Subclinical myositis in antisynthetase syndrome—Does it matter?

Antisynthetase syndrome is a clinical syndrome characterized by the presence of anti-aminoacyl-transfer RNA synthetase (anti-ARS) antibodies, interstitial lung disease (ILD), myositis, arthritis, Raynaud phenomenon, and mechanic's hand.1, 2 Although antisynthetase syndrome was initially identified as a subgroup of myositis, the prevalence of myositis has been reported to be lower than that of ILD in antisynthetase syndrome.2 In this issue of International Journal of Rheumatic Diseases, Ozaki et al.3 reports 3 antisynthetase syndrome patients with ILD who did not have muscle symptoms or elevated serum levels of creatine kinase (CK) but did show findings of myositis on electromyography (EMG) and/or magnetic resonance imaging (MRI). As these patients were recruited in a consecutive manner, the findings suggest that subclinical muscle inflammation is prevalent in antisynthetase syndrome. The study by Ozaki and colleagues has some limitations as mentioned in the article. One of them is the lack of histological assessment. Although both EMG and MRI are established measures that can discriminate patients with myositis from healthy subjects, neither EMG nor MRI proves the presence of inflammation in patients with no muscle symptoms. In our practice, we have also encountered multiple amyopathic anti-ARS antibody-positive cases who had abnormal findings on MRI suggestive of myositis. One of these patients agreed to undergo muscle biopsy, which demonstrated the presence of myositis (Figure 1), indicating that MRI-detected myositis actually represents inflammatory infiltrates at least in a certain proportion of clinically amyopathic patients. However, this needs to be validated in future studies. Another limitation is the lack of long-term follow-up that may suggest potential consequences of subclinical myositis. As Ozaki and colleagues argue, subclinical myositis may precede clinically overt myositis or cause insidious weakness of muscles. This is in analogy with subclinical synovitis which predicts arthritis development, flare, and radiographic progression.4-6 However, there is currently no evidence that supports the hypotheses for antisynthetase syndrome and unless there is clinical consequence, identifying the subclinical myositis is clinically irrelevant. Muscle is not the only organ in which inflammation occurs in patients with antisynthetase syndrome. Theoretically, the lungs, the skin, and the joints can be a lesion with no correspondent clinical symptoms (Table 1). However, the potential consequences of these lesions and their severity are variable. ILD can be refractory, relapsing, and life-threatening in patients with antisynthetase syndrome7, 8 therefore objective and quantitative assessments for ILD such as pulmonary function test and computed tomography are recommended even in patients without obvious respiratory symptoms to facilitate early intervention.9 On the other hand, the clinical significance of finding asymptomatic skin or articular lesions is less clear. The issue of subclinical myositis in antisynthetase syndrome also raises questions about specificity (ie comparison with other myositis-specific antibodies such as anti-MDA5 antibody) and heterogeneity (ie comparison among individual antibodies such as anti-Jo-1 and anti-PL-7 antibodies). However, capturing the transitional stage from subclinical to clinical disease has provided valuable insight into pathogenesis of other rheumatic diseases.10 The report by Ozaki and colleagues may herald a new era of deeper understanding of myositis-related diseases. KI conceived the idea and all authors discussed and structured the arguments. RM and KK collected data on the case. KI wrote the manuscript and all authors have read and approved the final manuscript. None. Kei Ikeda has received a research grant from Tanabe-Mitsubishi and lecture fees from Eli Lilly, AbbVie, and Astrazeneca. Reika Maezawa has no conflicts of interest to declare. Kazuhiro Kurasawa has received research grants from Pfizer, Eli Lilly, and Astellas. Data sharing is not applicable to this article as no new data were created or analyzed in this study.