Background Up to 28% of patients with anti-synthetase syndrome (AsyS) have dermatomyositis (DM)-type rashes. However, it is not clear whether ASyS patients with DM-type rashes should be treated similarly to patients with DM or classified as DM in a clinical trial setting. Furthermore, it is not known if presence of DM-type rashes confers an increased risk of DM-specific extramuscular manifestations, such as malignancy. Objectives To compare clinical characteristics, including the frequency of cutaneous, extramuscular features, and malignancy, between adults with ASyS and DM. Methods Using data from the MYONET registry, an adult cohort of DM patients with anti-Mi2/TIF1ɣ/NXP2/SAE/MDA5 autoantibodies, and an ASyS cohort of patients with anti-tRNA synthetase autoantibodies (anti-Jo1/PL7/PL12/OJ/EJ/KS), were identified. Patients with DM sine dermatitis and with dual autoantibody specificities were excluded. Sub-cohorts of ASyS patients with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). Results In total, 737 patients were included (DM, n=251; ASyS, n=486). Within the ASyS cohort, 34% (n=163) had DM-type skin involvement (ASyS-skin). A higher frequency of Raynaud's phenomenon differentiated ASyS-skin from DM (n=72, 44% vs n=34, 14%, p<0.01), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n=155, 62% vs n=73, 45%), V sign (n=69, 28% vs n=22, 14%), periorbital rash (n=53, 21% vs n=27, 17%), and shawl sign (n=89, 36% vs n=15, 9%) differentiated DM from ASyS-skin (all p<0.01). Cancer-associated myositis (CAM) was more frequent in DM (17%) compared to ASyS (3%) and ASyS-skin (3%) cohorts (both p<0.01) (Table 1). Conclusion DM-type rashes are frequent in patients defined as having ASyS; however, certain clinical features differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance or investigation. These findings will help to inform future ASyS-based classification criteria. References [1]Hervier, Baptiste et al. “Hierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity.” Autoimmunity reviews vol. 12,2 (2012): 210-7.[2]Lilleker, James B et al. “The EuroMyositis registry: an international collaborative tool to facilitate myositis research.” Annals of the rheumatic diseases vol. 77,1 (2018): 30-39. Acknowledgements This publication was supported by researchers at the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the United Kingdom (UK) National Health Service (NHS), the NIHR or the UK Department of Health. Disclosure of Interests Ryan Malcolm Hum: None declared, James B. Lilleker: None declared, Janine Lamb: None declared, Alexander Oldroyd: None declared, William Ollier: None declared, Guochun Wang: None declared, Chanakya Kodishala: None declared, Lucy Wedderburn: None declared, Louise Diederichsen Consultant of: Data safety monitoring board for Corbus Pharmaceuticals, Grant/research support from: Boehringer Ingelheim, Jens Schmidt: None declared, Maria Giovanna Danieli: None declared, Katalin Dankó: None declared, THI PHUONG THUY NGUYEN: None declared, Mónica Vázquez-Del Mercado Espinosa: None declared, Helena Andersson: None declared, Boel De Paepe: None declared, Jan De Bleecker: None declared, Britta Maurer Speakers bureau: Boehringer-Ingelheim, GSK, Novartis, Consultant of: Novartis, Boehringer Ingelheim, Janssen-Cilag, GSK, Grant/research support from: AbbVie, Protagen, Novartis, Medtalk, Pfizer, Roche, Actelion, Mepha, MSD, Liza McCann: None declared, Nicolo Pipitone: None declared, Robert Paul New: None declared, Niels Steen Krogh: None declared, Neil McHugh: None declared, Jiří Vencovský: None declared, Ingrid E. Lundberg Shareholder of: Roche, Novartis, Consultant of: Corbus Pharmaceuticals Inc, Advisory board for Corbus Pharmaceutical, EMD Serono, Argenx, Octapharma, Kezaar, Orphazyme, Pfizer, and Janssen., Grant/research support from: Astra Zeneca, Hector Chinoy: None declared.Table 1Clinical manifestations of diseaseDM (n=251)ASyS (n=486)ASyS-skin (n=163)ASyS-without-skin (n=323)DM vs ASyS Adjusted p-valueDM vs ASyS-skin Adjusted p-valueASyS-skin vs ASyS-without-skin Adjusted p-valueDM-type rashes n (%)Heliotrope Rash155 (62)73 (15)73 (45)0 (0)<0.01<0.01<0.01Gottron's Papules or Sign145 (58)110 (23)110 (68)0 (0)<0.010.66<0.01Violaceous Rash94 (38)51 (11)51 (31)0 (0)<0.010.23<0.01Erythroderma22 (9)9 (2)9 (6)0 (0)<0.010.11<0.01Periorbital Rash53 (21)27 (6)27 (17)0 (0)<0.010.04<0.01V Sign Rash69 (28)22 (5)22 (14)0 (0)<0.01<0.01<0.01Shawl Sign89 (36)15 (3)15 (9)0 (0)<0.01<0.01<0.01Extramuscular manifestations n (%)Periungual Erythema72 (29)75 (15)43 (26)32 (10)<0.010.045<0.01Calcinosis7 (3)9 (2)6 (4)3 (1)0.620.810.15Ulceration11 (4)5 (1)3 (2)2 (1)0.040.650.72Vasculitis4 (2)1 (0.2)0 (0)1 (0.3)0.0450.611Mechanic's Hands11 (4)142 (29)62 (38)80 (25)<0.01<0.01<0.01Raynaud's Phenomenon34 (14)178 (37)72 (44)106 (33)<0.01<0.01<0.01Arthritis29 (12)221 (46)77 (47)144 (45)<0.01<0.011Dysphagia72 (29)88 (18)35 (22)53 (16)<0.010.250.22Alopecia24 (10)26 (5)12 (7)14 (4)0.1710.21Interstitial Lung Disease28 (11)320 (66)100 (61)220 (68)<0.01<0.010.11Cardiac Involvement4 (2)30 (6)14 (9)16 (5)0.03<0.010.20CAM n (%)42 (17)16 (3)5 (3)11 (3)<0.01<0.010.90

BACKGROUND Intravenous immune globulin (IVIG) for the treatment of dermatomyositis has not been extensively evaluated. METHODS We conducted a randomized, placebo-controlled trial involving patients with active dermatomyositis. The patients were assigned in a 1:1 ratio to receive IVIG at a dose of 2.0 g per kilogram of body weight or placebo every 4 weeks for 16 weeks. The patients who received placebo and those without confirmed clinical deterioration while receiving IVIG could enter an open-label extension phase for another 24 weeks. The primary end point was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score reflecting the change in a core set of six measures of myositis activity over time; scores range from 0 to 100, with higher scores indicating greater improvement. Key secondary end points included at least moderate improvement (TIS ≥40) and major improvement (TIS ≥60), and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index. RESULTS A total of 95 patients underwent randomization: 47 patients were assigned to the IVIG group, and 48 to the placebo group. At 16 weeks, 79% of the patients in the IVIG group (37 of 47) and 44% of those in the placebo group (21 of 48) had a TIS of at least 20 (difference, 35 percentage points; 95% confidence interval, 17 to 53; P<0.001). The results with respect to the secondary end points, including at least moderate improvement and major improvement, were generally in the same direction as the results of the primary end-point analysis, except for the change in creatine kinase level (an individual core measure of the TIS), which did not differ meaningfully between the two groups. Over 40 weeks, 282 treatment-related adverse events occurred in the IVIG group, including headache (in 42% of patients), pyrexia (in 19%), and nausea (in 16%). A total of 9 serious adverse events that were considered to be related to IVIG occurred, including 6 thromboembolic events. CONCLUSIONS In this 16-week trial involving adults with dermatomyositis, the percentage of patients with a response of at least minimal improvement based on a composite score of disease activity was significantly greater among those who received IVIG than among those who received placebo. IVIG was associated with adverse events, including thromboembolism. (Funded by Octapharma Pharmazeutika; ProDERM ClinicalTrials.gov number, NCT02728752.).

Background:Overlap syndromes are autoimmune disorders in which classification criteria of at least two connective tissue diseases (CTDs) are fulfilled. The Division of Clinical Immunology in Debrecen, Hungary oversees patients with idiopathic inflammatory myopathies (IIMs) since the 1980’s.Objectives:In a work called The Myositis Antibody Research Project, which is coordinated together with the Bath Institute for Rheumatic Diseases (UK), authors investigated 330 patients with myositis, all treated in this Hungarian center.Methods:The aim of this retrospective study was to investigate the frequency, clinical and serological parameters and therapeutic options in myositis – rheumatoid arthritis overlap cases in this group of 330 patients.Results:The frequency of overlap cases, as seen in literature, was 13.64%. The importance of myositis-associated antibodies (MAAs) can be seen on this results: 44.44% of overlap patients, while only 7.02% of not overlap patients were MAA positive. Out of our 45 overlap patients twenty-seven myositis - RA overlap patients could be identified. Among these 27 patients the women:men ratio was 12.5:1, PM:DM ratio was 2.375:1. Muscle weakness and sceletal involvement was present in every patient, myalgia in 77.78% and Raynaud’s phenomenon in 48.15% of the patients; general symptoms during disease relapse (fatigue, weight loss, fever) were present in 59.26%, 18.52% and 14.82%, respectively. Ten cases had seropositive rheumatoid arthritis, with high titer of rheumatoid factor. Authors underline the importance of lung involvement as internal organ manifestation: 8 patients had anti-synthetase antibodies (six anti-Jo-1, one anti-PL-7 and one anti-PL-12). In anti-PL-7 and anti-PL-12 positive patients interstitial lung disease (ILD) appeared some years before myositis and early agressive management of ILD resulted in fast remission of muscle weakness. Anti-Mi-2 and anti-SRP could be detected in two patients. Most frequent used disease modifying antirheumatic drugs were cyclophosphamide, methotrexate and cyclosporine, 19 patients received DMARD combination therapy. Biological therapy was used in 3 patients, intravenous or subcutaneous immuneglobulin in 4 patients and one patient with RA – myositis – antiphospholipid syndrome died because of asipartion pneumonia.Conclusion:Authors conclude that it is really challenging to treat these overlap cases: they form a very heterogenous group of patients and management has to be personalized.Disclosure of Interests:None declared

Objectives: To determine prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of idiopathic inflammatory myopathy (IIM) patients. Methods: Adult patients with confirmed IIM recruited to the EuroMyositis registry (n = 1637) from four centres were investigated for the presence of MSAs/MAAs by radiolabelled-immunoprecipitation, with confirmation of anti-MDA5 and anti-NXP2 by ELISA. Clinical associations for each autoantibody were calculated for 1483 patients with a single or no known autoantibody by global linear regression modelling. Results: MSAs/MAAs were found in 61.5% of patients, with 84.7% of autoantibody positive patients having a sole specificity, and only three cases (0.2%) having more than one MSA. The most frequently detected auto antibody was anti-Jo-1 (18.7%), with a further 21 specificities each found in 0.2-7.9% of patients. Autoantibodies to Mi-2, SAE, TIF1, NXP2, MDA5, PMScl and the non-Jo-1 tRNA-synthetases were strongly associated (p < 0.001) with cutaneous involvement. Anti-TIF1 and anti-Mi-2 positive patients had an increased risk of malignancy (OR 4.67 and 2.50 respectively), and anti-SRP patients had a greater likelihood of cardiac involvement (OR 4.15). Interstitial lung disease was strongly associated with the anti-tRNA synthetases, anti-MDA5, and anti-U1RNP/Sm. Overlap disease was strongly associated with anti-PMScl, anti-Ku, anti-U1RNP/Sm and anti-Ro60. Absence of MSA/MAA was negatively associated with extra-muscular manifestations. Conclusions: Myositis autoantibodies are present in the majority of patients with IIM and identify distinct clinical subsets. Furthermore, MSAs are nearly always mutually exclusive endorsing their credentials as valuable disease biomarkers.

BackgroundAssessing disease activity in patients with myositis is an important goal. A method called Disease Activity Core Set Measures was established by International Myositis Assessment and Clinical Studies Group (IMACS) for evaluating activity of myositis. This assesses the manifestations of myositis which are thought to be reversible that result directly from the inflammatory process.ObjectivesIn this prospective study authors aimed to monitoring disease activity in Hungarian myositis patients treated at the Autoimmune Outpatient Clinic, Department of Clinical Immunology, University of Debrecen. First, disease activity data of poly (PM) – and dermatomyositis (DM) patients were compared. Secondly, by patients with active disease, the correlations between the components of Disease Activity Core Set Measures were studied.MethodsDuring the three-year follow-up period, at every single visit, authors evaluated disease activity using factors of Disease Activity Core Set Measures and patients filled Health Assessment Questionnaire (HAQ). Only those patients who appeared at least three times during the follow-up period were selected. Statistical analysis was made using SPSS 17.0 statistical software.ResultsCollection of data from 219 patients (age: 44.93 years, female: male ratio 2.98:1) happened in a total of 1101 outpatient visits. The 107 PM patients had statistically significant higher physician and patient visual analogue (VAS) and myositis disease activity assessment tools scores than the 61 DM patients, with the exception of cardiovascular disease activity. Activity of skin lesions was significant higher in DM patients. By the 44 patients, who had an active disease, the MMT scores gave significant negative correlations with HAQ scores (R=−0.536 and p<0.001) and CK levels (R=−0.387 and p<0.001). The physician and patient VAS gave strong negative correlations with MMT scores (R=−0.714 and p<0.001 and R=−0.730 and p<0.001, respectively) and positive correlations with HAQ scores and CK levels (physician VAS vs. HAQ R=0.691 and p<0.001; patient VAS vs. HAQ R=0.629 and p<0.001; physician VAS vs. CK R=0.622 and p<0.001; patient VAS vs. CK R=0.615 and p<0.001).ConclusionsAs far as we know, this is the first study which compares the activities of PM and DM patients based on the IMACS system. According to our data, we can conclude that PM patients had more severe muscle symptoms and extramuscular manifestations. Secondly, as seen in other previous studies, calculations in patients with active myositis showed a clear correlation between the most important components of Disease Activity Core Set Measures.Disclosure of InterestNone declared

Background Idiopathic inflammatory myopathies are chronic, heterogeneous systemic autoimmune diseases with symmetrical proximal muscle weakness. During the disease course, osteoporosis and bone fractures are more common compared to the healthy population, which can be explained by the chronic inflammation, immobilization, spontaneous falls and steroid treatment, and affect crucially the patients9 quality of life. Recently, a WHO fracture risk calculation tool, FRAX score is available, to measure the 10-year probability of osteoporotic fractures. It takes into account relevant clinical risk factors, such as rheumatoid arthritis, however myositis does not exist among the risk factors. Objectives Estimation the effect of myositis and myositis related bone mineral densities on bone fracture risk calculated by FRAX tool. Methods FRAX score was determined in 71 patients with idiopathic inflammatory myopathies and results were compared with the data from 50 age, sex and BMI matched patients with rheumatoid arthritis. Moreover, osteoporosis related biomarkers, disease related fractures and bone mineral densities were determined using DXA examinations. Statistical analysis was performed with IBM SPSS 20.0 software. Results There were no significant differences between the demographical data, biomarkers (Ca, Vitamin D, parathormone level) of the two groups. Disease duration and cumulative steroid dose were higher in the myositis group. Results of the FRAX score without BMD were significantly lower in the patients with myositis, in both fracture risk: major osteoporotic (8,61±6,36%, vs. 15,59±12,66%; p: 0,002) and femur neck (2,66±3,24%, vs. 6,34±9,018; p: 0.003). T score results of the DXA examination were not significantly different between the two populations (Lumbar1–4: -0,9±1,43 vs.-0,829±1,38; p:0,829; Femoral neck: -1,4±1,08 vs. -1,02±1,08; p: 0,93), but the presence of osteopenia (60% vs. 39,5%) and osteoporosis (13,5% vs. 7%) were more frequent in the myositis group (p: 0,045). Disease related fracture was associated with disease duration in the myositis group and with antibody (RF, ACPA) presence in the RA group. FRAX score with BMD results showed no significant differences between the two populations (Major osteoporotic: 9,44±6,72 vs. 13,25±9,43; p: 0,053; Hip: 2,77±3,01 vs. 3,57±5,08; p: 0,811). Conclusions As far as we know, this is the first study which examine the fracture risk using FRAX score in patients with idiopathic inflammatory myopathies. According to our data, we can conclude that existence of myositis might indicate similar, independent risk factor in fracture probability, like rheumatoid arthritis. Evaluation of fracture risk should be done with DXA result in patients with IIM, otherwise risk could be underestimated. An exact value of the “myositis related risk” could be determined by a 10-year prospective study. Disclosure of Interest None declared

Background The idiopathic inflammatory myopathies (IIM) represent a rare and heterogeneous group of multisystem autoimmune diseases. The rarity of IIM has hampered research efforts, resulting in remarkably limited therapeutic evidence. The EuroMyositis Registry was created to pool resources and expertise across the international IIM research community. Objectives To describe the phenotypic characteristics of different IIM subtypes. Associations with malignancy, interstitial lung disease (ILD), cardiac involvement and dysphagia were assessed. Methods Pooled data from the EuroMyositis Registry (from Belgium, China, Czech Republic, Hungary, Italy, Mexico, Norway, Sweden, Switzerland, UK, Vietnam) were obtained. Associations were assessed using logistic regression and multinomial logistic regression with polymyositis (PM) as the reference group. Results Data regarding 3,196 patients were analysed. The UK was the largest contributor (n=1,307). The most common diagnoses were dermatomyositis (34%), PM (32%) and connective tissue disease (CTD)-overlap myositis (15%). In those with anti-synthetase syndrome (7%), 85% had muscle weakness, 86% ILD and 58% arthritis. Overall, 43% had a myositis specific antibody, most commonly anti-Jo1 autoantibodies (20%). Glucocorticoid usage was noted in 98%. Most commonly used disease modifying agents were methotrexate (71%) and azathioprine (50%). Malignancy occurred in 9% and was associated with a diagnosis of dermatomyositis (Relative Risk Ratio [RRR] 1.68, 95% CI 1.09–2.56, p=0.018). Cardiac involvement occurred in 9%, most commonly in those with CTD-overlap myositis (13%), and was associated with a higher Health Assessment Questionnaire disability index (1 versus 0.75, OR 1.40, 95% CI 1.03–1.91, p=0.031). Dysphagia occurred in 39% and was associated with a diagnosis of CTD-overlap myositis (RRR 2.25, 95% CI 1.61–3.15, p<0.001). Conclusions This large international cohort demonstrates the heterogeneity of IIM and the burden of associated malignancy, ILD, cardiac and gastrointestinal involvement. The EuroMyositis Registry facilitates international collaborative research outputs, underlining the benefits of harmonised data collection methodology between centres. Acknowledgements This work was supported by researchers at the National Institute for Health Research (NIHR) Biomedical Research Unit. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR or the UK Department of Health Disclosure of Interest J. Lilleker: None declared, J. Vencovsky: None declared, G. Wang: None declared, L. Wedderburn Grant/research support from: The UK JDM Cohort and Biomarker study is supported by grants from the NIHR and Myositis UK, L. Diederichsen: None declared, J. Schmidt: None declared, P. Jordan: None declared, O. Benveniste: None declared, M. G. Danieli: None declared, K. Dankό: None declared, N. T. P. Thuy: None declared, M. Vazquez-Del Mercado: None declared, Ø. Molberg: None declared, B. De Paepe: None declared, J. De Bleecker: None declared, B. Maurer Grant/research support from: AbbVie, Protagen, EMDO, Novartis, Roche, Actelion, N. Pipitone Speakers bureau: GRAPPA Workshop, Alfa-Wassermann, N. McHugh: None declared, Z. Betteridge: None declared, P. New: None declared, R. Cooper: None declared, W. Ollier: None declared, J. Lamb Grant/research support from: MedImmune, N. S. Krogh: None declared, I. Lundberg Grant/research support from: Astra-Zeneca, Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Idera, H. Chinoy Grant/research support from: MedImmune, Novartis

Idiopathic inflammatory myopathies are systemic, chronic autoimmune diseases characterized by symmetrical, proximal muscle weakness. Homogeneous groups present with similar symptoms. The response to therapy and prognosis could be facilitated by myositis-specific autoantibodies, and in this way, give rise to immunoserological classification. The myositis-specific autoantibodies are directed against specific proteins found in the cytoplasm or in the nucleus of the cells. To date, literature suggests the rarity of the co-existence of two myositis-specific autoantibodies. In this study the authors highlight rare associations of myositis-specific autoantibodies. Three hundred and thirty-seven Hungarian patients with polymyositis or dermatomyositis were studied. Their clinical findings were noted retrospectively. Specific blood tests identified six patients with the rare co-existence of myositis-specific autoantibodies, anti-Jo-1 and anti-SRP, anti-Jo-1 and anti-Mi-2, anti-Mi-2 and anti-PL-12, anti-Mi-2 and anti-SRP, and anti-SRP and anti-PL-7, respectively. This case review aims to identify the clinical importance of these rare associations and their place within the immunoserological classification.

Background. Idiopathic inflammatory myopathies are chronic systemic autoimmune diseases characterized by symmetrical proximal muscle weakness. The clinicopathological subdivision nowadays appears to be obsolete which is why the immunoserological classification has been developed.Objectives. Dermatomyositis represents one the most important subsets of idiopathic inflammatory myopathy and dermatomyositis-specific autoantibodies play a significant role in this subset. The aim of this article was to present these autoantibodies with the help of the literature.Methods. This article presents the most important information about dermatomyositis including not only the classical anti-Mi-2 autoantibody but also the recently detected anti-TIF1 gamma, anti-NXP2, anti-SAE and anti-MDA5 autoantibodies. The focus is on the frequency of these autoantibodies, the associated symptoms in adult and juvenile dermatomyositis cases and some special aspects from the literature.Results. All of the studies confirmed that these autoantibodies are particularly detectable in dermatomyositis. The results from the literature have recently shown that the frequency of the autoantibodies detected in juvenile cases is higher than the frequency of traditional autoantibodies (e.g. anti-Jo-1, anti-Mi-2 and anti-SRP).Conclusion. It is useful to detect these autoantibodies in order to be able to make a better assessment of the clinical symptoms and prognosis during the course of the disease.

The idiopathic inflammatory myopathies are systemic, chronic autoimmune diseases characterized by proximal symmetrical muscle weakness. One of the main diseases in this group is inclusion body myositis (IBM), an underdiagnosed, progressive muscle disease characteristically affecting the middle-aged and older population. It has a slow, relentlessly progressive course. The precise pathogenesis of the disease remains unknown. In most of the cases it is diagnosed a few years after the appearance of the first symptoms. The muscle biopsy typically shows endomysial inflammation, with invasion of mononuclear cells into the non-necrotic fibers, and also rimmed vacuoles. It appers, that both inflammation and degeneration are present at the onset of the disease. Our aim is to raise awareness about this disease which leads to severe disability, with clinicopathological case presentations and literature overview, emphasizing the importance of collaboration between the clinician and the neuropathologist. No effective therapy is currently available but the rapid diagnosis is essential to slow disease progression. Although this is a relatively rare disease, patients are presenting not only in immunology outpatient clinics; our reports aims to raise awareness and facilitate accurate early diagnosis of IBM.

Die idiopathischen inflammatorischen Myositiden sind chronische, systemische Autoimmunkrankheiten, die durch symmetrische, proximale Muskelschwäche charakterisiert sind. Die klinisch-pathologische Einteilung scheint heutzutage obsolet zu sein, deshalb ist eine immunserologische Klassifikation erstellt worden.

Background The most frequent myositis specific antibody (MSA) in the serum of patients with idiopathic inflammatory myopathies is anti-Jo-1. The presence of anti-Jo-1 define a distinct clinical phenotype, antisynthetase syndrome (ASS), which is characterized by poor prognosis and multiple organ involvement, such as myositis, interstitial lung disease (ILD), non-erosive arthritis, Raynaud9s phenomen, mechanic9s hand, skin rashes, and fever. Objectives The aim of this study was to determine the clinical, serological, laboratory and genetic features of anti-Jo1 positive patients followed by our department. Methods Retrospective analysis of medical records of 49 patients (42 female, 7 male) were reviewed. Anti-Jo-1 titer was detected with enzyme-linked immunosorbent assay. HLA DRB1, DQA1 and DQB1 genotype was determined using commercial sequence-specific oligonucleotide kit. Statistical analysis was performed using Pearson Chi2, Fisher exact test, or Spearman correlation. Results The median age at diagnosis was 43±13,28 years (range: 18-70), 48 patients exhibited myositis (98%), 35 ILD (73%), 43 arthritis (88%), 32 Raynaud9s phenomen (65%), 21 fever (43%), 16 mechanic9s hand (33%), 27 skin rash (55%) and 6 dysphagia (12%). We could detect significant correlation between the initial anti-Jo-1 titer and the first CK (R=0,328; p=0,003) and CRP (R=0,374; p=0,016) level. Furthermore anti-Jo1 levels during disease course had significant correlation to the corresponding CK (R=0,497; p<0.001), and CRP (R=0,325; p<0.001) level. The most frequent antibody besides anti-Jo-1 was anti-SSA (28/49; 57%). The anti-Jo-1+/SSA+ population had younger age at the diagnosis (36,12±11,08 vs. 47,22±12,87; p=0,004), lower rate of ILD (53% vs. 81%; p=0,039), but higher maintaining steroid (methylprednisolone) dose (9,53 mg vs. 3,7 mg; p=0,031) compared to the Jo-1+/SSA- group. Higher (≥8 mg) maintaining steroid therapy was associated with higher initiating CRP (36,34 vs. 17,84 mg/l; p=0,014) ESR (33,87 vs. 19,81 mm/h; p=0,032) level and higher presence of fever (67% vs. 37%; p=0,038) at diagnosis but not with initiating CK (p=0,374), LDH (p=0,224) level or ILD presence (p=1). 68,96% of the patients were HLA DRB1*03 positive, where the CK level at diagnosis was significantly lower compared to the HLA DRB1*03 negative patients (2816,30 vs. 5969,44 U/l; p=0.04). 58.62% of the patients were positive for HLA DQA1*0501-DQB1*0201 haplotype, but no significant correlation was found regarding to any clinical or laboratory features. Conclusions Our results confirm previously reported data from other centers considering the clinical features of anti-Jo1 positive patients. HLA DRB1*03 positivity was associated with lower CK level but has no influence on clinical or serological features. It seems that anti-Jo1 level might reflect disease activity; ESR, CRP levels, associated fever and anti-SSA positivity at the diagnosis could be considered as prognostic markers. Disclosure of Interest None declared

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Background: The shared epitope (SE) is a group of alleles of the HLA- DRB1 gene and was thought to have the strongest effect on RA susceptibility. However, recently, HLA-DRB1 position 11, outside of the classical SE, has been shown to be a stronger predictor of RA susceptibility. Positions 11, 71 and 74 define 16 haplotypes, the effect of which ranges from risk to protective on RA susceptibility. Their effect on RA severity, treatment response or mortality in patients has not previously been studied. Our objectives were to assess whether HLA-DRB1 positions 11, 71 and 74 can also be used to predict radiological outcome, anti-TNF response and mortality in patients with RA. Methods: We used 3 independent prospective cohort studies: the Norfolk Arthritis Register (1691 patients with 2811 X-rays); the Early Rheumatoid Arthritis Study (421 patients with 3758 X-rays); and a cohort from 57 UK centres (BRAGGSS; 1846 patients with treatment response). HLA typing was determined using a reverse dot-blot method or dense genotyping of the HLA region by the ImmunoChip array, followed by imputation. Longitudinal modeling of the presence of erosions was performed with generalized estimating equation (GEE) models, whilst the Larsen score was modeled by Generalized Linear Latent and Mixed Modeling (GLLAMM). the was modeled with linear regression and EULAR response with ordinal logistic regression. Cox proportional models were used for all cause and cardiovascular mortality studies. ( n ¼ 931) strengthened the association with PTPN22 and suggested PM- specific loci including UBE3B/MMAB, NAB1 and IL18R1 . In a combined DM and JDM analysis ( n ¼ 1360), there is no evidence of association with PTPN22 , suggesting the association with total IIM is driven by the stronger association with the PM subgroup. There were fewer associa- tions of suggestive significance in DM and JDM; however, the GSDMB locus is of particular interest. Conclusion: This is the largest genetic association study to date in IIM. The data confirm that HLA is the most associated locus in IIM and its clinical subgroups, and that the association of PTPN22 in IIM may be driven by its preferential association with PM. Identification of further novel loci at a suggestive level of significance may differ between clinical subgroups of myositis. The IIMs are a heterogeneous set of diseases; additional clinical subgroup specific analyses as well as antibody specific analyses are thus planned. Disclosure statement: Theauthors havedeclaredno conflicts ofinterest. Background: Fibroblast-like synoviocytes (FLS) from patients with RA display an aggressive, invasive phenotype and play a key role in joint destruction. Increasing evidence indicates that alterations to the epigenome, including DNA methylation, contribute to the FLS phenotype in RA. Herein, we performed the first genome-wide profiling of DNA methylation in FLS derived from SF, as a more readily accessible source of disease-associated cells, in patients with RA. Methods: Synovial fluid samples were collected during routine arthrocentesis from 12 Caucasian patients with RA and OA. FLS were isolated and expanded in vitro using standard adherent cell culture methods. Genomic DNA was extracted, bisulfite-converted and subse- quently hybridized to HumanMethylation450 BeadChips for quantitative assessment of genome-wide DNA methylation at over 480000 CpG dinucleotides. Data were analyzed using NIMBL software. A CpG was considered to be differentially methylated in RA FLS relative to OA FLS if the mean difference in methylation b -value was at least 0.1 and was statistically significant following adjustment for multiple testing. Candidate genes were validated by bisulfite pyrosequencing. Results: Genome-wide profiling identified 328 CpGs (representing 195 genes) that were differentially methylated between RA and OA fluid-derived FLS. The majority ( (cid:5) 80%) of these sites/genes were hypo- methylated in RA FLS. Comparison of these 195 genes with those identified intwo studies of tissue-derived FLS revealed 73 genes ( (cid:5) 40%) that were common with at least one of these studies, and where 22 genes shared identity with both studies. Pyrosequencing analysis confirmed altered methylation of these genes and identified additional sites in some of the genes which also showed methylation changes similar to those determined at the array-identified site. We also identified 122 differentially methylated genes that were unique to fluid-derived FLS, and which perfectly segregated RA from OA-derived FLS. Conclusion: SF-derived RA FLS show altered DNA methylation across multiple genes and a significant proportion of these are common with those identified in tissue-derived FLS. These data identify a number of potential candidate genes and support the use of fluid-derived FLS for futureinvestigations ofepigeneticdysregulationinRA synovialfibroblasts. Disclosure Background: RA is a chronic and disabling disease with no known cure. RA has a strong genetic component and genetic studies have successfully identified over 100 loci associated with disease onset. After the HLA region and PTPN22 , the strongest association to both seropositive and seronegative RA is seen within the ANKRD55 gene, on chromosome 5q11. ANKRD55 is an unexplored gene thatcould provide novel insights into the biological pathways that underpin RA and also be a putative novel therapeutic target. The objective was to utilize well-powered genetic data in order to fine-map the region, and through bioinformatic data and functional experiments, to generate robust evidence for the causal variant and causal gene at the 5q11 locus. Methods: As part of the ImmunoChip project, 60 single nucleotide polymorphisms (SNPs) in a 0.1 cM recombination block around the previous lead genome-wide association study marker at the 5q11 locus, rs6859219, were analysed for their association in 11475 cases and 15870 controls. Conditional logistic regression and haplotype analysis were conducted in order to fully characterize the genetic architecture of the region. Bioinformatic tools were subsequently used in order to examine and prioritize SNPs based on their regulatory potential. Correlation of the putative variants with expression of nearby genes (eQTL) was carried out in whole blood, CD4 þ and CD8 þ T cell subsets, and chromatin immunoprecipitation (ChIP) experiments for the histone modification H3K4me1, a marker of enhancers was carried out in lymphoblastoid B cell lines. Results: Genetic fine-mapping using ImmunoChip data refined the association at the 5q11 locus to a single signal, rs71624119 ( P ¼ 5.59 10 –4 , OR 1.3). The association to PTPN22 in the PsA Immunochip data was not affected by the inclusion of the RA-GRS as a covariate. In addition, we find genome-wide significant association to the previously reported psoriasis risk loci; NOS2 (rs4795067, P ¼ 5.27 (cid:7) 10 –9 ). No other SNPs reached genome-wide significance in the combined dataset. Conclusion: For the first time, we report genome-wide significant association of PTPN22 (rs2476601) to PsA susceptibility, a locus associated with many autoimmune diseases. The risk allele (A) and direction of effect are consistent with previous reports for RA and type I diabetes, but opposite of that reported for Crohn’s disease. We provide evidence that this is a PsA-specific risk locus as no association to psoriasis was observed in the WTCCC2 cohort and the effect estimates are significantly different between PsA psoriasis when compared in multinomial logistic regression. Disclosure statement: The authors have declared no conflicts of interest. Background: Depression and reduced mental health are prevalent in RA. They associate with an impaired quality of life and increased healthcare utilization. Several studies have assessed causes of depression in established RA, reporting associations with pain, disability and tender joint counts. The cause of reduced mental health in early RA has received less attention. We evaluated potential causes of low mental health – assessed using the SF-36 mental component summary score (MCS) – in 424 early, active RA patients enrolled to a clinical trial. We tested the hypothesis that reduced mental health in early RA is driven by genetic risk of depression; RA severity [DAS

Several autoimmune diseases have been associated with accelerated atherosclerosis or other types of vasculopathy depending on the underlying disease, leading to increased cardio- and cerebrovascular risk. Polymyositis (PM) and dermatomyositis (DM), members of idiopathic inflammatory myopathies (IIMs) are also associated with elevated cardiovascular risk (CVD). Up until now, no specific data is known on the mechanisms, risk factors, or possible vasculopathy.

Background Idiopathic inflammatory myopathies (IIM) may present as a primary disorder, or may overlap with connective tissue diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis. The aetiology of IIM is largely unknown, but is thought to include a combination of genetic and environmental factors. To generate ethnically homogeneous IIM cohorts of sufficient size given its rarity, one of the largest European IIM initiatives has enabled Europe wide ascertainment of cases with EUMYONET. Numerous genome-wide association studies (GWAS) have identified many genetic variants associated with autoimmune disorders, several common to multiple disorders. This is supported by our recent dermatomyositis (DM) GWAS, suggesting genetic overlap with other autoimmune disorders1. Objectives We sought to identify additional novel genetic risk factors in adult and juvenile polymyositis (PM) and DM (not previously identified by DM GWAS), shared with other autoimmune disorders. Methods SNPs significantly associated with SLE, RA, juvenile idiopathic arthritis, coeliac disease, Crohn9s disease, ulcerative colitis, psoriasis, type 1 diabetes, multiple sclerosis or systemic sclerosis were identified from published Caucasian GWAS and from the national human genome research institute catalogue of published GWAS. 233 unique SNPs were identified (p <5×10-8), of which 99 had not been directly genotyped or captured through our MYOGEN GWAS1. SNPs were genotyped by Sequenom in a sample of 1001 European Caucasian individuals with definite or probable adult or juvenile PM or DM. 83 SNPs passed quality control criteria. GWAS data from EU contributors was imputed to the 1000G_phase1integrated_v3 reference panel. Association tests for IIM subgroups and random-effects meta-analysis of the individual country datasets were performed. Results Samples with >5% missing genotype data were excluded, resulting in 1149 cases and 3572 controls. Outside the MHC region, a non-synonymous SNP rs2304256 in the TYK2 gene was identified reaching Bonferroni-corrected significance in IIM and DM (β= -0.21, p value=0.00027; β= -0.25, p value=0.00020 respectively). Two further SNPs within the BLK gene and 2335bp 59 of BLK were associated with DM (rs2618476, β=0.24, p value=0.00062; rs13277113, β=0.25 p value=0.00045 respectively) but not with PM, supporting the results of our DM GWAS. Conclusions We have identified TYK2 as a novel association for DM, suggesting genetic overlap of DM with other autoimmune disorders, and indicating genetic heterogeneity between PM and DM. TYK2 has been associated previously with SLE, type 1 diabetes and multiple sclerosis. Further associations of the BLK gene with DM, suggests a role of B cells in its development. References Miller FW et al. Arthritis Rheum. 2013 Dec; 65(12):3239-3247 Acknowledgements Funding: Arthritis Research UK (grants 18474; 14518), Intramural Research Program of the NIH, Wellcome Trust (076113; 085860). We thank all other members of the EUMYONET and Myositis Genetics Consortium (MYOGEN). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2877

Background Immunological changes during pregnancy are in the centre of scientific researches. We already know that immunological pathways may go wrong during pregnancy in autoimmune diseases with some general complications like fetal loss and low birth weight but we have less informations about the outcome of pregnancy in idiopathic inflammatory myopathies, polymyositis (PM) and dermatomyositis (DM). Objectives Our aim was to assess the clinical features, organ complications, functional course, therapeutic response in patients with PM/DM according to the pregnancy status. Methods Medical records were retrospectively revised using a standardised protocol. 23 PM/DM patients with pregnancy were identified in four countries: Hungary (n=9), Czech Republic (n=8); Sweden (n=5) and Poland (n=1). Immunological and serological characteristics were measured by ELISA, immunoblot and immuneprecipitation. Autoantibodies to Jo-1, PL-7, PL-12, EJ, OJ, SRP, PM-Scl, Ku, Mi-2, U1-, SSA, SSB were detected by LIA. We used the Fisher’s exact test for statistical analysis. Results These 23 patients had 33 pregnancies after or at the time of disease onset. 10 of them suffered from PM and 13 had DM or JDM. The most frequent symptoms were ILD, mechanic’s hand, Raynaud phenomenon and arthritis. 19 pregnancies ended without complications giving life to healthy babies. In 13 cases complications, like intra-uterine growth retardation, intra-uterine death, abortion, extra-uterine gravidity occurred. These complications were most frequently seen in patients with PM than DM (p=0,0729). The relative risk of complicated pregnancy in PM was 1,923 (CI 95% 1,041-3,553). This “almost significant” finding could be caused by PM and by anti-Jo1 and anti-phospholipid autoantibodies as well, because we found these antibodies frequently associated to PM in these cases. 13 pregnancies started during the active phase of myositis and the majority of these patients didn’t reach remission after the delivery. The mean weight (2599g in active disease vs. 3342g in remission) and height (48 cm vs. 51 cm) of babies was lower in the active cases and the pregnancy ended earlier than in patients with remission. Most of the affected patients used only glucocorticoid treatment during pregnancy. Conclusions Complications during pregnancy were frequently reported in PM/DM although no myositis specific complications could be found. In patients with PM there was a tendency for a higher risk of fetal problems than in DM. Disclosure of Interest None Declared

The authors discuss a rare case of a 25-year-old female patient having dermatomyositis associated with celiac disease and ulcerative colitis. The idiopathic inflammatory myopathies are systemic, chronic, immune-mediated diseases characterized by proximal, symmetrical muscle weakness. Many examples from the literature refer that celiac disease occurs more often in patients with myositis than in the general population, but its association with ulcerative colitis is a real rarity in the international literature.

Idiopathic inflammatory myopathies (IIMs) may present as a primary autoimmune disorder, or overlap with other autoimmune/connective tissue diseases. The aetiology of IIM likely includes interactions between genetic and environmental factors. Several genetic variants common to multiple autoimmune disorders have been identified in recent genome-wide association studies (GWAS). A Myositis Genetics Consortium dermatomyositis (DM) GWAS also suggests genetic overlap with other autoimmune disorders.1 We sought to extend these findings to identify novel genetic risk factors in a large cohort of adult/juvenile patients with DM and polymyositis (PM), by genotyping immune-related single nucleotide polymorphisms (SNPs) not captured through the DM GWAS.1 SNPs significantly associated (p<5×10−8) with 10 autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, coeliac disease, Crohn's disease, ulcerative colitis, psoriasis, type 1 diabetes, multiple sclerosis and systemic sclerosis) were identified from published GWAS or the National Human Genome Research Institute GWAS catalogue.2 Unique SNPs were identified (n=233), of which 99 had not been directly genotyped or captured (r2≥0.8 with genotyped SNPs) through our DM GWAS.1 These 99 SNPs were genotyped using Sequenom in 1001 European Caucasian individuals with …

Several autoimmune rheumatic diseases have been associated with accelerated atherosclerosis or other different types of vasculopathy depending on the underlying disease, leading to increased cardio- and cerebrovascular disease risk. Polymyositis (PM) and dermatomyositis (DM), members of idiopathic inflammatory myopathies (IIMs), a group of systemic autoimmune diseases are also associated with elevated risk of cardiovascular diseases (CVD). Up until now, no specific data is known on the mechanisms, risk factors, or possible vasculopathy leading to increased CVD risk. The aims of the present study were to assess the flow-mediated dilatation of the brachial artery by a TensioClinic arteriograph and to measure the thickness of carotid artery intima–media, the augmentation index, and the pulse wave velocity using high-resolution ultrasonography in a cohort of PM and DM patients. We also investigated the correlation of these parameters with the traditional risk factors of atherosclerosis and overall cardiovascular status within PM and DM patients. Twenty-seven patients (21 females, six males) with IIMs were enrolled in this study, and 38 healthy individuals matched for sex and age served as controls. We found a decreased flow-mediated dilatation in the brachial artery (6.36 vs. 8.39 %) with increased arterial stiffness and carotid artery thickness in our patients compared to healthy controls. We found significantly decreased flow-mediated dilatation of the brachial artery (5.57 vs. 8.39 %) in DM patients. We also detected a correlation between these parameters and the traditional cardiovascular risk factors, as well as hypertriglyceridemy, hypertension, and peripheral arterial disease. In DM, overall, more vascular abnormalities were found than in PM. Our findings suggest that flow-mediated dilatation of the brachial artery, arterial stiffness, and carotid artery thickness measurements could be beneficial for predicting the CVD risk in myositis patients. Further investigations need to find the potential differences and role of inflammation and immune mechanisms in atherosclerotic processes in DM and PM.