung disease (ILD) or inflammatory myopathy, as a result of rarity, lack of awareness of the disease, as well as due to the lack of available testing for anti-ARS antibodies.

Epidemiology and Demographics

Age

The mean age at onset of antisynthetase syndrome in adults varies from 43 to 60 years.

Gender

Antisynthetase syndrome is 2–3 times more common in women than in men.

Race

Antisynthetase syndrome usually affects individuals of the black American ethnicity race.

Natural History, Complications and Prognosis

Main causes of death in antisynthetase syndrome is anti-Jo-1-positive patients included interstitial lung disease, neoplasm, infectious diseases including pneumonia, severe myositis and cardiovascular disorders. (Elsevier https://www.sciencedirect.com/science/article/abs/pii/S0049017220303085)

The cumulative ten-year survival rate in patients with antisynthetase syndrome was estimated as 76.8%. (Elsevier https://www.sciencedirect.com/science/article/abs/pii/S0049017220303085)

Poor prognostic factors associated with Antisynthetase syndrome
1) Anti-Ro 52
2) Rapidly progressive interstitial lung disease
3) Pulmonary hypertension
4) Malignancy
5) Male sex
6) Reduced diffusing capacity of lung for carbon monoxide
7) Elevated serum ferritin
8) Black American ethnicity

Diagnosis

Diagnostic Criteria

In 2010, Connors et al proposed a formal criteria for the diagnosis of antisynthetase syndrome. This criteria proposed that all patients must have a presence of an anti-aminoacyl tRNA synthetase antibody in addition to one or more of the following clinical features: mechanic’s hands, Raynaud’s phenomenon, myositis, ILD, arthritis, and/or unexplained fever.

In 2011, Solomon et al proposed alternative criteria, which is more strict. This criteria requires the presence of anti-aminoacyl tRNA synthetase antibody plus two major or one major and two minor criteria.

Major criteria includes: Interstitial Lung Disease (not attributable to another cause), and Polymyositis or dermatomyositis.

Minor criteria includes: arthritis, Raynaud’s phenomenon, and mechanic’s hands.

Connors et al (2010) criteria
Required: Presence of an anti-aminoacyl tRNA synthetase antibody
PLUS one or more of the following clinical features: 1) Raynaud’s phenomenon 2) Arthritis 3) Interstitial lung disease 4) Fever (not attributable to another cause) 5) Mechanic’s hands (thickened and cracked skin on hands, particularly at fingertips)

Solomon et al (2011) criteria
Required: Presence of anti-aminoacyl tRNA synthetase antibody
PLUS two major or one major and two minor criteria: Major: 1) Interstitial Lung Disease (not attributable to another cause) 2) Polymyositis or dermatomyositis Minor: 1) Arthritis 2) Raynaud’s phenomenon 3) Mechanic’s hands

Symptoms

Symptoms seen at the diagnosis of antisynthetase syndrome include the following:

Symptoms of antisynthetase syndrome
1) Fever
2) Weight loss
3) Anorexia
4) Dyspnea
5) Dry cough
6) Arthralgia
7) Joint swelling
8) Proximal muscle weakness
9) Myalgia
10) Raynaud's phenomenon

Physical Examination

Physical exam findings play an important role in diagnosis of antisynthetase syndrome as the findings may be classified into major and minor criteria. Clinical findings on examination includes:

Clinical findings
1) Polyarthritis
2) Mechanics hands (hyperkeratotic lesions on the radial and palmar aspects of the hands and fingers with fissuring and scaling of the skin)
3) Calcinosis cutis
4) Malar rash
5) Cutaneous ulcers
6) Crackles on chest auscultation

Laboratory Findings

Suggested lab findings based on the systems are as follows:

Domains	Suggested investigations
Bloodwork	CBC, creatinine, CK, LDH, aldolase, AST, ALT, ANA, ENA, RF, ACPA, MSAs and MAAs
Muscle	MMT8 and consider: MRI pelvic/thighs and shoulder girdle muscles, EMG, and Muscle biopsy
Joint	TJC, SJC
Lung	CXR, HRCT, PFT, 6MWT, echocardiogram for PAH if isolated decrease in DLCO, Referral to respirology for co-management if ILD
Skin	General assessment and consider documentation with CDASI Referral to dermatologists
Raynaud’s phenomenon	Conservative and pharmacological management review
Overall disease activity and damage assessment	Consider MDAAT, MDI
TJC: tender joint count; SJC: swollen joint count; PAH: pulmonary artery hypertension; MMT8: manual muscle testing 8 MRI: magnetic resonance imaging; EMG: electromyography; CXR: chest X-ray; HRCT: high-resolution computed tomography; PFT: pulmonary function test; 6MWT: 6-minute walk test; DLCO: diffusing capacity of lung for carbon monoxide; ILD: interstitial lung disease; CDASI: cutaneous dermatomyositis disease area and severity index; CBC: complete blood count; CK: creatine kinase; LDH: lactate dehydrogenase; AST: aspartate aminotransferase; ALT: alanine transaminase; ANA: antinuclear antibody; ENA: extractable nuclear antigens; RF: rheumatoid factor; ACPA: anti-citrullinated protein antibody; MSA: myositis-specific antibody; MAA: myositis-associated antibody; MDAAT: Myositis Disease Activity Assessment Tool; MDI: myositis damage index

Imaging Findings

As antisynthetase syndrome is associated with interstitial lung disease, and therefore, high resolution computed tomography (HRCT) plays an important role in its work up, as well as to monitor the disease activity. Radiographic features seen on HRCT at the initial diagnosis include traction bronchiectasis, ground glass opacities and reticulation.

Case courtesy of Dr David Cuete

Treatment

Medical Therapy

Various immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and/or tacrolimus, are used in the treatment of antisynthetase syndrome. Additionally, corticosteroids may be added for management of the myositis and pulmonary manifestations of anti-synthetase syndrome. The choice of immunosuppressive agent is dependent on the practitioner and is based on the potential risks of therapy as no agent is superior to the other.

Prednisone and azathioprine or mycophenolate mofetil may be used in patients with anti-synthetase syndrome related interstitial lung disease (ILD). In addition to that, tacrolimus may be added for rapid disease control in more severe cases of ILD.

In patients with severe progressive or refractory ILD, rituximab may be added; while cyclophosphamide is reserved for those with acute respiratory distress syndrome.

The physician must also been on the lookout for other co-morbid conditions associated with antisynthetase syndrome i.e. pulmonary hypertension and screening for malignancies.

Therapies for Anti-synthetase Syndrome-ILD
Drug	Clinical Use	Monitoring	Adverse effects*	Suggested Starting Dose
Corticosteroids	First-line therapy	Glucose, weight, blood pressure	Hypertension, weight gain, hyperglycemia	1 mg/kg/day
Azathioprine	Most common second-line agent	CBC, renal/liver function	Leukopenia, hepatic injury, pancreatitis	1 mg/kg/day
Mycophenolate mofetil	Second-line agent in addition to corticosteroids	CBC	Diarrhea, cytopenias	500 mg twice daily
Rituximab	Rescue therapy, added to standard immunosuppression	CBC	Infection, neutropenia, infusion reaction	**
Cyclophosphamide	Rescue therapy (e.g. ARDS)	CBC, urinalysis, renal function	Malignancy, cytopenias, hemorrhagic cystitis, sterility	1–2 mg/kg/day by mouth or 500–1000 mg IV every 4 weeks**
Tacrolimus	Add-on therapy	Renal function, blood pressure, electrolytes, CBC, drug level	Renal failure, hypertension, hyperglycemia	1 mg twice daily
IVIG	Add-on therapy	Immunoglobulin G levels	Infusion reaction, infection from donor	**
ILD = Interstitial lung disease; ARDS = acute respiratory distress syndrome; IVIG = intravenous immunoglobulin G; mg = milligram; kg = kilogram *all except IVIG increase the risk of opportunistic infection **rheumatology consult strongly advised

Surgery

Surgical intervention is not recommended for the management of antisynthetase syndrome.