[Show abstract][Hide abstract] ABSTRACT: Objectives:
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium.
The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM.
This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.
Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2015-208119 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microchimeric cells have been studied for over a decade, with conflicting reports on their presence and role in autoimmune and other inflammatory diseases. To determine whether microchimeric cells were pathogenic or mediating tissue repair in inflammatory myopathies, we phenotyped and quantified microchimeric cells in juvenile idiopathic inflammatory myopathies (JIIM), muscular dystrophy (MD), and noninflammatory control muscle tissues.
Fluorescence immunophenotyping for infiltrating cells with sequential fluorescence in situ hybridization was performed on muscle biopsies from ten patients with JIIM, nine with MD and ten controls.
Microchimeric cells were significantly increased in MD muscle (0.079 ± 0.024 microchimeric cells/mm(2) tissue) compared to controls (0.019 ± 0.007 cells/mm(2) tissue, p = 0.01), but not elevated in JIIM muscle (0.043 ± 0.015 cells/mm(2)). Significantly more CD4+ and CD8+ microchimeric cells were in the muscle of patients with MD compared with controls (mean 0.053 ± 0.020/mm(2) versus 0 ± 0/mm(2) p = 0.003 and 0.043 ± 0.023/mm(2) versus 0 ± 0/mm(2) p = 0.025, respectively). No differences in microchimeric cells between JIIM, MD, and noninflammatory controls were found for CD3+, Class II+, CD25+, CD45RA+, and CD123+ phenotypes, and no microchimeric cells were detected in CD20, CD83, or CD45RO populations. The locations of microchimeric cells were similar in all three conditions, with MD muscle having more microchimeric cells in perimysial regions than controls, and JIIM having fewer microchimeric muscle nuclei than MD. Microchimeric inflammatory cells were found, in most cases, at significantly lower proportions than autologous cells of the same phenotype.
Microchimeric cells are not specific to autoimmune disease, and may not be important in muscle inflammation or tissue repair in JIIM.
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
Clinical registries and biorepositories have proven extremely useful in many studies of diseases, especially rare diseases. Given their rarity and diversity, the idiopathic inflammatory myopathies, or myositis syndromes, have benefited from individual researchers' collections of cohorts of patients. Major efforts are being made to establish large registries and biorepositories that will allow many additional studies to be performed that were not possible before. Here, we describe the registries developed by investigators and patient support groups that are currently available for collaborative research purposes.
We have identified 46 myositis research registries, including many with biorepositories, which have been developed for a wide variety of purposes and have resulted in great advances in understanding the range of phenotypes, clinical presentations, risk factors, pathogenic mechanisms, outcome assessment, therapeutic responses, and prognoses. These are now available for collaborative use to undertake additional studies. Two myositis patient registries have been developed for research, and myositis patient support groups maintain demographic registries with large numbers of patients available to be contacted for potential research participation.
Investigator-initiated myositis research registries and biorepositories have proven extremely useful in understanding many aspects of these rare and diverse autoimmune diseases. These registries and biorepositories, in addition to those developed by myositis patient support groups, deserve continued support to maintain the momentum in this field as they offer major opportunities to improve understanding of the pathogenesis and treatment of these diseases in cost-effective ways.
Current Opinion in Rheumatology 09/2014; 26(6). DOI:10.1097/BOR.0000000000000119 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Autoantibodies are of growing interest in cancer research as potential biomarkers; yet the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population, and are more prevalent in women and older adults. Here we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women. Methods:We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 and older from the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence odds ratios (POR) and 95% confidence intervals (CI) were adjusted for age, race and poverty-income-ratio, and models were stratified by menopause status. Results:In premenopausal women ages 20 and older, ANA prevalence was associated with parity (p<0.001; parous versus nulliparous POR=2.0; 95%CI 1.2, 3.4), but in parous women ANA did not vary by number of births, age at first birth, years since last birth or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (p=0.019; age 16-20 versus 10-12 years POR=3.0, 95%CI 1.6, 5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence. Conclusions:Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women. Impact:These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women.
[Show abstract][Hide abstract] ABSTRACT: Autoimmune diseases include 80 or more complex disorders characterized by self-reactive, pathologic immune responses in which genetic susceptibility is largely insufficient to determine disease onset. In September 2010, the National Institute of Environmental Health Sciences (NIEHS) organized an expert panel workshop to evaluate the role of environmental factors in autoimmune diseases, and the state of the science regarding relevant mechanisms, animal models, and human studies. The objective of the workshop was to analyze the existing data to identify conclusions that could be drawn regarding environmental exposures and autoimmunity and to identify critical knowledge gaps and areas of uncertainty for future study. This consensus document summarizes key findings from published workshop monographs on areas in which "confident" and "likely" assessments were made, with recommendations for further research. Transcribed notes and slides were reviewed to synthesize an overview on exposure assessment and questions addressed by interdisciplinary panels. Critical advances in the field of autoimmune disease research have been made in the past decade. Collaborative translational and interdisciplinary research is needed to elucidate the role of environmental factors in autoimmune diseases. A focus on exposure assessment methodology is needed to improve the effectiveness of human studies, and more experimental studies are needed to focus on causal mechanisms underlying observed associations of environmental factors with autoimmune disease in humans.
International Journal of Molecular Sciences 08/2014; 15(8):14269-14297. DOI:10.3390/ijms150814269 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
We aimed to assess changes in myositis core set measures and ancillary clinical and laboratory data from the National Institutes of Health's subset of patients enrolled in the Rituximab in Myositis trial.
Eighteen patients (5 dermatomyositis, 8 polymyositis, 5 juvenile dermatomyositis) completed more in-depth testing of muscle strength and cutaneous assessments, patient-reported outcomes, and laboratory tests before and after administration of rituximab. Percentage change in individual measures and in the definitions of improvement (DOIs) and standardized response means were examined over 44 weeks.
Core set activity measures improved by 18-70% from weeks 0-44 and were sensitive to change. Fifteen patients met the DOI at week 44, 9 patients met a DOI 50% response, and 4 met a DOI 70% response. Muscle strength and function measures were more sensitive to change than cutaneous assessments. Constitutional, gastrointestinal, and pulmonary systems improved 44-70%. Patient-reported outcomes improved up to 28%. CD20+ B cells were depleted in the periphery, but B cell depletion was not associated with clinical improvement at week 16.
This subset of patients had high rates of clinical response to rituximab, similar to patients in the overall trial. Most measures were responsive, and muscle strength had a greater degree of change than cutaneous assessments. Several novel assessment tools, including measures of strength and function, extra-muscular organ activity, fatigue, and health-related quality of life, are promising for use in future myositis trials. Further study of B cell-depleting therapies in myositis, particularly in treatment-naïve patients, is warranted.
Clinical and experimental rheumatology 07/2014; 32(5). · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Because juvenile idiopathic inflammatory myopathies (IIMs) are potentially life-threatening systemic autoimmune diseases, we examined risk factors for juvenile IIM mortality.Methods
Mortality status was available for 405 patients (329 with juvenile dermatomyositis [DM], 30 with juvenile polymyositis [PM], and 46 with juvenile connective tissue disease–associated myositis [CTM]) enrolled in nationwide protocols. Standardized mortality ratios (SMRs) were calculated using US population statistics. Cox regression analysis was used to assess univariable associations with mortality, and random survival forest (RSF) classification and Cox regression analysis were used for multivariable associations.ResultsOf 17 deaths (4.2% overall mortality), 8 (2.4%) were in juvenile DM patients. Death was related to the pulmonary system (primarily interstitial lung disease [ILD]) in 7 patients, gastrointestinal system in 3, and multisystem in 3, and of unknown etiology in 4 patients. The SMR for juvenile IIMs overall was 14.4 (95% confidence interval [95% CI] 12.2–16.5) and was 8.3 (95% CI 6.4–10.3) for juvenile DM. The top mortality risk factors in the univariable analysis included clinical subgroup (juvenile CTM, juvenile PM), antisynthetase autoantibodies, older age at diagnosis, ILD, and Raynaud's phenomenon at diagnosis. In multivariable analyses, clinical subgroup, illness severity at onset, age at diagnosis, weight loss, and delay to diagnosis were the most important predictors from RSF; clinical subgroup and illness severity at onset were confirmed by multivariable Cox regression analysis.Conclusion
Overall mortality was higher in juvenile IIM patients, and several early illness features were identified as risk factors. Clinical subgroup, antisynthetase autoantibodies, older age at diagnosis, and ILD are also recognized as mortality risk factors in adult myositis.
[Show abstract][Hide abstract] ABSTRACT: Rationale:
Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.
The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).
A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.
Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
[Show abstract][Hide abstract] ABSTRACT: In environmental epidemiology, measurements of exposure biomarkers often fall below the assay's limit of detection. Existing methods for handling this problem, including deletion, substitution, parametric regression, and multiple imputation, can perform poorly if the proportion of "nondetects" is high or parametric models are misspecified. We propose an approach that treats the measured analyte as the modeled outcome, implying a role reversal when the analyte is a putative cause of a health outcome. Following a scale reversal as well, our approach uses Cox regression to model the analyte, with confounder adjustment. The method makes full use of quantifiable analyte measures, while appropriately treating nondetects as censored. Under the proportional hazards assumption, the hazard ratio for a binary health outcome is interpretable as an adjusted odds ratio: the odds for the outcome at any particular analyte concentration divided by the odds given a lower concentration. Our approach is broadly applicable to cohort studies, case-control studies (frequency matched or not), and cross-sectional studies conducted to identify determinants of exposure. We illustrate the method with cross-sectional survey data to assess sex as a determinant of 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration and with prospective cohort data to assess the association between 2,4,4'-trichlorobiphenyl exposure and psychomotor development.
American journal of epidemiology 04/2014; 179(8):1018-24. DOI:10.1093/aje/kwu017 · 5.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Studies of twin pairs discordant for autoimmune conditions provide a unique opportunity to explore contributing factors triggered by complex gene-environment interactions.
In this cross-sectional study, thirty-one monozygotic or dizygotic twin pairs discordant for myositis or systemic lupus erythematosus (SLE), along with matched healthy controls were evaluated for antibodies against a panel of 21 autoantigens.
Autoantibody profiling revealed that 42% of the affected twins showed significant seropositivity against autoantigens in the panel. In many of these affected twins, but none of healthy controls, there were high levels of autoantibodies detected against two or more autoantigens commonly seen in systemic autoimmune diseases including Ro52, Ro60, RNP-70 K and/or RNP-A. In contrast, only 10% (3/31) of the unaffected twins showed seropositivity and these immunoreactivities were against single autoantigens not seen in systemic autoimmune diseases. While no significant differences in autoantibodies were detected between the affected or unaffected twins against thyroid peroxidase, transglutaminase and several cytokines, 23% of the affected twins with myositis showed autoantibodies against the gastric ATPase. Analysis of the monozygotic twins separately also revealed a higher frequencies of autoantibodies in the affected twins compared to the unaffected twins (P = 0.046). Lastly, clinical analysis of both the affected monozygotic and dizygotic twins revealed that the autoantibody seropositive affected twins had a greater global disease activity score compared to seronegative affected twins (P = 0.019).
The findings of significantly more autoantibodies in the affected twins with myositis and SLE compared to the unaffected twins are consistent with potential non-genetic factors playing a role in autoantibody production and pathogenesis of these autoimmune disorders.
[Show abstract][Hide abstract] ABSTRACT: Background/Purpose:The myositis syndromes are rare systemic autoimmune diseases with poorly understood etiologies. We present the demographics, illness features and treatments of patients with juvenile dermatomyositis (JDM) who enrolled in a newly created national registry.Methods:Using a patient database from The Myositis Association and supplemental advertisements, a national registry of myositis patients was established. Between December 2010 and July 2012 questionnaires were mailed to 8847 myositis patients in the US and Canada. The questionnaire queried demographics, clinical features, environmental exposures, and quality of life. Descriptive statistics and multivariable logistic regression analysis were computed using GraphPad Prysm and SAS.Results:1956 patients (22%) returned the questionnaire and consented to participate; 1806 who met probable or definite Bohan and Peter criteria for myositis were included (708 DM, 483 PM, 466 IBM, 139 JDM, 10 JPM); juvenile patients were diagnosed before age 18 years. Of the 139 JDM patients, the median age at diagnosis was 6.9 years and median disease duration at enrollment was 10.3 years. Most JDM patients were female (78%) and Non-Hispanic Caucasian (88%), and the remainder were Hispanic (6.5%), Asian (2.9%), multiple races (2.2%), and Black (0.7%). Patients or their parents often completed a graduate degree (23%) or college degree (29%). JDM patients were primarily diagnosed by a pediatric rheumatologist (48%), with adult and pediatric dermatologists (22%), pediatric neurologists and primary care physicians (11% each) diagnosing most of the remaining patients; 67% were under the care of a pediatric rheumatologist. JDM patients frequently had skin rashes as a major manifestation (86%); arthritis (35%) and dysphagia (32%) were also common, whereas lung disease (12%) was less frequent. An additional autoimmune disease was present in 18% of JDM patients, with JIA (8%) and SLE and celiac disease (3% each) the most frequent. There were no recorded associated malignancies. 98% of JDM patients received prednisone therapy. Methotrexate was the most common steroid-sparing agent (84%), followed by hydroxychloroquine (60%), IV pulse solumedrol (54%), IVIG (48%), cyclosporine (19%), rituximab and anti-TNFs (10% each). Predictors of which agents were received varied among medications, but included age, year of JDM diagnosis, gender, and region of country. Pulse solumedrol and cyclosporine were more likely to be used in JDM patients with dysphagia, hydroxychloroquine in patients with skin rashes and less likely in those with fevers, and azathioprine was less likely in patients with arthritis. Of medications utilized, 45% of JDM patients reported responding best to IVIG, 39% responded best to prednisone, 33% to anti-TNFs, and 29% to cyclophosphamide.Conclusion:A nationwide myositis registry has been established and includes a subsample of JDM patients that appears demographically and clinically representative of other US populations. This registry may help identify environmental exposures associated with myositis, elucidate factors associated with quality of life, and serve as an important resource for future clinical investigations.
Arthritis and Rheumatology 03/2014; 66(S11). DOI:10.1002/art.38474
[Show abstract][Hide abstract] ABSTRACT: Objective:
To identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab.
We analyzed data for 195 patients with myositis (75 with adult polymyositis [PM], 72 with adult dermatomyositis [DM], and 48 with juvenile DM) in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of the following 6 core set measures of disease activity: physician's and patient's/parent's global assessment of disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, core set measures, rituximab treatment, and myositis autoantibodies (antisynthetase, anti-Mi-2, anti-signal recognition particle, anti-transcription intermediary factor 1γ [TIF-1γ], anti-MJ, other autoantibodies, and no autoantibodies). All measures were univariately assessed for association with improvement using time-to-event analyses. A multivariable time-dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement.
In the final multivariable model, the presence of an antisynthetase, primarily anti-Jo-1 (hazard ratio [HR] 3.08, P < 0.01), anti-Mi-2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P = 0.14) predicted a shorter time to improvement compared to the absence of autoantibodies. A lower physician's global assessment of damage (HR 2.32, P = 0.02) and juvenile DM (versus adult myositis) (HR 2.45, P = 0.01) also predicted improvement. Unlike autoantibody status, the predictive effect of physician's global assessment of damage and juvenile DM diminished by week 20. Rituximab treatment did not affect these associations.
Our findings indicate that the presence of antisynthetase and anti-Mi-2 autoantibodies, juvenile DM subset, and lower disease damage strongly predict clinical improvement in patients with refractory myositis.
[Show abstract][Hide abstract] ABSTRACT: Background/Purpose:Three disease courses can be distinguished in patients with juvenile idiopathic inflammatory myopathies (JIIM): monocyclic (M), polycyclic (P), and chronic continuous (CC). Predictors of disease course could result in improved therapy and help focus research efforts. We examined the association of immunogenetic and environmental factors with disease course in a large JIIM cohort.Methods:We enrolled 240 Caucasian patients with JIIM (204 dermato-, 21 poly-, and 15 overlap myositis) diagnosed from 1980–2010 in the US and Canada into IRB-approved studies. The ratio of girls to boys was 3:1. Median age at diagnosis was 7 years (IQR: 5–12). Physician questionnaires with clinical and demographic data and patient blood samples were obtained. Follow-up was through medical record review. The disease course classification was as follows: M—no active disease and off medication within 2 years of diagnosis (n = 62); P—disease recurrence after definite remission (n = 62); and CC—persistent disease or continuation of medication for more than 2 years (n = 116). Genetic data included: high resolution HLA-DRB1 and HLA-DQA1 alleles, and peptide binding motifs; immunoglobulin gamma heavy and kappa light chain phenotypes and allotypes; and TNFα (−238, −308), IL-1α (−889, +4845), and IL-1β (−511, −3953) polymorphisms. Environmental data included: documentation of infections within 6 months prior to illness onset; average and highest ultraviolet (UV) index for the month prior to illness onset and prior to diagnosis based on residential location; season of illness onset; and geoclimatic regions and planting zones of residential location at illness onset.Results:HLA-DRB1*1501 was present more frequently in the M group (22%) compared to the P (5%; OR [95% CI]=5.7 [1.1–29.0]; p=0.04) and CC groups (7%; OR=4.0 [12.4–1.3]; p=0.02). In patients with dermatomyositis only, the F25 peptide binding was present less frequently in the M group (18%) compared to the P (41%; OR = 0.3 [0.1–0.8]; p = 0.02) and CC groups (39%; OR = 0.3 [0.1–0.8]; p = 0.02). The other HLA alleles and peptide binding motifs, immunoglobulin gamma heavy and kappa light chain phenotypes and allotypes, and cytokine polymorphisms (including TNFα-308) were not associated with disease course. Infections 6 months prior to illness onset were more often present in the P group (40%) compared to the M (18%; OR = 3.0 [1.3–7.2]; p = 0.01) and CC groups (21%; OR = 2.5 [1.2–5.2]; p = 0.01). Three-quarter of these infections were respiratory. In girls, the average UV index in the month before diagnosis was higher in the P group (median [IQR] = 5.7 [4.0–6.6]) compared to the M group (median [IQR] = 4.3 [1.2–5.6]; p = 0.01). Season of illness onset, geoclimatic regions, and planting zones did not differ among the 3 disease courses.Conclusion:Immunogenetic factors, including HLA alleles, and environmental factors, including a history of preceding infections and the UV index at diagnosis, were significantly associated with disease course in this population of Caucasian patients with JIIM. Future studies are needed to confirm these associated factors and to identify the value of these factors in determining prognosis.
Arthritis and Rheumatology 03/2014; 66(S11). DOI:10.1002/art.38441
[Show abstract][Hide abstract] ABSTRACT: Background Inadequate classification criteria for IIM are a fundamental limitation in clinical studies. An international, multidisciplinary collaboration, the International Myositis Classification Criteria Project (IMCCP), supported by ACR and EULAR, was established to address this problem.
Objectives Develop and validate new classification criteria for adult and juvenile IIM and its major subgroups.
Methods Candidate variables were selected from published criteria and inclusion criteria in controlled trials of myositis. Comparator conditions confused with IIM were defined.
Clinical and laboratory data from IIM and comparator patients were collected from 47 rheumatology, dermatology, neurology and pediatrics clinics worldwide from 2008-2011.
Crude pair-wise associations among all measured variables and between each variable and clinicians’ diagnoses were assessed. The explored approaches were:
Internal validation using bootstrap methods was performed.
Results Data from 973 IIM patients (74% adults; 26% children), representing subgroups of IIM, and 629 comparators (81% adults; 19% children) were obtained. Two probability score models were developed: Model 1 comprised clinical variables on muscles, skin, and laboratory measures; Model 2 additionally comprised muscle biopsy variables. Model 1 performed nearly as well as Model 2 (specificity 87% vs. 88%, sensitivity 89% vs. 89%, and correctly classified 87% vs. 89%). Both models performed as well as, and often better than, the classification tree that was developed (sensitivity 88%, specificity 72%, and correctly classified 84%) and published criteria.
Conclusions New classification criteria for IIM with readily clinically assessable measurements and symptoms have been developed. They generally show superior performance compared with existing criteria. External validation is in progress.
Disclosure of Interest None Declared
Arthritis and Rheumatology 03/2014; 66(S11). DOI:10.1002/art.38463
[Show abstract][Hide abstract] ABSTRACT: Autoantibodies are a hallmark in the diagnosis of many systemic autoimmune rheumatic diseases (SARD) including idiopathic inflammatory myopathies (IIM). Based on their specificity, autoantibodies in IIM are grouped into myositis specific (MSA) and myositis associated autoantibodies (MAA). Among the MSA, autoantibodies against aminoacyl-tRNA synthetases (ARS) represent the most common antibodies and can be detected in 25-35 % of patients. The presence of ARS and other autoantibodies have become a key feature for classification and diagnosis of IIM and are increasingly used to define clinically distinguishable IIM subsets. For example, anti-ARS autoantibodies are the key features of what has become known as anti-synthetase syndrome (aSS), characterized by multiple organ involvement, primarily interstitial lung disease, often accompanied by myositis, non-erosive arthritis, Raynaud's phenomenon, fever, and "mechanic's hands". Autoantibodies directed to eight different ARS have been described: Jo-1 (histidyl), PL-7 (threonyl), PL-12 (alanyl), OJ (isoleucyl), EJ (glycyl), KS (asparaginyl), Zo (phenylalanyl) and Ha (tyrosyl). Each anti-ARS antibody seems to define a distinctive clinical phenotype. Although several research methods and commercial tests are available, routine testing for anti-ARS autoantibodies (other than anti-Jo-1/histidyl-tRNA synthetase) is not widely available, sometimes leading to delays in diagnosis and poor disease outcomes.
[Show abstract][Hide abstract] ABSTRACT: Objective
To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods
We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. ResultsCompared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10–8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of