Search

In 2016, there have been several major scientific achievements related to myositis, including the discovery of a novel autoantibody and the relationship between autoantibodies and distinct clinical phenotypes. Advances in the way clinical trials are conducted have also led to breakthroughs in treatment strategies.

Background:Idiopathic inflammatory myopathies (IIM) are rare chronic inflammatory diseases associated with high mortality and morbidity [1]. One sub-group of IIM, anti-synthetase syndrome (ASS), is characterized by the presence of autoantibodies that target aminoacyl transfer(t) RNA synthetases (aaRS), together with specific clinical manifestations such as myositis, interstitial lung disease (ILD), arthritis, mechanic’s hand, Raynaud’s syndrome and fever [2]. The most common anti-aaRS autoantibody, anti-Jo1 targeting histidyl tRNA synthetase (HisRS), is present in up to 20-30% of patients with IIM, and up to 90% of patients with myositis and ILD [3, 4]. Besides Jo1, there are today seven other identified autoantigens within the aaRS family.Objectives:A large part of patients with IIM, including individuals with clinical manifestations indicating ASS, test seronegative to all known myositis specific autoantibodies. However, these patients could potentially harbor autoantibodies against targets not tested for in clinic. In this study, we aimed at extending the detection of autoantibodies by including all cytoplasmic aaRS in the analysis of patients with IIM. We hypothesized the existence of new potential autoantigens within this protein family.Methods:The presence of anti-aaRS autoantibodies was determined using a multiplex suspension bead array assay on 242 IIM patients from the Karolinska University Hospital myositis cohort. A panel of 186 recombinant constructs, representing 57 proteins that included full-length or partial sequence overlaps between constructs of all cytoplasmic aaRS as well as other myositis related proteins, were coupled to magnetic color-coded beads and each plasma sample was tested against the complete antigen panel.Results:By the use of this multiplex method we identified patients with autoantibodies against many of the tested aaRS. Autoantibodies binding to HisRS have previously been shown to bind with higher reactivity to the WHEP domain of HisRS and this was also confirmed in this study. We confirmed reactivity against three of the other aaRS tested for in the clinic (PL-12, PL-7, and EJ). In addition, we identified patients positive for anti-Zo, -KS and -HA, autoantibodies usually not screened for in routine. Finally, our data indicates that there are autoantibodies binding to other aaRS than the previously known eight autoantigens, which will be presented.Conclusion:In this study, we could detect autoantibodies in plasma from patients with IIM, both against the most common aaRS autoantigens, but also against other aaRS that are usually not tested for in clinic. We conclude that it is important to continue the studies of anti-aaRS autoantibodies, and their correlation to clinical manifestations, and in the long run also include more aaRS autoantigens in clinical practice.References:[1]Dobloug, G.C., et al., Mortality in idiopathic inflammatory myopathy: results from a Swedish nationwide population-based cohort study. Ann Rheum Dis, 2018. 77(1): p. 40-47.[2]Barsotti, S. and I.E. Lundberg, Myositis an evolving spectrum of disease. Immunol Med, 2018. 41(2): p. 46-54.[3]Vencovsky, J., H. Alexanderson, and I.E. Lundberg, Idiopathic Inflammatory Myopathies. Rheum Dis Clin North Am, 2019. 45(4): p. 569-581.[4]Richards, T.J., et al., Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum, 2009. 60(7): p. 2183-92.Disclosure of Interests:Charlotta Preger: None declared, Antonella Notarnicola: None declared, Cecilia Hellström: None declared, Edvard Wigren: None declared, Catia Cerqueira: None declared, Peter Nilsson: None declared, Ingrid E. Lundberg Grant/research support from: Bristol Meyer Squibb, Corbus Pharmaceuticals, Inc and Astra Zeneca, Helena Persson: None declared, Susanne Gräslund: None declared, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca

In a pilot study we aimed to identify biomarkers in repeated muscle biopsies and paired blood samples, taken before and after conventional immunosuppressive therapy, in order to predict long-term therapeutic response in patients with idiopathic inflammatory myopathies (IIM).Muscle biopsies were selected from 13 new onset patients, six responders and seven non-responders. Repeated muscle biopsies after a median of 11 months follow-up were available from 9 patients and paired peripheral blood mononuclear cells (PBMCs) from 5 patients. Treatment response after 3 years was defined by MMT-8 measuring muscle strength and the ACR/EULAR 2016 improvement criteria. Frozen biopsy sections were immunohistochemically stained for expression of CD3, CD66b, IL-15, CD68, CD163 and myosin heavy chain neonatal (MHCn). PBMCs were analysed by flow cytometry for monocyte phenotypes (CD14, CD16, CD68, CX3CR1, and CCR2).Before treatment there were no significant differences in any clinical or muscle biopsy variables or monocyte subsets between responders and non-responders. MMT-8 was significantly higher compared to baseline in the responders at 3-year follow-up. In responders the expression of CD68 in the repeated biopsies was significantly lower compared to non-responders (p0.05).Baseline biopsy, monocyte profile or clinical data did not predict long-term treatment response, but in the repeated biopsy within 1 year of immunosuppressive treatment, the lower number of macrophages (CD68+) seemed to predict a more favourable long-term clinical response with regard to improved muscle strength.

Background We aimed to evaluate the 1-year and 2-year outcome of a health-enhancing physical activity (HEPA) support program on global pain, pressure pain sensitivity, and exercise-induced segmental and plurisegmental hypoalgesia (EIH) in persons with rheumatoid arthritis (RA). Methods Thirty participants (27 women and 3 men) were recruited from a larger intervention cohort that engaged in strength training and moderate-intensity aerobic activity. Assessments were performed before the HEPA intervention and at 1-year and 2-year follow-ups. Global pain was assessed on a visual analogue scale (0–100). Pressure pain thresholds (PPTs) and suprathreshold pressure pain at rest corresponding to 4/10 (medium pain) (SP4) and 7/10 (strong pain) (SP7) on Borg CR 10 scale were assessed by algometry. In a subsample (n = 21), segmental and plurisegmental EIH were assessed during standardized submaximal static contraction (30% of the individual maximum), by algometry, alternately at the contracting right M. quadriceps and the resting left M. deltoideus. Results Global pain decreased from before the intervention to 2-year follow-up (median 11 to median 6, P = 0.040). PPTs and SP4 pressure pain at rest did not change from before the intervention to 2-year follow-up, while SP7 decreased from mean 647 kPa to mean 560 kPa (P = 0.006). Segmental EIH during static muscle contraction increased from the assessment before the intervention (from mean 1.02 to mean 1.42, P = 0.001), as did plurisegmental EIH (from mean 0.87 to mean 1.41, P

OBJECTIVE Autoantibodies targeting histidyl-transfer RNA synthetase (HisRS; anti-Jo-1) are common in the idiopathic inflammatory myopathies (IIMs) and antisynthetase syndrome. This study was undertaken to investigate immunity against HisRS in the blood and lungs of patients with IIM/antisynthetase syndrome. METHODS Bronchoalveolar lavage (BAL) fluid, BAL fluid cells, and peripheral blood mononuclear cells (PBMCs) from patients with IIM/antisynthetase syndrome (n = 24) were stimulated with full-length HisRS protein or a HisRS-derived peptide (HisRS11-23 ). BAL fluid and PBMCs from patients with sarcoidosis (n = 7) and healthy subjects (n = 12) were included as controls. The CD4+ T cell response was determined according to levels of CD40L up-regulation and cytokine expression using flow cytometry. Anti-Jo-1 autoantibody responses in the serum and BAL fluid were assessed by enzyme-linked immunosorbent assay. Lung biopsy samples from patients with IIM/antisynthetase syndrome (n = 14) were investigated by immunohistochemistry. RESULTS In BAL fluid, CD4+ T cells from 3 of 4 patients with IIM/antisynthetase syndrome responded to stimulation with HisRS protein, as measured by the median fold change in CD40L expresssion in stimulated cells compared to unstimulated cells (median fold change 3.6, interquartile range [IQR] 2.7-14.7), and 2 of 3 patients with IIM/antisynthetase syndrome had the highest responses to HisRS11-23 (median fold change 88, IQR 27-149). In PBMCs, CD4+ T cells from 14 of 18 patients with IIM/antisynthetase syndrome responded to HisRS protein (median fold change 7.38, IQR 2.69-31.86; P < 0.001), whereas a HisRS11-23 response was present in 11 of 14 patients with IIM/antisynthetase syndrome (median fold change 3.4, IQR 1.87-10.9; P < 0.001). In the control group, there was a HisRS11-23 response in 3 of 7 patients with sarcoidosis (median fold change 2.09, IQR 1.45-3.29) and in 5 of 12 healthy controls (median fold change 2, IQR 1.89-2.42). CD4+ T cells from patients with IIM/antisynthetase syndrome displayed a pronounced Th1 phenotype in the BAL fluid when compared to the PBMCs (P < 0.001), producing high amounts of interferon-γ and interleukin-2 following stimulation. Anti-Jo-1 autoantibodies were detected in BAL fluid and germinal center (GC)-like structures were seen in the lung biopsy samples from patients with IIM/antisynthetase syndrome. CONCLUSION The results of this study demonstrate a pronounced presence of HisRS-reactive CD4+ T cells in PBMCs and BAL fluid cells from patients with IIM/antisynthetase syndrome as compared to patients with sarcoidosis and healthy controls. These findings, combined with the presence of anti-Jo-1 autoantibodies in BAL fluid and GC-like structures in the lungs, suggest that immune activation against HisRS might take place within the lungs of patients with IIM/antisynthetase syndrome.

To investigate anti-TIF1-γ antibodies in longitudinally followed patients with myositis and cancer.Serum levels of anti-TIF1-γ antibodies at different time-points in relation to myositis and cancer diagnosis were analysed by ELISA in 79 patients from a Swedish cohort with polymyositis (PM) and dermatomyositis (DM) and a Spanish cohort restricted to DM patients. Anti-TIF1-γ positive and negative patients were compared with Fisher's exact test, student t-tests and Wilcoxon test.Thirty-six patients (17 from cohort 1 and 19 from cohort 2) with myositis and cancer were anti-TIF1-γ antibody positive; all had DM. In 88% of anti-TIF1-γ positive patients, cancer was diagnosed within 3 years from DM diagnosis compared to 63% in anti-TIF1-γ negative. Four DM patients, anti-TIF1-γ positive at cancer diagnosis had positive serum samples even antedating cancer diagnosis up to five years. In cohort 1 the median (interquartile range) antibody level was higher, 2.13 au (1.82-2.15), in the seven patients who died1 year after cancer diagnosis, compared to the seven that died1 year after cancer diagnosis, 1.34 au (0.92-1.59), (p=0.004). Three patients were still alive and in remission from cancer and DM 14-16 years after cancer treatment of whom two became negative for anti-TIF1-γ antibodies. In the second cohort remission of cancer coincided with remission of DM and low or negative serum levels of autoantibodies.Anti-TIF1-γ antibodies may be detected before clinical symptoms of cancer and may disappear after successful treatment of cancer with remission of DM supporting DM being a paramalignant phenomenon.

Background B-cell activating factor of the tumour necrosis factor family (BAFF) plays a role in autoantibody production and is elevated in dermatomyositis (DM) and anti-Jo-1-positive polymyositis (PM). We investigated the inter-relationships between serum levels of BAFF, anti-Jo-1 autoantibodies, and disease activity. Methods Serum levels of BAFF and anti-Jo-1 antibodies measured by enzyme-linked immunosorbent assay (ELISA) were compared to levels of myoglobin, creatine kinase (CK), aminotransferases (alanine (ALT) and aspartate (AST)), C-reactive protein (CRP), and disease activity assessed by the Myositis Disease Activity Assessment Tool in 63 anti-Jo-1 antibody-positive DM/PM patients. Serial serum samples collected at 2 (46 cases) and 3–5 time points (23 cases) were included. Relationships between BAFF, anti-Jo-1, disease activity, CRP, and their longitudinal changes were evaluated using correlation analysis, multiple regression (MR), path analysis (PA), and hierarchical linear models (HLM). Results Cross-sectional assessment demonstrated significant correlations between the levels of BAFF and anti-Jo-1 antibodies which were associated with levels of CK, myoglobin, AST, and CRP, as well as multivariate associations between BAFF, anti-Jo-1 antibodies, and CK levels. PA revealed direct effects of anti-Jo-1 antibodies on CK (β = 0.41) and both direct (β = 0.42) and indirect (through anti-Jo-1 antibodies; β = 0.17) effects of BAFF on CK. Changes in levels of both BAFF and anti-Jo-1 between two time points (Δ) were associated with Δmyoglobin and Δaminotransferases and changes of BAFF correlated with ΔCK, Δcutaneous, Δmuscle, Δglobal, and Δskeletal disease activities. The longitudinal analysis showed a high intra-individual variability of serum levels of BAFF over time (97%) which could predict 79% of the variance in anti-Jo-1 levels. The anti-Jo-1 variability was explained by inter-individual differences (68%). The close longitudinal relationship between levels of BAFF, anti-Jo-1, and disease activity was supported by high proportions of their variance explained with serum levels of CK and CRP or pulmonary and muscle activities. Conclusion Our findings of associations between levels of BAFF and anti-Jo-1 antibodies in serum and myositis activity suggest a role of this cytokine in disease-specific autoantibody production as part of disease mechanisms, and support BAFF as a potential target for intervention in anti-Jo-1-positive myositis patients. Electronic supplementary material The online version of this article (10.1186/s13075-018-1650-8) contains supplementary material, which is available to authorized users.

Background Autoimmune myositis (rheumatic muscle inflammation) associated with interstitial lung disease (ILD) and arthritis is strongly correlated with the presence of anti-histidyl tRNA synthetase (HisRS) autoantibodies.1 Objectives The aims of this study were to investigate: 1) myositis IgG reactivity against HisRS conformational epitopes; and 2) association between clinical manifestations and anti-HisRS reactivity profiles. Methods Serum IgG was isolated using a protein G affinity column (from 25 anti-HisRS negative (-) and 19 anti-HisRS positive (+) myositis sera and 24 age/gender matched healthy controls, HC). Autoantibody reactivity was tested by in house ELISA developed against HisRS full-length protein and three HisRS conformational epitopes (WHEP domain – localised in the N-terminal; HisRS without WHEP (HisRS_WHEP); and ABD – anticodon-binding domain located in the C-terminal). Correlations between diagnosis, clinical manifestations and anti-HisRS IgG reactivity were evaluated. Results HisRS(+) myositis IgG displayed stronger reactivity against full-length HisRS and HisRS_WHEP (median 372 ng/mL and 334 ng/mL, respectively), compared to WHEP and ABD (6.38 and 6.48 ng/mL). The strongest anti-full-length HisRS reactivity (>371 ng/mL) was detected in patients presenting ILD (10/10 of patients), arthritis (6/10) and polymyositis diagnosis (PM 9/10), in comparison to patients with low anti-HisRS reactivity ( Conclusions This study provides evidences for a possible underlying role of anti-HisRS autoantibodies in the pathogenesis of myositis with interstitial lung disease and joint involvement. Reference [1] Hamaguchi Y, Fujimoto M, Matsushita T, et al. Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS One2013;8(4):e60442. Disclosure of Interest None declared

Background Idiopathic inflammatory myopathies (IIMs) are characterised by progressive muscle weakness and muscle fatigue. IIMs frequently appear with other organ involvement, e.g. the heart. Cardiac affection is often subclinical but associated with poor prognosis which makes early detection critical. Presence of autoantibodies is common in IIMs and autoantibodies are important biomarkers to confirm the diagnosis of IIMs. Autoantibodies may even predict organ involvement, e.g. the common myositis specific autoantibody anti-Jo1, which is a marker of lung involvement. So far, an autoantibody predicting cardiac involvement has yet to be identified. Objectives The aim of this study was to identify and estimate presence of cardiac involvement detected by electrocardiography (ECG) and to evaluate possible associations between ECG changes and autoantibodies in a Scandinavian cohort of patients with IIMs. Methods In a Scandinavian cross-sectional study, 241 patients with polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) and 48 healthy controls (HCs) were investigated by ECG, basic cardiovascular assessments, and autoantibody profile including myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs). Results Compared to HCs, patients with IIMs more frequently had prolongation of QTc (p=0.037) and QRS (p=0.031). All patient groups had significantly longer QTc and QRS duration than HCs. In multivariate regression analysis of patients with IIMs, increased CRP (p=0.006) was associated to increased QTc. Pooled data for patients with IIMs and HCs showed an association between diagnosis of IIM and increased QTc duration (p Conclusions Patients with IIMs, no matter of clinical subgroup, had a higher occurrence of cardiac abnormalities detected by ECG than HCs. Increased CRP and presence of any MAA were associated with increased QTc and QRS duration, respectively. These results support our notion of possible associations between inflammation and autoimmunity and cardiac affection in patients with IIMs. There is now a pressing need to set up a larger prospective study to validate the present findings. Disclosure of Interest None declared

Background Polymyositis (PM) and dermatomyositis (DM) are severe chronic autoimmune diseases, characterized by muscle fatigue and low muscle endurance. Conventional treatment includes high doses of glucocorticoids and immunosuppressive drugs; however, few patients recover full muscle function. One explanation of the persistent muscle weakness could be altered lipid metabolism in PM/DM muscle tissue as we previously reported. Using a targeted lipidomic approach we aimed to characterize serum lipid profiles in patients with PM/DM compared to healthy individuals (HI) in a cross-sectional study. Also, in the longitudinal study we compared serum lipid profiles in patients newly diagnosed with PM/DM before and after immunosuppressive treatment. Methods Lipidomic profiles were analyzed in serum samples from 13 patients with PM/DM, 12 HI and 8 patients newly diagnosed with PM/DM before and after conventional immunosuppressive treatment using liquid chromatography tandem mass spectrometry (LC-MS/MS) and a gas-chromatography flame ionization detector (GC-FID). Functional Index (FI), as a test of muscle performance and serum levels of creatine kinase (s-CK) as a proxy for disease activity were analyzed. Results The fatty acid (FA) composition of total serum lipids was altered in patients with PM/DM compared to HI; the levels of palmitic (16:0) acid were significantly higher while the levels of arachidonic (20:4, n-6) acid were significantly lower in patients with PM/DM. The profiles of serum phosphatidylcholine and triacylglycerol species were changed in patients with PM/DM compared to HI, suggesting disproportionate levels of saturated and polyunsaturated FAs that might have negative effects on muscle performance. After immunosuppressive treatment the total serum lipid levels of eicosadienoic (20:2, n-6) and eicosapentaenoic (20:5, n-3) acids were increased and serum phospholipid profiles were altered in patients with PM/DM. The correlation between FI or s-CK and levels of several lipid species indicate the important role of lipid changes in muscle performance and inflammation. Conclusions Serum lipids profiles are significantly altered in patients with PM/DM compared to HI. Moreover, immunosuppressive treatment in patients newly diagnosed with PM/DM significantly affected serum lipid profiles. These findings provide new evidence of the dysregulated lipid metabolism in patients with PM/DM that could possibly contribute to low muscle performance. Electronic supplementary material The online version of this article (10.1186/s13075-018-1579-y) contains supplementary material, which is available to authorized users.

OBJECTIVE To study the occurrence of ischemic stroke and hemorrhagic stroke in patients with idiopathic inflammatory myopathies (IIMs) compared to that in the general population and to investigate how it varies by sex, age, clinical subdiagnosis, and time since IIM diagnosis. METHODS All patients in Sweden with newly diagnosed IIM were identified from the National Patient Register, and general population comparators were identified from the Total Population Register. The study population was followed prospectively until death, emigration, December 2013, or first incident stroke. Incidence rates, rate differences, and hazard ratios (HRs) comparing patients with IIMs to the general population were estimated and stratified by age, sex, type of IIM, and time since diagnosis. To account for the competing risk of death, the subdistribution HR was estimated using Fine and Gray models. RESULTS We observed 34 and 229 stroke events in 663 IIM patients and 6,673 comparators, respectively. The HR was elevated for ischemic stroke (HR 2.1 [95% confidence interval (95% CI) 1.4, 3.0]). Few hemorrhagic stroke events were identified, but an increased risk was observed (HR 1.9 (95% CI 0.7, 5.5]). The association remained elevated for both outcomes when taking the competing risk of death into account. For ischemic stroke, the rate difference was highest in the oldest age group (≥68 years), while the HR was highest in the youngest age group (

Objective.To describe changes of health-enhancing physical activity (HEPA), health perception, and functioning during the second year of a 2-year support program, determine aspects of adherence and response, and describe perceptions of the program.Methods.Out of 220 individuals with rheumatoid arthritis (RA), 177 participated in the followup. Group support, strength training, and moderate-intensity aerobic activity were encouraged. Data collection included HEPA, perceived health, functioning, and perceptions of the program. Participants with unchanged/improved general health perception and at least 2 of aerobic capacity, grip strength, or timed standing were considered responders.Results.Current and maintained HEPA decreased from 82% to 75% (p = 0.0141) and from 41% to 27% (p < 0.0001) during the second year. Minor declines in quality of life and activity limitation occurred (p = 0.0395 and 0.0038, respectively), while outcome expectations for benefits of physical activity increased (p = 0.0010 and 0.0186) and waist circumference tapered off (p = 0.0070). Strength training was performed on average 41 and 35 times among responders (n = 54) and nonresponders (n = 105), respectively (p = 0.2708); HEPA 194 and 171 days, respectively (p = 0.0828); and support group meetings 12 and 10 times, respectively (p = 0.0943). Strength training, aerobic activity, and short text message reminders were perceived as most valuable; step registration and the self-monitoring walk tests were less appreciated.Conclusion.About one-fourth of the originally sedentary individuals with RA sustained their new HEPA behaviors after 2 years and most improvements of health and functioning were sustained. Structured use of behavior change techniques and a second year to support maintenance with a reduced program might help patients with RA to sustain HEPA behavior.

Objective To establish how guided physical activity in patients with rheumatoid arthritis (RA) without known cardiovascular disease affected vascular and cardiac function, and how these two entities were prospectively interconnected in this patient group. Methods Prospective substudy of 29 participants in the Physical Activity in RA (PARA) 2010 trial. All subjects were examined at baseline, at year 1 and 2 with measures of pulse wave velocity and arterial augmentation index, as well as echocardiographic evaluation of diastolic parameters and ventricular-arterial coupling. Muscle strength and aerobic exercise capacity were assessed at baseline and yearly. All participants performed physiotherapist-guided aerobic and muscle strength exercise during two years and were reminded through SMS to report physical activity progress. Results This cohort of patients with RA exhibited increased vascular stiffness despite normal blood pressure. At baseline, lower muscle strength was associated with increased vascular stiffness (β = 0.68; P = 0.004), whereas lower aerobic working capacity was associated with left ventricular diastolic dysfunction (β = 0.85; P = 0.03). There was a significant positive correlation between vascular stiffness and diastolic dysfunction at baseline (R2 = 0.64) and for the changes in those parameters observed during two years of guided physical activity. Finally, a significant improvement in ventricular-arterial coupling was observed after exercise (P < 0.001). Conclusion These results indicate that although differentially associated with physical capacity parameters, improved vascular stiffness, and improved diastolic dysfunction are interrelated, and that an optimization of the ventricular-arterial coupling may contribute to the beneficial effects of physical activity in RA patients. This article is protected by copyright. All rights reserved.

Objective To determine the occurrence of traditional cardiovascular (CV) risk factors and coronary artery calcification (CAC) in adults with polymyositis (PM) or dermatomyositis (DM) compared to healthy controls and to assess the association between CV risk factors, PM/DM, and CAC score. Methods Traditional CV risk factors were assessed in a cross-sectional, observational study of 76 patients with PM/DM and in 48 sex- and age-matched healthy controls. CAC was quantified by means of cardiac computed tomography scan and expressed in Agatston units. The associations between CV risk factors, PM/DM, and CAC were studied by multivariate analyses. Results Thirty-three percent of the patients were obese compared to 11% of the controls (P = 0.005). Hypertension and diabetes mellitus were more frequent in patients (71% versus 42%; P = 0.002, and 13% versus 0%; P = 0.007), and patients had higher levels of triglycerides (P = 0.0009). High CAC score occurred more frequently in patients (20% versus 4%; P = 0.04). In multivariate analysis of patient factors associated with CAC were age (P = 0.02) and smoking (P = 0.02). Conclusion In this study, traditional CV risk factors and severe CAC were commonly found in patients with PM/DM. However, severe CAC was not associated with PM/DM per se, but rather with age and smoking in these patients.

To estimate the minimal clinically important difference (MCID) in seven self-administered measures assessing fatigue in Swedish patients with systemic lupus erythematosus (SLE).The participants (n = 51, women 98%, age 52.8 ± 12.1 years, disease duration 18.7 ± 13.6 years) met in groups of six to nine persons. After completing seven fatigue questionnaires [the Fatigue Severity Scale (FSS); the Multidimensional Assessment of Fatigue (MAF) scale; the 20-item Multidimensional Fatigue Inventory (MFI); the Chalder Fatigue Scale (CFS); the Short Form-36 Vitality subscale (VT); the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scale; and the Numeric Rating Scale (NRS)], each respondent had a minimum of five face-to-face discussions, followed by an individual comparative assessment of their own level of fatigue (seven-grade scale). This method resulted in 260 contrasting assessments; MCIDs were first calculated using the paired differences and then established by a regression approach. Patients were asked to comment on their experience with the questionnaires and whether they captured their fatigue adequately.The paired approach (using 'little more fatigue' as an anchor for MCID during the face-to-face comparative assessments) provided estimates of 4.6-17.0; the regression approach provided estimates of 4.3-10.8. Estimates using the regression approach were consistently lower than those using the paired model. The MCID estimates were least favourable and fewer respondents supported the use of the NRS compared to the other self-reported questionnaires.All seven instruments detect MCIDs for fatigue in Swedish patients with SLE. However, the single-question measure was not supported by the MCID estimates or by comments from the respondents.

We read with interest the letter titled ‘Performance of the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies in clinical practice’ by Hocevar et al published in the Annals of the Rheumatic Diseases .1 In the letter the authors report the sensitivity and specificity of the recently published ‘ 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups ’2 observed in a retrospective cohort of 95 patients with idiopathic inflammatory myopathies (IIM) collected between 2010 and 2017 in a Slovenian rheumatology centre. As comparators, they used 72 subjects who had had a work-up for …

BACKGROUND Collaborative reasoning occurs in clinical practice but is rarely developed during education. The computerized virtual patient (VP) cases allow for a stepwise exploration of cases and thus stimulate active learning. Peer settings during VP sessions are believed to have benefits in terms of reasoning but have received scant attention in the literature. OBJECTIVE The objective of this study was to thoroughly investigate interactions during medical students’ clinical reasoning in two-party VP settings. METHODS An in-depth exploration of students’ interactions in dyad settings of VP sessions was performed. For this purpose, two prerecorded VP sessions lasting 1 hour each were observed, transcribed in full, and analyzed. The transcriptions were analyzed using thematic analysis, and short clips from the videos were selected for subsequent analysis in relation to clinical reasoning and clinical aspects. RESULTS Four categories of interactions were identified: (1) task-related dialogue, in which students negotiated a shared understanding of the task and strategies for information gathering; (2) case-related insights and perspectives were gained, and the students consolidated and applied preexisting biomedical knowledge into a clinical setting; (3) clinical reasoning interactions were made explicit. In these, hypotheses were followed up and clinical examples were used. The researchers observed interactions not only between students and the VP but also (4) interactions with other resources, such as textbooks. The interactions are discussed in relation to theories of clinical reasoning and peer learning. CONCLUSIONS The dyad VP setting is conducive to activities that promote analytic clinical reasoning. In this setting, components such as peer interaction, access to different resources, and reduced time constraints provided a productive situation in which the students pursued different lines of reasoning.

PURPOSE OF REVIEW Idiopathic inflammatory myopathies (IIMs) are complex multisystemic autoimmune diseases. Glucocorticoids remain the cornerstone of treatment in IIM, and the benefit of additional immunosuppressors is still debated. A limited number of controlled clinical trials have been available to support treatment guidelines, but in the last year, several clinical trials have been published. In this review, the highlights of recently published and on-going clinical trials in IIM will be summarized and discussed. RECENT FINDINGS Post hoc analyses of a large randomized controlled trial (RCT) suggested new predictive factors of response to rituximab in refractory IIM individuals. An international collaboration enabled the completion of a large RCT in early juvenile dermatomyositis that will orient first-line treatment in that population. New approaches are showing encouraging results in inclusion body myositis. SUMMARY Recent advances in molecular mechanisms underlying IIM pathogenesis and the development of novel targeted therapies have influenced recent and on-going clinical research.

NEW AUTOIMMUNE TARGETS IN IDIOPATHIC INFLAMMATORY MYOPATHIES - AN ANTIGEN BEAD ARRAY APPROACH

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

ObjectivesAutoantibodies directed against cytosolic 5′-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5′-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis.Materials and methodsData from various European inclusion body myositis registries were pooled. Anticytosolic 5′-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression.ResultsData from 311 patients were available for analysis; 102 (33%) had anticytosolic 5′-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients.InterpretationDifferences were observed in clinical and histopathological features between anticytosolic 5′-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5′-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

Background Polymyositis (PM) and dermatomyositis (DM) are chronic autoimmune diseases, characterised by muscle fatigue and low muscle endurance. Conventional treatment includes high doses of glucocorticoids and immunosuppressive drugs; however, few patients recover muscle function. We recently reported that immunosuppressive treatment affected the expression of genes related to lipid/fatty acid (FA) metabolism, suggesting altered lipid/FA-profiles in PM/DM patients. Objectives To analyse lipid and FA profiles in sera from patients with polymyositis or dermatomyositis in comparison to healthy individuals and relation to immunosuppressive treatment. Methods Serum samples were obtained from 13 patients with established PM or DM and 12 healthy individuals. The second cohort consisted of eight untreated patients diagnosed with definite PM or DM with available follow-up serum sample after eight months of immunosuppressive treatment. Functional Index 2 (muscle function) was assessed in the second cohort. Serum lipids were extracted by using liquid-liquid extraction. FA composition of total serum lipids was determined by gas chromatography provided with flame ionisation detector (GC-FID). FA composition of several lipid classes, e.g. triacylglycerols, phospholipids, sphingolipids, and lysophospholipids was analysed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results The FA composition of total serum lipids was altered in myositis patients compared to healthy individuals; the levels of C16:0 acid was significantly higher in myositis patients whereas the levels of C20:4 (n-6) acid was significantly lower. The levels of serum lipid species within phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and triacylglycerol (TG) were significantly changed in myositis patients compared to healthy individuals. Immunosuppressive treatment resulted in increased levels of C20:2 (n-6) acid and C20:5 (n-3) acid as well as changed serum PC, PE and LPC profiles in myositis patients. Furthermore, a positive correlation was observed between the Functional index and the levels of PC(38:4) in serum from patients after treatment. Conclusions FA composition of total serum lipids is altered in myositis patients compared to healthy controls. Immunosuppressive treatment resulted in changed FA composition of serum PC, PE, and LPC. These findings indicate that FA metabolism might be deregulated in PM and DM patients contributing to muscle inflammatory responses and loss of muscle function.

Patients with idiopathic inflammatory myopathies (IIMs) suffer an increased burden of comorbidities, but data on mortality in recently diagnosed IIM are conflicting. Also, little is known when, if ever, in relation to IIM diagnosis, mortality is increased.MethodsA population-based IIM cohort of patients diagnosed between 2002 and 2011 and general population comparators were identified using healthcare registers. They were linked to the cause of death register for follow-up.Results224 (31%) of the 716 patients with IIM and 870 (12%) of the 7100 general population died during follow-up. This corresponded to a mortality rate of 60/1000 person-years in IIM and 20/1000 person-years in the general population. The cumulative mortality at 1 year after diagnosis was 9% in IIM and 1% in the general population, and increased in both IIM and the general population with time. The overall hazard ratio (HR) 95%CI of death comparing IIM with the general population was 3.7 (3.2 to 4.4). When we stratified on time since diagnosis, we noted an increase in mortality already within the first year of diagnosis compared with the general population, HR 9.6 (95% CI 6.9 to 13.5). This HR then plateaued around 2 after >10 years with the disease, although the estimates were not statistically significant. Malignancies, diseases of the circulatory and respiratory system were common causes of death.ConclusionMortality is increased in patients with contemporary IIM. The increased mortality was noted within a year of diagnosis, which calls for extra vigilance during the first year of IIM diagnosis.

Background Systemic inflammatory diseases, such as systemic lupus erythematosus (SLE) and idiopathic inflammatory myositis (IIM), have largely unknown aetiology and represent a disease area with major unmet medical needs. Treatment often give a clinical effect, but not in all patients; and symptoms often remain. In collaboration with the Structural Genomics Consortium (SGC), we have investigated in vitro B-cell effects of about 50 different chemical probes which bind and inhibit epigenetic enzymes and regulators, such as bromodomains and histone methyltransferases, as well as kinases and other intracellular protein targets. These probes are small molecules that can enter cells and selectively inhibit potential new drug-targets at therapeutically relevant doses. The read out are expression of molecules which have been shown to be of pathological relevance in systemic inflammatory diseases. Materials and methods Peripheral blood mononuclear cells (PBMC) from patients with SLE or IIM and healthy controls were incubated in presence of different chemical probes at 1 or 0,1 uM for 6 days in culture medium containing B-cell stimulating factors; IL4, IL10, IL21, sCD40L and CpG2006. Cell viability was determined by flow cytometry using the live/dead marker viability IR® and B-cell maturation was investigated using markers for memory B cells (CD27), plasmablasts (CD38) and surface IgG. Secretion of IgG was quantified by ELISA. Results The percentage of memory B cells, plasmablasts and IgG-expressing B cells, as well as IgG secretion, was induced by the B-cell stimulating factors. These parameters were suppressed by a set of the epigenetic probes, as well as by some of the probes targeting other intracellular proteins. A few of the probes decreased cell viability. Both B cells from SLE and IIM were affected. Conclusions We have found a set of chemical probes, with documented target selectivity and potent inhibitory effects of these targets, which affect in vitro B-cell maturation and secretion of IgG. Further analysis is required to better understand the pathways that are affected.

Background Previous studies have demonstrated that CD4+ T cells from peripheral blood of anti-histidyl-tRNA synthetase (anti-His-tRNA) also known as anti-Jo-1 positive patients proliferate in response to stimulation with full-length His-tRNA and a N-terminal fragment comprising residues 1–60. In this study we present a novel epitope that identifies patients with moderate-severe interstitial lung disease (ILD). Materials and Methods Sixteen anti-Jo-1 positive patients with antisynthetase syndrome followed at the Karolinska University Hospital were enrolled. As controls we included HLA-DRB1*03-positive healthy individual (HCs, n=8). Peripheral blood mononuclear cells were isolated by Ficoll-Hypaque density centrifugation and in vitro stimulated with: a) full length His-tRNA protein; b) a novel HLA-DR*03:01 binding peptide from native His-tRNA; c) an altered peptide ligand (APL) variant of His-tRNA designed to prevent recognition by HLA-DR3/His-tRNA-specific TCRs. T cell activation was assessed by CD40L up-regulation and expression of pro-inflammatory cytokines (IFN-g, IL-2 and IL-17A) by flow cytometry. Clinical and laboratory data were documented and analysed by Student’s T test or Mann-Withney U-test. Results At the time of blood sampling the patients had a mean age of 58 years (48–83 years), median disease duration of 50 months (11–70 months), MMT8 score 80 (79-80), HAQ 0.25 (0 13-0.75). Eighty-four percent were female, 13/16 patients had ILD and 13/16 had muscle weakness. T cell activation towards the novel His-tRNA peptide was observed in 2/16 anti-Jo-1 positive patients. When stimulating with the APL, no T cell activation was observed in one of the patients that was reactive for the peptide. For evaluation of pro-inflammatory features, the His-tRNA-specific T cells displayed significant up-regulated levels of IFN-γ (p Conclusion In this study, we demonstrate the presence of His-tRNA-reactive CD4+ T cells in peripheral blood from anti-Jo-1 positive patients and a novel His-tRNA peptide, characterised by the expression of IFN-g. This phenotype seemed to correlate to a moderate-severe clinical progression of ILD.

Idiopathic inflammatory myopathies (IIMs), collectively called myositis, are a heterogeneous group of diseases affecting adults and children. The IIMs are characterized by symmetrical, proximal muscle weakness and by inflammatory infiltrates in skeletal muscles. Based on differences in clinical and histopathological features, they can be divided into different subgroups, the most common forms being dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (sIBM), and in children juvenile dermatomyositis (JDM). Other organs are frequently involved in patients with IIM eg, lungs, gastrointestinal tract, and the heart, emphasizing that these are systemic inflammatory diseases. IIMs are associated with increased mortality, and cardiovascular involvement has been recognized as the main prognostic factor for death. Processes affecting the heart in IIM include coronary artery disease and cardiac affection caused by inflammation. In this chapter, we focus on adult PM and DM and JDM as little is known about cardiac involvement in the other subsets.

We thank Cavagna et al 1 for their thoughtful analysis relating to our recent publication.2 Several important points are raised, many of which we also referred to. It is of great interest and reassurance that the demographics and clinical features of antisynthetase syndrome (ASS) are broadly similar between the AENEAS (American and European NEtwork of Anti-Synthetase syndrome) and EuroMyositis cohorts. Clearly the frequency of interstitial lung disease and arthritis differs due to the sources of case ascertainment. This highlights …

Objectives. The aims of this study were to document adherence to and changes in health-enhancing physical activity (HEPA) levels and self-reported and assessed functioning and to explore aspects of adherence and response during the first year of an outsourced 2-year HEPA programme in people with RA. Methods. Two-hundred and twenty patients participated in this observational cohort study, which included daily physical activity, twice-weekly circuit training and biweekly support group meetings. Self-reported data included current (past week) and maintained (past 6 months) HEPA levels, sociodemographics and disease-related and psychosocial factors. Tests of aerobic capacity and muscle function were performed and anthropometric data were collected. Results. Eighty-eight per cent of the participants completed 1 year assessments. Self-reported current and maintained HEPA increased. General health perception and a number of other self-reported disease-related and psychosocial factors improved, while exercise self-efficacy declined. Aerobic capacity, timed standing and grip strength improved and waist circumference decreased. The mean number of circuit training sessions performed was 48, the mean number of days with HEPA was 189 and the mean number of support group meetings attended was 9. Better adherence to circuit training improved general health, and better adherence to group meetings improved timed standing. Exercise self-efficacy improved among those adhering more to circuit training or support group meetings. Conclusion. The outsourced HEPA programme had high retention and reasonable adherence. A number of health outcomes improved. Relationships between adherence to the programme components and response were not clear-cut and need further attention. Trial registration: ISRCTN register; http://www.controlled-trials.com. Trial registration number ISRCTN25539102.

Objectives To determine the prevalence of myasthenia gravis (MG) and the rate of concurrent autoimmune diseases in patients with MG. Design and setting Using the Swedish health and population registers, during the period 2005–2010, we conducted a nested case–control study of patients with MG (n = 2045) with five age- and sex-matched population-based controls per case. Register-based MG diagnosis was validated against the Stockholm MG Cohort. Similar nested case–control studies were conducted in patients with multiple sclerosis (MS), as a neuroinflammatory disease control, and siblings of patients with MG. Main outcome measure Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated as a measure of the association between MG and other autoimmune diseases. Results The prevalence of MG was 24.8/100 000, and patients with MG had an increased risk of another autoimmune disease compared to controls (22.0% vs. 8.9%; OR: 2.82, 95% CI: 2.49–3.20); this risk was stronger amongst younger persons and women. Polymyositis/dermatomyositis, systemic lupus erythematosus and Addison's disease, three conditions regulated by the HLA-B8-DR3 haplotype, were most strongly associated with MG, especially early-onset disease. HLA typing in the Stockholm MG Cohort showed that early-onset MG was indeed dominated by HLA-B8-DR3. The risk of another autoimmune disease was increased in both patients with MS and siblings of patients with MG, compared to their respective controls, but to a lesser extent than in patients with MG. Conclusions Our results suggest that MG shares risk factors with other autoimmune diseases, to a greater degree than MS, with a particular role of the HLA-B8-DR3 haplotype, especially amongst younger and female patients.

To assess the serum levels of interleukin (IL)-15 and IL-17 in patients with idiopathic inflammatory myopathies (IIM) and correlate them with levels of IL-1 receptor antagonist (IL-1ra), IL-6, IL-10, interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and MIP-1β. Possible correlations with disease activity parameters were also evaluated.Sera from 14 patients with new-onset polymyositis (PM), 10 with dermatomyositis (DM), seven with anti-synthetase syndrome (ASS) and 19 healthy controls (HC) were analysed by multiplex immunoassay. Sera from 19 patients were analysed after a median follow-up of 5 months. All patients underwent physical examination, manual muscle testing (MMT) using the five-point MMT scales, the Health Assessment Questionnaire (HAQ), and serum creatine kinase (CK) measurement. All patients received glucocorticoids, and 13 were taking immunosuppressive therapy.At baseline, serum levels of IL-15, IL-17, MCP-1, and MIP-1β were significantly higher in IIM patients than in HC. IL-17 serum levels were directly correlated (r = 0.39, p = 0.02) with disease duration while a significant inverse correlation was detected between IL-17 levels and MMT scores (r = -0.4, p = 0.02). The highest IL-15 levels were present in DM patients (p = 0.02 vs. PM). The most striking finding was the strong correlation between IL-15 and IL-17 levels (r = 0.60, p = 0.0001), and this correlation was even stronger in DM patients (r = 0.82, p = 0.006).The strong correlation between IL-15 and IL-17 in IIM patients, and especially in DM, suggests that there may be an interplay between the two cytokines in the pathogenesis of myositis. Further studies of larger patient cohorts and of muscle biopsies are needed to confirm these preliminary data.

Objective Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca2+ handling and specific force production. Methods Nitric oxide synthase (NOS) expression, degree of nitrosative stress and composition of the major intracellular Ca2+ release channel (ryanodine receptor 1, RyR1) complex were measured in muscle. Changes in cytosolic free Ca2+ concentration ([Ca2+]i) and force production were assessed in single-muscle fibres and isolated myofibrils using atomic force cantilevers. Results The total neuronal NOS (nNOS) levels were increased in muscles both from collagen-induced arthritis (CIA) mice and patients with RA. The nNOS associated with RyR1 was increased and accompanied by increased [Ca2+]i during contractions of muscles from CIA mice. A marker of peroxynitrite-derived nitrosative stress (3-nitrotyrosine, 3-NT) was increased on the RyR1 complex and on actin of muscles from CIA mice. Despite increased [Ca2+]i, individual CIA muscle fibres were weaker than in healthy controls, that is, force per cross-sectional area was decreased. Furthermore, force and kinetics were impaired in CIA myofibrils, hence actin and myosin showed decreased ability to interact, which could be a result of increased 3-NT content on actin. Conclusions Arthritis-induced muscle weakness is linked to nitrosative modifications of the RyR1 protein complex and actin, which are driven by increased nNOS associated with RyR1 and progressively increasing Ca2+ activation.

The newly formed Outcome Measures in Rheumatology (OMERACT) Myositis Special Interest Group (SIG) was established to examine patient-reported outcome measures (PROM) in myositis. At OMERACT 11, a literature review of PROM used in the idiopathic inflammatory myopathies (IIM) and other neuromuscular conditions was presented. The group examined in more detail 2 PROM more extensively evaluated in patients with IIM, the Myositis Activities Profile, and the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire, through the OMERACT filter of truth, discrimination, and feasibility. Preliminary results from a qualitative study of patients with myositis regarding their symptoms were discussed that emphasized the range of symptoms experienced: pain, physical tightness/stiffness, fatigue, disease effect on emotional life and relationships, and treatment-related side effects. Following discussion of these results and following additional discussions since OMERACT 11, a research agenda was developed. The next step in evaluating PROM in IIM will require additional focus groups with a spectrum of patients with different myositis disease phenotypes and manifestations across a range of disease activity, and from multiple international settings. The group will initially focus on dermatomyositis and polymyositis in adults. Qualitative analysis will facilitate the identification of commonalities and divergent patient-relevant aspects of disease, insights that are critical given the heterogeneous manifestations of these diseases. Based on these qualitative studies, existing myositis PROM can be examined to more thoroughly assess content validity, and will be important to identify gaps in domain measurement that will be required to develop a preliminary core set of patient-relevant domains for IIM.

Objective: The aim of this study was to investigate signs of inflammation in muscle of patients with prior polio, since the main symptoms in these patients are muscle pain, weakness and fatigue. In the context of pain and inflammation, the prostaglandin E 2 pathway is of interest. Prostaglandin E 2 has many biological actions and is a mediator of inflammation and pain. Patients and methods: Skeletal muscle biopsies from 8 patients with prior polio and post-polio symptoms, presenting with pain and muscular weakness, and from 6 healthy controls were studied. Immunohistochemistry, conventional microscopy, and computerized image analysis were performed. Results: There was statistically significant higher expression of enzymes of the prostaglandin E 2 synthetic pathway, in muscle from patients, compared with controls. Expression of prostaglandin enzymes was mainly in scattered cells and blood vessels, and may indicate an inflammatory process of the muscle, which could be secondary to systemic inflammation. Conclusion: This data may indicate an inflammatory process in muscle of prior polio patients. Up-regulation of the prostaglandin E 2 pathway reveals a potential background to the pain experienced by these patients, and may provide opportunities for directed pharmacological and physical therapies, which could lead to better outcomes of rehabilitation interventions.

We agree with the notions made by Infantino et al 1 in their reply to our previously published report2 concerning the need for multicentre studies to obtain large enough number to validate new methods for detection of myositis-specific antibodies (MSA) and myositis-associated autoantibodies (MAA). We also …

We have with great interest read the letter entitled ‘Response to: ‘Idiopathic inflammatory myopathies and antisynthetase syndrome: contribution of antisynthetase antibodies to improve current classification criteria’ by Greco et al ’ by Knitza et al , to be published in the Annals of the Rheumatic Diseases .1 We appreciate the thoughtful comments made by the authors and agree on the importance of aminoacyl transfer RNA synthetase (ARS) autoantibodies, as well as other autoantibodies for correct classification of the associated diseases. The discussion stems from the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) …

Objective. To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods. We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results. Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10(-8) ) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion. Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. � 2013 American College of Rheumatology.

Purpose of review The idiopathic inflammatory myopathies myositis are rare diseases with limited information on risk factors for disease and prognosis. The aim of this review is to give an overview of how registries can be used in myositis research. Recent findings Population-based registries have been used in a number of incidence and prevalence studies in the review period and have shown myositis to be more common than previously reported. Disease-specific registries have been used for detailed studies on subphenotypes and longitudinal studies to identify prognostic markers and treatment outcomes. Summary Registries, both national healthcare and health insurance registries, as well as disease-specific clinical registries, are useful sources to investigate a rare disease like myositis. To achieve increased understanding of whether different subphenotypes differ in treatment outcome and prognosis, a large number of patients need to be followed longitudinally in a systematic way. A novel international, multidisciplinary registry, EUROMYOSITIS, has been developed. This is an open source registry with to date 20 centers and more than 2500 patients with myositis, many of whom are followed longitudinally. This registry has clear potentials for clinical and epidemiological research, as well as for clinical trial in myositis, and welcomes investigators from all over the world.

Objective To perform a mechanistic study on the effect of interleukin (IL)-1 blockade by anakinra in patients with refractory myositis and to explore possible predictive biomarkers. Methods Fifteen patients with refractory myositis were treated with anakinra for 12 months. Clinical response was assessed by the six-item core set measures of disease activity International Myositis Assessment and Clinical Studies (IMACS) and functional index (FI). Repeated muscle biopsies were investigated for cellular infiltrates, IL-1α, IL-1β, IL-1Ra and major histocompatibility complex-class I by immunohistochemistry. Serum levels of IL-1Ra and granulocyte colony-stimulating factor (G-CSF) were measured by ELISA. T cell phenotype and functional assays were investigated by multicolour flow cytometry. Results Seven patients had clinical response according to IMACS, four of them also showed improved FI. Responders had higher baseline extramuscular score compared with non-responders. In muscle biopsies, baseline CD163 macrophages and IL-1α expression were inversely correlated with muscle performance after 6 months treatment; all responders had IL-1Ra expression in the post-treatment biopsies but only 3/8 non-responders. In serum, IL-1Ra levels were increased and G-CSF was decreased after 6 months treatment, but their levels and changes were not related to clinical response. For T cells, an inverse correlation between baseline frequency of CD4 activated/memory T cells and decreased creatine kinase levels was observed. Five of six patients demonstrated less IL-17A and more IFN-γ secreting CD4 T cells after 6 months treatment. Moreover, anakinra reduced IL-17A secretion in vitro. Conclusions Patients with myositis may respond to anakinra. Extramuscular score, muscle CD163 macrophages and IL-1α expression, blood CD4 activated/memory T cells might associate with anakinra treatment response. Blocking the IL-1 receptor disfavoured Th17 cell differentiation both in vivo and in vitro.

OBJECTIVE: Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy characterized by both degenerative and autoimmune features. In contrast to other inflammatory myopathies, myositis-specific autoantibodies had not been found in sIBM patients until recently. We used human skeletal muscle extracts as a source of antigens to detect autoantibodies in sIBM and to characterize the corresponding antigen. METHODS: Autoantibodies to skeletal muscle antigens were detected by immunoblotting. The target antigen was immunoaffinity-purified from skeletal muscle extracts and characterized by mass spectrometry. A cDNA encoding this protein was cloned and expressed in vitro, and its recognition by patient sera was analyzed in an immunoprecipitation assay. Epitopes were mapped using microarrays of overlapping peptides. RESULTS: An Mr 44,000 polypeptide (Mup44) was frequently targeted by sIBM autoantibodies. The target protein was purified, and subsequent mass spectrometry analysis revealed that Mup44 is the cytosolic 5'-nucleotidase 1A (cN1A). By immunoprecipitation of recombinant cN1A, high concentrations of anti-Mup44 autoantibodies were detected in 33% of sIBM patient sera, whereas their prevalence in dermatomyositis, polymyositis, and other neuromuscular disorders appeared to be rare (4.2%, 4.5%, and 3.2%, respectively). Low concentrations of anti-Mup44 antibodies were found in myositis as well as other neuromuscular disorders, but not in healthy controls. Three major autoepitope regions of cN1A were mapped by using microarrays containing a set of overlapping peptides covering the complete cN1A amino acid sequence. INTERPRETATION: Anti-Mup44 autoantibodies, which are targeted to cN1A, represent the first serological biomarker for sIBM and may facilitate the diagnosis of this type of myositis.

Background The aim of this project was to analyze and compare the educational experience in rheumatology specialty training programs across European countries, with a focus on self-reported ability. Method An electronic survey was designed to assess the training experience in terms of self-reported ability, existence of formal education, number of patients managed and assessments performed during rheumatology training in 21 core competences including managing specific diseases, generic competences and procedures. The target population consisted of rheumatology trainees and recently certified rheumatologists across Europe. The relationship between the country of training and the self-reported ability or training methods for each competence was analyzed through linear or logistic regression, as appropriate. Results In total 1079 questionnaires from 41 countries were gathered. Self-reported ability was high for most competences, range 7.5–9.4 (0–10 scale) for clinical competences, 5.8–9.0 for technical procedures and 7.8–8.9 for generic competences. Competences with lower self-reported ability included managing patients with vasculitis, identifying crystals and performing an ultrasound. Between 53 and 91 % of the trainees received formal education and between 7 and 61 % of the trainees reported limited practical experience (managing ≤10 patients) in each competence. Evaluation of each competence was reported by 29–60 % of the respondents. In adjusted multivariable analysis, the country of training was associated with significant differences in self-reported ability for all individual competences. Conclusion Even though self-reported ability is generally high, there are significant differences amongst European countries, including differences in the learning structure and assessment of competences. This suggests that educational outcomes may also differ. Efforts to promote European harmonization in rheumatology training should be encouraged and supported. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1114-y) contains supplementary material, which is available to authorized users.

Objective To identify changes in skeletal muscle microRNA expression after endurance exercise and associate the identified microRNAs with mRNA and protein expression to disease-specific pathways in polymyositis (PM) and dermatomyositis (DM) patients. Methods Following a parallel clinical trial design, patients with probable PM or DM, exercising less than once a week, and on stable medication for at least one month were randomized into two groups at Karolinska University Hospital: a 12-week endurance exercise group (n = 12) or a non-exercised control group (n = 11). Using an Affymetrix microarray, microRNA expression was determined in paired muscle biopsies taken before and after the exercise intervention from 3 patients in each group. Ingenuity pathway analysis with a microRNA target filter was used to identify microRNA transcript targets. These targets were investigated at the mRNA (microarray) and protein (mass spectrometry) levels in patients. Results Endurance exercise altered 39 microRNAs. The microRNAs with increased expression were predicted to target transcripts involved in inflammatory processes, metabolism, and muscle atrophy. Further, these target transcripts had an associated decrease in mRNA expression in exercised patients. In particular, a decrease in the NF-κB regulator IKBKB was associated with an increase in its target microRNA (miR-196b). At the protein level, there was an increase in mitochondrial proteins (AK3, HIBADH), which were associated with a decrease in microRNAs that were predicted to regulate their expression. Conclusion Improvement in disease phenotype after exercise is associated with increasing microRNAs that target and downregulate immune processes at the transcript level, as well as decreasing microRNAs that target and upregulate mitochondrial content at the protein level. Therefore, microRNAs may improve disease by decreasing immune responses and increasing mitochondrial biogenesis. Trial registration ClinicalTrials.gov NCT01184625

The type I interferon (IFN) system has recently been suggested to play important and essential roles in the pathogenesis of myositis. However, a clarification of how type I IFNs could function as triggering factor(s) in the pathogenesis of myositis has yet failed. Through activation of the type I IFN system, the host defense peptide LL-37 carries numerous immunomodulatory properties and is implicated in the pathogenesis of several other autoimmune diseases, including systemic lupus erythematosus (SLE). The expression of LL-37 can be regulated by various endogenous factors including the active form of vitamin D (25(OH)D3). The aim of this study was to explore a potential role of LL-37 in relation to the type I IFN system in patients with polymyositis (PM) and dermatomyositis (DM) and to compare these with SLE patients and healthy controls. We investigated muscle (3 PM, 5 DM) and symptomatic (5 DM) and non-symptomatic (3 PM, 3 DM) skin biopsies from patients with short disease duration and muscle biopsies (3 PM, 1 DM) from patients with long disease duration. Six SLE patients with symptomatic and non-symptomatic skin and five muscle and six skin biopsies from healthy individuals served as controls. Tissue specimens were immunohistochemically stained for LL-37, neutrophils (CD66b), plasmacytoid dendritic cells (BDCA-2), myxovirus resistance protein A (MxA), and macrophages (CD68, CD163). In addition, LL-37 and CD66b double staining was also performed. Serum levels of 25(OH)D3 were investigated in PM and DM patients with short disease duration (3 PM, 5 DM) and in 40 healthy controls. We found that the expression of LL-37, BDCA-2 (the major producer of type I IFNs), MxA (an interferon-inducible protein), and macrophages were higher in muscle tissue of PM and DM patients compared to healthy controls. The LL-37 expression was mainly derived from neutrophils. Neutrophils were increased in both symptomatic and non-symptomatic skin of myositis and SLE patients and BDCA-2 was increased in symptomatic DM skin when compared to healthy controls. Moreover, the expression of MxA in symptomatic and non-symptomatic skin of SLE patients was higher when compared to both myositis patients and healthy controls. There was no difference in the expression of LL-37 in skin of myositis and SLE patients compared to healthy controls. All PM and DM patients with a short disease duration had low 25(OH)D3 levels compared to healthy controls. In conclusion, the present study supports our hypothesis that LL-37 may activate type I IFNs, which could initiate and perpetuate an inflammatory process. The prolonged exposure of the immune system to type I IFNs may eventually break tolerance and lead to autoimmune myositis.

Idiopathic inflammatory myopathies (IIM) include the main subgroups polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and juvenile DM ( JDM). The mentioned subgroups are characterised by inflammation of skeletal muscles leading to muscle weakness and other organs can also be affected as well. Even though clinically significant heart involvement is uncommon, heart disease is one of the major causes of death in IIM. Recent studies show an increased prevalence of traditional cardiovascular risk factors in JDM and DM/PM, which need attention. The risk of developing atherosclerotic coronary artery disease is increased twofold to fourfold in DM/PM. New and improved diagnostic methods have in recent studies in PM/DM and JDM demonstrated a high prevalence of subclinical cardiac involvement, especially diastolic dysfunction. Interactions between proinflammatory cytokines and traditional risk factors might contribute to the pathogenesis of cardiac dysfunction. Heart involvement could also be related to myocarditis and/or myocardial fibrosis, leading to arrhythmias and congestive heart failure, demonstrated both in adult and juvenile IIM. Also, reduced heart rate variability (a known risk factor for cardiac morbidity and mortality) has been shown in long-standing JDM. Until more information is available, patients with IIM should follow the same recommendations for cardiovascular risk stratification and prevention as for the corresponding general population, but be aware that statins might worsen muscle symptoms mimicking myositis relapse. On the basis of recent studies, we recommend a low threshold for cardiac workup and follow-up in patients with IIM.

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases, collectively named myositis, sharing symptoms of muscle weakness and muscle fatigue and inflammation in muscle tissue. Other organs are frequently involved supporting that these are systemic inflammatory diseases. The IIMs can be sub-grouped into dermatomyositis, polymyositis and inclusion body myositis. The myositis-specific autoantibodies (MSAs) identify other and often more distinct clinical phenotypes, such as the anti-synthetase syndrome with antisynthetase autoantibodies and frequent interstitial lung disease (ILD) and anti-SRP and anti-HMGCR autoantibodies that identify necrotizing myopathy. The MSAs are important both to support myositis diagnosis and to identify subgroups with different patterns of extramuscular organ involvement such as ILD. Another cornerstone in the diagnostic procedure is muscle biopsy to identify inflammation and to exclude non-inflammatory myopathies. Treatment effect and prognosis varies by subgroup. To develop new and better therapies, validated classification criteria that identify distinct subgroups of myositis are critical.. The lack of such criteria was the main rationale for the development of new classification criteria for inflammatory myopathies, which are summarized in this review, along with an historical background on previous diagnostic and classification criteria. As these are rare diseases with a prevalence of 10 in 100 000 individuals an international collaboration was essential, as was the interdisciplinary effort including adult and paediatric experts in rheumatology, neurology, dermatology and epidemiology. The new criteria have been developed based on data from more than 1 500 patients from 47 centers world-wide and are based on clinically easily available variables.

Biologic treatment has revolutionised treatment in rheumatology in the last decades. Patients with idiopathic inflammatory myopathies (IIM) have so far only been treated with biologics off-label, with little published follow-up on those who are treated and how they are treated. We therefore set out to characterise the Swedish IIM patients who have been treated with biologics.By linking Swedish registers we identified 95 patients with IIM who were treated with biologics between 2000 and 2011. Via chart review the diagnoses were validated and clinical characteristics extracted.In total, 95 individuals with IIM and biologic treatment were identified. Median disease duration was 5.5 years at start of biologics. All patients had been treated with prednisolone and failed at least one previous DMARD before the start of first biologic. Rituximab was the most common biologic drug, followed by anakinra and TNFinhibitors. Median overall treatment length was 10 months and varied between 5 and 12.5 months or the different therapies.Off-label treatment of IIMs is often tried and seldom successful. This study shows a large unmet need for novel treatments and therapies in IIM. It is therefore important to follow these patients in a structured way to learn about effects and potential risks for different subgroups of IIM associated with different therapies.