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Recent findings suggest cytokines as important key molecules in the pathogenic mechanisms of idiopathic inflammatory myopathies, myositis. In this review, we focus on cytokines with a potential role in disease mechanisms in myositis and present some general information on individual cytokines and an updated summary from the literature concerning cytokines in these disorders. The idiopathic inflammatory myopathies is a heterogeneous group of disorders clinically characterized by symmetric proximal muscle weakness and by certain defined histolopathological findings, including inflammatory infiltrates in muscle tissue. Other prominent findings in the target tissue of these patients are defined molecular changes of blood vessels and muscle fibers, including reformation to high endothelial venule (HEV)-like blood vessels and intensive MHC class I expression in muscle fibers. The predominant clinical symptoms of muscle weakness and decreased muscle endurance are shared by all subsets of inflammatory myopathies and indicate that some pathogenic mechanisms related to muscle function may be shared by the different disease groups. Studies on cytokine gene, RNA and protein expression in muscle tissue from patients with various forms of the disease also indicate similar profiles, despite different phenotypes of the inflammatory cells present in muscle tissue from the different subsets of myositis. There is a pronounced expression of various cytokines in muscle tissue, among which the proinflammatory cytokines TNF-alpha and IL-1 are most widely explored in the inflammatory myopathies, which has made them into potential therapeutic targets. The use of targeted cytokine therapy has been successful in several other chronic inflammatory diseases and although the exact role of cytokines in chronic idiopathic inflammatory myopathies remains to be delineated their potential role as targets for new therapies in this disorder will be discussed in this review.

Objective To investigate T cell receptor (TCR) expression in 3 different compartments that could be involved in patients with myositis: muscle, lung, and peripheral blood. Methods Nine patients with polymyositis (PM), dermatomyositis, or inclusion body myositis underwent bronchoscopy and bronchoalveolar lavage (BAL) as well as muscle biopsy and blood sampling. A panel of 19 monoclonal antibodies specific for TCR Vβ (BV) and Vα (AV) were used to characterize the TCR profile in CD4+ and CD8+ T cell populations in BAL fluid and peripheral blood by flow cytometry. Muscle biopsy tissues were analyzed by immunohistochemistry. Patients were also typed for HLA–DRB1 and DRB3 alleles. Results A total of 17 T cell expansions were detected in BAL fluid, 6 in the CD4+ T cell population and 11 in the CD8+ T cell population. Four T cell expansions were detected in peripheral blood. A selective TCR V usage was found in muscle. Two PM patients, both of whom had BAL fluid BV3+ T cell expansions in the CD4 population and in whom BV3 was also a prominent TCR V segment in muscle tissue, shared the HLA–DRB1*03 allele. These 2 patients were the only ones who were positive for anti–Jo-1 antibody. Conclusion We found a restricted accumulation of T lymphocytes expressing selected TCR V-gene segments in the target organ compartments (i.e., lung and muscle). The occurrence of shared TCR gene segment usage in muscle and lungs could suggest common target antigens in these organs.

Objective: To study whether formal education and occupational class are associated with incidence of rheumatoid arthritis overall and with the incidence of the two major subgroups of rheumatoid arthritis—seropositive (RF+) and seronegative (RF−) disease. Methods: 930 cases and 1126 controls participated in a population based case–control study using incident cases of rheumatoid arthritis, carried out in Sweden during the period May 1996 to June 2001. The relative risk (RR) of developing rheumatoid arthritis with 95% confidence interval (CI) was calculated for different levels of formal education compared with university degree and for different occupational classes compared with higher non-manual employees. Results: Subjects without a university degree had an increased risk of rheumatoid arthritis compared with those with a university degree (RR = 1.4 (95% CI, 1.2 to 1.8)). For manual employees, assistant and intermediate non-manual employees together, the risk of developing rheumatoid arthritis was about 20% more than for non-manual employees. These increased risks were more pronounced for RF+ than for RF− rheumatoid arthritis and were mainly confined to women. Smoking could not of its own explain the observed associations between risk of rheumatoid arthritis in different socioeconomic groups in Sweden. Conclusions: There was an association between high socioeconomic status and lower risk of rheumatoid arthritis in a population based investigation that was representative for the Swedish population. The study shows that as yet unexplained environmental or lifestyle factors, or both, influence the risk of rheumatoid arthritis, even in the relatively egalitarian Swedish society.

The objective of this review is to provide an update on exercise and clinical assessment in the idiopathic inflammatory myopathies.Polymyositis, dermatomyositis and inclusion body myositis are rare conditions with muscle weakness as a common prominent feature. Earlier, these patients were discouraged from active exercise due to a fear of increased muscle inflammation with recommendations to rest, perform range of motion exercises and in some cases, isometric exercises. However, beginning in the 1990s, studies reported reduced disability in patients with chronic polymyositis/dermatomyositis following resistive mild/moderate to intensive muscular training and aerobic endurance training, without signs of increased muscle inflammation. Patients with active, recent onset disease seem to benefit from mild/moderate muscular exercise without signs of increased muscle inflammation. There is no evidence of increased muscle inflammation following exercise in inclusion body myositis. However the beneficial effects are unclear as one study report increased muscle strength, while the other could not achieve impairment reduction.Studies evaluating active exercise in IIM support the notion of safety and benefits. However, large multi-center studies are needed to fully establish the safety and benefits of different types of exercise. Data indicate that active exercise, adapted to disease activity and disability should be included in the rehabilitation of patients in all stages of IIM. The newly developed and validated outcome measures for patients with polymyositis and dermatomyositis help assess the effects of interventions on disease activity and disability in clinical trials and in clinical practice. However, there are no sensitive and valid outcome measure for patients with inclusion body myositis.

Objective Cardiovascular disease with premature atherosclerosis is common in patients with systemic lupus erythematosus (SLE). We previously identified elevated levels of oxidized low-density lipoprotein (OxLDL) together with elevated levels of autoantibodies related to OxLDL as risk factors for cardiovascular disease in female patients with SLE. Autoantibodies to OxLDL are common in SLE and cross-react with anticardiolipin antibodies (aCL). We therefore hypothesized that lipid peroxidation is enhanced in patients with SLE in general. Methods One hundred forty-seven female patients with SLE and 60 age- and sex-matched controls were compared. A monoclonal antibody to oxidized phospholipids, EO6, was used to determine oxidation epitopes on LDL. Anti-OxLDL and autoantibodies to malondialdehyde (MDA)–modified LDL, cardiolipin, and oxidized aCL were determined by chemiluminescence technique. Results As determined by binding of EO6, patients with SLE had a higher level of oxidized phospholipids on LDL (P = 0.005) compared with controls. The level of OxLDL (e.g., oxidized phospholipid/apolipoprotein B) was associated with arterial disease (P = 0.006) and renal manifestations (P = 0.04). As reported previously, levels of aCL, autoantibodies to OxLDL, and autoantibodies to MDA-modified LDL were enhanced and were closely correlated in SLE. Anticardiolipin antibodies from these SLE patients recognized mainly oxidized forms of cardiolipin, indicating that antigenic epitopes on cardiolipin are related to lipid peroxidation in patients with SLE. Conclusion In general, patients with SLE (particularly those with cardiovascular disease) had more oxidized epitopes on LDL compared with controls. Furthermore, aCL in these patients recognized epitopes generated during lipid peroxidation. Thus, “neo” self antigens on lipoproteins, generated during oxidation, are present in SLE and may be of importance for the development of premature cardiovascular disease and possibly also for other autoimmune phenomena observed in SLE.

Muscular adaptation to physical exercise has previously been described as a repair process following tissue damage. Recently, evidence has been published to question this hypothesis. The purpose of ...

Objectives: To estimate the prevalence and predictors of interstitial lung disease in newly diagnosed polymyositis and dermatomyositis. Methods: A prospective study in which consecutive patients with newly diagnosed poly- and dermatomyositis, regardless of clinical symptoms of pulmonary disease, were investigated with chest x ray, high resolution computed tomography (HRCT), pulmonary function tests, and biochemical and autoantibody analysis. Patients with inclusion body myositis, malignancy, other defined inflammatory connective tissue diseases (CTDs), or antibody profile indicating other CTDs were excluded. Results: Between March 1998 and September 2000, 26 new cases of poly- or dermatomyositis were diagnosed; 17 of those patients were included in the study. Interstitial lung disease (ILD), defined as radiological signs on chest x ray examination/HRCT or restrictive ventilatory defect, were found in 11 (65%) patients and were more common in men than in women. Arthritis and occurrence of anti-Jo-1 antibodies were found more often in patients with ILD than in those without. There was no statistically significant association between respiratory symptoms, other serological or laboratory variables and ILD. Conclusions: ILD is a common early manifestation in patients with poly- and dermatomyositis and is not always related to clinical symptoms. Chest x ray examination, HRCT, pulmonary function tests, and analysis of anti-Jo-1 antibodies should be included in the initial investigation of patients with myositis regardless of respiratory symptoms.

Corticosteroids form the basis of treatment in many inflammatory rheumatic diseases, both as systemic treatment and as treatment with local injections to reduce inflammation. In 1948 the first systemic treatment of a patient with a rheumatic disease was given to a woman with severe rheumatoid arthritis (RA); the impressive effect in this patient, and in another 15 patients, was reported by Dr Hench and co-workers in 1949. Systemic corticosteroid treatment was rapidly adopted and used not only for patients with RA but also for those with other rheumatic diseases such as systemic lupus erythematosus-as well as other disorders such as asthma-with a similar positive effect. In the following year, 1950, the Nobel Prize was awarded for the discovery of the structure and biological effects of the adrenal cortex hormones. This open trial was followed by several controlled trials conducted in the UK in which the effects of cortisone were compared with the effects of aspirin in patients with RA-interestingly, without any significant clinical benefit for the cortisone-treated patients. It was not until 1959, in yet another multi-centre trial in Britain, that a significant effect on functional capacity and general well-being was reported after 2 years of treatment with prednisolone, compared to aspirin, in patients with early RA. Despite the dramatic effects that were observed in the severely ill RA patients reported by Hench and co-workers it took 10 years to demonstrate that this effect was superior to the effect of aspirin when the two compounds were compared in controlled trials. Why was this so? One explanation could be in the study designs and the different outcome measures used in the various studies. Perhaps the results in the first comparative studies would have been different if individual response criteria had been used. This is discussed in this chapter.

Department of Neurology, University Medical Center, Heidelberg laan 100, Utrecht, CX 3584, The Netherlands Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA The Walton Centre for Neurology and Neurosurgery, Liverpool, UK Department of Rheumatology, King’s College Hospital, London, UK Rheumatology Unit, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden King’s Neurosciences Centre, King’s College Hospital, London, UK Institute of Rheumatology, Prague, Czech Republic Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands Department of Clinical Neurosciences, Guy’s, King’s and Thomas’ School of Medicine, London, UK

Objective To investigate how blood lipid levels are related to disease activity, clinical characteristics, and serum levels of tumor necrosis factor α (TNFα) and its soluble type 1 and 2 receptors, sTNFR1 and sTNFR2, in systemic lupus erythematosus (SLE). Methods Fasting blood samples were obtained from an unselected cohort of SLE patients at Karolinska Hospital (n = 208, mean ± SD age 45.7 ± 14.2 years). Disease activity was estimated using the SLE Disease Activity Measure (SLAM). Levels of circulating TNFα, sTNFR1, and sTNFR2 were determined by enzyme-linked immunosorbent assay. Blood lipid levels obtained after overnight fasting were analyzed by routine chemistry. Results Triglyceride (TG) levels were associated with the SLAM score (r = 0.48, P < 0.0001) and with the activities of TNFα (r = 0.29, P = 0.0001), sTNFR1 (r = 0.38, P < 0.0001), and sTNFR2 (r = 0.40, P < 0.0001). High-density lipoprotein (HDL) levels were negatively associated with the SLAM score (r = −0.27, P = 0.0003) and with the activities of TNFα (r = −0.15, P = 0.04) and sTNFR2 (r = −0.19, P = 0.01). High levels of TGs, total cholesterol, TNFα, sTNFR1, and sTNFR2 all showed close correlations with the presence of nephritis and arterial disease (P < 0.05). In multiple logistic regression models, the TNFα activity and TG levels were independent determinants (P = 0.003 for both) of active disease (SLAM score ≥7). Conclusion Dyslipoproteinemia with high TG/low HDL levels correlates with disease activity in SLE, and enhanced activity in the TNFα/sTNFR system seems to be an important underlying factor. Both dyslipoproteinemia and enhanced activity of the TNFα system are closely related to cardiovascular and renal manifestations in SLE, and thus both may serve as markers of more severe disease.

Idiopathic inflammatory myopathies are inflammatory disorders of unknown origin, characterized by muscle weakness. The aim of our study was to establish and characterize an animal model for chronic inflammatory myopathy which would permit investigations of the role of T-cells in chronic myositis as well as of the mechanisms for muscle weakness in chronic inflammatory muscle disorders. CBA/J mice were infected with the protozoan parasite Trypanosoma cruzi. Immunohistochemistry was used to characterize the distribution and composition of inflammatory infiltrates, and demonstrated a chronic focal inflammation comprised mainly of T-cells and macrophages in infected mice. The inflammatory infiltrates were predominantly found in the endomysium and, to a lesser extent, in perivascular areas. CD8+ T-cells were found to have invaded nonnecrotic muscle fibers. Degenerating muscle fibers were also found, as well as an increased number of central muscle nuclei. The murine model described in this article may be useful in studying certain aspects of idiopathic inflammatory myopathies such as the role of T-cells in chronic muscle inflammation and chronic myocytotoxicity. Muscle Nerve 27:442–448, 2003

Objective: To evaluate the safety and effect of a home training program on muscle function in 7 patients with sporadic inclusion body myositis. Design: The patients performed exercise 5 days a week over a 12-week period. Methods: Safety was assessed by clinical examination, repeated muscle biopsies and serum levels of creatine kinase. Muscle strength was evaluated by clinical examination, dynamic dynamometer and by a functional index in myositis. Results: Strength was not significantly improved after the exercise, however none of the patients deteriorated concerning muscle function. The histopathology was unchanged and there were no signs of increased muscle inflammation or of expression of cytokines and adhesion molecules in the muscle biopsies. Creatine kinase levels were unchanged. A significant decrease was found in the areas that were positively stained for EN-4 (a marker for endothelial cells) in the muscle biopsies after training. Conclusion: The home exercise program was considered as not harmful to the muscles regarding muscle inflammation and function. Exercise may prevent loss of muscle strength due to disease and/or inactivity.

The limitations associated with the different approaches into the pathogenesis of the IIM have resulted in incomplete knowledge of disease mechanisms in myositis. In most research, in which muscle tissue was used to study the different aspects of disease, biopsies with inflammatory infiltrates have been selected. Although inflammatory cell infiltrates are a characteristic feature of myositis, selecting patients with inflammatory cell infiltrates for investigations naturally introduces a selection bias. Only a few studies have been published on patients without inflammatory infiltrates but with muscle weakness, and few studies have included follow-up biopsies after different therapies. The heterogeneity of the population of patients with myositis is another limitation of the studies of pathogenic mechanisms. Although most studies classify patients according to the Bohan and Peter criteria [118, 119], some studies used histopathologic criteria [6], and only a few studies included characterization with myositis-specific autoantibodies. Because myositis-specific autoantibodies are often associated with certain clinical profiles, classification according to autoantibody profiles could be important to define differences in the pathogenesis of different phenotypes [3]. From available data on pathogenic mechanisms it is evident that cellular and humoral immune responses are involved in disease mechanisms of myositis, but whether there is a muscle-specific immune response cannot be answered by current studies. It is likely that other mechanisms are important for development of muscle weakness, including metabolic disturbances, and muscle weakness could be caused by different mechanisms in different IIM subsets or in patients in different phases of the disease. There could be early changes, which reversibly affect the metabolism, and later, irreversible changes, that could be dependent on muscle fiber damage and replacement of muscle tissue by connective tissue and fat. Current findings suggest that cytokines, which are produced in muscle tissue from different cell sources including inflammatory cells, endothelial cells, and muscle fibers, could affect muscle function. Careful follow-up studies, including the effect of therapies targeting different molecules on molecular expression in muscle tissue, are likely to increase our knowledge on disease mechanisms. A better understanding of which molecules and mechanisms affect muscle function is likely to lead to improved, less toxic therapies in patients with myositis. Many possible target molecules for blocking therapies, especially the proinflammatory cytokines IL-1 and TNF-alpha, have been identified and should be studied in appropriate clinical settings given the currently poor outcomes of many patients with IIM.

We are grateful for the insightful and highly relevant question raised by Dr Malaviya1 concerning the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. The question concerns autoantibodies, and in particular myositis-specific autoantibodies (MSAs), and why only the anti-Jo-1 autoantibody is included in the new classification criteria. We understand the concern that was raised and we have discussed the limitation of having limited data on MSAs in our publication.2 This letter gives us a possibility to expand on this limitation and include some more explanations. Our study was initiated more than 10 years ago, and during the last decade we have seen a great advancement in the knowledge of autoantibodies specific for and associated with idiopathic inflammatory myopathies (IIM). This includes identification of several new MSAs, as well as advancement in methods used to detect MSAs that have made it possible to …

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

Objective: To assess the risk of cancer in patients with systemic lupus erythematosus (SLE). Methods: A population-based cohort of 5 715 hospitalised SLE patients was followed 1964-1995 through linkage of the Hospital Discharge Register to the National Swedish Cancer Register. Results: In all, 443 malignancies occurred during the observation-period. The overall risk was increased by 25% (SIR = 1.25, CI 95% 1.14-1.37) and lymphomas constituted the major excess risk. The risk of non-Hodgkin's lymphoma (NHL) was nearly 3-fold increased (SIR = 2.86, CI 95% 1.96-4.04). There was also an increased risk of lung cancer (SIR = 1.73, CI 95% 1.25-2.32) and squamous cell skin cancer (SIR = 1.53, CI 95% 0.98-2.28), which was most pronounced at more than 15 years of follow-up. Conclusion: The major finding was a bimodal incidence pattern with an increased risk of lymphoma, mainly NHL, early during follow-up, but lung cancer and squamous skin cancer later on.

Introduction Anti-Jo-1 and anti-Ro52 autoantibodies are common in patients with myositis, but the mechanisms behind their production are not known. Survival of autoantibody-producing cells is dependent on B-cell-activating factor of the tumour necrosis factor family (BAFF). BAFF levels are elevated in serum of anti-Jo-1-positive myositis patients and are influenced by type-I interferon (IFN). IFN-producing cells and BAFF mRNA expression are present in myositis muscle. We investigated expression of the receptors for BAFF in muscle tissue in relation to anti-Jo-1 and anti-Ro52/anti-Ro60 autoantibodies and type-I IFN markers. Methods Muscle biopsies from 23 patients with myositis selected based on autoantibody profile and 7 healthy controls were investigated for expression of BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). Nineteen samples were assessed for plasma (CD138) and B-cell (CD19) markers. The numbers of positive cells per area were compared with the expression of plasmacytoid dendritic cell (pDC) marker blood dendritic cell antigen-2 (BDCA-2) and IFNα/β-inducible myxovirus resistance-1 protein (MX-1). Results BAFF-R, BCMA and TACI were expressed in five, seven and seven patients, respectively, and more frequently in anti-Jo-1-positive and/or anti-Ro52/anti-Ro60-positive patients compared to controls and to patients without these autoantibodies (P = BAFF-R: 0.007, BCMA: 0.03 and TACI: 0.07). A local association of receptors with B and plasma cells was confirmed by confocal microscopy. The numbers of CD138-positive and BCMA-positive cells were correlated (r = 0.79; P = 0.001). Expression of BDCA-2 correlated with numbers of CD138-positive cells and marginally with BCMA-positive cells (r = 0.54 and 0.42, respectively; P = 0.04 and 0.06, respectively). There was a borderline correlation between the numbers of positively stained TACI cells and MX-1 areas (r = 0.38, P = 0.08). Conclusions The expression pattern of receptors for BAFF on B and plasma cells in muscle suggests a local role for BAFF in autoantibody production in muscle tissues of patients with myositis who have anti-Jo-1 or anti-Ro52/anti-Ro60 autoantibodies. BAFF production could be influenced by type-I IFN produced by pDCs. Thus, B-cell-related molecular pathways may participate in the pathogenesis of myositis in this subset of patients. Electronic supplementary material The online version of this article (doi:10.1186/s13075-014-0454-8) contains supplementary material, which is available to authorized users.

To give an update on reported use and effects of biological and physical therapies in patients with myositis.The most promising biological treatment in polymyositis, dermatomyositis and juvenile dermatomyositis is B-cell blockade by rituximab. Anti-Jo or anti-Mi-2 antibodies were predictors of response suggesting different molecular pathways in different subsets of myositis. T-cell blockade with abatacept is a new possibility, as is blockade of interleukin-1, interleukin-6 or type I interferon, but controlled studies are needed. Metabolic abnormalities may contribute to muscle impairment, lending support to combine pharmacological therapy with exercise in patients with polymyositis and dermatomyositis. Exercise improved the aerobic milieu in the muscle, along with improved aerobic capacity, and reduced disability. Support is also provided for the safety of exercise in patients with recent-onset polymyositis and dermatomyositis and exercise is well tolerated in patients with juvenile dermatomyositis.There is a strong need to develop new therapies in patients with myositis. To achieve this, more knowledge is needed on the molecular pathogenesis. Targeted therapies using biologics or exercise can be employed to achieve an improved understanding of molecular pathways, provided that clinical outcome measures are combined with molecular studies on muscle and blood.

With recommended treatment, a majority with idiopathic inflammatory myopathy (IIM) develop muscle impairment and poor health. Beneficial effects of exercise have been reported on muscle performance, aerobic capacity and health in chronic polymyositis and dermatomyositis and to some extent in active disease and inclusion body myositis (IBM). Importantly, randomized controlled trials (RCTs) indicate that improved health and decreased clinical disease activity could be mediated through increased aerobic capacity. Recently, reports seeking mechanisms underlying effects of exercise in skeletal muscle indicate increased aerobic capacity (i.e. increased mitochondrial capacity and capillary density, reduced lactate levels), activation of genes in aerobic phenotype and muscle growth programs, and down regulation in genes related to inflammation. Altogether, exercise contributes to both systemic and within-muscle adaptations demonstrating that exercise is fundamental to improve muscle performance and health in IIM. There is a need for RCTs to study effects of exercise in active disease and IBM.

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.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.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).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.

Objectives Physical activity has been shown to decrease inflammatory markers; here we investigate the effect on the clinical presentation of rheumatoid arthritis (RA). Methods We used the cases from the population-based EIRA study (N=617), followed in the Swedish Rheumatology Quality Register, calculating the odds of having above median level of 28-joint disease activity score (DAS28), physician assessment, pain (visual-analogue scale (VAS), VAS-pain) and activity limitation (health assessment questionnaire (HAQ)) at diagnosis, as an effect of physical activity 5 years before diagnosis, investigated both in categories and dichotomised. Results Dose–response relationships were seen for all measures; the higher the level of physical activity, the lower the likelihood of having outcome measure above median. Further, regular physical activity associated with 42% reduced odds of having DAS28 above median (OR=0.58 (95% CI 0.42 to 0.81)). Effects were similar for VAS-pain (OR=0.62 (95%CI 0.45 to 0.86)) and physician assessment (OR=0.67 (95%CI 0.47 to 0.95)) but not for HAQ. Statistically significant effects were also found both for the combined objective components and the combined subjective components of DAS28. Conclusions Physically active individuals seem to present with milder RA, which adds to the evidence of beneficial effects of physical activity on inflammatory diseases. The observation should be important for both health professionals and individuals seeking to reduce their risk.

The aim of the present study was to develop a 12-week hand exercise intervention for patients with polymyositis (PM) and dermatomyositis (DM) and evaluate adherence, patients' opinions of the programme design and overall feasibility, and the effect on hand function and activity limitation after the intervention.A pilot hand exercise intervention was conducted on a convenience sample of 15 patients with reduced handgrip strength and established, inactive PM and DM. Acceptable adherence was set at 75%. The programme was evaluated based on patients' opinions regarding exertion, the movements involved and overall feasibility. Hand- and pinch-grip strength, grip ability, dexterity and activity limitation were assessed.Eleven of 15 patients completed the intervention, with acceptable adherence of 78-100%. Measures of handgrip strength, dexterity and activity limitation were reduced at baseline compared with normative data from the literature. Throughout the intervention, rates of perceived exertion were scored between 'moderate' and 'fairly strong'. Finger abduction and adduction were excluded from the hand exercise programme because they were not feasible to perform. Repetitions of the exercise increased gradually to a maximum of 30 per movement. Patients regarded this as too time-consuming and suggested ten repetitions daily or 10-20 repetitions 2-4 times per week. There were some individual, clinically meaningful improvements in hand function and activity limitation. A comparison between baseline and after the intervention showed that the three-jaw (tripod) pinch-grip strength (left hand) had increased (p 0.007; z = -2.7).A hand exercise programme was found to be feasible to perform by patients with established PM or DM. The effect was limited, with few individual improvements in hand function and activity limitation, indicating a need to increase the resistance in the movements and to limit the duration of each exercise session.

Muscle atrophy and weakness are often observed in patients with chronic inflammatory diseases, and are the major clinical features of the autoimmune myopathies, polymyositis and dermatomyositis. A general understanding of the pathogenesis of muscle atrophy and the impaired muscle function associated with chronic inflammatory diseases has not been clarified. In this context, arachidonic acid metabolites, such as the prostaglandin and leukotriene subfamilies, are of interest because they contribute to immune and nonimmune processes. Accumulating evidence suggests that prostaglandins and leukotrienes are involved in causing muscular pain and inflammation, and also in myogenesis and the repair of muscles. In this Review, we summarize novel findings that implicate prostaglandins and leukotrienes in the muscle atrophy and weakness that occur in inflammatory diseases of the muscles, with a focus on inflammatory myopathies. We discuss the role of the arachidonic acid cascade in skeletal muscle growth and function, and individual metabolites as potential therapeutic targets for the treatment of inflammatory muscle diseases.

Objective Cardiomyopathy has emerged as a leading cause of death in patients with systemic sclerosis (SSc). However, the pathogenesis of SSc-related cardiomyopathy is poorly understood, and new therapies as well as platforms for testing are needed. The aim of this study was to characterize the histopathologic features of cardiomyopathy in patients with SSc and in common mouse models of SSc. Methods The histopathologic features of myocardial tissue specimens obtained at autopsy from 5 subjects with SSc and 5 control subjects matched for sex, age, and cardiovascular risk factors were evaluated and compared with those of myocardial tissue specimens obtained from 3 common mouse models of SSc with systemic manifestations: Fra-2–transgenic mice, mice with sclerodermatous chronic graft-versus-host disease (GVHD), and TSK-1 mice. Results Myocardial tissue from autopsy subjects with SSc and no clinically manifest cardiac involvement showed endothelial cell apoptosis with reduced capillary density, perivascular inflammation, myofibroblast differentiation, and accumulation of collagen. Only selected features of SSc-related cardiomyopathy were observed in the mice with chronic GVHD and TSK-1 mice. However, the myocardial tissue of Fra-2–transgenic mice mimicked all features of SSc-related cardiomyopathy and also demonstrated comparable vascular, inflammatory, and fibrotic manifestations. Of note, the expression of Fra-2 was also increased in the myocardium of autopsy subjects with SSc. Conclusion We demonstrate that all typical manifestations of SSc-related cardiomyopathy are mimicked in Fra-2–transgenic mice. Moreover, overexpression of Fra-2 in the myocardium of autopsy subjects with SSc may suggest similar underlying pathogenic mechanisms. Thus, Fra-2–transgenic mice might be a suitable preclinical model with which to study the mechanisms of and therapeutic approaches to myocardial involvement in SSc.

The idiopathic inflammatory myopathies (IIMs) represent a complex spectrum of overlapping connective tissue diseases which have skeletal muscle involvement as one of their major components. While recent immunogenetic research has shown that myositis-specific and myositis-associated autoantibodies (MSAs/MAAs) are clearly associated with and thus define many clinical IIM subsets, future research is needed to clarify whether these antibodies (Abs) are just a secondary epiphenomenon, i.e., representing surrogate markers for underlying human leukocyte antigen (HLA) genes and or genotypes, or whether they play some prime role in the immune processes characterizing the IIM. There is increasing evidence suggesting that the IIM disease subtype an individual will get following any environmental triggering event is likely predetermined by their genotype at HLA, and that epistatic genetic interactions in this region critically determine overall disease phenotype, including disease severity and treatment outcomes. It seems clear in inclusion body myositis (IBM), but not yet in other IIM, that HLA gene dosage determines disease severity, again highlighting the importance of epistatic genetic interactions in determining disease characteristics, including outcome. As for rheumatoid arthritis (RA), it appears that HLA genes and the environment interact to modify IIM disease susceptibility. That a specific IIM subtype (necrotizing myopathy characterized by infiltrating macrophages without the usual T and B cells) can be induced in some genetically susceptible individuals by the specific environmental trigger, i.e., the use of certain lipid-lowering statin drugs, suggests that this may represent a potential human model to further study IIM disease-induction mechanisms.

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

Nitric oxide donors and inhaled nitric oxide (iNO) may decrease ischemia/reperfusion injury as reported in animal and human models. We investigated whether the attenuation of reperfusion injury, seen by others, in patients undergoing knee arthroplasty could be reproduced when patients had spinal anesthesia. 45 consecutive patients were randomized into three groups (n=15). Groups 1 and 3 were receiving iNO 80 ppm or placebo (nitrogen, N2) throughout the entire operation, and group 2 only received iNO in the beginning and at the end of the operation. Blood samples were collected before surgery, at the end of the surgery, and 2 hours postoperatively. Muscle biopsies were taken from quadriceps femoris muscle before and after ischemia. There were no increases in plasma levels of soluble adhesion molecules: ICAM, VCAM, P-selectin, E-selectin, or of HMGB1, in any of the groups. There were low numbers of CD68+ macrophages and of endothelial cells expression of ICAM, VCAM, and P-selectin in the muscle analyzed by immunohistochemistry, prior to and after ischemia. No signs of endothelial cell activation or inflammatory response neither systemically nor locally could be detected. The absence of inflammatory response questions this model of ischemia/reperfusion, but may also be related to the choice of anesthetic method EudraCTnr.

Idiopathic inflammatory myopathies, such as polymyositis (PM), may present with general symptoms such as fever and fatigue and only minimal muscle weakness, making it difficult to make a definite diagnosis and provide adequate treatment. Here a case is described in which interstitial lung disease was the first and most prominent manifestation of PM. Later, when muscle weakness became apparent and inflammatory muscle disease was suspected the first muscle biopsy was non-diagnostic. However, magnetic resonance imaging (MRI) scans of the clinically weak thigh muscles showed high signal on T2 weighted images, suggesting muscle inflammation more proximal to the first biopsy site. A second biopsy at this site disclosed typical histopathological findings for myositis. After treatment with prednisolone in combination with cyclophosphamide both pulmonary and muscle function improved. CONCLUSION—MRI scans of muscles may be helpful in selection of a site for muscle biopsy in patients with suspected inflammatory myopathy when a first muscle biopsy turns out to be negative. Additionally, patients with interstitial lung disease of unknown cause should be tested for muscular function to exclude an associated inflammatory muscle disorder.

The idiopathic inflammatory myopathies (IIMs) encompass a group of muscle disorders of unknown origin and pathogenesis characterized by symmetrical, proximal muscle weakness and by inflammatory infiltrates in muscle tissue. The mechanisms behind the loss of muscle function are largely unknown. It is often anticipated that the muscle weakness is caused by the inflammatory cells. However, inflammatory infiltrates are not always present in the muscle tissue and the infiltrates sometimes have a patchy distribution, which makes it difficult to explain the generalized muscle weakness merely by infiltration of inflammatory cells. We investigated patients at different stages of myositis: early myositis without detectable inflammatory infiltrates, active myositis with pronounced inflammatory infiltrates and chronic myositis with persisting muscle weakness but without detectable inflammatory cells in muscle tissues. In these studies, a better correlation was observed between the clinical symptoms and involvement of the capillaries with expression of the cytokine interleukin (IL)-1alpha and by the presence of major histocompatibility complex (MHC) class I expression on muscle fibres. Whether these molecules could affect muscle function is not known. Using phosphorus P-31 magnetic resonance spectroscopy decreased values of adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were observed at rest. These metabolic abnormalities were further accentuated by exercise and increased PCr levels correlated with improved clinical status. The underlying mechanisms responsible for these biochemical abnormalities have not been defined but could be related to a disturbed tissue oxygenation.

To investigate the levels and relationship between IL-10, TNF-alpha, anti-U1snRNP antibodies and disease activity in longitudinally collected serum samples from patients with mixed connective tissue disease (MCTD).Six patients followed for 17-138 months were investigated with ELISA for estimation of cytokine levels and antibodies to the different epitopes of the U1snRNP. Disease activity was assessed by systemic lupus activity measure (SLAM).IL-10 and TNF-alpha levels fluctuated with time in at least half of the patients. Three patients had increased IL-10 levels and two had increased TNF-alpha in all samples. There was no correlation between cytokine levels and disease activity or clinical manifestations. All patients had increased levels of antibodies to the main components of the U1snRNP. Both antibody levels and disease activity decreased with time. A correlation between TNF-alpha and U1snRNP antibody levels were observed in five patients.Increased and fluctuating levels of IL-10 or TNF-alpha without correlation to disease activity were observed in MCTD patients. In some patients increased cytokine levels were observed over several years irrespective of disease activity indicating that they could be constitutively increased in these individuals.

We have described suggestive linkage between microsatellite markers within the cytogenetic region 18q21-23 and SLE, a region where linkage with other autoimmune diseases has also been detected. The Bcl-2 gene located within this region, is a candidate gene because of its role in apoptosis, a physiological mechanism that could be deregulated in autoimmune disease. Furthermore, several studies have found abnormalities of Bcl-2 expression in SLE patients. We therefore sought to determine if the Bcl-2 gene is involved in SLE by studying members of a large cohort of Mexican SLE patients (n = 378) and 112 Swedish simplex families. Using a microsatellite marker and two single nucleotide polymorphisms located within the gene, we were unable to detect association between Bcl-2 and SLE in either population. We also tested whether combinations of alleles of the Bcl-2 and IL-10.G microsatellites would increase the risk for SLE. Our results do not support such hypothesis. Our findings suggest that linkage between SLE and the 18q21-23 region is due to a gene other than Bcl-2.

The objective was to investigate whether a 12-week resistive home exercise program in addition to conventional medical treatment could be safely performed regarding muscle inflammation, muscle function, and quality of life in patients with active polymyositis (PM) or dermatomyositis (DM). Eleven patients diagnosed with active PM or DM were included. Muscle biopsies and Magnetic Resonance Imaging (MRI) of the thighs were performed. Quality of life, function, and subjective global disease impact (SGDI) were assessed and creatine phosphokinase levels (CPK) were analysed. The patients exercised with the exercise program for 15 minutes and took a 15-minute walk five days a week for 12 weeks. After the exercise period there was no sign of increased muscle inflammation. The group showed significantly improved function and quality of life compared to the start of study. It seems that this exercise program safely can be employed in patients with active PM or DM, and we suggest that physical exercise should be included in the rehabilitation of these patients.

Objective. To evaluate the production of interleukin-10 (IL-10) as well as levels of IgG and antinuclear antibodies (ANA) in systemic lupus erythematosus (SLE) patients and their first-degree relatives and spouses in Icelandic SLE multicase families. Methods. IL-10 production was studied by enzyme-linked immunospot assay of freshly isolated peripheral blood mononuclear cells. Total IgG and ANA were also investigated. Subjects consisted of 23 SLE patients and 47 of their first-degree relatives in 9 Icelandic multicase families. Subjects were ethnically matched by a group of healthy controls. A separate study investigated 12 SLE patients (also from SLE multicase families) and their spouses and a matched group of healthy controls. A predefined protocol was used to obtain both clinical and laboratory data, including information about SLE and other autoimmune disorders. Results. The SLE patients had a significantly higher number of IL-10‐producing cells compared with both first-degree relatives and healthy controls (P 5 5 0.0005 and P < < 0.0001, respectively). First-degree relatives also had a significantly higher number of IL-10‐ producing cells compared with healthy controls (P 5 5 0.01). This was also true for the spouses of SLE patients, who had a higher number of IL-10‐producing cells compared with matched healthy controls (P 5 0.02). Conclusion. SLE patients and their first-degree relatives, as well as a limited number of healthy spouses of SLE patients, had increased numbers of spontaneous IL-10‐producing cells. These data support the hypothesis that IL-10 production may be genetically determined, and may predispose one toward development of SLE. This has previously been suggested by studies of SLE patients and their relatives in another ethnic population, using another method for measuring IL-10 production. Although these data are based on a small number of observations, they suggest that not only genetic but also environmental factors may be of importance in determining IL-10 production, since the spouses of SLE patients also had an increased number of IL-10‐producing cells.

The Structural Genomics Consortium (SGC) and its clinical, industry and disease-foundation partners are launching open-source preclinical translational medicine studies.

It is controversial whether mixed connective tissue disease (MCTD) should be regarded as a distinct disease entity. In the present study, we investigated immunological parameters in patients with MCTD by studying serum levels of immunoglobulins, C-reactive protein (CRP) and cytokines and compared the results to the corresponding values in systemic lupus erythematosus (SLE), in rheumatoid arthritis (RA) patients and in healthy controls. Using the ELISA technique, serum levels of the cytokines interferon-gamma (IFN-gamma), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-alpha) were investigated. Cytokine levels in SLE and MCTD were correlated to disease activity as assessed by systemic lupus activity measure (SLAM). They were also correlated to serum levels of CRP, IgG, IgA and IgM in the three patient groups. The MCTD patients had the highest levels of immunoglobulins, followed by the SLE patients. In contrast, the highest CRP levels were observed in RA patients, followed by the MCTD patients. The MCTD patients had the highest serum levels of IL-10, but also had elevated IFN-gamma and TNF-alpha levels similar to the RA patients. There was no correlation between the investigated cytokine levels and disease activity, as assessed by SLAM. We conclude that MCTD patients have high immunoglobulin levels as well as high CRP levels and that this situation is compatible with the observed increase in both type 1 and type 2 cytokine levels. The findings imply that MCTD shares some distinct immunological properties with both RA and SLE and that MCTD may also be considered as a separate disease entity according to these properties.

To examine both possible correlations between anti-Ro/SS-A and anti-La/SS-B levels and their correlation with clinical disease activity in patients with Sjögren's syndrome (SS) or systemic lupus erythematosus (SLE), an ELISA was developed using purified recombinant Ro 60 kDa, Ro 52 kDa and La antigens. The ELISA was used for testing sequential serum samples from 16 patients with either SS or SLE. The patients were followed for periods between 15 and 128 months, and 3-15 serum samples per patient were analysed and compared with clinically apparent disease activity at the time of sampling in 14 patients. A temporal correlation of antibody levels to Ro and La antigens was found, and antibodies to different epitopes of the Ro 60 kDa protein showed parallel variation in seven of eight patients tested. Co-variation of autoantibody levels and disease activity was found in 11 of 14 patients. In seven of these 11 patients the anti-Ro and anti-La levels were stable and changes in disease activity were minimal during the observation period. In the other four of these 11, changes in disease activity were noted, with an associated change in autoantibody levels. The results suggest that the serological response to Ro and La antigens, as well as to different epitopes of the Ro 60 kDa protein, is antigen driven and regulated by common mechanisms, and indicate a correlation of Ro and La antibodies with pathogenic events.

Objective To study cytokine expression in muscle tissues of patients with inflammatory myopathies and to compare the profiles of patients with polymyositis (PM), inclusion body myositis (IBM), and dermatomyositis (DM). Methods We performed indirect immunohistochemistry studies of muscle tissue sections with a panel of 16 different cytokine-specific monoclonal antibodies, directed against interleukin-1alpha, (IL-1alpha), IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-13, interferon-gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor beta1 (TGF beta1), TGF beta2, and TGF beta3 in 5 untreated patients each with PM, DM, and IBM and in 4 normal controls. Fresh frozen muscle tissue sections were fixed in formaldehyde before the procedure. The use of saponin as a detergent to permeabilize the cell membranes enabled identification of intracellular cytokine production. Results The most prominent finding was the expression of IL-1alpha observed in all patients but in none of the normal controls. In all patients with PM, DM, and IBM, IL-1alpha was expressed in endothelial cells of capillaries, arterioles, and venules in areas surrounded by inflammatory cells, and also in areas with no or scarce inflammatory cells in both endomysium and perimysium. Furthermore, IL-1alpha was also expressed in mononuclear inflammatory cells in all 15 cases. IL-1beta was observed in inflammatory cells in 10 of the 15 patients but, in contrast to IL-1alpha, it was not expressed in blood vessel walls. TGF beta1, TGF beta2, and TGF beta3 were strongly positive in all 15 patients, but only scattered cells were positive in the normal controls. The remaining cytokines were observed only in relatively few cells and only in occasional patients (although the patients were selected for the presence of large infiltrates), and in none of the controls. The patterns were similar in PM, DM, and IBM. Conclusion Cytokine expression in muscle tissue of patients with inflammatory myopathy is dominated by IL-1alpha, IL-1beta, and TGF beta1-3. The predominant IL-1alpha expression in the blood vessels indicates an importance of the endothelial cells in the inflammatory process in PM, IBM, and DM. A sustained, local release of T cell-derived cytokines may not be a requirement for tissue injury in the inflammatory myopathies. There does not appear to be a qualitative difference in cytokine expression patterns in PM, IBM, and DM.

The aim of this study was to compare ongoing production of anti-C1q antibodies (anti-C1q) in peripheral blood with serum anti-C1q levels in patients with systemic lupus erythematosus (SLE), especially in patients with nephritis. Using the ELISPOT technique for the detection of IgG and IgA anti-C1q production, 21 patients with active SLE were investigated. ELISAs for IgG and IgA anti-C1q were compared with the ELISPOT results. Six of the patients were found to have proliferative nephritis (WHO grade III/IV) confirmed by renal biopsy. High numbers of IgG anti-C1q spot-forming cells (SFC), defined as > 20/10(5) plated peripheral blood mononuclear cells (PBMC), were exclusively observed in patients with proliferative nephritis (P < 0.0001). Serum levels of IgG anti-C1q were significantly increased in patients with proliferative nephritis (P = 0.039). High ongoing IgG anti-C1q production was observed in all patients with proliferative nephritis, which may be a contributory factor in the pathogenesis of this disorder. The detection of IgG anti-C1q production may be valuable in the clinical investigation of patients with suspected SLE nephritis.

Patients with rheumatoid arthritis (RA), particularly those with severe disease, have increased risk of cardiovascular disease (CVD). Previous studies suggest that endothelial cell activation may contribute to this co-morbidity, and that treatment with tumour necrosis factor (TNF) inhibitors could reduce the risk of CVD in these patients. The aim of this study was to investigate endothelial cell activation markers in muscle tissue of patients after adalimumab treatment.Patients with active RA who started treatment with adalimumab 40 mg every two weeks were included. Muscle biopsies taken before and 3 months after start of treatment were available from 11 patients (9 females, mean age 54.2 years, median disease duration 6.5 years, 91% anti-CCP positive, 7 on methotrexate [median dose 20 mg/week]). None of the patients had clinical signs of myopathy. IL-1α and HLA-DQ were investigated by immunohistochemistry. Quantification was performed by computer assisted image analysis.Disease activity, measured by DAS28 decreased (mean 5.5 vs. 4.1; p=0018). A good or moderate EULAR response was seen in 6/11 patients. HLA-DQ was mainly expressed in endothelial cells in capillaries, whereas IL-1α was mainly seen in larger vessels. HLA-DQ expression decreased significantly after treatment (p=0.041). There was a similar trend for IL-1α, in particlar in EULAR good/moderate responders.Adalimumab treatment was associated with decreased expression of endothelial markers previously associated with severe systemic inflammation in RA. Our findings indicate a reduced endothelial activation in patients treated with anti-TNF drugs, which might contribute to a lower risk of cardiovascular co-morbidity.

ObjectivesTo study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity.Methods55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers’ ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy.ResultsInter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity.ConclusionsThe JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM.

PM and DM are characterized clinically by weakness and low endurance of skeletal muscle. Other organs are frequently involved, suggesting that idiopathic inflammatory myopathies (IIMs) are systemic inflammatory diseases. Involvement of immune mechanisms in IIMs is supported by the presence of T cells, macrophages and dendritic cells in muscle tissue, by the presence of autoantibodies and by HLA-DR being a strong genetic risk factor. T cells may have direct and indirect toxic effects on muscle fibres, causing muscle fibre necrosis and muscle weakness, but the target of the immune reaction is not known. A newly identified T cell subset, CD28(null) T cells, may have cytotoxic effects in the CD4(+) and CD8(+) T cell phenotype. These cells are apoptosis resistant and may contribute to treatment resistance. Several myositis-specific autoantibodies have been identified, but they are all directed against ubiquitously expressed autoantigens and the specificity of the T cell reactivity is not known. These autoantibodies are associated with distinct clinical phenotypes and some with distinct molecular pathways; e.g. sera from patients with anti-Jo-1 autoantibodies may activate the type I IFN system and these sera also contain high levels of B cell activating factor compared with other IIM subsets. The characterization of patients into subgroups based on autoantibody profiles seems to be a promising way to learn more about the specificities of the immune reactions. Careful phenotyping of infiltrating immune cells in muscle tissue before and after specific therapies and relating the molecular findings to clinical outcome measures may be another way to improve knowledge on specific immune mechanism in IIMs. Such information will be important for the development of new therapies.

The purpose of the study was to examine muscle strength and pain sensitivity in postmenopausal women with and without RA.Ten women with and ten without early RA were recruited. All were postmenopausal, and did not use hormone replacement therapy. Measurements of isokinetic muscle strength in knee flexors/extensors, hand grip strength, timed standing, pressure pain thresholds (PPT), suprathreshold pressure pain, and segmental and plurisegmental endogenous pain inhibitory mechanisms during muscle contraction were assessed.Participants with early RA were weaker in knee flexors, in hand grip strength and they needed more time for the timed standing. Women with early RA had higher sensitivity to threshold pain and suprathreshold pressure pain compared to women without RA. PPTs increased in the contracting muscle as well as in a distant resting muscle during static contractions in both groups.Our results indicate differences in muscular strength between postmenopausal women with and without RA. Furthermore, women with RA had decreased PPT and hyperalgesia, but no dysfunction of segmental or plurisegmental pain inhibitory mechanisms during static exercise compared to healthy controls. The normal function of endogenous pain inhibitory mechanisms despite chronic pain in women with RA might contribute to the good effects of physical activity previously reported.

Background The human antimicrobial peptide LL-37, exhibits a variety of biological functions such as activation of plasmacytoid dendritic cells (pDC) to produce type I interferon and mediate tissue damage. In autoimmune diseases such as systemic lupus erythematosus, rheumatic arthritis, and psoriasis LL-37 released by neutrophils is overexpressed at inflammatory sites and may have a role in pathogenesis by induction of type I interferon pathway. Type I interferon pathway is activated in subgroups of patients with idiopathic inflammatory myopathies (IIM). The mechanisms that drive type I interferon in IIM is unclear. We hypothesized that LL-37 in muscle and/or skin may be a factor that can activate type I interferon in these conditions. Objectives The aim of our study was to investigate the expression of LL-37 and type I interferon related proteins (MxA) in the affected organs of patients with polymyositis (PM) and dermatomyositis (DM). Methods Twelve muscle and 5 skin biopsies were obtained from 6 PM and 6 DM patients. Additional 3 skin biopsies taken from non-affected skin in 3 of DM patients. Five muscle and 7 skin biopsies from healthy subjects were selected as controls (HC). Immunohistochemistry staining of LL-37, CD66b (neutrophil), MxA (type I interferon), BDCA-2 (pDC), CD68 and CD163 (both macrophage markers) were performed in all muscle and skin specimens. Western blot (WB) was utilized to confirm the expression of LL-37 in muscle and skin tissues. Co-localization of LL-37 and neutrophils in muscle and skin tissue was confirmed by double-staining. The relationship of the markers were analyzed and compared with the clinical features of PM/DM patients. Results The expression of LL-37, CD66b, BDCA-2, and MxA in muscle as well as in skin tissue was significantly higher in PM/DM patients when compared to HC (P Conclusions The presence of the antimicrobial peptide LL-37 in affected muscle and skin tissues of patients with PM and DM together with the correlation of expression of LL-37 to the type I inducible protein MxA might indicate a role of LL-37 as an inducer of interferon production in patients with PM and DM. Thus, LL-37 may be involved in the pathogenesis of these diseases. References Hoffmann MH, Bruns H, Backdahl L, et al. The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats. Ann Rheum Dis. 2013 Jul;72(7):1239–48. Disclosure of Interest None declared

Background Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy characterized by an auto-inflammatory immune response in muscle and skin. Multiple lines of evidence suggest Toll-like receptors (TLRs), central components of the innate immune system, play a key role in DM pathogenesis. A retrospective study evaluating muscle biopsy samples showed that TLR9, TLR4 and TLR2 were significantly over-expressed in skeletal muscle and infiltrating cells in DM subjects compared to controls. Over-expression of type I and type II interferons and other cytokines has been demonstrated in DM, suggesting involvement of the NF-κβ pathway. Expression of certain cytokines also had significant positive correlations with expression of TLR9 and TLR4. IMO-8400 is an investigational oligonucleotide-based antagonist of TLRs 7, 8 and 9 that has demonstrated clinical activity in patients with psoriasis. We hypothesize that inhibition of TLR activity in patients with DM with IMO-8400 has the potential to reduce chronic inflammation in affected tissue. Objectives Our objective was to design a Phase 2 clinical trial of IMO-8400 in DM patients using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) as the primary efficacy endpoint. Specifically, we wished to estimate the placebo response for the CDASI and calculate optimal treatment effect in order to estimate optimal subject numbers and length of trial. Methods Retrospective analyses were conducted using longitudinal CDASI assessments for 115 unique DM patients seen at the Stanford University outpatient dermatology clinic. Patients with multiple assessments approximately 12 or 24 weeks apart were grouped by the first visit CDASI activity score ( Results Over 24 weeks, a 5 point or greater decrease in CDASI activity score was observed at 31.8% of patient visits, with the change in CDASI activity score ranging from -23 to +27 points across all patients. Because some patients experienced clinically meaningful changes of 4 to 5 points on the CDASI following treatment with standard of care therapies, a 7 point treatment effect was targeted for the IMO-8400 trial. Sample size calculations resulted in 10 patients per treatment group, assuming a standard deviation of 8.5 points over 24 weeks using a Repeated Measures Mixed Model analysis of change from baseline on monthly CDASI assessments (>80% power on a 1-sided test; alpha=0.05). Conclusions Based on these analyses, we initiated a double-blind, placebo-controlled, 24-week Phase 2 clinical trial in DM patients (NCT number: NCT02612857). Key entry criteria include adults with DM aged 18–75 years, CDASI activity score ≥15, clinical symptoms of active muscle disease, and abnormal serum CK or ALD, EMG, muscle biopsy or MRI. Additional outcome measures include MMT-8, timed function tests including 10-meter run walk, and exploratory biomarkers of disease activity. Disclosure of Interest P. Gordon Grant/research support from: Idera Pharmaceuticals, Inc., R. Cooper Grant/research support from: Idera Pharmaceuticals, Inc., H. Chinoy Grant/research support from: Idera Pharmaceuticals, Inc., D. Isenberg Consultant for: Idera Pharmaceuticals, Inc., I. Lundberg Consultant for: Idera Pharmaceuticals, Inc., V. Werth Consultant for: Idera Pharmaceuticals, Inc., K. Gruis Employee of: Idera Pharmaceuticals, Inc., M. Hurtt Employee of: Idera Pharmaceuticals, Inc., J. Brevard Employee of: Idera Pharmaceuticals, Inc., L. Granlund Employee of: Idera Pharmaceuticals, Inc., D. Fiorentino Grant/research support from: Idera Pharmaceuticals, Inc., Consultant for: Idera Pharmaceuticals, Inc.

Background Histidyl-transfer RNA synthetase (HisRS) is a major autoantigen in myositis with lung involvement 1–4 . Simultaneous presence of anti-HisRS and anti-Ro52 antibodies has been demonstrated in patients with myositis 5–7 . Objectives We investigated the presence of HisRS in the extracellular compartments plasma, sera and bronchoalveolar lavage fluid (BAL). In addition, the occurrence of anti-HisRS antibody isotypes as well as other auto-reactivities was evaluated in BAL and sera from patients with myositis. Methods HisRS was measured in sera, plasma and BAL from myositis (anti-HisRS antibody positive, anti-Jo1+ and negative, anti-Jo1-), sarcoidosis, rheumatoid arthritis (RA) patients and healthy controls (HC) by dot-blot, western-blot, immunoprecipitation and mass spectrometry. The presence in BAL and sera of anti-Jo1 isotypes and other ANA-associated autoantibodies was analysed by ELISA and addressable laser bead immunoassay. Results HisRS was detected in sera, plasma and BAL of patients with myositis, sarcoidosis and RA and in HC. HisRS systemic levels were elevated in anti-Jo1+ myositis (14 out of 20 sera) compared to anti-Jo1- myositis (10/18), sarcoidosis (0/8) and RA (3/15) patients, and HC (5/23). In BAL, significant levels of HisRS were detected in 6/8 HC and 5/8 sarcoidosis, compared to 4/8 myositis (2 anti-Jo1+ and 2 anti-Jo1-). Our results demonstrated the presence of a factor in BAL with high binding capacity for HisRS and HisRS complexed with anti-HisRS-N-terminal antibody. C1q-binding immune complexes (IC) containing HisRS were not the binding factor. However, anti-Jo1 isotypes as well as anti-Ro52 IgG were identified in both BAL (5/8 patients were positive for anti-Jo1 IgG, 3/8 for anti-Jo1 IgA, 3/8 for anti-Jo1 IgM and 4/8 for anti-Ro52 IgG) and sera (5/8 for anti-Jo1 IgG, 3/8 for anti-Jo1 IgA, 4/8 for anti-Jo1 IgM and 3/8 for anti-Ro52 IgG) from patients with myositis. Furthermore, a positive correlation between the presence of anti-Jo1 IgG and anti-Ro52 IgG in BAL was identified (r 2 =0,881; p=0,007). Conclusions HisRS was detected both in blood and BAL fluid. The identification of extracellular HisRS, anti-Jo1 isotypes and anti-Ro52 in myositis BAL may provide additional clues for the development of autoimmunity in the lungs. References Bernstein RM., et al. Br Med J (Clin Res Ed). 1984 Jul 21;289(6438):151–2; Marguerie C., et al. Q J Med. 1990 Oct;77(282):1019–38; Hervier B., et al. Eur Respir J. 2013 Nov;42(5):1271–82; Hamaguchi Y., et al. PLoS One. 2013;8(4):e60442; La Corte R., et al. Autoimmunity. 2006 May;39(3):249–53; Brouwer R., et al. Ann Rheum Dis. 2001 Feb;60(2):116–23; Rutjes SA., et al. Clin Exp Immunol. 1997 Jul;109(1):32–40. Disclosure of Interest None declared

Background and objectives Upregulation of type I IFN response genes is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). While IFNα contributes to SLE pathology, IFNβ therapy is beneficial in MS, implying different immunoregulatory roles for these IFNs. This study aimed to investigate potential diversification of IFNα-and IFNβ-mediated response programs in autoimmune diseases. Materials and methods Peripheral blood gene expression of 23 prototypical type I IFN response genes (IRGs) was determined in healthy controls (HCs, n = 54), SLE (n = 47), IFNβ-treated MS (n = 71), untreated MS (n = 160), IIM (n = 78) and RA patients (n = 76). An IFN score was calculated and patients with a type I IFN signature (IFN score >mean+2SD in HC) were selected for analysis. Results We identified IFNα- and IFNβ-specific response programs by comparing IRG expression in SLE (IFNα-mediated) and IFNβ-treated MS patients. Statistical testing revealed increased expression of 5 IRGs in SLE (Gene cluster (GC-)A, p ≤ 0.006) and 13 IRGs in IFNβ-treated MS (Gene cluster (GC-)B, p ≤ 0.044). Concordantly, the GC-A/GC-B log-ratio was positive for all SLE patients and negative for virtually all IFNβ-treated MS patients. Applying this information to other autoimmune diseases, IIM patients displayed positive GC-A/GC-B log-ratios, indicating predominant IFNα activity. The GC-A/GC-B log-ratios in RA were lower and approached zero in part of the patients, implying relative importance of both clusters. Remarkably, GC-A/GC-B log-ratios appeared most heterogeneous in IFNβ-naive MS; half of the patients displayed GC-A dominance, whereas others showed GC-B dominance or log-ratios near zero. We confirmed these results for SLE, RA and MS using two public microarray datasets containing 22 SLE patients, 112 RA patients, 58 IFNβ-treated MS patients and 62 untreated MS patients. Exploring functional differences between GC-A and GC-B genes revealed enrichment of the ISGF3-binding response element ISRE and IRF8 binding sites only in GC-B, suggesting that IFNβ is more potent in activating these transcription factors than IFNα. Conclusions Conclusively, we demonstrated that type I IFN signatures in autoimmune diseases appear less uniform than generally assumed. The diversification of the type I IFN response in autoimmune diseases suggests different pathogenic roles of the type I IFNs.