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In order to develop a preliminary core set of disease outcome measures for use in clinical trials of idiopathic inflammatory myopathies (IIM), we evaluated those measures used in previous trials, assessed the validation of published instruments and discussed these at an international consensus conference. The initial proposals were further refined by a multidisciplinary group of adult and paediatric specialists experienced in IIM using the Delphi method. The proposed preliminary core set of disease activity measures consists of five domains: physician and patient/parent global assessments of disease activity; muscle strength; physical function; serum activity of muscle enzymes; and an assessment tool to capture extra-skeletal muscle disease activity. The group recommended further development of a core set of disease damage measures for assessment of persistent changes in anatomy, pathology and function of at least 6 months' duration. The group recommended that patient-reported outcomes should include generic health-related quality of life assessments using the Medical Outcomes Study 36-item Short Form (SF-36) health survey in adult IIM patients and a validated quality of life instrument for paediatric patients. We propose the core set of outcome measures as a minimum group of assessments to include in all IIM therapeutic studies. The use of this core set should assist in standardizing outcome measurement and in optimizing therapeutic trials in myositis.

IL-10 is an anti-inflammatory cytokine which may modulate disease expression in RA. Three dimorphic polymorphisms within the IL-10 gene promoter have recently been identified and appear to influence regulation of its expression. The -1082*A allele has been associated with low and the -1082*G allele with high in vitro IL-10 production. We have analysed 117 unrelated Caucasoid RA patients and 119 ethnically matched controls. No significant differences in the allele frequencies of the three polymorphisms were found between controls and RA patients. In contrast, a significant association between the -1082*A allele and the (-1082*A/ -819*C/ -592*C) haplotype and IgA RF+ve/IgG RF-ve patients was observed. The association of genotypes encoding low IL-10 production with IgA RF in RA is incompatible with its suggested role in antibody isotype switching. IgA RF has been associated with severe RA and may thus be indirectly correlated with a genotype encoding low IL-10 production.

To the Editor: Pregnancy in autoimmune diseases may be complicated for both the fetus and the mother. Polymyositis (PM) and dermatomyositis (DM) are autoimmune diseases that affect women more often than men, and can occur before childbearing years1,2. Complications during pregnancy were frequently reported in patients with PM/DM with active disease, whereas there seems to be a low risk for the fetus and mother in women with a well-controlled disease at time of conception2,3,4,5,6,7,8,9,10. Our aims were to assess the pregnancy outcome in myositis. Based on international collaboration, records for women with PM/DM who had been pregnant after the diagnosis of myositis were searched in 4 countries using the clinical databases of contributing hospitals. There were 23 women identified: Czech Republic (n = 8), Hungary (n = 9), Sweden (n = 5), and Poland (n = 1). All 23 women were white. Medical records were retrospectively reviewed using a standardized protocol. Normal delivery was defined when a healthy newborn weighing > 2500 g was delivered after 37 weeks of pregnancy. Premature delivery was defined when the pregnancy … Address correspondence to Dr. M. Nagy-Vincze, Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen, Moricz Zs. u. 22, H-4032 Debrecen, Hungary. E-mail: melinda.nagyvincze{at}gmail.com

Idiopathic inflammatory myopathies (IIM) belong to a group of autoimmune disorders, primarily characterized by chronic inflammation of human skeletal muscle tissue. The etiology of these diseases is unknown, however, genetic predisposition plays a significant role in disease onset. Beside the known genetic risk located in the MHC complex, the epigenetic modifications including changes in miRNAs expression profiles have been recently implicated recently in many autoimmune diseases. Micro RNA molecules are involved in many physiological processes, including the regulation of the immune response.In our study we have focused on the miR-23b, as it represents a novel promising autoimmunity regulator molecule. Downregulation of miR-23b was recently described in patients with rheumatoid arthritis and systemic lupus erythematosus. We have measured the expression miR-23b peripheral blood mononuclear cells of patients with dermatomyositis and polymyositis. No meaningful difference was found in comparison with healthy controls.

Background Adipocytokines are soluble mediators secreted by adipose tissue and immune cells with potent immune regulatory functions. Some adipocytokines have been previously associated with disease activity and radiographic progression in patients with rheumatoid arthritis (RA) 1 . Objectives To investigate associations between adipocytokines, clinical and traditional laboratory markers as well as with ultrasound synovitis in patients with RA. Methods A total of 82 patients with RA (62 females, median disease duration 4.2 years) were enrolled into this study. All patients underwent clinical examination (swollen joint count - SJC, tender joint count – TJC, Disease activity score - DAS28-ESR and DAS28-CRP, Clinical disease activity index - CDAI, Simplified disease activity index - SDAI). Moreover, ultrasound examination of 7 selected joints mostly affected in RA (wrist, second and third metacarpophalangeal and proximal interphalangeal, and second and fifth metatarsophalangeal joints) was performed to measure synovial hypertrophy in Grey Scale (GS) and pathological neovascularization in Power Doppler (PD) using semi-quantitative grading 0–3 3 . Blood samples were taken at the same day as clinical and ultrasound assessments. Serum concentrations of adiponectin, resistin, visfatin, leptin and CRP were measured. Clinical and laboratory measures were correlated with ultrasound findings using Spearman9s correlation coefficient. Results Serum visfatin and resistin levels were associated with the disease activity (Figure 1) and correlated significantly with DAS28-ESR (r=0.473, p Conclusions Our study supports circulating visfatin and resistin as promising serum pro-inflammatory biomarkers reflecting clinical, laboratory as well as ultrasound parameters of synovial inflammation in RA. References Senolt L, Krystufkova O, Hulejova H, Kuklova M, Filkova M, Cerezo LA, Belacek J, Haluzik M, Forejtova S, Gay S, Pavelka K, Vencovsky J: The level of serum visfatin (PBEF) is associated with total number of B cells in patients with rheumatoid arthritis and decreases following B cell depletion therapy. Cytokine 2011, 55: 116–121 Acknowledgement This work was supported by the project (Ministry of Health, Czech Republic) for consensual development of research organization 023728, IGA grant No. NT12437 and GAUK grant No. 1010213. Disclosure of Interest None declared

Autoantibodies against several aminoacyl-transfer-RNA synthetases have been described in patients with myositis; anti-threonyl-tRNA synthetase (anti-PL-7) is one of the rarest. We describe the clinical and laboratory characteristics of a cohort of European anti-PL-7 patients, and compare them with previously reported cases. This multicenter study of patients positive for anti-PL-7, identified between 1984 and 2011, derives from the EUMYONET cohort. Clinical and serologic data were obtained by retrospective laboratory and medical record review, and statistical analyses were performed with chi-squared and Fisher exact tests. Eighteen patients, 15 women, were anti-PL-7 antibody positive. Median follow-up was 5.25 years (interquartile range, 2.8-10.7 yr), and 4 patients died. All patients had myositis (12 polymyositis, 5 dermatomyositis, and 1 amyopathic dermatomyositis), 10 (55.6%) had interstitial lung disease, and 9 (50%) had pericardial effusion. Occupational exposure to organic/inorganic particles was more frequent in patients with interstitial lung disease than in the remaining patients (5 of 10 vs. 1 of 7; p = 0.152), although the difference was not significant. Concurrent autoantibodies against Ro60 and Ro52 were seen in 8 of 14 (57%) patients studied. In the literature review the most common manifestations of anti-PL-7 antisynthetase syndrome were interstitial lung disease (77%), myositis (75%), and arthritis (56%). As in other subsets of the antisynthetase syndrome, myositis and interstitial lung disease are common features of the anti-PL-7 antisynthetase syndrome. In addition, we can add pericarditis as a possible manifestation related to anti-PL-7 antibodies.

BackgroundPsoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD).MethodsThe recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement.ResultsTen recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined.ConclusionThese recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

Objectives HLA-DRB1*03 is strongly associated with anti-Jo-1-positive idiopathic infl ammatory myopathies (IIM) and there is now increasing evidence that Jo-1 antigen is preferentially expressed in lung tissue. This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive IIM. Methods IIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specifi c oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation. Results 557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1positive IIM cases, and reached statistical signifi cance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p

ObjectiveDickkopf-1 (DKK-1) is an inhibitor of osteoblastogenesis, and its lower levels are linked to new bone formation. The aim of this study was therefore to explore serum levels of DKK-1 and to evaluate DKK-1's association with the severity of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH).MethodsSerum levels of total and functional DKK-1 and C-reactive protein (CRP) were measured in 37 patients with DISH and 22 healthy age and sex-matched controls. Plain radiographs of the cervical and thoracic spine were performed, and the diagnosis of DISH was defined using the Resnick criteria. Patients were divided into three groups based on spinal involvement. Bone mineral density (BMD) and bone turnover markers were evaluated in patients with DISH.ResultsThe levels of total serum DKK-1 were significantly lower in patients with DISH than in healthy controls (pConclusionThese observations indicate that DKK-1 may play a significant role in bone formation during DISH.

ObjectiveThe first 3 months after symptom onset represent an important therapeutic window for rheumatoid arthritis (RA). This study investigates the extent and causes of delay in assessment of patients with RA in eight European countries.MethodData on the following levels of delay were collected from 10 centres (Berlin, Birmingham, Heraklion, Lund, Prague, Stockholm, Umeå, Vienna, Warsaw and Zurich): (1) from onset of RA symptoms to request to see healthcare professional (HCP); (2) from request to see HCP to assessment by that HCP; (3) from initial assessment by HCP to referral to rheumatologist; and (4) from referral to rheumatologist to assessment by that rheumatologist.ResultsData were collected from 482 patients with RA. The median delay across the 10 centres from symptom onset to assessment by the rheumatologist was 24 weeks, with the percentage of patients seen within 12 weeks of symptom onset ranging from 8% to 42%. There were important differences in the levels underlying the total delays at individual centres.ConclusionsThis research highlights the contribution of patients, professionals and health systems to treatment delay for patients with RA in Europe. Although some centres have strengths in minimising certain types of delay, interventions are required in all centres to ensure timely treatment for patients.

Objective To test the interrater reliability, internal consistency and aspects of validity of the myositis damage index (MDI) in the assessment of damage in adult patients with idiopathic infl ammatory myopathy (IIM). Methods 95 patients were assessed in six centres as part of this cross-sectional international study. Two parts of a MDI were used to assess disease damage, the MDI and the myositis damage score (MYODAM). The myositis disease activity assessment tool (MDAAT) was used to assess disease activity. Interrater reliability was assessed using intraclass correlation coeffi cient (ICC). Spearman’s rank correlation coeffi cient was used to measure the convergent validity of cross-sectional scores between the two parts of the damage tool and to determine the correlation between the respective components of the damage and activity tools. Results In general, the damage index appears to have good interrater reliability for most of the systems with an ICC greater than 0.65. Convergent validity between the two parts of the damage tool showed good correlation for the individual organ systems (r>0.8). There were weak correlations between some parts of the MDI and corresponding components of the MDAAT. Conclusion The MDI is a comprehensive tool to assess damage in patients with myositis. With physician education and emphasis to record items that have been diagnosed since the myositis diagnosis, the MDI will provide a valuable tool to assess damage in future clinical trials and longitudinal studies.

When confronted with a dermatomyositis or polymyositis patient not responding to immunosuppressive treatment, physicians must first ask whether the original diagnosis was correct. In this review, we provide a guide to the clinical features and ancillary tests, which might be helpful in the differential diagnosis of myositis. Particular attention is paid to the role of autoantibody detection, as some of them are not only relatively specific for the disease but also associated with unique clinical features including resistance to treatment. Subsequently, other possible explanations of treatment resistance are listed and a short overview of treatment options for resistant myositis patients is given.

OBJECTIVE: To test the interrater reliability and validity of the Myositis Disease Activity Assessment Tool, which consists of the Myositis Intention-to-Treat Activity Index and the Myositis Disease Activity Assessment Visual Analog Scales. METHODS: Two phases of the study were conducted to assess the reliability and validity of the tool, which was modified following the first phase. In the first phase of the reliability study, 123 adult myositis patients were evaluated in 7 centers, and in the second phase 40 patients were evaluated in 2 centers. The validity study included 294 patients in 5 centers in the first phase and 65 patients in 3 centers in the second phase. The interrater reliability was assessed using intraclass correlation coefficients. The criterion validity was calculated using sensitivity, specificity, and positive predictive value (PPV) of a grade of A in any system. Spearman's rank correlation coefficient was used to measure the convergent validity of cross-sectional scores between the 2 instruments. RESULTS: There was a 2:1 ratio of female to male patients. There was no significant difference in mean age at diagnosis (46.3 versus 46.8 years) and mean disease duration (7.7 versus 10 years) between the 2 groups recruited for the different phases of the study. There was an improvement in interrater reliability in the second phase of the study. There was a significant improvement in the validity of the assessment tool following modification of the tool. The sensitivity, specificity, and PPV of a grade of A in any system improved from 86%, 92%, and 67% in the first phase to 96%, 94%, and 83%, respectively, in the second phase. Convergent validity between the 2 activity tools showed good correlation, ranging from 0.8 to 0.94, for the individual organ systems. CONCLUSION: This is the first major attempt to assess the reliability and validity of a disease activity index in myositis. Our findings indicate that, following within-study modification, the tool appears to be a reliable and valid instrument to assess myositis disease activity.

Background and objectives MicroRNAs (miRNAs) are small RNAs that regulate gene expression by targeting mRNA. It was proved that some miRNAs are significantly deregulated in rheumatoid arthritis (RA). MicroRNA-125b negatively regulates expression of TNF-α, which plays a crucial role in RA pathogenesis. The aim of this study was to evaluate the expression of miRNA-125b in peripheral blood mononuclear cells (PBMCs) and its association with disease activity and treatment response in early RA patients. Materials and methods A total of 58 (42 females; mean age 54.3 ± 16.4 years) early RA patients and 54 (41 females; mean age 50.9 ± 15.11 years) healthy controls (HC) were studied. Total RNA was isolated from PBMCs collected from patients before and after three months of glucocorticoid/disease modifying antirheumatic drugs treatment and from HC. The expression of miRNA-125b was determined by quantitative PCR. RNU44 was used for normalisation. Disease activity was defined using 28-Joint Count Disease activity Score (DAS28-ESR). The expression of miRNA-125b was studied in order to predict treatment response characterised by achieving remission or alternatively low disease activity (DAS28 Results The expression of miRNA-125b was significantly lower in early RA patients compared to HC (p = 0.001) and increased after three months of therapy (p = 0.006), mainly in responders (p = 0.019). At baseline, miRNA-125b expression negatively correlated with DAS28 (r = -0.462; p = 0.0003). In addition, baseline miRNA-125b expression predicted treatment response after three months which was performed by ROC curve analysis (AUC: 0.663 [95% CI 0.520 to 0.805]; p = 0.048). Conclusion Monitoring of miRNA-125b could be used as a biomarker of disease activity and treatment response in early RA. Acknowledgement IGA project No NT 14498; GAUK-367615.

Background Heat shock proteins (Hsps) are molecular chaperones playing a key role in muscle physiology, adaptation to exercise or stress, and in activation of inflammatory cells. Increased Hsp90 expression was demonstrated in regenerating and atrophic muscle fibres, and in inflammatory infiltrates. The aim of this study was to evaluate Hsp90 in the circulation of patients with idiopathic inflammatory myopathies (IIM) and characterise its potential association with IIM-related features. Methods A total of 277 patients with IIM (198 females, 79 males; mean age 54.8; disease duration 4.1 years; dermatomyositis (DM, 104), polymyositis (PM, 104) cancer associated myositis (CAM, 42), necrotizing myopathy (IMNM, 27)) and 100 healthy individuals matched by age/sex were included. Plasma levels of Hsp90 were measured by ELISA (eBioscience, Vienna, Austria). Data are presented as median (IQR). Results Extracellular Hsp90 was increased in IIM patients compared to healthy controls (20.2 (14.3–40.1) vs. 9.2 (7.2–12.6) ng/ml, p Conclusions We demonstrate increased extracellular Hsp90 in IIM patients that is associated with damage and disease activity, with the involvement of proximal skeletal muscles, the heart and lungs. Hsp90 might become a useful biomarker of disease activity and muscle involvement in IIM. Acknowledgement Supported by BT Cure and MHCR 023728.

Objective The cartilage proteins melanoma inhibitory activity (MIA) and human cartilage gp-39 (HC gp-39) are candidate autoantigens in rheumatoid arthritis (RA). The present study was undertaken to investigate the endogenous HLA–DR4–restricted presentation of these self proteins, in order to seek in vivo evidence in support of their potential immunologic role. Methods MIA and HC gp-39 were assessed in synovial fluid (SF) by enzyme-linked immunosorbent assay and in synovial tissue (ST) by immunohistochemistry. Presentation by SF cells was investigated using specific, HLA–DR–restricted T cell hybridomas. Results MIA and HC gp-39 were detected in RA SF and ST, as well as in specimens from patients with other forms of arthritis. When HC gp-39–specific and MIA-specific HLA–DR4–restricted T cell hybridomas raised in HLA–DR4–transgenic mice were incubated with RA SF cells as antigen-presenting cells in the presence of HC gp-39 or MIA peptides, the corresponding T cell hybridomas showed strong responses, which were blocked by anti–HLA–DR antibodies. Weaker but qualitatively similar responses were observed with exogenous protein, indicating uptake and processing of these antigens by SF cells. More importantly, without addition of peptide or protein, endogenous presentation of MIA and HC gp-39 was detected in SF cells from 53% and 80% of HLA–DRB1*0401–positive RA patients, respectively. In addition, SF cells from 3 of 10 patients with spondylarthritis exhibited endogenous HC gp-39 presentation. Conclusion These data indicate that immunodominant epitopes of MIA and HC gp-39 are actively presented in an HLA–DR–restricted manner in the inflamed RA joint. The question remains as to whether this leads to activation of autoreactive T cells, which could play a role in either the immunopathology or the immunomodulation of arthritis.

Background Of patients with RA, ∼40% of do not achieve a minimal acceptable improvement (ACR20) despite modern biologic therapy.1,2,3 Granulocyte-macrophage colony-stimulating factor (GM–CSF) is implicated in RA pathogenesis via myeloid and granulocyte cell lineage activation. In a 12-week Phase IIa study, mavrilimumab, a first-in-class inhibitor of the GM–CSF receptor-α demonstrated a sustained effect via this novel therapeutic pathway in RA.4 Objectives To evaluate the efficacy and safety of mavrilimumab in patients with moderate to severe, adult-onset RA in a 24-week, Phase IIb study. Methods Patients (18–80 yrs; inadequate response to ≥1 DMARDs; DAS28–CRP ≥3.2; ≥4 SJC) receiving MTX were randomized to receive 1 of 3 SC mavrilimumab dosages (150, 100, 30 mg every other week [eow]) or placebo (PBO) plus MTX (7.5–25.0 mg/week). Co-primary endpoints were change in DAS28–CRP (Day 1 to Week 12) and ACR20 response rate (Week 24). Safety and tolerability were measured through assessment of AEs and pulmonary parameters. Results were analyzed using the modified ITT population. Results 326 patients from Europe, South America, and South Africa (mean [SD] age, 51.8 [11.1] yrs; female, 86.5%; mean [SD] DAS28–CRP, 5.8 [0.9]; RF+/anti-CCP+, 81.9%) received mavrilimumab 150, 100 or 30 mg eow or PBO (N=79, 85, 81 and 81, respectively). At Week 12, a statistically significant difference in DAS28–CRP change from baseline (p 90% of patients entered a long-term, open-label extension study. Conclusions This Phase IIb study demonstrated the potential benefit of inhibiting macrophage activity via the GM–CSF receptor-α pathway on RA disease activity. The study met both co-primary endpoints with a clear dosage response. Mavrilimumb was well-tolerated over the 24-week study period. References Weinblatt ME, et al. N Engl J Med 1999;340:253–9. Lipsky PE, et al. N Engl J Med 2000;343:1594–602. Weinblatt ME, et al. Arthritis Rheum 2003;48:35–45, Burmester GR, et al. Ann Rheum Dis 2013;72:1445–52. Acknowledgements Funded: MedImmune. Editorial assistance: N Panagiotaki, QXV Communications, UK †Joint senior authors. Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, BMS, Novartis, MedImmune, MSD, Pfizer, UCB, Roche, Speakers bureau: AbbVie, BMS, Novartis, MSD, Pfizer, UCB, Roche, I. McInnes Grant/research support from: MedImmune (Research award to University of Glasgow), Consultant for: MedImmune, AstraZeneca, J. Kremer Shareholder of: Corrona, Grant/research support from: AbbVie, Amgen, Genentech, Lilly, Pfizer, Consultant for: AbbVie, Amgen, Genentech, Lilly, Pfizer, BMS, Employee of: Corrona, P. Miranda Grant/research support from: MedImmune (to support protocol), M. Korkosz: None declared, J. Vencovsky: None declared, A. Rubbert-Roth Grant/research support from: Pfizer, Chugai, Consultant for: MSD, USB, Abbott, Pfizer, Roche, BMS, Chugai, Speakers bureau: Roche, Pfizer, UCB, E. Mysler Grant/research support from: Medimmune, Roche, BMS, Pfizer, M. Sleeman Shareholder of: AstraZeneca, Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche

Background Macrophages are pivotal to the pathogenesis of rheumatoid arthritis (RA), and their inflammatory products drive many of the signs and symptoms of disease. Mavrilimumab inhibits macrophage activation and survival via blockade of granulocyte-macrophage colony-stimulating factor receptor-α (GM–CSFR-α) and has demonstrated sustained clinical benefit in patients with RA. 1 Objectives To examine time to onset of clinical response to mavrilimumab in the EARTH EXPLORER 1 study. Methods In a 24-week, Phase IIb study (NCT01706926), patients with adult-onset RA (18–80 years; Disease Activity Score 28 C-reactive protein [DAS28–CRP] >3.2; ≥4 swollen joints; inadequate response to ≥1 disease-modifying antirheumatic drugs [DMARDs]) receiving concomitant methotrexate were enrolled. Patients received mavrilimumab (150, 100, or 30 mg every other week [eow]) or placebo, administered subcutaneously with methotrexate (7.5–25.0 mg/week). Efficacy assessments included DAS28–CRP, American College of Rheumatology (ACR)20/50/70 responses, CRP, erythrocyte sedimentation rate (ESR), swollen joint count (SJC), tender joint count (TJC), and pain assessments. Results 326 patients with mean (SD) DAS28–CRP 5.8 (0.9) were randomized to mavrilimumab (150, 100, or 30 mg eow) or placebo (N=79, 85, 81, and 81, respectively). At Week 1 (first assessment), all mavrilimumab dosages demonstrated significant reductions from baseline in DAS28–CRP ( p p =0.003 to p Conclusions By targeting activated macrophages via inhibition of GM–CSFR-α, mavrilimumab substantially reduced patients9 RA disease activity early in their treatment, from first dose (Week 1) to final assessment for many patients, as evaluated by several clinical outcomes. References Burmester GR, et al. Ann Rheum Dis. 2013;72:1445–52. Acknowledgements Funded: MedImmune Ltd. Editorial assistance: N Panagiotaki, QXV Communications, UK Disclosure of Interest I. McInnes Grant/research support from: MedImmune (Research award to University of Glasgow), Consultant for: MedImmune, AstraZeneca, G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, BMS, Novartis, MedImmune, MSD, Pfizer, UCB, Roche, Speakers bureau: AbbVie, BMS, Novartis, MSD, Pfizer, UCB, Roche, J. Kremer Shareholder of: Corrona, Grant/research support from: AbbVie, Amgen, Genentech, Lilly, Pfizer, Consultant for: AbbVie, Amgen, Genentech, Lilly, Pfizer, BMS, Employee of: Corrona, P. Miranda Grant/research support from: MedImmune (to support protocol), M. Korkosz: None declared, J. Vencovsky: None declared, A. Rubbert-Roth Grant/research support from: Pfizer, Chugai, Consultant for: MSD, UCB, Abbott, Pfizer, Roche, BMS, Chugai, Speakers bureau: Roche, Pfizer, UCB, E. Mysler Grant/research support from: MedImmune, Roche, BMS, Pfizer, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune, M. Sleeman Shareholder of: AstraZeneca, Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo bioscience, Lilly, Pfizer, UCB, Roche

Objectives: To assess the clinical implications of autoantibodies directed against different parts of the Mi-2β autoantigen in patients with myositis. Methods: A systematic assessment of the clinical, laboratory, and histological characteristics of 48 anti-Mi-2 positive patients from six European centres was made. Anti-Mi-2 autoantibodies were determined with an ELISA using four overlapping fragments spanning the entire amino acid sequence of the autoantigen. Data were compared with results for a large group of anti-Mi-2 negative patients with myositis published previously. Results: Anti-Mi-2 autoantibodies were found in dermatomyositis, polymyositis, and inclusion body myositis. In general, myositis with anti-Mi-2 autoantibodies was characterised by relatively mild disease, sometimes accompanied by extramuscular symptoms, including arthralgia, arthritis, Raynaud’s phenomenon, and interstitial lung disease. Cardiac disease was not seen, and treatment response was fair. No differences were found between patients with autoantibodies to different fragments of the Mi-2β antigen, except for a potentially increased risk of cancer in patients with antibodies directed to the N-terminal fragment of the autoantigen. Conclusions: Anti-Mi-2 autoantibodies are not a marker of a specific subtype of myositis. No significant differences between patients with autoantibodies to different fragments of the Mi-2β autoantigen are found, with the possible exception of an increased risk of cancer in patients with antibodies to the N-terminal fragment.

Contains fulltext : 36100.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To elucidate the clinical importance of the anti-signal recognition particle (SRP) autoantibody in patients with myositis. METHODS: Retrospective systematic assessment of the clinical, laboratory and histological characteristics of 23 anti-SRP-positive patients from six European centres. Data were compared with a large group of anti-SRP-negative patients with myositis published previously. RESULTS: Clinically, patients with anti-SRP autoantibodies often had a severe symmetric proximal muscle weakness resulting in marked disability, dysphagia and highly elevated levels of serum creatine kinase. Three patients had typical dermatomyositis rashes. The disease was associated with the occurrence of extramuscular signs and symptoms including interstitial lung disease. No association was found with an increased risk of cardiac involvement, and the disease carried a reasonably favourable prognosis with most patients responding to treatment. None of the patients had the typical histological features of myositis. Most muscle biopsy specimens showed the presence of necrotic muscle fibres and no inflammatory infiltrates. CONCLUSIONS: Anti-SRP autoantibodies are associated with a syndrome of a necrotising myopathy in the spectrum of immune-mediated myopathies that differs from typical polymyositis. Further studies are needed to elucidate the pathogenesis and to clarify the role of the anti-SRP autoantibodies in this unique disease.

OBJECTIVE: To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). METHODS: An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. RESULTS: The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.

Background Our previous study demonstrated that Heat shock protein 90 (Hsp90) is overexpressed in the skin of patients with systemic sclerosis (SSc), in cultured SSc fibroblasts and preclinical models of SSc in a TGF-β dependent manner. We showed that Hsp90 is a new regulator of canonical TGF-β signalling and its inhibition prevents the stimulatory effects of TGF-β on collagen synthesis and dermal fibrosis in three preclinical models of SSc. 1 The aim of this study was to evaluate Hsp90 in the circulation of SSc patients and characterise its potential association with skin changes and SSc-related features. Methods A total of 40 patients (36 females; mean age 53.9; disease duration 5.0 years; dcSSc/lcSSc = 9/31) who met the ACR classification criteria for SSc and 39 healthy individuals matched by age and sex were included. Plasma Hsp90 levels were measured by ELISA (eBioscience, Vienna, Austria). SSc-related manifestations were obtained from the Czech Registry of SSc patients. Skin changes were assessed using the modified Rodnan skin score and EUSTAR SSc activity score was determined. Data are presented as median (IQR). Results Plasma levels of Hsp90 were comparable between SSc patients and healthy controls (10.8 (9.2–15.5) vs. 10.1 (8.2–12.8) ng/ml, p = 0.250) and between patients with diffuse cutaneous (dc) SSc and limited cutaneous (lc)SSc (11.6 (9.3–15.8) vs. 10.4 (8.6–15.6) ng/ml, p = 0.710). Of particular interest, the levels of Hsp90 positively correlated with EUSTAR SSc activity score (r = 0.418, p = 0.007). Furthermore, Hsp90 plasma levels negatively correlated with forced vital capacity (FVC), forced expiratory volume in 1s (FEV1) and diffusing capacity for carbon monoxide (DLCO) (r = - 0.457, p = 0.004; r = - 0.346, p = 0.033; r = - 0.444, p = 0.005, respectively). In addition, only in patients with dcSSc, Hsp90 levels positively correlated with the modified Rodnan skin score (r = 0.742, p = 0.022). Using Bonferroni’s correction (p Conclusions We demonstrate that plasma levels of Hsp90 are comparable between SSc patients and healthy controls. However, increased plasma levels of HSP90 in SSc patients are associated with higher disease activity, deteriorated parameters of lung involvement, and, particularly in dcSSc patients, with skin involvement. These data further highlight the role of Hsp90 as a regulator of fibroblast activation and tissue fibrosis in SSc. Reference Tomcik M, Zerr P, Pitkowski J, et al . Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis. Ann Rheum Dis 2014; 73 (6):1215–22.

Background and objectives Genes within the major histocompatibility complex (MHC) region has a strong genetic relevance in autoimmunity development. The involvement of the class I and class II genes, as well as class III (non-Class I/II MHC) genes has been proposed. For the myositis development, the HLA-DRB1*03 is a known risk factor in Caucasian population. However, there are another genes appearing to be significant players in the ethiology of myositis located near the HLA-DRB1 locus. In the present study the authors have focused on one of these risk factors – the regulation of MHC-linked inducible HSP70 genes expression and their relation to the known immunogenetic risk factor located within the MHC (HLA-DRB1*03). Materials and methods The authors have investigated the gene specific HSP70 expression in 20 patients with dermatopolymyositis and 15 healthy people matching in age as control samples. Expression levels of the two inducible HSP70 genes ( HSPA1A , HSPA1B ) were analysed both in patients and controls. Both of the groups were additionally genotyped for HLA-DRB1 locus. Myositis-specific and associated autoantibodies were also identified in patients. Results The expression of both, the HSPA1A and HSPA1B genes was significantly upregulated (p HSPA1A was found to be associated with the presence of the HLA-DRB1*03 risk allele in patients. However, this was not observed for the HSPA1B gene. In contrast, the authors found a positive correlation between the expression regulation of the HSPA1B gene and the presence of disease specific autoantibodies in myositis patients. Additionally, positive correlation between the presence of disease specific autoantibodies and the HLA-DRB1*03 risk allele was found. None of these observations were found in healthy controls. Conclusions The results suggest that the two MHC-linked inducible genes are differentially expressed in dependence on the autoantibody or HLA risk allele presence. The differential gene expression regulation shows that the HSPA1B is an – on HLA-DRB1 – independent molecular marker for myositis development.

Background Idiopathic inflammatory myopathies (IIM) belong to the group of systemic autoimmune diseases. IIM are characterized clinically by chronic muscle inflammation leading to a dysfunction and/or destruction of muscle cells. Like many other autoimmune diseases, IIM have its major genetic predisposition linked to the MHC genes. In this study, we have analyzed MHC haplotypes involving alleles of HLA class II genes (DQB1, DRB1) and 6 polymorphisms located within the HSP70 genes (HSPA1A, HSPA1B and HSPA1L). Frequencies of all polymorphisms and haplotypes were studied in a cohort of patients with IIM and compared with healthy controls. Objectives The aim of this study was to investigate the relation between MHC haplotypes and the risk of IIM development in a single center cohort. Methods We have analyzed 82 patients with dermatomyositis (DM) and 70 patients with polymyositis (PM) diagnosed according to Bohan and Peter criteria and compared them with 150 healthy controls. In total, six genetic polymorphisms located within the three HSP70 genes were analyzed by direct genomic DNA sequencing. Additionally, HLA-DRB1 and HLA-DQB1 loci were genotyped using the commercial LABType® SSO kit (One Lambda, USA). The statistical analysis was done using Fisher9s exact test with calculated p Results The most frequent MHC haplotype in controls, total IIM, as well as in DM and PM subgroups was found to be the HLA-DQB1*02-DRB1*03:01-T-C-C-G-C-INS haplotype. However, the difference in frequency between patients and controls reached statistical significance only for IIM overall (p The HLA-DQB1*05–DRB1*16:01-T-A-G-A-G-DEL haplotype was found to have the strongest disease association in all patient subgroups. The difference was the highest in the IIM overall (p When comparing the MHC background of DM and PM, we have found another haplotype (HLA-DQB1*03-DRB1*11:01-T-A-G-A-G-DEL) differentially associated with these diagnoses. The difference in frequency of this haplotype between DM and PM reached statistical significance with p Conclusions Our results show a strong association between distinct MHC haplotypes and IIM in general. Additionally, we have identified one MHC haplotype suggesting, that DM and PM may have partially different genetic background. HSP70 polymorphisms are located nearby the HLA-DRB1 gene. Therefore, combination of distinct HLA-DRB1 alleles and HSP70 polymorphisms can help in identification of higher genetic risk for development of myositis. Acknowledgements This study was supported by the Internal Grant Agency of the Ministry of Health in the Czech Republic [MZCR NT 13699], and Institutional support of MHCR VZ (00023728). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4166

Microparticles are recently recognised players of intercellular communication. They are involved in signal transduction, cell activation and apoptosis. Their importance is also suggested in autoimmune diseases such as rheumatoid arthritis and systemic sclerosis. We investigated the role of microparticles in polymyositis/dermatomyositis, a group of rare autoimmune diseases characterised by …

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 …

Rheumatoid arthritis (RA) is an inflammatory disease in which the precise etiology is still unknown (1,2). Hormonal and genetic factors are involved with a threefold predominance of RA in women, and an HLA class II epitope shared between diseasesusceptible haplotype carriers (3). However, the discordant disease development between identical twins suggests that nongenetic factors such as infectious agents also play a role in the etiology of RA (4). The prime site of disease activity is the synovial joint, but in severe cases other organs can also be affected. Many mononuclear leukocytes infiltrate the synovium of RA patients and the joint fluid becomes highly enriched in polymorphonuclear leukocytes (PMNs) (5,6). This cellular infiltrate initiates a cascade of humoral and cell -mediated inflammatory events, ultimately resulting in the failure of the diseased joint. During the development of RA, the normally two- to three-cell thick layer lining the synovium proliferates, and the whole synovial membrane becomes hypertrophied and inflamed under the influence of the inflammatory leukocytes. This results in the formation of a pannus, an area rich in aggressively growing cells, particularly fibroblastlike and macrophage-like cells. The junction between the synovium, cartilage, and bone is the site where the irreversible damage originates. During disease development, the pannus grows over the cartilage and into the subchondral bone. The cells in the pannnus release a variety of cytokines and destructive enzymes, including matrix metalloproteinases (MMIPs), which cause cartilage and bone erosions that ultimately lead to the destruction of the joint (7–12).

Background and Objectives Classical (CM), non-classical (NCM) and intermediate populations of human monocytes are characterised by differential expression of CD14 and CD16. NCM and IM are potent antigen presenting cells and producers of pro-inflammatory cytokines. They are enriched in patients with established rheumatoid arthritis (RA) and their numbers correlate with disease activity and response to therapy with methotrexate (MTX) and glucocorticoids (GCS). CD11c plays a role in antigen presentation and production of pro-inflammatory cytokines. Increased expression of CD11c on mononuclear blood cells and a predictive role of higher CD11c mRNA expression for response to TNFα blocking treatment in RA were described. We evaluated the expression of CD11c on monocyte subpopulations in patients with early rheumatoid arthritis (ERA) and its changes after three months of treatment with GCS and non-biological disease modifying drugs. Materials and Methods 29 patients with ERA and 10 gender and age-matched healthy controls (HC) were included in this study. ERA patients had symptom duration for + CD16 - , NCM:CD14 dim CD16 ++ ) using multicolour flow cytometry. Based on isotype and FMO controls for CD14 and CD16; two intermediate (IM) populations were evaluated (CD14 + CD16 dim and CD14 + CD16 ++ ). CD11c expression was analysed by median fluorescence intensity. Results Expansion of both intermediate populations (IM-CD16 dim , p ++ , p = 0.02) and reduction of CM (p + or ++ and NCM: rs = -0.64, -0.55 or -0.50 and -0.40; p = 0.004, 0.08 or 0.02 and 0.09) at month three. No associations with disease activity or with MTX dosage were found. Conclusions The expansion of intermediate monocyte subpopulations in ERA patients and enhancement of CD11c expression with reduction after three months of treatment with GCS suggest their possible role in the pathogenesis of RA at early stages of the disease. Acknowledgement Institutional support MZCR0002372801

Background and Objectives MicroRNAs can regulate the gene expression and cellular functions such as cell cycle, differentiation, or apoptosis. Emerging evidence has demonstrated that miRNAs play a vital role also in the regulation of immunological functions, including the development of autoimmunity. Like in most of other autoimmune diseases, the etiopathogenesis of Idiopathic inflammatory myopathy (IIM) is also believed to be triggered by environmental factors in combination with susceptible genetic background. Beside a genetic risk located within the MHC complex, the role of epigenetic regulations including changes in miRNAs expression profiles in autoimmunity development have recently also been implicated. The aim of this study was to look for specific miRNA expression patterns in the serum, peripheral blood mononuclear cells (PBMCs) and muscle biopsies of patients suffering from idiopathic inflammatory myopathy. Materials and Methods RNA was isolated from serum, PBMCs and muscle biopsy samples of patients suffering from IIM using modified Trizol-chloroform method. The expression profile of miRNAs was determined by 60K high density microarray from Agilent Company. Results In total, 87 miRNAs were found to be differentially expressed at a significant level (p Conclusions This is the first study providing information about complete expression profile of miRNA molecules found in the serum, PBMCs and muscle biopsy samples of patients with IIM. We have found that a number of miRNAs were differentially expressed in diverse tissue samples indicating tissue specific expression of miRNAs. The “missregulated” miRNAs might potentially act as biomarkers of initiated systemic inflammatory response, or functional molecules related to muscle tissue injury, or molecules involved in regulation of immune response. Acknowledgement This study was supported by the Internal Grant Agency of the Ministry of Health in the Czech Republic [MZCR NT 12452-4], Institutional support of MHCR VZ (00023728) and The Charles University Grant Agency (No.621812).

Background Interleukin-35 (IL-35) is a newly described hetero-dimeric cytokine of the IL-12 family. Studies of immunopathogenesis in idiopathic inflammatory myopathies (IIM) are of interest for future biological therapies. Objective To analyze expression of IL-35 in muscle biopsies and to study its effects on peripheral blood mononuclear cells (PBMC) in vitro to assess its pathogenetic and diagnostic value. Materials and methods Immunoexpression of IL-35 subunits (p35, EBI3) was studied immunohistochemically in 23 muscle biopsies of IIM (12 dermatomyositis, 11 polymyositis), 10 noninflammatory myopathies and 10 controls. PBMCs were stimulated with human recombinant IL-35 protein or TNF-α in vitro. Taq-Man RT-PCR was performed to analyze gene expression after 6hours and ELISA assays were used to confirm the protein secretion after 24 hours of stimulation. Results We showed localization of both IL-35 subunits in B-cells, T-cells and macrophages of the inflammatory infiltrates in IIM. No immunoreactivity was observed in controls. We found that gene expression of both IL-35 subunits were dose- and time-dependently induced by TNF-α in PBMCs. Conclusion Our data suggest pro-inflammatory properties of IL-35 and its potential role in the pathogenesis of IIM. The immunohistochemical expression of IL-35 might be also of diagnostic help in muscle biopsy.

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 microRNAs (miRNA) are small, non-coding RNA with a role in regulation of gene expression at post-transcriptional level and some of them are suggested to be involved in the adaptive and innate immunity regulation. MiRNA have been identified not only intracellularly, but in body fluid as well. Some of the serum miRNA serve as biomarkers of various diseases particularly autoimmune like systemic lupus erythematosus (SLE). Objectives The aim of our work was to identify differences in serum miRNA profile in SLE patients and healthy individuals. Methods Altogether, 11 patients suffering from active SLE without active lupus nephritis (average SLEDAI: 14,63, average age 41,36 years) and 16 healthy individuals (average age 39,81 years) as control group were investigated. Serum miRNA was isolated from serum by trisol-acid phenol precipitation. The expression of 1347 to date known miRNA was tested using microarray analysis. Paired comparisons between experimental groups were performed by the nonparametric Mann-Whitney U test. Pearson’s and Spearman’s correlation coefficients were calculated to determine the correlation between miRNA expression levels of two genes. The statistical analyses were performed using WinSTAT® software. Results Total 106 miRNA of all tested miRNA show significant differences in expression between SLE patients and healthy controls. Only 8 miRNA show significantly decreased expression in SLE whereas 98 of all miRNA were upregulated in SLE. Interestingly, only in a part of the identified SLE - associated miRNA have been known their immunological functions, the other miRNA have a role in apoptosis, cell proliferations, drug resistance or their function have not been identified yet. Conclusions Our work demonstrated the differences between serum miRNA profile in active SLE patients and healthy controls. The serum miRNA profile is different than miRNA profile of peripheral mononuclear cells and may reflect the intercellular communication. This pilot study identifies potential SLE - associated miRNA, which are connected to higher risk of active SLE with severe organ manifestation. The next step of our work is to quantify potential risk miRNA and establish some serum miRNA as biomarker of active SLE. References Wang G, et al. Serum and urinary free microRNA levels in patients with systemic lupus erythematosus. Lupus 2011, 20: 493-500. Shen N, et al. MicroRNAs – novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol 2012, 8: 701-9 Acknowledgements This study is supported by research project of Czech Ministry of Health IGA NT 13707. 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

Backgroundand objectives The interferon (IFN) signature has been described to be present in many autoimmune diseases, including myositis. The extent of this signature appears to be related to disease activity, however, the underlying mechanism resulting in such a signature has not been revealed yet. Detailed insight into such a mechanism would increase the understanding of role of the IFN systems in myositis and autoimmunity. In this study, the authors investigated the association between (the extent of) the IFN signature and autoantibody profiles in myositis. Materials and methods RNA samples, obtained from whole blood from 94 patients with polymyositis, dermatomyositis, and inclusion body myositis recruited from the Karolinska University Hospital and Prague University, were assessed for expression levels of 9 IFN related genes using BioMark Dynamic Arrays. IFN score was determined as the average gene expression level of these genes. Median IFN score (4.38) was used to define patients as IFN high or IFN low . ANA positivity was determined by indirect immunofluorescence test and myositis specific autoantibodies against Jo-1 and SRP, and myositis associated autoantibodies PM-Scl, Ro52, Ro60 (SSA), La and U1RNP were detected by a line blot and in-house immunoblot assay. Results IFN signature in peripheral blood was present in a subgroup of patients with myositis. In order to determine the relevance of the differential expression of IFN type I activity in myositis the authors studied the association between IFN score and the presence of ANA or specific autoantibodies. No significant difference in the extent of the IFN score was observed between ANA negative (n=44) and ANA positive (n=50) nor in the number of IFN high or IFN low patients. Comparison of IFN score in patients positive for myositis associated or specific autoantibodies revealed that the highest IFN score was found in U1RNP positive patients (mean IFN score=23.66, 7/9 were IFN high ), followed by La positive patients (mean IFN score=11.94, all were IFN high n=4). In addition, a majority of Jo-1(16 out of 23), Ro-52 (15 out of 22), Ro-60 (8 out of 10) positive patients were characterised by an IFN high expression profile. Detailed analysis revealed that IFN high patients were characterised by multi-autoantibody specificity, that is, 17 out of 23 patients positive for 2 or more autoantibodies were IFN high (70%) versus 30 out of 71 of the patients positive for 1 or none of the specific autoantibodies (45%) (Pearson Chi square p=0.008). Conclusions An IFN score in myositis patients is associated with the presence of myositis specific or associated autoantibodies Jo-1, U1RNP, Ro-52, Ro-60 or La and the association was stronger when 2 or more autoantibodies were present. Based on these data and on previous studies the authors hypothesise that these autoantibodies could act as an endogenous trigger of the type I IFN pathway and contribute to the chronicity of these diseases.

Background Treatment with biologics is associated with increased risk of tuberculosis (TB). 1,2 Before starting an anti-TNF, patients (pts) should undergo screening for latent TB, including Purified Protein Derivation (PPD) skin test. WHO guidelines recommend a PPD positivity cut-off value of ≥5mm. 3 Higher cut-offs were considered in some countries with a high TB vaccination rate in the population. Objectives To examine the effect of introducing more stringent screening rules on TB in clinical trials of the anti-TNF certolizumab pegol (CZP). Methods The CZP safety database of TB cases from rheumatoid arthritis (RA) clinical trials was reviewed up to 30 Nov 2011. In the initial RA trials for CZP, pts were included if PPD was negative according to respective national guidelines. As many pts originated from high TB incidence countries and were TB-vaccinated, criteria for PPD positivity varied from Results The CZP safety database included 4049 pts (9277 PY). 44 TB cases were confirmed (IR: 0.47/100 PY), with the majority from Eastern Europe (21 cases, IR: 1.02/100 PY) and Central Europe (18 cases, IR: 0.58/100 PY). In Western Europe 3 cases (IR: 0.23/100 PY) were reported and in North America 1 case (IR: 0.05/100 PY). Early trials had higher rates of TB (42 cases, IR: 0.51/100 PY) compared to recent trials (cut-off PPD Conclusions Most TB cases occurred in regions with high background levels of latent TB. Following implementation of the WHO recommendations for PPD cut-off, the TB rate in CZP trials was similar to that seen with other anti-TNFs. 4 Implementation of the 5mm rule had benefits even in pts already treated by anti-TNFs. References Solovic I. ERJ 2010;36:1185-1206, Tubach F. Arthritis Rheum 2009;60:1884-1894, WHO Global Tuberculosis Control 2010; Accessed 2012, Burmester G. Ann Rheum Dis 2007;66:732-739 Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma. Disclosure of Interest J. Vencovsky Consultant for: UCB Pharma, Roche, Abbott, Pfizer, MSD, Speakers bureau: UCB Pharma, Pfizer, Roche and MSD, O. Lortholary Grant/research support from: MSD, Consultant for: MSD, Astellas, Gilead, Pfizer, Speakers bureau: Astellas, Gilead, Merck/Schering, Pfizer, J. Gomez-Reino Grant/research support from: MSD, Roche, UCB Pharma, Consultant for: BMS, GSK, MSD, Pfizer, Roche, UCB Pharma, Speakers bureau: Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB Pharma, R. van Vollenhoven Grant/research support from: Abbott, Bristol Myers Squibb, GSK, MSD, Pfizer, Roche and UCB Pharma, Consultant for: Abbott, Bristol Myers Squibb, GSK, MSD, Pfizer, Roche and UCB Pharma, M. de Longueville Employee of: UCB Pharma, X. Mariette Grant/research support from: Pfizer, Roche, Consultant for: BMS, GSK, Pfizer, Roche, UCB Pharma

Background Certolizumab pegol (CZP) has been shown to be efficacious and have an acceptable safety profile as a monotherapy (FAST4WARD/NCT00548834) or in combination with methotrexate (014/NCT00544154) for the treatment of rheumatoid arthritis (RA). 1,2 Objectives To evaluate the long-term safety and efficacy of CZP monotherapy, or in combination with other DMARDs, over 5 years. Methods The open-label extension (OLE) study (NCT00160693) enrolled patients (pts) who withdrew/completed the 24Wk FAST4WARD/014 studies. Pts received CZP 400mg Q4W for the duration of the study. The OLE objectives were to monitor safety and evaluate efficacy. Pts were permitted to take DMARDs in the OLE. Pt retention and efficacy (observed only) are reported up to Wk280 (5.4 years; last time point all sites open) and safety up to Wk364 (7 years; final data cut-point) in the OLE. Safety population included all OLE pts who received CZP (N=402; n=276 combination therapy, n=126 monotherapy), including PBO/CZP pts who completed/withdrew from either feeder study and entered OLE. Sub-populations analyzed for efficacy were (1) CZP feeder study completers who had received another DMARD at any point during either feeder/OLE studies (n=123; CZP combination completers) and (2) FAST4WARD CZP completers who entered OLE and did not receive any other DMARD at any point during either feeder/OLE studies (n=48; CZP monotherapy completers). Results The pattern and frequency of adverse events (AEs), including injection site reaction (Event Rate/100-pt years: monotherapy 1.4, combination therapy 0.9), and serious AEs were consistent with those reported previously with CZP (Table). Serious infection and malignancy rates were low (Table). 11 deaths were reported: 7 cardiovascular events, 2 infectious, 1 injury and 1 malignancy. Retention at Wk280 was similar between CZP monotherapy (24/48, 50%) and combination therapy (67/123, 55%) completers. Mean(SD) DAS28-3(CRP) and change from feeder study baseline (CFB) were 3.9(1.2) and -1.9(1.4) in the monotherapy and 4.1(1.2) and -1.8(1.2) in the combination completers at OLE entry, and 2.9(1.1) and -3.1(1.6) in the monotherapy and 2.9(1.0) and -3.0(1.3) in the combination completers at Wk280. Mean(SD) HAQ and CFB were 0.9(0.8) and -0.6(0.7) in the monotherapy and 1.1(0.7) and -0.3(0.5) in the combination completers at OLE entry, and 0.8(0.9) and -0.7(0.8) in the monotherapy and 0.8(0.6) and -0.5(0.5) in the combination completers at Wk280. Conclusions CZP monotherapy was confirmed to have a favourable risk-benefit profile within this study. Similar long-term efficacy was observed between pts who received CZP monotherapy and pts who received CZP in combination with other DMARDs; retention rates were also similar between these two groups. References Fleischmann R. Ann Rheum Dis 2009;68:805-811; Choy E. Rheumatology 2012;51(7):1226-1234 Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma. Disclosure of Interest R. Fleischmann Grant/research support from: Genetech, Roche, Abbott, Amgen, UCB Pharma, Pfizer, BMS, Lilly, Sanofi-Aventis, Lexicon, MSD, Novartis, BiogenIdec, Astellas, AstraZeneca, Janssen, Consultant for: Roche, Abbott, Amgen, UCB Pharma, Pfizer, BMS, Lilly, Sanofi-Aventis, Lexicon, Novartis, Astellas, AstraZeneca, Janssen, HGS, R. van Vollenhoven Grant/research support from: Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB Pharma, Consultant for: Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB Pharma, J. Vencovsky Consultant for: UCB Pharma, Roche, Abbott, Pfizer, MSD, Speakers bureau: UCB Pharma, Pfizer, Roche, MSD, R. Alten Consultant for: UCB Pharma, O. Davies Shareholder of: UCB Pharma, Employee of: UCB Pharma, C. Stach Shareholder of: UCB Pharma, Employee of: UCB Pharma, M. de Longueville Employee of: UCB Pharma, B. VanLunen Employee of: UCB Pharma, E. Choy Grant/research support from: Abbott, Allergan, AstraZeneca, Boehringer Ingelheim, Chelsea Therapeutics, Chugai, Daiichi Sankyo, Eli Lilly, Ferring Pharmaceutical, GSK, Jazz Pharmaceuticals, MedImmune, Merrimack Pharmaceutical, MSD, Novartis, Pfizer, Pierre Fabre Medicament, Roche, Schering-Plough, Synovate, UCB Pharma, Consultant for: Abbott, Allergan, AstraZeneca, Boehringer Ingelheim, Chelsea Therapeutics, Chugai, Daiichi Sankyo, Eli Lilly, Ferring Pharmaceutical, GSK, Jazz Pharmaceuticals, MedImmune, Merrimack Pharmaceutical, MSD, Novartis, Pfizer, Pierre Fabre Medicament, Roche, Schering-Plough, Synovate, UCB Pharma

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

Background Certolizumab pegol (CZP) administered every 4 weeks (Q4W) for RA was shown to have an acceptable safety profile when given as monotherapy in FAST4WARD (NCT00548834) or with MTX in the 014 study (NCT00544154). 1,2 Objectives To evaluate the long-term safety of 400mg CZP Q4W for RA over 5 years. Methods Patients (pts) in FAST4WARD were randomized to CZP 400mg Q4W monotherapy or placebo (PBO) for 24 weeks (Wks). Study 014 was similar, but CZP was taken concomitantly with MTX. Those who completed or withdrew on/after Wk12 in either study were eligible to enter an open-label extension (OLE) of CZP 400mg Q4W as per original protocol (NCT00160693). Pts from FAST4WARD were permitted to take DMARDs in OLE. The primary OLE objective was to monitor safety. Pt retention rates are reported up to Wk280 (5.4yrs) (last time point all sites open), and safety results up to Wk364 (final data cut-point). Safety population consisted of all pts who entered the OLE. Results From the CZP and PBO groups of the feeder studies, 210 and 192 pts, respectively, entered the OLE. At Wk280, 105 (50%) pts originally randomized to CZP and 89 (46%) pts originally randomized to PBO were still enrolled. Rates of adverse events (AEs), AEs leading to withdrawal, AEs leading to death, serious AEs and serious infections were similar between CZP$→ $CZP and PBO→CZP and in the range previously reported for anti-TNFs (Table). AEs of TB, candida and herpes viral infections occurred at 0 vs. 0.38, 1.41 vs. 0.63 and 5.84 vs. 5.25 events per 100 pt-yrs in the CZP$→ $CZP vs. PBO→CZP groups, respectively. Safety data was also available for the subset of pts from FAST4WARD who stayed on CZP monotherapy in the OLE (Table). At entry into OLE, DAS28-3(CRP) was 4.38 vs. 5.13 and HAQ-DI was 1.09 vs. 1.43 in the CZP vs PBO groups. On receiving CZP, prior PBO pts improved, but never attained the same level of disease activity and physical functioning as the CZP→CZP group at Wk280, the mean DAS28-3(CRP) was 2.98 and 3.12, and mean HAQ-DI was 0.83 and 1.09 in the CZP→CZP and PBO→CZP groups, respectively. Conclusions Use of CZP 400mg Q4W combination or monotherapy has been confirmed to have an acceptable long-term safety profile in line with what would be expected from an anti-TNF. In this population, delayed CZP treatment resulted in higher disease activity and poorer function through 280 Wks. References Fleischmann R et al. Ann Rheum Dis. 2009;68:805-811. Choy E et al. Accepted for publication in Rheumatology Nov 2011 Disclosure of Interest R. Fleischmann Grant/Research support from: UCB Pharma, Consultant for: UCB Pharma, R. van Vollenhoven Grant/Research support from: UCB Pharma, Consultant for: UCB Pharma, J. Vencovsky Consultant for: UCB Pharma, Speakers Bureau: UCB Pharma, R. Alten Grant/Research support from: UCB Pharma, Consultant for: UCB Pharma, Speakers Bureau: UCB Pharma, O. Davies Employee of: UCB Pharma, C. Stach Employee of: UCB Pharma, M. de Longueville Employee of: UCB, B. van Lunen Employee of: UCB Pharma, E. Choy Grant/Research support from: UCB Pharma, Consultant for: UCB Pharma, Speakers Bureau: UCB Pharma