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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

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

Objective: To investigate the intracellular and soluble cytokine levels and T cell subsets in peripheral blood of patients with active and inactive polymyositis and dermatomyositis. Methods: The frequencies of T and B lymphocytes, T helper (Th), and T cytotoxic (Tc) cells and of interferon γ (IFNγ), interleukin (IL)4, and IL10 expression of CD4+ or CD8+ cells were determined by flow cytometry. The concentrations of soluble cytokines were measured with commercial enzyme linked immunosorbent assays. Results: In active dermatomyositis there was a decreased percentage of T (CD3+) lymphocytes and Tc (CD8+) lymphocytes, decreased IFNγ expression of CD4+ and CD8+ cells, but an increase in B and IL4 producing CD4+ lymphocyte frequencies. These prominent changes disappeared in the inactive stage of the disease. In polymyositis no significant change in these lymphocyte subsets or in intracellular cytokine expression could be detected in either the active or the inactive form. The frequency of IL4+/IFNγ+ Th cells was calculated and a significantly increased Th2/Th1 frequency was found in active dermatomyositis, and a decreased frequency in inactive dermatomyositis, compared with the control population. Conclusions: There appears to be a difference between polymyositis and dermatomyositis in the level of peripheral blood lymphocytes and their intracellular cytokine content. These findings provide further evidence for a difference in the pathogenesis of polymyositis and dermatomyositis.

Objective: To describe the methodology used to develop new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. Methods: An international, multidisciplinary group of myositis experts produced a set of 93 potentially relevant variables to be tested for inclusion in the criteria. Rheumatology, dermatology, neurology, and pediatric clinics worldwide collected data on 976 IIM cases (74% adults, 26% children) and 624 non-IIM comparator cases with mimicking conditions (82% adults, 18% children). The participating clinicians classified each case as IIM or non-IIM. Generally, the classification of any given patient was based on few variables, leaving remaining variables unmeasured. We investigated the strength of the association between all variables and between these and the disease status as determined by the physician. We considered three approaches: (1) a probability-score approach, (2) a sum-of-items approach criteria, and (3) a classification-tree approach. Results: The approaches yielded several candidate models that were scrutinized with respect to statistical performance and clinical relevance. The probability-score approach showed superior statistical performance and clinical practicability and was therefore preferred over the others. We developed a classification tree for sub-classification of patients with IIM. A calculator for electronic devices, such as computers and smart phones, facilitates the use of the EULAR/ACR classification criteria. Conclusions: The new EULAR/ACR classification criteria provide a patient’s probability of having IIM for use in clinical and research settings. The probability is based on a score obtained by summing the weights associated with a set of criteria items.

BackgroundLow serum vitamin D concentrations have been reported in several autoimmune disorders.ObjectiveTo assess whether low serum vitamin D concentrations are related to disease activity of patients with systemic lupus erythematosus (SLE).Methods378 patients from several European and Israeli cohorts were pooled and their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. In order to combine the two systems the scores were converted into standardised values (z-scores), enabling univariate summary statistics for the two variables (SLEDAI-2K and ECLAM). The commercial kit, LIAISON 25-OH vitamin D assay (310900-Diasorin) was used to measure serum concentration of 25-OH vitamin D in 378 patients with SLE.ResultsA significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (Pearson's correlation coefficient r=−0.12, p=0.018).ConclusionsIn a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.

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, Crohn's 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% 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 5' 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 1. 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 Polymyositis (PM) and dermatomyositis (DM) are usually treated with glucocorticoids (GC) and immunosuppressive drugs. Controlled trials are scarce and include low numbers of patients. Early addition of methotrexate (MTX) to GC is often used in clinical practice; however evidence of the benefit for this strategy is lacking. Objectives The aim of the trial was to assess the efficacy and safety of the combination therapy with MTX as compared to GC treatment only from the early phases of PM and DM. Methods Patients naive to methotrexate were randomized into 2 groups treated with GC alone (group A) or with added MTX (group B). This was an open label study with the efficacy assessor being unaware of the treatment assignment. Duration of treatment was 48 weeks with monthly assessments. Primary endpoint was the total dose of GC in mg/kg body weight administered between baseline and the end of treatment in the two groups. GC were initially given at 1 mg/kg and tapered according to a pre-defined scheme if definition of improvement (DOI, IMACS) was achieved. Maximal duration of previous GC treatment was 8 weeks. Maximum dose of MTX was 20 mg/week. Secondary endpoints were individual disease activity core set parameters, muscle endurance, functional disability and safety. Results Five centers enrolled a total of 31 patients (17 PM, 14 DM). 16 patients were randomized in group A, 15 into group B. Groups A and B showed similar baseline characteristics. There were 4 dropouts during the study (3 in A, 1 in B). 85% (group A) and 86% (group B) of patients fulfilled DOI at week 48. There was no significant difference in the total prednisone dose (124±16 mg/kg in group A vs. 135±14 mg/kg in group B, p=0.6). None of the secondary efficacy parameters differed significantly between the two groups at the end of the study. There were 92 reported adverse events (AE). The overall number of AE in the 2 groups was similar. AE related to GC use were more frequent in the group A (5 cases) than in the group B (2 cases). Conclusions Patients with PM and DM do not significantly benefit from upfront methotrexate addition to GC during one year treatment, when the two strategies are commenced in the early stages of the disease. Acknowledgements Supported by EULAR and by Institutional Project No. 00023728. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3886

Screening for autoantibodies associated with idiopathic inflammatory myopathies (IIM) has conventionally been performed using radio-immunoprecipitation techniques which are not suitable for use in routine diagnostic laboratories. The authors have therefore investigated the use of line-immunoassay technology employing recombinant antigens as an alternative for this purpose. Sera and clinical data were collected on 486 patients (256 PM,183 DM, 20 JDM, 9 IBM, 18 overlap syndrome) with IIM, according to Bohan …

Background The idiopathic inflammatory myopathies (IIM) are systemic autoimmune disease characterised with proximal muscle weakness. The epidemiology of these multifactorial diseases is partially known. These are rare diseases and Immunological or Rheumatological centres or international collaborations are required to carry the majority or all of these patients. Nowadays there are studies for establishing national or international registry of IIM patient. The Myositis study group of Division of Clinical Immunology, Institution of Internal Medicine, University of Debrecen Medical and Health Science Centre have been found in 1975. Most of the Hungarian patients are carried in this department since then. So we have preliminary epidemiological data of Hungarian IIM patients. The database is under continuous development. Objectives The aim of this report is to show our epidemiological findings. Sex and age were analysed in each IIM subgroup. Standardized incidence rates were calculated as new cases/million population/year with 95% confidence interval (CI). Results Between 1999 and 2010 1119 patients were hospitalized due to IIM in Hungary. We selected the data of these years because we have less information about the patients before 1999 (no computerized data before this date). 288 patients were carried in our department. 61,93% suffered from polymyositis (PM), 32,17 % had dermatomyositis (DM), 4,15% had juvenile dermatomyositis (JDM), 0,69% was diagnosed with amyopathic dermatomyositis (ADM) and we found other myositis (OTM) in 1,03% of the patients. The mean age of patients was 47,73 years (ys), respectively 48,46 ys (PM) – 52,19 ys (DM) -9,66 ys (JDM) – 34 ys (ADM) – 32 ys (OTM) in the subgroups. 67,82% of the patients were adult woman (mean age: 50,07 ys), we found 27,68 % of adult man (mean age:49,11 ys) and 4,5% children (9,6 ys). Cancer associated myositis was found in 31 cases (10,72%), the mean age of patients were 53,51 years. The most frequent tumor types were breast and lung cancer but gastrointestinal, reproductive and hematological malignancies were also presented. Overlap syndromes, preciously the association of IIM with other autoimmune diseases have been found in 14 cases (4,84%), the mean age of these patients were 44,64 years. The mainly presented overlap syndrome was Systhemic sclerosis and Sjogren’s syndrome. The average incidence rate was 0.95 cases per 100.000 persons per year. Conclusions Our results represented that the epidemiological data of Hungarian IIM population correlate with the former publicised findings. IIM commonly developed in middle-aged woman. The male/female ratio is 1/2. Dermatomyositis can occur in children and in adults as well, however PM is mainly the disease of adults. These are rare diseases with incidence of 0.1-1 /100.000/year. Our next goal is to develop a National Registry for IIM patients to have more information about epidemiological, clinical and serological characteristics of Hungarian patients. Disclosure of Interest None Declared

Background The idiopathic inflammatory myopathies (IIM) are autoimmune disorders characterised by acquired proximal muscle weakness, inflammatory cell infiltrates in muscle biopsies and myositis-specific or associated autoantibodies. Myositis may present as a primary disorder, or may overlap with other 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 both genetic and environmental factors. To generate ethnically homogeneous IIM cohorts of sufficient size, given the rarity of IIM, and to allow statistically meaningful research, one of the largest European IIM initiatives has enabled UK-wide ascertainment of cases with UK MYONET. Numerous recent genome-wide association studies (GWAS) have identified many genetic variants associated with autoimmune disorders, several of which are common to multiple disorders. Objectives To test the hypothesis that genetic risk factors associated with other autoimmune disorders also predispose to IIM. Methods SNPs significantly associated with SLE, RA, juvenile idiopathic arthritis, coeliac disease, Crohn’s 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 (NHGRI) catalogue of published GWAS. 233 unique SNPs were identified (p -8 ), of which 99 had not been directly genotyped or captured through our MYOGEN GWAS. These SNPs were genotyped on the Sequenom platform in a sample of 391 UK Caucasian individuals with definite or probable adult or juvenile dermatomyositis or polymyositis. Genotype data was obtained from controls of European ancestry and imputation carried out for non-genotyped SNPs using HapMap Phase 3 and One Thousand Genomes data. Preliminary analysis was carried out using logistic regression in PLINK incorporating multi-dimensional scaling factors derived from the GWAS data as covariates to correct for population substructure. Results 391 individuals and 83 SNPs were successfully genotyped and passed quality control filtering criteria. Two SNPs within the HLA region were significantly associated with IIM (rs2040406 near HLA-DQA1 , p =6.21×10 -25 ; rs615672 near HLA-DRB1 , p =1.65×10 -9 ). Although no SNPs outside the HLA region achieved Bonferroni corrected significance levels for the number of SNPs tested, four SNPs previously associated with RA and SLE reached nominal significance (RA: rs13315591 in FAM107A , p =0.001; SLE: rs13385731 in RASGRP3 , p =0.001, rs5029939 in TNFAIP3 , p =0.004; rs2230926 in TNFAIP3 ; p =0.005). Conclusions The association of HLA SNPs confirms the autoimmune nature of IIM. The nominal association of four SNPs previously associated with SLE and RA suggests that IIM may share genetic risk factors with other autoimmune disorders. These results require confirmation in an independent replication sample. Disclosure of Interest None Declared

Background The most frequent myositis associated autoautoantibodies are directed to Ro52-kd protein (12-26%). Antibodies to the immunodominant epitope (p200) of Ro52 are associated with SLE and Sjogren’s syndrome (SjS) with suggestion for a pathogenic effect in development of neonatal heart block. The role of anti-Ro52 autoantibodies in myositis is not clear. Presence of anti-Ro52 in combination with anti-Jo-1 autoantibodies is associated with interstitial lung disease (ILD). Objectives The aim was to investigate the associations of reactivity to Ro52 epitopes with disease manifestations, autoantibody profile, smoking status and HLA-DRB1 alleles in myositis. In order to test the hypothesis of epitope spreading the association of disease duration with polyreactivity was evaluated. Methods Serum samples from 468 myositis patients were collected in three countries: Czech (n=133); Hungary (n=202), Sweden (n=133). The reactivity with recombinant full length (FL) Ro52 antigen, its four deletion fragments (Ro52-3,-4,-5 and -6) and 7 overlapping synthetic peptides (p136-200) covering the major immunodominant region (Ro52-3) was measured by ELISA. Autoantibodies to Jo-1, PL-7, PL-12, EJ, OJ, SRP, PM-Scl, Ku, Mi-2β, U1-RNP were detected by LIA. 417 patients were genotyped for HLA-DRB1. Smoking status was known in 434 patients. Results 184 patients with dermatomyositis (DM), 250 polymyositis (PM), 11 inclusion body myositis, 20 juvenile DM/PM and three with mixed connective tissue disease were included in the analysis. Median disease duration was 4.7 (0-41.5) years. ILD was present in 132 (29%) of patients. In total 175 (40%) patients were smokers. Reactivity to Ro52-FL was present in 97 (21%) samples; 87 (90%) of these showed specificity to Ro52-3 and anti-p176 dominated (66; 76%) whereas only 44 (51%) had reactivity to the p200 epitope. Anti-Ro52FL positivity was associated with presence of ILD (OR 3.8; p Conclusions Our results confirm the association between anti-Ro52 positivity with ILD, anti-Jo-1 autoantibodies and HLA-DRB1*03 allele in myositis. The dominance of reactivity to epitope p176 in myositis patients differs from dominant p200 in SLE and SjS, but its clinical significance is not clear. There was no effect of smoking or evidence for epitope spreading in anti-Ro52 response. Supported by EU 6.FP integrated project AutoCure LSHB CT-2006-018661 and Grant NT 12438 of IGA MZCR Disclosure of Interest O. Krystufkova Grant/Research support from: EU 6.FP integrated project AutoCure LSHB CT-2006-018661 and Grant NT 12438 of IGA MZCR, V. Dzikatite: None Declared, P. Charles: None Declared, H. Mann: None Declared, L. Ekholm: None Declared, M. Vincze: None Declared, I. Putova: None Declared, N. Kasprikova: None Declared, L. Padyukov: None Declared, K. Danko: None Declared, P. Novota: None Declared, J. Vencovsky: None Declared, M. Wahren-Herlenius: None Declared, I. Lundberg: None Declared

Background Specific or associated autoantibodes are present in a majority of patients with idiopathic inflammatory myopathies (IIM). The most frequent myositis associated autoautoantibodies are directed to Ro52-kd protein (present in 12–26%). Antibodies towards the immunodominant epitope (p200) of Ro52 are associated with neonatal heart block (CHB) in SLE and Sjogren9s syndrome (SjS) with the increasing evidence for their pathogenic role. Less is known about possible pathogenic involvement of anti-Ro52 in IIM. Presence of anti-Ro52 in patients with anti-Jo-1 autoantibody is associated with interstitial lung disease (ILD) and suggested decreased survival rate. Objective To investigate possible associations of reactivity to Ro52 epitopes with disease manifestations, autoantibody profile and HLA-DRB1 alleles in myositis. In order to confirm the hypothesis of ongoing epitope spreading with time, the association of disease duration with polyreactivity was evaluated. Methods Serum samples from 468 myositis patients were collected in three countries: Czech (n=133); Hungary (n=202), Sweden (n=133). Antibody specificity against recombinant full length (FL) Ro52 antigen, its four deletion fragments (Ro52-3, -4, -5 and -6) and 7 overlapping synthetic peptides (p136–200) covering the major immunodominant region (Ro52-3) was measured by ELISA. Myositis specific and associated autoantibodies (Jo-1, PL-7, PL-12, EJ, OJ, SRP, PM-Scl, Ku, Mi-2β, U1-RNP) were detected by line-blot immunoassay. 417 patients were genotyped for HLA-DRB1. Results One hundred and eighty-four patients with dermatomyositis (DM), 250 polymyositis (PM), 11 inclusion body myositis, 20 juvenile DM/PM and three with mixed connective tissue disease were included in the analysis. Overlap with other systemic disease (OM) was present in 67 (14%) and ILD in 132 (29%) of patients. Median disease duration was 4.7 (0–41.5) years. Reactivity to Ro52-FL was present in 97 (21%) samples. Of these, 87 (90%) patients showed specificity to Ro52-3. Within these anti-p176 dominated (66; 76%) compared to anti-p200 in 44 (51%) patients. Anti-Ro52FL positivity was associated with presence of ILD (OR 3.8; p Conclusion Our results confirm the association between anti-Ro52 autoantibody positivity with lung involvement, anti-Jo-1 autoantibodies and HLA-DRB1*03 allele in myositis. The predominance of reactivity to epitope p176 in myositis patients is different from that which has been reported in patients with SLE and SjS, but the clinical significance is not clear. There was no evidence of epitope spreading in anti-Ro52 response. Acknowledgement Supported by European Union 6.FP integrated project AutoCure LSHB CT-2006-018661; by MSM 0021620812 from Ministry of Education, Youth and Sports in the Czech Republic and by Grant NT 12438 of IGA Ministry of Health in the Czech Republic.

The role of vitamin D as an immune-modulator has been emphasised in recent years, and low levels of this hormone were observed in several autoimmune diseases.1 Vitamin D mediates its effect through binding to vitamin D receptor (VDR) and activation of VDR-responsive genes. VDR-gene polymorphism was found to associate with …