TY - JOUR
AU - Yamada, Hidehiro
AB - Abstract Objective: To characterize clinical features of polymyositis/dermatomyositis (PM/DM) patients with different anti-aminoacyl transfer RNA synthetase (ARS) antibodies and their association with anti-Ro52. Methods: Autoantibodies in sera from 97 Japanese patients (36 PM, 56 DM, and 5 clinically amyopathic DM), who satisfied Bohan and Peter or modified Sontheimer's criteria, were characterized by immunoprecipitation and enzyme-linked immunosorbent assay. Clinical information was from medical records. Features associated with different anti-ARS and anti-Ro52 antibodies were analyzed. Results: The prevalence of anti-ARS was similar to other studies (Jo-1, 22%; EJ, 4%; OJ, 1%; PL-12, 1%), except for a high prevalence of anti-PL-7 (12%), which allowed us to characterize patients carrying this specificity. Serum creatine kinase >3000 IU/l was less common in anti-PL-7-positive patients (57%) than anti-Jo-1-positive patients (18%) (p = 0.0328) and was not found in anti-EJ-positive individuals. Interstitial lung disease was common in anti-ARS-positive patients (97%) (p < 0.0001 vs. 48% in anti-ARS-negative). Anti-Ro52 antibodies were frequently detected with anti-ARS (59%) (57% in anti-Jo-1, 67% in anti-PL-7) (vs. 21% in anti-ARS-negative, p < 0.0002). Anti-Ro52 was associated with overlap syndrome (26%) (vs. 7% in anti-Ro52-negative, p = 0.0119). Conclusions: Patients with different anti-ARS in combination with anti-Ro52 appear to be associated with distinctive clinical subsets. Amyopathic dermatomyositis, Anti-aminoacyl transfer RNA synthetase (ARS) antibodies, Anti-PL-7 antibodies, Anti-Ro52 antibodies, Polymyositis/dermatomyositis Introduction Idiopathic inflammatory myopathies (IIM) such as polymyositis (PM) and dermatomyositis (DM) are systemic autoimmune diseases of unknown etiology characterized by skeletal muscle inflammation. Some autoantibodies are tightly linked with specific clinical manifestations of PM/DM and its peculiar subset, clinically amyopathic dermatomyositis (ADM). Anti-aminoacyl tRNA synthetase (ARS) antibodies are a disease marker of PM/DM associated with a unique subset designated as anti-synthetase syndrome, characterized by myositis, interstitial lung disease (ILD), arthritis, mechanic’s hands, and Raynaud’s phenomenon [1,2]. To date, autoantibodies recognizing eight different ARSs, including histidyl (Jo-1), threonyl (PL-7), alanyl (PL-12), glycyl (EJ), isoleucyl (OJ), asparaginyl (KS), tyrosyl (Ha), and phenylalanyl tRNA synthetase (Zo), have been identified [3]. Compared with the analysis on clinical characteristics associated with anti-Jo-1, which is the most prevalent myositis-specific autoantibody found in up to 30% of PM/DM [1,4,5], much less information is available on those associated with anti-ARS antibodies other than anti-Jo-1 because of their low prevalence, usually less than 5% in IIM patients [1,6–10]. Clinical features associated with different anti-ARS antibodies have been considered similar [1,2], however, detailed comparisons suggest that each anti-ARS and anti-Ro52 is associated with distinctive clinical subset. We previously showed unusually high frequency of anti-PL-7 antibodies in PM/DM patients in our cohort, which might be associated with unidentified environmental factors [11]. Additionally, anti-PL-7-positive myositis was characterized by milder muscle involvement than anti-Jo-1-positive myositis [11]. Anti-Ro/SSA is recognized as one of the myositis-related autoantibodies. This specificity has been described as a serological marker for Sjögren syndrome, but is also identified in patients with various systemic rheumatic diseases including PM/DM. Ro52 and Ro60 are not the part of a stable macromolecular complex. Autoantibodies to them have different clinical associations [12]. Now Ro52 is identified as a member of the tripartite motif (TRIM) family of proteins known as TRIM21 that functions as an E3 ubiquitin ligase [13]. One previous study found anti-Ro52 reactivity in 58% of anti-Jo-1-positive sera [14]. Here, we have extended our previous PM/DM cohort for a larger population to further characterize the clinical characteristics in patients with individual anti-ARS and analyzed the association of anti-Ro52 antibodies with anti-ARS. Patients and methods Patients Sera from 97 Japanese patients with IIM were cross-sectionally obtained from rheumatology clinic at St. Marianna University Hospital (Kawasaki, Japan). The protocol was approved by the Ethical Review Board of St. Marianna University School of Medicine. All patients seen from October 2010 to May 2012 and agreed to enroll to the study with written informed consent were included. Among them, 13 patients with IIM, who joined our previous myositis cohort in 2004 [11], were included. Of the 13 patients, 12 carried autoantibodies against Jo-1 (n = 6), PL-7 (n = 3), PL-12 (n = 1), Ku (n = 1), and MJ/NXP-2 (n = 1). The diagnosis of PM/DM was based on the Bohan and Peter criteria [15,16]. Clinically ADM, which is the combination of ADM and hypomyopathic DM (HDM) and is considered to be a peculiar DM subset, was diagnosed by the modified Sontheimer’s definitions [17–19]. Patients without EMG or muscle biopsy was classified as possible clinically ADM if they fulfilled other definitions of ADM/HDM. Patients with premyopathic DM [20] in whom fatal ILD developed within 6 months of their disease course were also included in clinically ADM. Overlap myositis was diagnosed when patients overlapped other systemic rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus, or systemic sclerosis (SSc). Immunoprecipitation The proteins recognized by human sera were evaluated by immunoprecipitation of radiolabeled K562 cell extract and sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) as previously described [21]. Briefly, cells were labeled with 35S-methionine and cysteine, lysed in 0.5M NaCl, 2 mM EDTA, 50 mM Tris, pH 7.5, 0.3% Nonidet P40 (NET/NP40) buffer containing 0.5 mM phenylmethylsulfonyl fluoride and 0.3 TIU/ml aprotinin, and immunoprecipitated with protein A–Sepharose beads coated with 8 μl of human sera. Immunoprecipitates were washed with 0.5M NaCl–NET/NP40 followed by SDS-PAGE and autoradiography. The specificity of the autoantibodies was confirmed using human reference sera [21]. Enzyme-linked immunosorbent assay (ELISA) Antibodies to Jo-1 and Ro52 were tested by ELISA. Jo-1 antigen was purchased from Abazyme (Needham, MA) and Ro52 recombinant protein (a gift from Dr. Edward K.L.Chan, University of Florida) was prepared as described [22]. The wells of microtiter plates (Immobilizer Amino; Nunc Naperville, IL) were coated with recombinant protein followed by blocking with 0.5% bovine serum albumin (BSA)-NET/NP40 for 1 h at room temperature. Patients’ sera were diluted 1:500 with 0.5% BSA-NET/NP40. Goat anti-human IgG antibodies (γ-chain specific; Southern Biotechnology, Birmingham, AL) diluted 1:1000 in 0.5% BSA-NET/NP40 were used as secondary antibodies. A standard curve was made with a serial 1:5 dilution of high-titer prototype serum. The optical density at 405 nm was converted to units using a standard curve. Clinical features All patients received an initial prospective standardized evaluation of organ involvement. Clinical information was collected from medical record and entered to the database. Muscle weakness was evaluated by standard manual muscle testing (MMT). Scoring of muscle weakness on MMT was based on the evaluation of 18 proximal muscle groups as previously described [23]. The responses were rated from 0 (= lowest score) to 5 (= highest score), with a total maximum score of 90. ILD was diagnosed by chest X-ray and high-resolution computed tomography of the lungs. Myocarditis was defined on the basis of new onset of abnormal electrocardiography findings, abnormal echocardiography findings, elevation of serum troponin T, or abnormal multiple patchy defects in the thallium-scintigraphy after ruling out coronary artery disease. Myocarditis was diagnosed when either of the findings was positive. Statistical analysis Statistical analysis was performed using Prism 4.0c for Macintosh (GraphPad Software, Inc, San Diego, CA). For comparisons involving binary data, Fisher’s exact test was used. For comparison involving continuous data, Student’s t-test or Mann–Whitney U test was used. Kruskal–Wallis tests with Dunn’s post-test were applied for multiple comparisons. Results Screening of autoantibodies by immunoprecipitation Frequency of myositis-specific and -associated autoantibodies in 97 patients with IIM is illustrated in Figure 1. Figure 1. Open in new tabDownload slide Frequency of myositis-specific and -associated autoantibodies in 97 patients with PM/DM and clinically ADM. No overlap of anti-ARS antibodies and other myositis-specific and -associated autoantibodies were observed except each one anti-U1RNP-positive patient with anti-EJ and anti-Ku. Figure 1. Open in new tabDownload slide Frequency of myositis-specific and -associated autoantibodies in 97 patients with PM/DM and clinically ADM. No overlap of anti-ARS antibodies and other myositis-specific and -associated autoantibodies were observed except each one anti-U1RNP-positive patient with anti-EJ and anti-Ku. No overlap of anti-ARS and other myositis-specific antibodies were found except 2 of 4 anti-U1RNP-positive patients who had anti-EJ (n = 1) and anti-Ku (n = 1), consistent with previous studies [1]. The prevalence of autoantibodies to ARS such as histidyl (Jo-1) (22%), glycyl (EJ) (4%), isoleucyl (OJ) (1%), and alanyl tRNA synthetase (PL-12) (1%) were comparable to other previous studies from the USA and Japan (6-7,9-10). High prevalence of anti-PL-7 antibodies (12%) in our cohort was persistently observed, which was in contrast to previous studies from other institutes in Japan (12% vs. 2%, p = 0.0342 vs. Hirakata) [9] (12% vs. 5%, p = 0.0806 vs. Sato) [24] as well as other countries such as the USA (12% vs. 4%, p = 0.0341) [6], Italy (12% vs. 0%, p = 0.0038) [25], and Mexico (12% vs. 0%, p = 0.0003) [26]. A total of 39 patients (40%) carried anti-ARS. Other myositis-specific and -associated autoantibodies detected in this study included autoantibodies to Ku (7%), TIF1γ/α (5%), signal recognition particle (SRP) (4%), melanoma differentiation-associated gene 5 (MDA5) (4%), Mi-2 (n = 3) (3%), TIF1β (1%), MJ/NXP-2 (1%), and U1RNP (2%). Demographic and clinical characteristics of 97 myositis patients Table 1 shows demographic and clinical characteristics of 97 patients with IIM, consisted of 56 with DM (58%), 36 with PM (37%), and 5 with clinically ADM (5%). Mean age (SD) was 53 (±13) and 72% were female. Out of them, 13 (13%) had other systemic rheumatic diseases such as RA (10%) or SSc (3%). Three patients with DM (5%) were associated with cancer. Of the 28 patients diagnosed to have myocarditis in our study, abnormalities were found by the examinations such as thallium-scintigraphy (62%), echocardiography (29%), and electrocardiography (46%). Clinical characteristics of patients with clinically ADM, DM, and PM are also compared (Table 1). By definition, patients with clinically ADM had low serum CK levels and almost normal MMT resulting in differences with each of other subtypes of myositis (p < 0.05). Patients with CK < 200 IU/L were more common in DM (25%) than PM (6%) (p = 0.0427). Table 1. Clinical characteristics of patients with clinically ADM, DM, and PM. Total (n = 97) Clinically ADM (n = 5) DM (n = 56) PM (n = 36) Age, mean (±SD) 53 (±13) 51 (±12) 53 (±13) 56 (±13) Sex, female (%) 72 80 73 70 Overlap syndrome (%) 13 0 13 17 Cancer-associated (%) 3 0 5 0 Raynaud’s phenomenon (%) 17 20 20 11 Arthritis (%) 38 0 41 39 Skin ulcers (%) 1 0 2 0 Dysphagia (%) 18 0 19 19 MMT Median (IQR) 84 (74–90) 90 (90–90)a 86 (74–90) 80 (71–90) ≥80 score (%) 64 100b 70 50 ILD (%) 68 80 75c 56 Myocarditis (%) 29 0 29 33 Creatine kinase, median 896 148 755 1594 (IQR) (IU/l) (274–3153) (98–168)d (234–3153) (234–3726) <200 (IU/l) (%) 20 100e 21f 6 >3000 (IU/l) (%) 25 0 25 28 Total (n = 97) Clinically ADM (n = 5) DM (n = 56) PM (n = 36) Age, mean (±SD) 53 (±13) 51 (±12) 53 (±13) 56 (±13) Sex, female (%) 72 80 73 70 Overlap syndrome (%) 13 0 13 17 Cancer-associated (%) 3 0 5 0 Raynaud’s phenomenon (%) 17 20 20 11 Arthritis (%) 38 0 41 39 Skin ulcers (%) 1 0 2 0 Dysphagia (%) 18 0 19 19 MMT Median (IQR) 84 (74–90) 90 (90–90)a 86 (74–90) 80 (71–90) ≥80 score (%) 64 100b 70 50 ILD (%) 68 80 75c 56 Myocarditis (%) 29 0 29 33 Creatine kinase, median 896 148 755 1594 (IQR) (IU/l) (274–3153) (98–168)d (234–3153) (234–3726) <200 (IU/l) (%) 20 100e 21f 6 >3000 (IU/l) (%) 25 0 25 28 All p values are either by Fisher’s exact test or Mann–Whitney U test unless indicated otherwise. ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. a p < 0.05 vs. DM, PM (by the Kruskal–Wallis/Dunn’s multiple comparison test). b p = 0.0567 vs. PM. c p = 0.0690 vs. PM. d p < 0.05 vs. DM, PM (by the Kruskal–Wallis/Dunn’s multiple comparison test). e p = 0.0010 vs. DM. f p = 0.0427 vs. PM. Open in new tab Table 1. Clinical characteristics of patients with clinically ADM, DM, and PM. Total (n = 97) Clinically ADM (n = 5) DM (n = 56) PM (n = 36) Age, mean (±SD) 53 (±13) 51 (±12) 53 (±13) 56 (±13) Sex, female (%) 72 80 73 70 Overlap syndrome (%) 13 0 13 17 Cancer-associated (%) 3 0 5 0 Raynaud’s phenomenon (%) 17 20 20 11 Arthritis (%) 38 0 41 39 Skin ulcers (%) 1 0 2 0 Dysphagia (%) 18 0 19 19 MMT Median (IQR) 84 (74–90) 90 (90–90)a 86 (74–90) 80 (71–90) ≥80 score (%) 64 100b 70 50 ILD (%) 68 80 75c 56 Myocarditis (%) 29 0 29 33 Creatine kinase, median 896 148 755 1594 (IQR) (IU/l) (274–3153) (98–168)d (234–3153) (234–3726) <200 (IU/l) (%) 20 100e 21f 6 >3000 (IU/l) (%) 25 0 25 28 Total (n = 97) Clinically ADM (n = 5) DM (n = 56) PM (n = 36) Age, mean (±SD) 53 (±13) 51 (±12) 53 (±13) 56 (±13) Sex, female (%) 72 80 73 70 Overlap syndrome (%) 13 0 13 17 Cancer-associated (%) 3 0 5 0 Raynaud’s phenomenon (%) 17 20 20 11 Arthritis (%) 38 0 41 39 Skin ulcers (%) 1 0 2 0 Dysphagia (%) 18 0 19 19 MMT Median (IQR) 84 (74–90) 90 (90–90)a 86 (74–90) 80 (71–90) ≥80 score (%) 64 100b 70 50 ILD (%) 68 80 75c 56 Myocarditis (%) 29 0 29 33 Creatine kinase, median 896 148 755 1594 (IQR) (IU/l) (274–3153) (98–168)d (234–3153) (234–3726) <200 (IU/l) (%) 20 100e 21f 6 >3000 (IU/l) (%) 25 0 25 28 All p values are either by Fisher’s exact test or Mann–Whitney U test unless indicated otherwise. ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. a p < 0.05 vs. DM, PM (by the Kruskal–Wallis/Dunn’s multiple comparison test). b p = 0.0567 vs. PM. c p = 0.0690 vs. PM. d p < 0.05 vs. DM, PM (by the Kruskal–Wallis/Dunn’s multiple comparison test). e p = 0.0010 vs. DM. f p = 0.0427 vs. PM. Open in new tab Clinical characteristics of patients with myositis according to autoantibody specificities Clinical characteristics of myositis patients according to autoantibody specificity are summarized in Table 2. Although a female predominance (72%) was seen overall in patients with IIM, the percentage of male patients was higher in the anti-ARS-positive group (44%) compared with the myositis-related autoantibodies-negative group (None) (16%) (p = 0.0195). As previously shown [27], all patients with anti-TIF1γ/α antibodies were DM (p = 0.0473 vs. 45% in none). Compared with myositis-related antibodies-negative patients (none) and with anti-ARS-positive patients, anti-Ku-positive patients more commonly exhibited overlapping features with other systemic rheumatic diseases characterized by higher frequency of Raynaud’s phenomenon (57%) (p = 0.0458 vs. 18% in anti-ARS, p = 0.0245 vs. 13% in none) and arthritis (86%) (p = 0.0284 vs. 32% in none). All patients having anti-SRP exhibited severe muscle weakness (MMT scores < 80). These findings were also consistent with previous observations [28,29]. No patients possessing anti-Mi-2 showed MMT scores <80 (p = 0.0278 vs. 100% in anti-SRP). As high as 97% and 86% of the patients carrying anti-ARS and anti-Ku, respectively, had ILD. The frequency of ILD in patients with anti-ARS was high compared with those with anti-TIF1γ/α (20%) (p = 0.0002), anti-SRP (25%) (p = 0.0013), or those without myositis-related antibodies (none) (48%) (p < 0.0001). Median serum CK levels were higher in anti-ARS- and anti-SRP-positive patients compared with myositis-related antibodies-negative patients (none) (p < 0.05). Patients possessing anti-SRP antibodies had higher levels of serum CK than those possessing anti-MDA5 (p < 0.05). Frequency of serum CK > 3000 IU/l was significantly lower in patients carrying no myositis-related antibodies (none) (3%) when compared with those carrying anti-ARS (39%) (p = 0.0004) and with those carrying anti-SRP (50%) (p = 0.0290). Table 2. Clinical characteristics of myositis patients according to antibody specificities. Anti-ARS (n = 39) Anti-Ku (n = 7) Anti-TIF1γ/α (n = 5) Anti-SRP (n = 4) Anti-MDA5 (n = 4) Anti-Mi-2 (n = 3) None (n = 31) Age, mean (±SD) 54 (±12) 46 (±14) 51 (±10) 52 (±19) 44 (±9) 65 (±12) 54 (±13) Sex, female (%) 56a 86 60 75 75 100 84 Type of myositis Clinically ADM (%) 3 0 0 0 50 33 3 DM (%) 69 43 100b 0 50 67 45 PM (%) 28 57 0 100 0 0 52 Overlap syndrome (%) 15 29 0 0 0 0 16 Cancer-associated (%) 5 0 20 0 0 0 0 Raynaud’s phenomenon (%) 18 57c 0 0 0 33 13 Arthritis (%) 44 86d 20 25 25 33 32 Skin ulcers (%) 3 0 0 0 0 0 0 Dysphagia (%) 18 0 40 50 25 0 10 MMT Median (IQR) 85 (77–90) 79 (76–90) 85 (66–90) 67 (62–71) 82 (70–90) 86 (82–90) 86 (74–90) ≥80 score (%) 72 50 50 0e 50 100 64 ILD (%) 97f 86g 20 25 75 67 48 Myocarditis (%) 33 14 20 50 25 33 26 Creatine kinase, median 1594h 1518i 382 3000j 124 492 305 (IQR) (IU/l) (451–4163) (698–6062) (122–3062) (1734–17,899) (67–209) (170–4380) (126–1607) <200 (IU/l) (%) 10k 0 40 0 75 33 29 >3000 (IU/l) (%) 39l 29m 20 50n 0 33 3 Anti-ARS (n = 39) Anti-Ku (n = 7) Anti-TIF1γ/α (n = 5) Anti-SRP (n = 4) Anti-MDA5 (n = 4) Anti-Mi-2 (n = 3) None (n = 31) Age, mean (±SD) 54 (±12) 46 (±14) 51 (±10) 52 (±19) 44 (±9) 65 (±12) 54 (±13) Sex, female (%) 56a 86 60 75 75 100 84 Type of myositis Clinically ADM (%) 3 0 0 0 50 33 3 DM (%) 69 43 100b 0 50 67 45 PM (%) 28 57 0 100 0 0 52 Overlap syndrome (%) 15 29 0 0 0 0 16 Cancer-associated (%) 5 0 20 0 0 0 0 Raynaud’s phenomenon (%) 18 57c 0 0 0 33 13 Arthritis (%) 44 86d 20 25 25 33 32 Skin ulcers (%) 3 0 0 0 0 0 0 Dysphagia (%) 18 0 40 50 25 0 10 MMT Median (IQR) 85 (77–90) 79 (76–90) 85 (66–90) 67 (62–71) 82 (70–90) 86 (82–90) 86 (74–90) ≥80 score (%) 72 50 50 0e 50 100 64 ILD (%) 97f 86g 20 25 75 67 48 Myocarditis (%) 33 14 20 50 25 33 26 Creatine kinase, median 1594h 1518i 382 3000j 124 492 305 (IQR) (IU/l) (451–4163) (698–6062) (122–3062) (1734–17,899) (67–209) (170–4380) (126–1607) <200 (IU/l) (%) 10k 0 40 0 75 33 29 >3000 (IU/l) (%) 39l 29m 20 50n 0 33 3 All p values are either by Fisher’s exact test or Mann–Whitney U test unless the statistical method is indicated. ARS, aminoacyl tRNA synthetase; SRP, signal recognition particle; MDA5, melanoma differentiation-associated protein 5; ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. a p = 0.0195 vs. none. b p = 0.0473 vs. none. c p = 0.0458 vs. anti-ARS, p = 0.0245 vs. none. d p = 0.0284 vs. none, p = 0.0525 vs. anti-ARS. e p = 0.0278 vs. none, p = 0.0667 vs. anti-Mi-2. f p < 0.0001 vs. none, p = 0.0002 vs. anti-TIF1γ/α, p = 0.0013 vs. anti-SRP. g p = 0.0720 vs. anti- TIF1γ/α, p = 0.0879 vs. anti-SRP. h p <0.05 vs. none (by the Kruskal–Wallis/Dunn’s multiple comparison test). i p = 0.0061 vs. anti-MDA5, p = 0.0190 vs. none. j p <0.05 vs. anti-MDA5 (by the Kruskal–Wallis/Dunn’s multiple comparison test), p = 0.0111 vs. None, p = 0.0195 vs. anti- TIF1γ/α. k p = 0.0641 vs. none. l p = 0.0004 vs. none. m p = 0.0813 vs. none. n p = 0.0290 vs. none. Open in new tab Table 2. Clinical characteristics of myositis patients according to antibody specificities. Anti-ARS (n = 39) Anti-Ku (n = 7) Anti-TIF1γ/α (n = 5) Anti-SRP (n = 4) Anti-MDA5 (n = 4) Anti-Mi-2 (n = 3) None (n = 31) Age, mean (±SD) 54 (±12) 46 (±14) 51 (±10) 52 (±19) 44 (±9) 65 (±12) 54 (±13) Sex, female (%) 56a 86 60 75 75 100 84 Type of myositis Clinically ADM (%) 3 0 0 0 50 33 3 DM (%) 69 43 100b 0 50 67 45 PM (%) 28 57 0 100 0 0 52 Overlap syndrome (%) 15 29 0 0 0 0 16 Cancer-associated (%) 5 0 20 0 0 0 0 Raynaud’s phenomenon (%) 18 57c 0 0 0 33 13 Arthritis (%) 44 86d 20 25 25 33 32 Skin ulcers (%) 3 0 0 0 0 0 0 Dysphagia (%) 18 0 40 50 25 0 10 MMT Median (IQR) 85 (77–90) 79 (76–90) 85 (66–90) 67 (62–71) 82 (70–90) 86 (82–90) 86 (74–90) ≥80 score (%) 72 50 50 0e 50 100 64 ILD (%) 97f 86g 20 25 75 67 48 Myocarditis (%) 33 14 20 50 25 33 26 Creatine kinase, median 1594h 1518i 382 3000j 124 492 305 (IQR) (IU/l) (451–4163) (698–6062) (122–3062) (1734–17,899) (67–209) (170–4380) (126–1607) <200 (IU/l) (%) 10k 0 40 0 75 33 29 >3000 (IU/l) (%) 39l 29m 20 50n 0 33 3 Anti-ARS (n = 39) Anti-Ku (n = 7) Anti-TIF1γ/α (n = 5) Anti-SRP (n = 4) Anti-MDA5 (n = 4) Anti-Mi-2 (n = 3) None (n = 31) Age, mean (±SD) 54 (±12) 46 (±14) 51 (±10) 52 (±19) 44 (±9) 65 (±12) 54 (±13) Sex, female (%) 56a 86 60 75 75 100 84 Type of myositis Clinically ADM (%) 3 0 0 0 50 33 3 DM (%) 69 43 100b 0 50 67 45 PM (%) 28 57 0 100 0 0 52 Overlap syndrome (%) 15 29 0 0 0 0 16 Cancer-associated (%) 5 0 20 0 0 0 0 Raynaud’s phenomenon (%) 18 57c 0 0 0 33 13 Arthritis (%) 44 86d 20 25 25 33 32 Skin ulcers (%) 3 0 0 0 0 0 0 Dysphagia (%) 18 0 40 50 25 0 10 MMT Median (IQR) 85 (77–90) 79 (76–90) 85 (66–90) 67 (62–71) 82 (70–90) 86 (82–90) 86 (74–90) ≥80 score (%) 72 50 50 0e 50 100 64 ILD (%) 97f 86g 20 25 75 67 48 Myocarditis (%) 33 14 20 50 25 33 26 Creatine kinase, median 1594h 1518i 382 3000j 124 492 305 (IQR) (IU/l) (451–4163) (698–6062) (122–3062) (1734–17,899) (67–209) (170–4380) (126–1607) <200 (IU/l) (%) 10k 0 40 0 75 33 29 >3000 (IU/l) (%) 39l 29m 20 50n 0 33 3 All p values are either by Fisher’s exact test or Mann–Whitney U test unless the statistical method is indicated. ARS, aminoacyl tRNA synthetase; SRP, signal recognition particle; MDA5, melanoma differentiation-associated protein 5; ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. a p = 0.0195 vs. none. b p = 0.0473 vs. none. c p = 0.0458 vs. anti-ARS, p = 0.0245 vs. none. d p = 0.0284 vs. none, p = 0.0525 vs. anti-ARS. e p = 0.0278 vs. none, p = 0.0667 vs. anti-Mi-2. f p < 0.0001 vs. none, p = 0.0002 vs. anti-TIF1γ/α, p = 0.0013 vs. anti-SRP. g p = 0.0720 vs. anti- TIF1γ/α, p = 0.0879 vs. anti-SRP. h p <0.05 vs. none (by the Kruskal–Wallis/Dunn’s multiple comparison test). i p = 0.0061 vs. anti-MDA5, p = 0.0190 vs. none. j p <0.05 vs. anti-MDA5 (by the Kruskal–Wallis/Dunn’s multiple comparison test), p = 0.0111 vs. None, p = 0.0195 vs. anti- TIF1γ/α. k p = 0.0641 vs. none. l p = 0.0004 vs. none. m p = 0.0813 vs. none. n p = 0.0290 vs. none. Open in new tab Clinical characteristics of patients with anti-ARS antibodies Table 3 shows clinical characteristics of patients having the anti-ARS compared with those having no anti-ARS. Consistent with previous reports on anti-synthetase syndrome [1,6,11], all except one with anti-ARS had ILD (97%) while only 28% of patients without anti-ARS had ILD (p < 0.0001). Serum CK levels were higher in patients possessing anti-ARS than those possessing no anti-ARS (p = 0.0122). Prevalence of patients with serum CK > 3000 IU/l was higher in patients with anti-ARS (39%) than those without anti-ARS (16%) (p = 0.0157). Then we compared clinical characteristics among patients carrying anti-Jo-1, anti-PL-7, and anti-EJ. Though 29% and 50% of the anti-Jo-1 and anti-PL-7-positive patients had myocarditis, none of the anti-EJ-positive patients carried this complication. Serum CK levels were higher in the anti-Jo-1 group than in the anti-PL-7 group, though it did not reach statistical significance (p = 0.0866). Serum CK levels > 3000 IU/l was more frequent in patients having anti-Jo-1 (57%) compared with those having anti-PL-7 (17%) (p = 0.0328). None with anti-EJ exhibited serum CK levels > 3000 IU/l (p = 0.0957 vs. anti-Jo-1). Table 3. Clinical characteristics of patients with anti-ARS antibodies. Anti-Jo-1 (n = 21) Anti-PL-7 (n = 12) Anti-EJ (n = 4) Anti-ARS-positive (n = 39) Anti-ARS-negative (n = 58) Age, mean (±SD) 54 (±11) 54 (±14) 55 (±8) 54 (±12) 52 (±14) Sex, female (%) 48a 75 75 56b 83 Type of myositis Clinically ADM (%) 0 0 25 3 7 DM (%) 62 75 75 69 50 PM (%) 38 25 0 28 43 Overlap syndrome (%) 19 17 0 15 12 Cancer-associated (%) 0 8 25 5 2 Raynaud’s phenomenon (%) 10 25 50 18 16 Arthritis (%) 57 25 25 44 35 Skin ulcers (%) 5 0 0 3 0 Dysphagia (%) 19 18 25 18 18 MMT Median (IQR) 85 (71–90) 84 (82–90) 90 (90–90) 85 (77–90) 82 (73–90) ≥80 score (%) 65 90 75 72 61 ILD (%) 100c 92d 100 97e 48 Myocarditis (%) 29 50 0 33 26 Creatine kinase, median 3726 942 715 1594 627 (IQR) (IU/l) (756–5534)f (360–2679) (246–1308) (451–4163) (168–1998) <200 (IU/l) (%) 5 8 25 10 26 >3000 (IU/l) (%) 57g 17 0h 39 i 16 Anti-Jo-1 (n = 21) Anti-PL-7 (n = 12) Anti-EJ (n = 4) Anti-ARS-positive (n = 39) Anti-ARS-negative (n = 58) Age, mean (±SD) 54 (±11) 54 (±14) 55 (±8) 54 (±12) 52 (±14) Sex, female (%) 48a 75 75 56b 83 Type of myositis Clinically ADM (%) 0 0 25 3 7 DM (%) 62 75 75 69 50 PM (%) 38 25 0 28 43 Overlap syndrome (%) 19 17 0 15 12 Cancer-associated (%) 0 8 25 5 2 Raynaud’s phenomenon (%) 10 25 50 18 16 Arthritis (%) 57 25 25 44 35 Skin ulcers (%) 5 0 0 3 0 Dysphagia (%) 19 18 25 18 18 MMT Median (IQR) 85 (71–90) 84 (82–90) 90 (90–90) 85 (77–90) 82 (73–90) ≥80 score (%) 65 90 75 72 61 ILD (%) 100c 92d 100 97e 48 Myocarditis (%) 29 50 0 33 26 Creatine kinase, median 3726 942 715 1594 627 (IQR) (IU/l) (756–5534)f (360–2679) (246–1308) (451–4163) (168–1998) <200 (IU/l) (%) 5 8 25 10 26 >3000 (IU/l) (%) 57g 17 0h 39 i 16 All p values are either by Fisher’s exact test or Mann–Whitney U test unless the statistical method is indicated. Jo-1, histidyl; PL-7, threonyl; EJ, glycyl; ARS, aminoacyl tRNA synthetase; ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. a p = 0.0034 vs. anti-ARS-negative. b p = 0.0059 vs. anti-ARS-negative. c p < 0.0001 vs. anti-ARS-negative. d p = 0.0110 vs. anti-ARS-negative. e p < 0.0001 vs. anti-ARS-negative. f p <0.05 vs. anti-ARS negative (by the Kruskal–Wallis/Dunn’s multiple comparison test), P = 0.0886 vs. anti-PL-7. g p = 0.0328 vs. anti-PL-7. h p = 0.0957 vs. anti-Jo-1. i p = 0.0157 vs. anti-ARS-negative. Open in new tab Table 3. Clinical characteristics of patients with anti-ARS antibodies. Anti-Jo-1 (n = 21) Anti-PL-7 (n = 12) Anti-EJ (n = 4) Anti-ARS-positive (n = 39) Anti-ARS-negative (n = 58) Age, mean (±SD) 54 (±11) 54 (±14) 55 (±8) 54 (±12) 52 (±14) Sex, female (%) 48a 75 75 56b 83 Type of myositis Clinically ADM (%) 0 0 25 3 7 DM (%) 62 75 75 69 50 PM (%) 38 25 0 28 43 Overlap syndrome (%) 19 17 0 15 12 Cancer-associated (%) 0 8 25 5 2 Raynaud’s phenomenon (%) 10 25 50 18 16 Arthritis (%) 57 25 25 44 35 Skin ulcers (%) 5 0 0 3 0 Dysphagia (%) 19 18 25 18 18 MMT Median (IQR) 85 (71–90) 84 (82–90) 90 (90–90) 85 (77–90) 82 (73–90) ≥80 score (%) 65 90 75 72 61 ILD (%) 100c 92d 100 97e 48 Myocarditis (%) 29 50 0 33 26 Creatine kinase, median 3726 942 715 1594 627 (IQR) (IU/l) (756–5534)f (360–2679) (246–1308) (451–4163) (168–1998) <200 (IU/l) (%) 5 8 25 10 26 >3000 (IU/l) (%) 57g 17 0h 39 i 16 Anti-Jo-1 (n = 21) Anti-PL-7 (n = 12) Anti-EJ (n = 4) Anti-ARS-positive (n = 39) Anti-ARS-negative (n = 58) Age, mean (±SD) 54 (±11) 54 (±14) 55 (±8) 54 (±12) 52 (±14) Sex, female (%) 48a 75 75 56b 83 Type of myositis Clinically ADM (%) 0 0 25 3 7 DM (%) 62 75 75 69 50 PM (%) 38 25 0 28 43 Overlap syndrome (%) 19 17 0 15 12 Cancer-associated (%) 0 8 25 5 2 Raynaud’s phenomenon (%) 10 25 50 18 16 Arthritis (%) 57 25 25 44 35 Skin ulcers (%) 5 0 0 3 0 Dysphagia (%) 19 18 25 18 18 MMT Median (IQR) 85 (71–90) 84 (82–90) 90 (90–90) 85 (77–90) 82 (73–90) ≥80 score (%) 65 90 75 72 61 ILD (%) 100c 92d 100 97e 48 Myocarditis (%) 29 50 0 33 26 Creatine kinase, median 3726 942 715 1594 627 (IQR) (IU/l) (756–5534)f (360–2679) (246–1308) (451–4163) (168–1998) <200 (IU/l) (%) 5 8 25 10 26 >3000 (IU/l) (%) 57g 17 0h 39 i 16 All p values are either by Fisher’s exact test or Mann–Whitney U test unless the statistical method is indicated. Jo-1, histidyl; PL-7, threonyl; EJ, glycyl; ARS, aminoacyl tRNA synthetase; ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. a p = 0.0034 vs. anti-ARS-negative. b p = 0.0059 vs. anti-ARS-negative. c p < 0.0001 vs. anti-ARS-negative. d p = 0.0110 vs. anti-ARS-negative. e p < 0.0001 vs. anti-ARS-negative. f p <0.05 vs. anti-ARS negative (by the Kruskal–Wallis/Dunn’s multiple comparison test), P = 0.0886 vs. anti-PL-7. g p = 0.0328 vs. anti-PL-7. h p = 0.0957 vs. anti-Jo-1. i p = 0.0157 vs. anti-ARS-negative. Open in new tab Prevalence of anti-Ro52 in patients with or without anti-ARS Prevalence of anti-Ro52 according to each of myositis-related antibodies is presented in Figure 2. As expected, frequency of anti-Ro52 antibodies in patients carrying anti-Jo-1 antibodies (57%) was higher compared with those carrying non-anti-ARS myositis-related autoantibodies such as anti-Ku, anti-TIF1γ/α, anti-MDA5, anti-SRP, anti-Mi-2, anti-U1RNP, anti-TIF1β, and anti-MJ/NXP2 (non-anti-ARS group) (22%) (p = 0.00180) and with those carrying no myositis-related antibodies (none) (19%) (p = 0.0076). Interestingly, higher frequency of anti-Ro52 antibodies was also seen in patients with anti-PL-7 (67%) than in those with non-anti-ARS group (22%) (p = 0.0123) and in those without myositis-related antibodies (none) (19%) (p = 0.0085). Anti-Ro52 was also detected in half of the patients possessing anti-EJ (50%). As a whole, frequency of anti-Ro52 antibodies was significantly higher in the anti-ARS-positive group (59%) than in the anti-ARS-negative group (21%) (p = 0.0002) (see Figure 2 for details). Figure 2. Open in new tabDownload slide Frequency of anti-Ro52 in patients with myositis-related antibodies. Twelve of 21 (57%) patients with anti-Jo-1 and 8 of 12 patients (67%) with anti-PL-7 had anti-Ro52 antibodies, respectively. Additionally, 50% of the patients with anti-EJ also had anti-Ro52. Fifty-nine percent of the patients with anti-ARS had anti-Ro52 vs. only 22% with non-anti-ARS myositis-related autoantibodies such as anti-Ku, anti-TIF1γ/α, anti-MDA5, anti-SRP, anti-Mi-2, anti-U1RNP, anti-TIF1β, and anti-MJ/NXP2 (non-anti-ARS group) (p = 0.0051) and 19% in no myositis-related antibodies (none) (p = 0.0013). ap = 0.0051 vs. non-anti-ARS, p = 0.0431 vs. anti-Ku, p = 0.0393 vs. anti-MDA5, p = 0.0013 vs. None. bp = 0.0180 vs. Non-anti-ARS. cp = 0.0123 vs. non-anti-ARS, p = 0.0085 vs. none. Figure 2. Open in new tabDownload slide Frequency of anti-Ro52 in patients with myositis-related antibodies. Twelve of 21 (57%) patients with anti-Jo-1 and 8 of 12 patients (67%) with anti-PL-7 had anti-Ro52 antibodies, respectively. Additionally, 50% of the patients with anti-EJ also had anti-Ro52. Fifty-nine percent of the patients with anti-ARS had anti-Ro52 vs. only 22% with non-anti-ARS myositis-related autoantibodies such as anti-Ku, anti-TIF1γ/α, anti-MDA5, anti-SRP, anti-Mi-2, anti-U1RNP, anti-TIF1β, and anti-MJ/NXP2 (non-anti-ARS group) (p = 0.0051) and 19% in no myositis-related antibodies (none) (p = 0.0013). ap = 0.0051 vs. non-anti-ARS, p = 0.0431 vs. anti-Ku, p = 0.0393 vs. anti-MDA5, p = 0.0013 vs. None. bp = 0.0180 vs. Non-anti-ARS. cp = 0.0123 vs. non-anti-ARS, p = 0.0085 vs. none. Clinical features were compared between patients with vs. without anti-Ro52 (Table 4). Overlap syndrome (7 patients with RA and 2 with SSc) was more frequently found (26% vs. 7%, p = 0.0119) and prevalence of ILD appeared to be higher in anti-Ro52-positive patients (80% vs. 61%, p = 0.0714). When 12 patients with and 46 without anti-Ro52 were compared after excluding 39 carrying anti-ARS, higher frequency of overlap syndrome in the anti-Ro52-positive group than in the anti-Ro52-negative group was still observed (33% vs. 7%, p = 0.0279). The prevalence of ILD was not significantly different between anti-Ro52-positive patients (42%) and anti-Ro52-negative patients (50%) after excluding patients with anti-ARS (p = 0.7492). Table 4. Clinical characteristics in patients with anti-Ro52 antibodies. Anti-Ro52- positive (n = 35) Anti-Ro52- negative (n = 62) p Age, mean (±SD) 55 (±14) 52 (±13) ns Sex, female (%) 71 73 ns Type of myositis Clinically ADM (%) 3 7 ns DM (%) 57 58 ns PM (%) 40 36 ns Overlap syndrome (%) 26 7 0.0119 Cancer-associated (%) 6 2 ns Raynaud’s phenomenon (%) 23 13 ns Arthritis (%) 43 36 ns Skin ulcers (%) 3 0 ns Dysphagia (%) 17 18 ns MMT Median (IQR) 88 (76–90) 83 (74–90) ns ≥ 80 score (%) 72 60 ns ILD (%) 80 61 0.0714 Myocarditis (%) 37 24 ns Creatine kinase, median 923 890 ns (IQR) (IU/l) (307–2246) (220–3260) ns <200 (IU/l) (%) 14 23 ns >3000 (IU/l) (%) 23 21 Anti-Ro52- positive (n = 35) Anti-Ro52- negative (n = 62) p Age, mean (±SD) 55 (±14) 52 (±13) ns Sex, female (%) 71 73 ns Type of myositis Clinically ADM (%) 3 7 ns DM (%) 57 58 ns PM (%) 40 36 ns Overlap syndrome (%) 26 7 0.0119 Cancer-associated (%) 6 2 ns Raynaud’s phenomenon (%) 23 13 ns Arthritis (%) 43 36 ns Skin ulcers (%) 3 0 ns Dysphagia (%) 17 18 ns MMT Median (IQR) 88 (76–90) 83 (74–90) ns ≥ 80 score (%) 72 60 ns ILD (%) 80 61 0.0714 Myocarditis (%) 37 24 ns Creatine kinase, median 923 890 ns (IQR) (IU/l) (307–2246) (220–3260) ns <200 (IU/l) (%) 14 23 ns >3000 (IU/l) (%) 23 21 All p values are either by Fisher’s exact test or Mann–Whitney U test. ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. Open in new tab Table 4. Clinical characteristics in patients with anti-Ro52 antibodies. Anti-Ro52- positive (n = 35) Anti-Ro52- negative (n = 62) p Age, mean (±SD) 55 (±14) 52 (±13) ns Sex, female (%) 71 73 ns Type of myositis Clinically ADM (%) 3 7 ns DM (%) 57 58 ns PM (%) 40 36 ns Overlap syndrome (%) 26 7 0.0119 Cancer-associated (%) 6 2 ns Raynaud’s phenomenon (%) 23 13 ns Arthritis (%) 43 36 ns Skin ulcers (%) 3 0 ns Dysphagia (%) 17 18 ns MMT Median (IQR) 88 (76–90) 83 (74–90) ns ≥ 80 score (%) 72 60 ns ILD (%) 80 61 0.0714 Myocarditis (%) 37 24 ns Creatine kinase, median 923 890 ns (IQR) (IU/l) (307–2246) (220–3260) ns <200 (IU/l) (%) 14 23 ns >3000 (IU/l) (%) 23 21 Anti-Ro52- positive (n = 35) Anti-Ro52- negative (n = 62) p Age, mean (±SD) 55 (±14) 52 (±13) ns Sex, female (%) 71 73 ns Type of myositis Clinically ADM (%) 3 7 ns DM (%) 57 58 ns PM (%) 40 36 ns Overlap syndrome (%) 26 7 0.0119 Cancer-associated (%) 6 2 ns Raynaud’s phenomenon (%) 23 13 ns Arthritis (%) 43 36 ns Skin ulcers (%) 3 0 ns Dysphagia (%) 17 18 ns MMT Median (IQR) 88 (76–90) 83 (74–90) ns ≥ 80 score (%) 72 60 ns ILD (%) 80 61 0.0714 Myocarditis (%) 37 24 ns Creatine kinase, median 923 890 ns (IQR) (IU/l) (307–2246) (220–3260) ns <200 (IU/l) (%) 14 23 ns >3000 (IU/l) (%) 23 21 All p values are either by Fisher’s exact test or Mann–Whitney U test. ADM, amyopathic dermatomyositis; DM, dermatomyositis; PM, polymyositis; MMT, manual muscle testing; ILD, interstitial lung disease. Open in new tab Discussion The frequent association of overlap syndrome with PM/DM has been shown among anti-Ro52-positive patients with SSc [30]. Here, we showed that patients with anti-Ro52 tended to have overlap features among IIM patients. Higher frequency of overlap syndrome in the anti-Ro52-positive group than in the anti-Ro52-negative group was still observed even after excluding patients with anti-ARS, indicating anti-Ro52 had the potential to be a good serologic marker for overlap syndrome [30]. The association of anti-Ro52 with ILD remains to be clarified among IIM patients; however, it should be evaluated carefully because anti-Ro52-positive patients often have co-existing anti-ARS, which is strongly associated with ILD. Though our current study implied a trend to higher prevalence of ILD in the anti-Ro52-positive group than in the anti-Ro52-negative group, the prevalence of ILD was comparable between patients with (42%) and without anti-Ro52 (50%) after excluding anti-ARS-positive patients. Frequent co-occurrence of anti-Ro52 and anti-Jo-1 antibodies in myositis patients was reported [12,14]. In the present study, anti-Ro52 was frequently detected not only with anti-Jo-1 but also with anti-PL-7. The association of anti-Ro52 and anti-ARS needs to be further elucidated with extended patient population since one study from Europe reported only 22% prevalence of coexistent anti-Ro52 in anti-PL-7-positive patients [31]. Previously, Sato et al. analyzed clinical characteristics in 7 Japanese patients with anti-PL-7 and found an association with PM-SSc overlap syndrome (71%) or sclerodactyly (14%). Only one (14%) had typical skin manifestation of DM [24]. In the present study, only 17% of anti-PL-7-positive patients overlapped with RA or SSc. In addition, 75% of the patients showed typical skin manifestation of DM in contrast to their study. Anti-Ro52 may be associated with a particular clinical subset in anti-ARS-positive patients and this may partly explain the differences in clinical characteristics among anti-PL-7-positive patients between the 2 studies. Anti-ARS antibodies are found in patients with a distinct clinical phenotype known as anti-synthetase syndrome, comprising myositis, ILD, arthritis, fever, Raynaud’s phenomenon, and mechanic’s hands [1,2]. Although the similarity of the clinical features among patients with different anti-ARS is striking, recent detailed analyses have shown that individual anti-ARS was associated with a unique subset of the disease [11,24]. We previously reported that muscle weakness was milder in anti-PL-7-positive patients than in anti-Jo-1-negative patients [11]. Marie et al. recently confirmed our observation that myalgia and muscle weakness were milder in patients carrying anti-PL-7/PL-12 compared with those carrying anti-Jo-1 [32]. The difference of serum CK levels was still observed in this study between anti-PL-7-positive and anti-Jo-1-postive patients. Additionally, we showed in the study that none of the patients with anti-EJ antibodies had serum CK levels higher than 3000 IU/l, which indicated that muscle involvement in anti-EJ-positive patients could be milder than anti-Jo-1-positive and even than anti-PL-7-positive patients. Extramuscular involvement in IIM such as ILD and myocarditis remains to be characterized among patients with each anti-ARS. Though ILD is a common finding in patients with anti-ARS, clinical characteristics of ILD are reported to be heterogeneous by each anti-ARS. Aggarwal et al. found that patients possessing anti-ARS other than anti-Jo-1 carried worse survival compared with those possessing anti-Jo-1 in the USA [5], suggesting individual anti-ARS may be associated with different severity of ILD. This cross-sectional study could not provide the severity and impact of ILD on survival of each anti-ARS in our patient population. Further studies regarding the severity of ILD within anti-ARS-positive patients may contribute to more appropriate therapeutic approach in each anti-ARS positive subset. Less attention has been paid to myocardial involvement because clinically apparent myocarditis is relatively infrequent in IIM [33]. Since cardiac involvement is associated with reduced survival in IIM [34], it is important to identify the risk factors for developing heart failure among IIM patients. The present study revealed that as high as 30–50% of the patients with anti-Jo-1 and anti-PL-7 had myocardial involvement, whereas none of 4 patients with anti-EJ carried this complication. It may suggest that the frequency or the severity of myocarditis is different in patients with different anti-ARS though it needs to be confirmed with extended patient population. In conclusion, each anti-ARS and anti-Ro52 was associated with a unique subset of the disease. Anti-Ro52 was frequently detected with anti-PL-7 as well as anti-Jo-1 and was associated with overlap syndrome. Acknowledgments We would like to thank Ms. Yuriko Morosawa, a medical coordinator in Rheumatology and Allergology, for assisting the study. Conflict of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. References Targoff IN Update on myositis-specific and myositis-associated autoantibodies. 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TI - Clinical subsets associated with different anti-aminoacyl transfer RNA synthetase antibodies and their association with coexisting anti-Ro52
JF - Modern Rheumatology
DO - 10.3109/14397595.2015.1091155
DA - 2016-05-03
UR - https://www.deepdyve.com/lp/oxford-university-press/clinical-subsets-associated-with-different-anti-aminoacyl-transfer-rna-fuxaDY02dd
SP - 403
EP - 409
VL - 26
IS - 3
DP - DeepDyve
ER -