Analysis of anti-melanoma differentiation-associated gene 5 antibody in Hong Kong Chinese patients with idiopathic inflammatory myopathies: diagnostic utility and clinical correlations.

AIM: To compare the prevalence of the anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) in Hong Kong Chinese patients with dermatomyositis (DM) and polymyositis (PM); in addition, to examine the association of anti-MDA5 Ab and the clinical characteristics of these patients. METHODS: Twenty consecutive existing patients with DM being followed up at the Rheumatology Clinic of Kwong Wah Hospital, Hong Kong were recruited. Twenty patients with PM were recruited from the same clinic as the controls. A commercial line blot immunoassay was used to detect the anti-MDA5 Ab in all the participants. The frequencies of anti-MDA-5 Ab in the two groups were compared. The clinical characteristics of the patients with and without the antibody were analyzed. RESULTS: Anti-MDA5 Ab was found in 30% of patients with DM but not in patients with PM. All patients with the antibody exhibited the clinically amyopathic DM (CADM) phenotype. These patients were predominantly male, younger and with shorter disease duration. Anti-MDA5 Ab was significantly associated with rapidly progressive interstitial lung disease (RP-ILD) and digital ulcers. No statistically significant association was found between other disease or treatment variables and the antibody. CONCLUSION: Anti-MDA5 Ab is found exclusively in DM patients of the CADM subtype and is associated with RP-ILD and digital ulcers, suggesting that examination of this antibody is clinically useful in Hong Kong Chinese patients with idiopathic inflammatory myopathies. However, further studies are required to assess its prognostic significance, and to explore the difference of its presentations in various populations.

A single-nucleotide polymorphism of CCL21 rs951005 T>C is associated with susceptibility of polymyositis and such patients with interstitial lung disease in a Chinese Han population.

OBJECTIVES: Our objective was to better understand the roles of single nucleotide polymorphisms (SNPs) in the CCL21, ERBB3, and TERT genes region in the development of idiopathic inflammatory myopathies (IIMs), we explored the associations between SNPs in the mentioned three genes and IIMs susceptibility in a Chinese Han population. METHODS: Chinese polymyositis (PM) patients (n =291), dermatomyositis (DM) patients (n=526) and ethnically-matched healthy controls (n =968) were genotyped for the CCL21 region SNPs (rs951005 and rs2492358), ERBB3 (rs2292239 and rs11171739), and TERT (rs2853676 and rs10069690), by using the Sequenom MassArray system. RESULTS: Our study indicated strong allele and genotype associations between rs951005 (OR: 1.65, 95%CI: 1.18-2.30, Pc=0.015; Pc=0.041, respectively) in CCL21 gene and PM patients. Additionally, rs951005 was associated with interstitial lung disease (ILD) in PM patients (Pc =0.01), and was associated with PM patients in additive model. However, the Chinese Han PM/DM patients and controls had statistically similar frequencies of alleles, genotypes and different genetic models (additive, dominant, and recessive) of ERBB3 and TERT polymorphisms. CONCLUSIONS: This was the first study to demonstrate that the CCL21 gene SNP (rs951005) might confer genetic predisposition to PM patients or such patients with ILD in a Chinese Han population.

Distinct profiles of myositis-specific autoantibodies in Chinese and Japanese patients with polymyositis/dermatomyositis.

The study aims to comprehensively assess the profiles of myositis-specific autoantibodies (MSAs) in Chinese patients with polymyositis (PM)/dermatomyositis (DM) and compare them with a Japanese cohort. One hundred forty-five Chinese patients (68 classic DM, 25 clinically amyopathic DM [CADM], and 52 PM) and 165 Japanese patients (56 classic DM, 52 CADM, and 57 PM) were recruited. MSAs were measured with immunoprecipitation, enzyme-linked immunosorbent assay, or immunoprecipitation-immunoblotting. MSA frequencies were compared. The overall frequency of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies was significantly higher in the Chinese patients than in the Japanese cohort (36.6 % [53/145] versus 15.8 % [26/165], respectively, P < 0.001), whereas the frequencies of anti-signal recognition particle (SRP) antibodies (1.4 % [2/145] versus 7.9 % [13/165], respectively, P = 0.008) and anti-aminoacyl-transfer RNA synthetase (anti-ARS) antibodies (27.6 % [40/145] versus 40 % [66/165], respectively, P = 0.02,) were significantly lower. The significantly lower frequency of anti-ARS antibodies and significantly higher frequency of anti-MDA5 antibodies in the Chinese patients were observed in the classic DM subset (14.7 % [10/68] versus 46.4 % [26/56], respectively, P < 0.001, and 45.6 % [31/68] versus 5.4 % [3/56], respectively, P < 0.001) and CADM subset (8.0 % [2/25] versus 28.8 % [15/52], respectively, P = 0.04, and 88.0 % [22/25] versus 44.2 % [23/52], respectively, P = 0.0002), but not in the PM subset. The first detailed profile of MSAs in Chinese patients with PM/DM was established. The differences in MSA frequencies in the Chinese cohort and Japanese cohort suggest underlying genetic and/or environmental differences between these two populations. Key Messages • A significantly higher frequency of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies was observed in Chinese patients with polymyositis/dermatomyositis (PM/DM) than in Japanese patients. • Our findings suggest that distinct genetic and/or local environmental factors affect Chinese and Japanese patients with PM/DM, who have been considered a "homogeneous" population in previous studies.

The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases.

OBJECTIVE: The Norwegian nationwide MCTD cohort was established to obtain unbiased data on key disease issues, and thereby reappraise the concept of MCTD. In the current study, the aims were to obtain detailed HLA profile data on the large Norwegian MCTD cohort and compare these with the HLA profiles of ethnically matched healthy controls and related CTD controls. METHODS: HLA profiles, determined by sequence-based typing of HLA-B* and DRB1*, were compared between four control groups of Norwegian ancestry, SLE (n = 96), SSc (n = 95), PM/DM (n = 84), healthy individuals (n = 282), the complete MCTD cohort (n = 155) and MCTD subsets defined by key clinical parameters. RESULTS: HLA-B*08 [odds ratio (OR) 2.05, P = 1.31 × 10(-4)) and DRB1*04:01 (OR 2.82, P = 3.64 × 10(-8)) were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE and PM/DM were B*08 and DRB1*03:01. SSc risk was associated with DRB1*08:01. Analyses of MCTD subsets identified B*18 [OR 3.32 (95% CI 1.38, 8.01)] and DRB1*03:01 [OR 1.83 (95% CI 1.03, 3.25)] as independent risk factors for lung fibrosis. CONCLUSION: Novel HLA alleles associated with MCTD and disease subsets were identified and DRB1*04:01 was confirmed as a major risk allele. Altogether, the data reinforce the notion of MCTD as a disease entity distinct from SLE, SSc and PM/DM.

Genetic association study of TNFAIP3, IFIH1, IRF5 polymorphisms with polymyositis/dermatomyositis in Chinese Han population.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the TNFAIP3, IFIH1, and IRF5 genes have been associated with several auto-inflammation diseases, while the susceptibility between these genes and idiopathic inflammatory myopathies (IIMs) were not reported. This study aimed to investigate whether TNFAIP3, IFIH1, and IRF5 gene polymorphisms confer susceptibility for the IIMs in Chinese Han population. METHODS: A large case-control study of Chinese subjects with polymyositis (PM) (n = 298) and dermatomyositis (DM) (n = 530) was accomplished. 968 healthy and ethnically matched controls were available for comparison. Six SNPs in the TNFAIP3 region (rs2230926 and rs5029939), the IFIH1 gene (rs1990760 and rs3747517) and the IRF5 region (rs4728142 and rs729302) were assessed and genotyped using the Sequenom MassArray iPLEX platform. RESULTS: Our study indicated a strong allele association was observed in PM/DM and PM patients for rs2230926 (OR: 1.61, 95%CI: 1.20-2.16, P(c) = 7.5×10(-3); OR: 1.88, 95%CI: 1.30-2.74, P(c) = 4.0×10(-3), respectively) and rs5029939 (OR: 1.64, 95%CI: 1.21-2.21, P(c) = 6.0×10(-3); OR: 1.88, 95%CI: 1.28-2.76, P(c) = 5.5×10(-3), respectively). And rs2230926 and rs5029939 were significantly associated with interstitial lung disease (ILD) in PM/DM and PM patients (P(c) = 0.04 and P(c) = 0.016; P(c) = 0.02 and P(c) = 0.03, respectively). In addition, rs4728142 allele and genotype had significant association with PM/DM patients (P(c) = 0.026 and P(c) = 0.048, respectively). Further analysis with three logistic regression genetic models revealed statistically significant difference in the genotypic distribution in the PM/DM, PM or DM patients when the additive and dominant models were used. CONCLUSIONS: This was the first study to reveal TNFAIP3 and IRF5 polymorphisms were associated with PM/DM patients or these patients with ILD, indicating that TNFAIP3 and IRF5 might be the susceptibility gene for PM/DM patients in Chinese Han population.

Incidence and prevalence of polymyositis and dermatomyositis in a health management organization in Buenos Aires.

BACKGROUND: Polymyositis (PM) and dermatomyositis (DM) are infrequent diseases. Data on incidence and prevalence are scarce and conflicting. There are no such data in Latin America and in Argentina in particular. OBJECTIVES: We undertook to examine the incidence and prevalence of PM/DM in the prepaid health maintenance organization (HMO) of our hospital, in the city of Buenos Aires. METHODS: Members of the HMO between January 1999 and June 2009 were identified from medical records of patients followed up by us at the HMO. Incident cases and prevalence were calculated at the end of the period. RESULTS: During the study period, 146,747 persons contributed a total of 937,902.6 person-years (mean age was 46.6 [SD, 18.4] years, and 59% were female). Ten incident cases were detected, 7 women and 3 men with a global incidence rate (IR) of 1.07 per 100,000 person-years (95% confidence interval [CI], 0.5-1.84). Three subjects had DM with an IR of 0.32 per 100,000 person-years (95% CI, 0.1-0.99), and 7 had PM with an IR of 0.75 per 100,000 person-years (95% CI, 0.35-0.16). On June 1, 2009, 17 prevalent cases were detected, with a mean age of 48.9 (SD, 17.7) years; 76% were female, representing a prevalence of 17.4 per 100,000 persons (95% CI, 10.1-27.8). Among the 17 patients with idiopathic inflammatory myopathy, 10 patients had DM, with a prevalence of 10.22 per 100,000 persons (95% CI, 4.9-18.8), and 7 had PM (prevalence, 7.2 per 100,000 persons [95% CI, 2.9-14.7]). CONCLUSIONS: It is difficult to compare studies from different populations and using different ascertainment techniques. These first data from Latin America are in general agreement with many studies.

Brief report: ultraviolet radiation exposure is associated with clinical and autoantibody phenotypes in juvenile myositis.

OBJECTIVE: Genetic and environmental factors may contribute to the etiology of the juvenile idiopathic inflammatory myopathies (IIMs), which are systemic autoimmune diseases that are characterized by muscle and skin inflammation. We undertook this study to investigate the association between ultraviolet radiation (UVR) exposure and the clinical and autoantibody expression of juvenile IIM. METHODS: The relationship between UVR exposure in the month before symptom onset and the prevalence of juvenile dermatomyositis (DM), compared to juvenile polymyositis (PM), was assessed in 298 juvenile IIM patients. Among the patients with juvenile DM, the association between UVR exposure and presence of myositis autoantibodies was assessed. Regression models were stratified by sex and race. The association between the regional UV index in US geoclimatic zones and the clinical and autoantibody subgroups was examined by weighted least squares regression analysis. RESULTS: Among girls in this population, the odds of having juvenile DM, compared to juvenile PM, increased per unit increase in the patients' highest UV index in the month before symptom onset (odds ratio [OR] 1.18, 95% confidence interval 1.00-1.40). Moreover, both the mean and highest UV indices were associated with increasing odds of having anti-p155/140 autoantibodies, with the strongest odds in white males (ORs of 1.30 and 1.23, respectively). No association was observed between the UV index and presence of anti-MJ autoantibodies or lack of any myositis autoantibodies. Across all 9 US geoclimatic regions, the mean UV index was associated with increasing odds of having juvenile DM and anti-p155/140 autoantibodies, but decreasing odds of having anti-MJ autoantibodies. CONCLUSION: Short-term UVR exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis. Further research examining the mechanisms of action of UVR in the pathogenesis of juvenile IIM is suggested from these findings.

Idiopathic inflammatory myopathy associated with malignancy: a retrospective cohort of 151 Korean patients with dermatomyositis and polymyositis.

OBJECTIVE: To define the standardized incidence ratio (SIR) of malignancy and factors associated with malignancies in Korean patients with dermatomyositis (DM) and polymyositis (PM). METHODS: The demographic, clinical, and laboratory features of 151 patients diagnosed with DM/PM were compared in patients with and without malignancies. RESULTS: Malignancies were found in 23 of 98 patients with DM (23.5%) and in 2 of 53 with PM (3.8%). Lung cancer (8 patients) was the most common malignancy. Compared with the period-specific, sex-matched, and age-matched Korean population, the SIR for malignancy in patients with DM was 14.2 (95% CI 9.0-21.3). Univariate analysis showed that factors associated with malignancy included older age (p < 0.001), DM (p = 0.002), dysphagia (p < 0.001), the absence of interstitial lung disease (ILD; p = 0.001), and lower elevations in aspartate aminotransferase (p = 0.005) and lactate dehydrogenase concentrations (p < 0.001). Multivariate analysis showed that factors independently associated with malignancy included older age (per 10 years, OR 2.3, 95% CI 1.6-3.5, p < 0.001), DM (OR 5.9, 95% CI 1.3-26.2, p = 0.020), dysphagia (OR 2.6, 95% CI 1.2-6.6, p = 0.042), and the absence of ILD (OR 0.1, 95% CI 0.01-0.9, p = 0.040). CONCLUSION: DM was associated with a greater risk of concomitant malignancies, especially lung cancer, than PM. Independent factors associated with malignancies in patients with DM/PM were older age, the presence of dysphagia, and the absence of ILD.

Malignancies associated with dermatomyositis and polymyositis in Taiwan: a nationwide population-based study.

BACKGROUND: Previous studies showed that idiopathic inflammatory myopathies (IIM) carried an increased risk of cancers. However, no large-scale study of IIM has been conducted in the Chinese population. OBJECTIVES: We sought to delineate the association of IIM and various cancer types from a nationwide database in Taiwan. METHODS: We analysed the published national data from records of National Health Insurance claims. Cases of dermatomyositis (DM) and polymyositis (PM) from 2000 to 2005 and cancers registered in the catastrophic illness profile from 1997 to 2006 were collected. A nationally representative cohort of 1,000,000 enrollees was included for comparison. RESULTS: In total, 136 patients (12.8%) among 1059 cases of DM and 46 persons (7.0%) among 661 cases of PM carried internal malignancies. Patients with DM tended to have cancers of nasopharynx, lung and breast. On the other hand, patients with PM tended to have breast, uterine cervix and lung cancers. Compared with the general population, DM gave a 10-fold increased risk for cancers, in which a 66-fold increased risk for nasopharyngeal carcinoma and a 31-fold increased risk for lung cancer were the two most significant. For patients with PM, a 6-fold increased risk for cancer was observed. Juvenile DM had a 16-fold increased risk for haematopoietic or lymphoid malignancy. Two thirds of comorbid malignancies were detected shortly after the diagnoses of IIM, within a mean of 1-2 years. Overall, younger patients with IIM carried the highest risk for malignancies, especially those in their twenties and thirties. CONCLUSIONS: This is the first large-scale study to report the associated malignancies and the cancer risk of IIM in Taiwan.

Autoantibody to signal recognition particle in African American girls with juvenile polymyositis.

Anti-signal recognition particle (anti-SRP) is a myositis-specific autoantibody that is linked to a severe polymyositis (PM) associated with interstitial lung disease (ILD) and esophageal dysmotility in adults. We describe 3 African American adolescent girls with anti-SRP juvenile PM. One child required aggressive treatment to control her disease and 2 were refractory to multiple immunosuppressants. Patient 1 developed ILD and cardiac disease; Patient 2 developed ILD; Patient 3 developed esophageal dysmotility and cardiac disease. Organ system involvement was comparable to that seen in adults. We conclude that testing for anti-SRP in children with PM may facilitate diagnosis and management.

Interferon-gamma and interleukin-4 gene polymorphisms in Caucasian idiopathic inflammatory myopathy patients in UK.

OBJECTIVE: To determine whether interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) genes confer susceptibility for the idiopathic inflammatory myopathies (IIMs). METHODS: A large cross-sectional study of UK caucasian adults with polymyositis (PM, n = 101), dermatomyositis (DM, n = 94) and myositis overlapping with a connective tissue disease (myositis/CTD-overlap, n = 70) was completed. 177 ethnically matched controls were available for comparison. Single-nucleotide polymorphisms (SNPs) within intronic regions coding for IL-4, IFN-gamma and a microsatellite marker within intron 1 of the IFN-gamma gene were typed. RESULTS: Strong linkage disequilibrium was present between SNPs in each gene. In the IFN-gamma gene, a weak allelic association was observed in PM versus controls at rs1861493 (odds ratio (OR) 1.6, 95% confidence interval (CI) 1.03 to 2.4). The microsatellite IFN-gamma CA(14) allele was associated with risk for IIMs overall (OR 3.3, 95% CI 1.4 to 7.8), the strongest association being observed within the anti-U1-ribonucleoprotein (RNP) group (OR 6.0, 95% CI 1.5 to 23.1), and persisting after adjustment for known myositis human leucocyte antigen (HLA) class II associations. CONCLUSIONS: Genetic markers in the IFN-gamma gene demonstrate significant allelic associations with the IIMs in a UK Caucasian population. The SNPs tested in this study within the region coding for IL-4 fail to show significant associations with susceptibility to IIM disease.

Novel autoantibodies against 7SL RNA in patients with polymyositis/dermatomyositis.

OBJECTIVE: Autoantibodies against signal recognition particle (SRP) are detected in patients with polymyositis/dermatomyositis (PM/DM). The SRP consists of 7SL RNA and 6 protein components. We examined autoantibodies against deproteinized 7SL RNA in PM/DM patients with anti-SRP antibodies and evaluated the association of anti-7SL RNA antibodies with PM/DM clinically and serologically. METHODS: Sera from 10 Japanese and 22 North American PM/DM patients with anti-SRP antibodies were tested for the presence of anti-7SL RNA antibodies, using the sera to immunoprecipitate deproteinized RNA extracts derived from HeLa cells. RESULTS: The immunoprecipitation analysis indicated that 5 Japanese (50%) and one North American (5%) patient with anti-SRP antibodies had novel autoantibodies against deproteinized 7SL RNA. The frequency of anti-7SL RNA antibodies was significantly higher in Japanese than North American patients (p = 0.006). The presence of anti-7SL RNA antibodies appeared to be associated with DM (2 patients) and finger swelling (2 PM patients). The seasonal onset of the disease was different (p = 0.008) for Japanese PM/DM patients with anti-7SL RNA antibodies, who developed the disease between October and January (mean month November; p = 0.01) from that of patients without these antibodies, who developed it between June and August (mean month July; p = 0.01). CONCLUSION: Novel autoantibodies against 7SL RNA were identified in patients with PM/DM, and the presence of these antibodies was correlated to ethnic background, clinical features, and season of disease onset. These findings indicated that autoantibodies against 7SL RNA are a novel serological marker for a subset of PM/DM cases.

Clinical characteristics of Japanese patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies.

OBJECTIVE: The clinical and laboratory features of seven Japanese patients with anti-aminoacyl-tRNA synthetase (ARS) autoantibodies against PL-7 (anti-threonyl-tRNA synthetase) were analyzed and compared with previously published findings. METHODS: Serum samples from 1,135 Japanese patients with various autoimmune diseases were screened for anti-PL-7 antibodies using RNA and protein immunoprecipitation assays. The patients whose sera contained anti-PL-7 antibodies were assessed regarding clinical symptoms and clinical course. RESULTS: Sera from seven patients were found to have anti-PL-7 antibodies. These autoantibodies were associated with polymyositis/dermatomyositis (PM/DM) and/or interstitial lung disease (ILD). The clinical diagnoses of these seven patients were PM - systemic sclerosis (SSc) overlap (5 patients), DM (1 patient) and idiopathic pulmonary fibrosis (IPF) (1 patient). All patients had ILD with a chronic course and six also had arthritis (85%) and five sclerodactyly (71%). CONCLUSIONS: These results indicate that anti-PL-7 autoantibodies are closely associated with PM-SSc overlap as well as ILD, arthritis and sclerodactyly in our series of Japanese patients.

Adult onset polymyositis/dermatomyositis: clinical and laboratory features and treatment response in 75 patients.

OBJECTIVES: To determine possible similarities and differences in clinical and laboratory features and treatment response between patients in Singapore with polymyositis (PM) and dermatomyositis (DM) and reported series. METHODS: Case records of adult patients (16 years old and above) referred to the 3 main electromyographic (EMG) laboratories in Singapore between 1 June 1986 and 31 May 1991 were reviewed if the referring diagnosis was myositis or myopathy for investigation. A computer search for adult patients with a diagnosis of PM/DM (ICD codes 710.3, 710.4, 517.8) who attended the main rheumatology and neurology centre during this period was also carried out. The criteria for PM/DM proposed by Bohan and Peter was adopted. RESULTS: The incidence of PM/DM was 7.7 cases per million population per year. There were 35 PM and 40 DM cases with a median age at diagnosis of 50.7 years (SD: 16.7) and significantly more females in the PM group (p < 0.05). At presentation, 86.7% had proximal myopathy, 34.7% had arthralgia/arthritis and 18.7% had cutaneous vasculitis. The creatine kinase level was elevated in 89.3% of patients and positive EMG and muscle biopsy in 79.4% and 76.4% respectively. Systemic lupus erythematosus was the commonest associated connective tissue disease. The percentage of patients with malignancy was higher in DM compared with PM (p < 0.01) and they were significantly older (mean age 61.8 years) (p < 0.001). Patients who achieved remission were significantly younger (mean age 46.4 years, p < 0.05). The overall mortality rate was 26.7% with infection and malignancy as the main causes of death. CONCLUSION: The results of the study suggest ethnicity does not influence the expression of PM/DM in view of the considerable similarities in frequency and clinical expression of disease in the population studied compared with series from other countries.