Anti‐Synthetase Syndrome—Advancing Disease Phenotyping, Classification and Treatment

Anti-synthetase syndrome (ASyS) is characterized by the presence of antibodies against aminoacyl transfer RNA (tRNA) synthetase and distinct clinical constellations including interstitial lung disease (ILD), myositis, arthritis, mechanic's hands, fever and raynaud's phenomenon (RP). Since the discovery of anti-histidyl-tRNA synthetase (Anti-Jo1) antibody four decades ago, tremendous progress was made in discovering additional anti-synthetase antibodies [1]. There are 20 different aminoacyl-tRNA synthetase enzymes, and 10 distinct anti-synthetase antibodies (ASA) have been identified so far (Table 1). These antibodies are central to disease classification and may influence clinical phenotypes. There are evolving insights into pathophysiology, clinical heterogeneity, and treatment approaches in ASyS. This article aims to review and discuss the recent research advancements in disease sub-phenotyping, classification and therapeutics in ASyS. ASyS exhibits significant clinical heterogeneity with varying disease courses and clinical manifestations among patients. Patients with non-Jo1 ASA were previously reported to have a worse survival than Jo1 patients (10-year cumulative survival of 47% vs. 70%, p < 0.005) by Aggarwal et al. [2], probably related to a delay in diagnosis by 8 months in the non-Jo1 positive patients. However, data from a multicenter registry in Hong Kong did not identify a similar survival difference between Jo1 and non-Jo1 positive patients [3]. Clinical phenotypes might exert a greater impact on survival than the presence of specific ASA. Wu et al. performed cluster analysis on more than 700 ASyS patients from China and identified three unique clinical phenotypes independent of ASA specificity: rapidly-progressive ILD (RP-ILD) cluster (23.7% of patients), dermatomyositis (DM)-like cluster (14.5%) and arthritis cluster (61.8%) [4]. The worst prognosis was observed in the RP-ILD cluster with a 10-year survival rate of 37.0%, compared to 69.5% in the DM-like cluster and 87.4% in the arthritis cluster, but the survival rates were comparable among different ASA. Transcriptomic analysis also revealed distinct gene signatures and biological processes in each cluster. Gene signatures implicated in coagulation and platelet activation were enhanced in the RP-ILD cluster, pathways related to viral infection and interferon-mediated signaling were enriched in the DM-like cluster, and lastly, B cell receptor signaling pathways were upregulated in the arthritis cluster. Whether or not the distinct biological pathways can predict treatment responses to targeted therapy, such as janus kinase inhibitors (JAKi) in the DM-like cluster or anti-CD20 in the arthritis cluster will require further research. Apart from predicting prognosis, clinical manifestations are crucial in disease classification though there are controversies on universally accepted classification criteria of ASyS, which pose a great hurdle in research and clinical trials enrollment. Multiple criteria to classify ASyS were published over the years. In 2010, Connors et al. classified ASyS by positive ASA and any one of the following: myositis by Bohan and Peter criteria, presence of ILD, arthritis, unexplained and persistent fever, RP, or mechanic's hands [5]. In the subsequent year, Solomon et al. developed another set of classification criteria and defined myositis or ILD as major criteria while arthritis, RP, and mechanic's hands were considered minor criteria. The presence of ASA with two major criteria, or one major plus two minor criteria was classified as ASyS [6]. However, these criteria were not developed using a data-driven method. The American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) published the first validated classification criteria of idiopathic inflammatory myopathy (IIM) in 2017 [7]. The presence of anti-Jo1 antibody, in addition to classic DM cutaneous manifestations, pattern of muscle weakness, and muscle enzyme elevation contributed to the disease classification. However, the 2017 EULAR/ACR criteria did not include the presence of ILD or non-Jo1 ASA, nor did they define ASyS as a distinct IIM subtype. Recently, a new Classification Criteria for Anti-synthetase Syndrome (CLASS) was presented to address the current gaps in ASyS classification [8]. A large international database of more than 2000 ASyS patients and controls, in which 16.7% were Asians, was utilized to identify key clinical and serological variables that define ASyS. The weighted scoring system with clinical (ILD, muscle involvement, joint involvement, Mechanic's hands, inflammatory rashes, RP, unexplained fever and pulmonary hypertension) and serological domains (presence of anti-Jo1 and non-anti-Jo1 antibody, anti-Ro52 or antinuclear antibodies (ANA) with cytoplasmic pattern) is used for disease classification. Though contributing to a lower weighted score than ASA positivity, the inclusion of anti-Ro52 positivity or ANA positivity with cytoplasmic pattern might facilitate ASyS classification in some APLAR regions in which myositis specific antibody testing is not widely available. However, external validation after final release of the new classification criteria, especially from populations not included in the CLASS database (such as Chinese or Southeast Asians), is essential before wide application in research and clinical trials. Advancement in disease phenotyping and classification can potentially facilitate therapeutic development in ASyS, as there is a lack of evidence from RCTs to guide treatment of ASyS. Presence of major organ involvement, such as ILD reported in roughly 90% of ASyS patients [3, 4], often determines the intensity of treatment. Glucocorticoids (GCs) are commonly used as initial treatment. Conventional immunosuppressants, for example, mycophenolate mofetil (MMF) or calcineurin inhibitors (CNI), were frequently added; a recent systemic review revealed potential effectiveness in improving lung function parameters, but there was no conclusive difference in effectiveness between conventional immunosuppressants [9]. Cyclophosphamide (CYC) was usually reserved for severe ASyS-ILD, while the use of biologics and janus kinase inhibitors (JAKi) is emerging. CYC and rituximab improved forced vital capacity (FVC) and lung diffusion capacity (DLCO) to a similar extent [9]. Another retrospective cohort reported that anti-CD20 is more effective than conventional immunosuppressants to achieve low disease activity (LDA) and reduce GCs dosage in anti-Jo1 + ASyS patients [10]. Of note, this study proposed using LDA, a concept well studied in other rheumatological conditions, as a primary endpoint. The definition and long-term benefits of LDA in ASyS warrant further studies. Abatacept showed a trend to improve FVC and DLCO at week 48 but not week 24 in 20 ASyS-ILD patients compared to placebo [11]. Tocilizumab demonstrated potential efficacy in joint, muscle and lung involvement in refractory ASyS in case reports [12]. JAKi was reported to improve rashes, myositis and ILD in 14 out of 20 refractory ASyS patients in a retrospective cohort study [13]. Future ASyS research on validating the new classification criteria and exploring targeted therapies based on distinct clinical phenotypes would be important to improve patient outcomes. Iris Yan Ki Tang: conceptualization, writing – original draft, writing – review and editing. Lijun Liu: writing – original draft, writing – review and editing. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.