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Clinical manifestations and treatment of antisynthetase syndrome

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Abstract

Antisynthetase syndrome (ASyS) is an autoimmune disease clinically manifested most often by interstitial lung disease, myositis, and arthritis. Raynaud's syndrome, fever, and rashes are also commonly seen. This syndrome is characterized by the highly specific presence of antibodies against various aminoacyl transfer RNA synthetases, including Jo-1 and others. In this chapter, we provide an overview of ASyS, including pathogenesis, common clinical manifestations, and treatment strategies. We discuss the spectrum of disease seen with specific antisynthetase antibodies and examine the differences in phenotype between patients with different antisynthetase antibodies. We outline common treatment strategies, which should generally target the most severe and life- or organ-threatening disease manifestations. Finally, we discuss short- and long-term prognosis in ASyS.

Section snippets

Origins of antisynthetase syndrome

The most unique serological feature of antisynthetase syndrome (ASyS) is the finding of autoantibodies to aminoacyl transfer RNA (tRNA) synthetases. These synthetases are intracellular enzymes that play a critical role in protein synthesis. They attach amino acids to the appropriate tRNA molecule in the preparation for building a peptide chain. There is a different aminoacyl tRNA synthetase for each amino acid, and the autoantibodies seen in ASyS each target a unique synthetase [1]. For

Clinical manifestations

In the original Bohan and Peter classification criteria for idiopathic inflammatory myopathy (IIM) [9], as well as the modern ACR/EULAR classification criteria [10], ASyS is generally categorized by clinical manifestations as either dermatomyositis (DM) or polymyositis (PM). Other authors suggest that although clinically ASyS may share features with DM and PM, it has unique serological and pathological features that indicate it represents its own separate disease entity within the IIMs [[11],

Interstitial lung disease

ILD is the hallmark pulmonary manifestation of ASyS. It is one of the most common clinical features and is the major contributor to morbidity and mortality in ASyS [18]. Patients with ASyS-ILD tend to have worse pulmonary function and radiographic manifestions of ILD than patients with other myositides [19]. In 15–30% of ASyS patients, ILD is the presenting disease manifestation [17,20]. Various studies have reported the prevalence of ILD in ASyS to range from 69% [21] to 100% [22,23]. The

Muscular manifestations

The IIM of ASyS is typically symptomatic, with significant weakness and myalgias. Proximal muscle groups are primarily affected, and the legs are often more affected than the arms or neck [11]. Creatine kinase (CK) is typically elevated. The mean peak CK was over 4000 in one ASyS study [11].

A subset of ASyS patients may lack significant signs or symptoms of myopathy, while still having abnormal CK and/or electromyography (EMG). These patients are termed hypomyopathic or amyopathic. This finding

Joint manifestations

Polyarthralgia and polyarthritis are the most common articular manifestations of ASyS, seen in 58–70% of ASyS patients [16,22,38]. Arthritis is more common among ASyS patients with anti-Jo-1 Ab than with the other antisynthetase antibodies, but the characteristics of arthritis tend to be similar regardless of the underlying antisynthetase antibody [39]. About 70% of ASyS patients with arthritis have a symmetric polyarticular arthritis; the remaining 30% have an oligoarticular or asymmetric

Cutaneous manifestations

The characteristic cutaneous lesions of ASyS are “mechanic's hands.” Mechanic's hands are fissured, erythematous, hyperkeratotic eruptions on the hands, resembling the type of occupational dermatosis that might be seen in a manual laborer. The lesions are classically on the lateral edges of the fingers and thumbs, largely sparing the palmar, and dorsal aspects of the digits (Fig. 3) [46]. Recent studies have found that mechanic's hands are seen in 16–21% of ASyS patients [23]. These lesions

Cardiac

Myocarditis is much less common in ASyS than in typical DM, occurring in only 3.4% of cases in a study by Dieval et al. [53] It may be asymptomatic or may present with typical heart failure symptoms. In the above study, myocarditis only occurred in conjunction with active myositis. Pericardial effusions are commonly found on imaging in some groups, but typically do not cause significant morbidity [54].

Malignancy

Links between other IIMs and malignancy raise the question of whether ASyS may be associated

Autoantibody profiles

Eight antisynthetase antibodies have been described thus far: anti-Jo-1 (anti-histidyl), anti-PL12 (anti-alanyl), anti-PL7 (anti-threonyl), anti-OJ (anti-isoleucyl), anti-EJ (anti-glycl), anti-KS (anti-asparaginyl), anti-YRS/Ha (anti-tyrosyl), and anti-Zo (anti-phenylalyl) [23]. Most commercially available myositis panels in the United States include anti-Jo-1, anti-PL12, anti-PL7, anti-EJ, anti-KS, and anti-OJ only [59].

Anti-Jo-1 is the most common antisynthetase antibody, accounting for 60.3%

Summary of autoantibody profiles

In summary, anti-Jo-1 is the most common antisynthetase antibody, and is the most consistent with the classic presentation of ILD, myositis, and arthritis. Patients with anti-Jo-1 antibody have better outcomes than other patients, possibly related to better recognition of the syndrome and earlier diagnosis and treatment. Anti-PL7, anti-PL12, and anti-EJ most commonly present with ILD and later develop myositis; these patients tend to have somewhat less arthritis than is seen in anti-Jo-1 ASyS [

General treatment paradigm

Treatment for ASyS can be challenging given that there are no FDA-approved medications for ASyS and very few comparative studies for various proposed therapies. Most data for treatment of ASyS are retrospective or uncontrolled. In general, treatment of ASyS should be targeted based on organ systems involved, and severity of symptoms.

Careful diagnostic testing is needed to determine the extent of disease in ASyS. Patients with this diagnosis should undergo HRCT and PFTs to assess for ILD, CK,

Prognosis

As described above, different antisynthetase antibodies may be associated with differences in survival. 1 Among a cohort of 202 patients with ASyS, cumulative survival was 90% at 5 years and 70% at 10 years for patients with a positive anti-Jo-1 antibody compared to 75% at 5 years and 47% at 10 years for patients with non-anti-Jo-1 antisynthetase antibodies [17]. Cause of death was most often pulmonary fibrosis (49%) in this cohort. Among patients with ASyS-ILD, features associated with

Conclusions

Antisynthetase syndrome is a complex autoimmune disorder characterized by autoantibodies against aminoacyl tRNA synthetases. Although there is some variation in clinical phenotype by specific antisynthetase antibody, the syndrome is generally characterized by some combination of ILD, myositis, arthritis, and cutaneous findings such as mechanic's hands. Most patients have only one or two classic disease manifestations at disease onset. Anti-Jo-1 ASyS tends to have more arthritis than is seen

Conflicts of Interest

The authors do not have any conflicts of interest related directly or indirectly to this article.

Funding

The authors received no specific funding for this work.

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