Clinical phenotype, autoantibody profile and HLA-DR-type in Vietnamese patients with idiopathic inflammatory myopathies

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In patients of Kinh ethnicity, the most frequent myositis specific autoantibody was anti-signal recognition particle. Sir, We investigated clinical phenotypes, autoantibody profiles and HLA-DRB1 genotypes and their relationships in a Vietnamese cohort of patients with idiopathic inflammatory myopathies (IIM) of Kinh ethnicity, the predominate ethnic group in Vietnam. A cross-sectional study was performed including patients having probable or definite PM or DM seen at the Rheumatology Department, Bach Mai Hospital, Hanoi, Vietnam, between March 2011 and December 2013 [1]. Patients with overlap syndromes were excluded. Clinical data on muscle performance, extra-muscular involvement, disease activity according to the international myositis assessment and clinical studies were collected [2]. Myositis specific and associated autoantibodies (MSA and MAA) were tested using a line blot assay (myositis panel 4, Euroimmun, Lübeck, Germany) including: anti-Jo1 (histidyl), anti-PL-7 (threonyl), anti-PL-12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl-tRNAsynthetase), anti-SRP (signal recognition particle), anti-Mi-2 (alpha and beta chains investigated separately), anti-MDA5, anti-TIF-1 gamma, anti-NXP2, anti-SAE, anti PM-Scl (100 kDa and 75 kDa units tested separately) and anti-Ku [3]. HLA-DRB1 genotyping was performed using the Olerup SSP method including DRB1*01, DRB1*03, DRB1*04, DRB1*07, DRB1*08, DRB1*09, DRB1*10, DRB1*11, DRB1*12, DRB1*13, DRB1*14, DRB1*15 and DRB1*16 [4]. Imputation of HLA-DRB1 for control individuals from a genome wide association study (GWAS) was performed with SNP2HLA software [5]. Sera and DNA were collected from 116 healthy controls, 69 women and 47 men, recruited from a community in North Vietnam, mean age: 50.3 years ± 13.2. For the genetic association study, we also used publicly available data from a recent GWAS including 2019 Vietnamese individuals as controls [6]. The study complied with the Declaration of Helsinki and was approved by the local ethics committee at Hanoi Medical University. Signed informed consent was obtained from all subjects. Consecutive patients (n = 151; 116 women) with PM (n = 88)/DM (n = 63), with a predominance of Kinh ethnicity, mean age of 42.3 ± 15.5 years and mean disease duration of 21.9 ± s.d. 27.9 months were enroled. At the time of investigation, muscle weakness was present in 97% with a mean manual muscle test (MMT)-8 of 57.1 (± 17.6). Extra-muscular manifestations were found in 84%, the most frequent being constitutional symptoms, dysphagia and arthralgia/arthritis. Interstitial lung disease (ILD) was present in 34%, and pulmonary hypertension in 44%. There was no association between pulmonary hypertension and ILD. Other cardiovascular manifestations were present in 21%, the most frequent being pericarditis (15%), whereas myocarditis and arrhythmia were less common. In patients with DM, erythroderma was the most common cutaneous manifestation (Table 1), followed by heliotrope rash, Gottron’s papules, erythematous rashes (43%) and periungual telangiectasia (43%). Cutaneous ulcerations occurred in 13 patients with DM (21%). Clinical and laboratory features, frequency of autoantibodies in the Vietnamese patient population at time of study Values are presented as n (%) unless stated otherwise. P-values <0.05 were considered to be statistically significant. Bold indicates statistical significance. MSA: myositis specific antibody; MAA: myositis associated antibody; MYOACT: Myositis Disease Activity Assessment VAS; MITAX: Myositis Intention-to-Treat Activity Index; NS: non- significant; ref: reference values. Clinical and laboratory features, frequency of autoantibodies in the Vietnamese patient population at time of study Values are presented as n (%) unless stated otherwise. P-values <0.05 were considered to be statistically significant. Bold indicates statistical significance. MSA: myositis specific antibody; MAA: myositis associated antibody; MYOACT: Myositis Disease Activity Assessment VAS; MITAX: Myositis Intention-to-Treat Activity Index; NS: non- significant; ref: reference values. Autoantibodies (MSA and/or MAA) were present in 54%. A higher prevalence of MSA was observed in patients with DM (60%) than in PM (50%). The most commonly detected MSA was anti-SRP (n = 17; 11%), followed by anti-Jo1 (9%) present in both PM and DM. The most common MAA was anti-Ku (7%) (Table 1). Patients with anti-aminoacyl-tRNA synthetase (anti-aaRS) antibodies (Jo1, PL-7 and EJ, n = 23) had higher frequencies of fever, arthritis, ILD, pericarditis and raised CRP compared with patients who were autoantibody negative. The anti-aaRS-positive patients had significantly higher prevalence of ILD (52% vs 24%), arthritis (52% vs 12%) and Raynaud’s phenomenon (35% vs 18%) compared with the anti-SRP positive patients. The anti-SRP-positive subset had higher serum levels of Creatine kinase (CK) compared with the antibody negative group (p < 0.01). Demographic features were comparable in the SRP-positive patients and the aaRS-positive patients, with the exception of longer disease duration in the SRP-positive patients (31.7 vs 16.0 months). Anti-TIF-1γ autoantibodies were found in five (3.3%) of the patients including two with PM and three with DM. Patients with pulmonary hypertension had a higher frequency of anti Jo1 antibodies (13.6% vs 4.7%) and total anti-aaRS antibodies (19.7% vs 11.8%) compared with patients without pulmonary hypertension. The frequency of HLA-DRB1*13 was significantly higher in patients with idiopathic inflammatory myopathy compared with controls, while the frequency of HLA-DRB1*07 was lower in patients. After stratification for disease subgroups, HLA-DRB1*13 remained a possible risk factor for PM, but not for DM, while the negative association to HLA-DRB1*07 was reduced. HLA-DRB1*09 showed a trend for protection against DM. In conclusion, in the present study, including adult Vietnamese patients with PM and DM of Kinh ethnicity, we found that joint involvement was common and pulmonary hypertension was more frequent than previously reported. The antibody pattern was different to previously reported patterns in both Caucasian and Asian patients, in that the most prevalent autoantibody was anti-SRP followed by anti-Jo1 [7]. Moreover, the HLA-DRB1 associations were different compared with Caucasians, suggesting that genetic and environmental factors may influence the idiopathic inflammatory myopathy phenotype [8]. The clinical phenotypes associated with the respective antibody specificities were in most cases similar to those previously reported in Caucasians [7]. We appreciate help with sharing data by Dr Chiea Chuen KHOR and Zheng Li from Genome Institute of Singapore. I.E.L. appreciates support from the Swedish Rheumatism Association and King Gustaf V 80-year Foundation. Funding: T.N.T.P. was supported by a research grant from APLAR in 2013 for doctors under the age of 40 years. I.E.L was supported by grants from the Swedish Research Council K2014-52X-14045-14, and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. Disclosure statement: I.E.L. has received honoraria from Bristol Myers Squibb and from Corbus Pharmaceuticals, Inc and is currently receiving a research grant from Bristol Myers Squibb and from Astra Zeneca. The other authors have declared no conflicts of interest.

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