Responsiveness and meaningful thresholds of PROMIS pain interference, fatigue, and physical function forms in adults with idiopathic inflammatory myopathies: Report from the OMERACT Myositis Working Group.

BACKGROUND: A series of qualitative studies conducted by the OMERACT Myositis Working Group identified pain interference, fatigue, and physical function as highly important life impact domains for adults with idiopathic inflammatory myositis (IIM). In this study, our goal was to assess the responsiveness and minimal important difference of PROMIS pain interference (6a), fatigue (7a), and physical function (8b). METHODS: Adults with IIM from USA, Netherlands, Korea, Sweden, and Australia with two "clinical" visits were enrolled in this prospective study. Anchor questions on a Likert scale were collected at baseline, and manual muscle testing (MMT), physician and patient reported global disease activity, and PROMIS instruments were collected at both visits. Responsiveness was assessed with i) ANOVA, ii) paired t-test, effect size and standardized response mean, and iii) Pearson correlation. Minimal important difference (MID), minimal important change (MIC) and minimal detectable change (MDC) values were calculated. RESULTS: 114 patients with IIM (median age 60, 60 % female) completed both visits. Changes in PROMIS instruments were significantly different among anchor categories. Patients who reported improvement had a significant improvement in their PROMIS scores with at least medium effect size, while patients who reported worsening and stability did not show a significant change with weak effect size. PROMIS instruments had weak to moderate correlations with MMT, patient and physician global disease activity. MID was approximately 2-3 points for Pain Interference and 3-4 points for Fatigue and Physical Function forms based on the method used. MIC was approximately 4-5 for improvement of all the instruments, while MDC was 1.7-2 points for Pain Interference and Physical Function and 3.2-3.9 for Fatigue. CONCLUSION: This study provides evidence towards the responsiveness of the PROMIS instruments in a large international prospective cohort of adults with IIM supporting their use as PROMs in adult myositis.

Evaluation of an individually tailored smoking-cessation intervention for patients with rheumatoid arthritis in an outpatient clinic.

OBJECTIVE: The aim of this study was to evaluate an individually tailored smoking-cessation intervention delivered in rheumatology care and compare the characteristics of patients who quit smoking with those who did not. METHOD: This was an open single-group prospective intervention study over 24 months, with assessments at baseline and at 6, 12, 18, and 24 months. Current smokers with rheumatoid arthritis (RA) were invited to a smoking-cessation programme including behavioural change support, with or without pharmacotherapy. Data on disease activity, medical treatment, and patient-reported outcomes were retrieved from the Swedish Rheumatology Quality Register. The primary outcome was the proportion of patients at month 24 who reported having quit smoking with self-reported 7 day smoking abstinence. RESULTS: In total, 99 patients participated in the study. Median age was 58 years (interquartile range 50-64); 69% were female and 88% rheumatoid factor and/or anti-cyclic citrullinated peptide positive. At 24 months, 21% of the patients had quit smoking. At 6, 12, and 18 months, 12%, 12%, and 14% of patients, respectively, had quit smoking. For patients still smoking at 24 months, the median number of cigarettes per day was significantly reduced from 12 to 6 (p ≤ 0.001). Among patients who had quit smoking at 24 months, a smaller proportion reported anxiety at baseline compared to those still smoking (28% vs 58%, p = 0.02). CONCLUSION: A smoking-cessation intervention including behavioural change support with or without pharmacotherapy can be helpful for a substantial number of RA patients. Anxiety is associated with lower smoking-cessation success rates.

Evaluation of risk factors and biomarkers related to arterial and venous thrombotic events in idiopathic inflammatory myopathies.

Objectives: This study aimed to assess the contribution of traditional/disease-related risk factors and biomarkers linked to arterial and venous thrombotic events (TEs) in patients with idiopathic inflammatory myopathies (IIMs).Method: The occurrence of arterial and/or venous TEs at the time of or after IIM diagnosis was retrospectively evaluated in a cohort of 253 patients with IIMs, resulting in a final population of 246 IIM patients, 51 with reported TE (cases) and 195 without a history of TE (comparators). Information on disease characteristics and traditional risk factors for arterial and venous TE (essential hypertension, diabetes, dyslipidaemia, smoking, malignancy) was retrieved. Serum levels of anti-phospholipid antibodies (aPLs) and adhesion molecules were analysed at the time of IIM diagnosis and at the time of the TE in cases.Results: One in five IIM patients (21%) had experienced a TE, arterial TE in 22 and venous TE in 29 patients, with a peak prevalence within 5 years after diagnosis. Among traditional/disease-related risk factors, only older age was associated with both arterial and venous TEs, after adjusting for other covariates. Low serum levels of e-selectin were associated with higher odds of developing a TE, without specific association with either arterial or venous TEs. Only 6% of IIM patients had aPLs, with no significant difference between cases and comparators.Conclusions: An increased risk of both venous and arterial TEs should be considered in IIM patients, particularly close to diagnosis and in elderly people. Low serum levels of e-selectin may predict TE in IIM patients, but the underlying biological mechanism is not known.

Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients.

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

Enhanced ventricular-arterial coupling during a 2-year physical activity programme in patients with rheumatoid arthritis: a prospective substudy of the physical activity in rheumatoid arthritis 2010 trial.

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 2 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 (ß = 0.68; P = 0.004), whereas lower aerobic working capacity was associated with left ventricular diastolic dysfunction (ß = 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 2 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 patients with RA.

Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis.

OBJECTIVES: Autoantibodies 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 METHODS: Data 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. RESULTS: Data 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. INTERPRETATION: Differences 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.

Diagnosis and classification of idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases, collectively termed myositis, sharing symptoms of muscle weakness, fatigue and inflammation. Other organs are frequently involved, supporting the notion that these are systemic inflammatory diseases. The IIMs can be subgrouped into dermatomyositis, polymyositis and inclusion body myositis. The myositis-specific autoantibodies (MSAs) identify other and often more distinct clinical phenotypes, such as the antisynthetase syndrome with antisynthetase autoantibodies and frequent interstitial lung disease 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 interstitial lung disease. Another cornerstone in the diagnostic procedure is muscle biopsy to identify inflammation and to exclude noninflammatory myopathies. Treatment effect and prognosis vary 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 IIMs, which are summarized in this review; the historical background regarding previous diagnostic and classification criteria is also reviewed. As the IIMs are rare diseases with a prevalence of 10 in 100 000 individuals, an international collaboration was essential, as was the interdisciplinary effort including experts in adult and paediatric rheumatology, neurology, dermatology and epidemiology. The new criteria have been developed based on data from more than 1500 patients from 47 centres worldwide and are based on clinically easily available variables.

Autoantibody Specificities and Type I Interferon Pathway Activation in Idiopathic Inflammatory Myopathies.

Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN-inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti-IFNAR or anti-IFN-α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA-binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti-IFNAR or anti-IFN-α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA-binding proteins and with autoantibody multispecificity. These studies identify IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN-α as a possible target for therapy in these patients.

Effects of a one-year physical activity programme for women with systemic lupus erythematosus - a randomized controlled study.

OBJECTIVES: To study the effects of a one-year physical activity programme on aerobic capacity, physical activity and health-related quality of life (HRQL) in patients with systemic lupus erythematosus (SLE) by a randomized control design. METHODS: Thirty-five women with low or moderate disease activity and organ damage were randomized to intervention (I) or control (C) group. The intervention during months 0-3 consisted of education, supervised aerobic exercise at high intensity and individual coaching, as well as self-managed physical activity at low-to-moderate intensity. During months 4-12, the physical activity was self-managed and the coaching was successively reduced over time. Outcome measures included: maximal oxygen uptake (VO2 max) from a bicycle ergometer test, self-reported physical activity and HRQL (SF-36). RESULTS: VO2 at sub-max. and max. increased, independent of group, during the one-year study period (main effect of time p < 0.0001). VO2 max. increased between baseline and month 3 (p < 0.0001), between months 3 and 6 (p = 0.01) and the increase was sustained at month 12 (ns). Frequency of physical activity at high intensity also increased, independent of group, during the study period. It was increased at months 3, 6 and 12 compared to baseline (p = 0.02, p < 0.001, p = 0.03). Improvement in mental health between baseline and month 6 (p = 0.002) was seen for the I-group, not the C-group (p = 0.03). Disease activity and organ damage did not change. CONCLUSIONS: Physical activity and aerobic capacity increased after supervised exercise and coaching, and the improvement was sustained during the one-year programme. However, no interactions between the group differences were seen, which suggests that repeated measurements could motivate to increased physical activity and thereby to increased aerobic capacity. As sub-max. VO2 increased over time, training-induced changes in VO2 on-kinetics could be another explanation. Little influence on HRQL was seen after the programme. The study indicates that physical activity at high intensity over one year is tolerated by patients with mild to moderate SLE.

Cardiac Abnormalities in Adult Patients With Polymyositis or Dermatomyositis as Assessed by Noninvasive Modalities.

OBJECTIVE: Cardiac events are a major cause of death in patients with idiopathic inflammatory myopathies. The study objective was in a controlled setting to describe cardiac abnormalities by noninvasive methods in a cohort of patients with polymyositis (PM) or dermatomyositis (DM) and to identify predictors for cardiac dysfunction. METHODS: In a cross-sectional study, 76 patients with PM/DM and 48 matched healthy controls (HCs) were assessed by serum levels of cardiac troponin I, electrocardiography, Holter monitoring, echocardiography with tissue Doppler imaging, and quantitative cardiac (99m) Tc-pyrophosphate ((99m) Tc-PYP) scintigraphy. RESULTS: Compared to HCs, patients with PM/DM more frequently had left ventricular diastolic dysfunction (LVDD) (12% versus 0%; P = 0.02) and longer QRS and QT intervals (P = 0.007 and P < 0.0001, respectively). In multivariate analysis, factors associated with LVDD were age (P = 0.001), disease duration (P = 0.004), presence of myositis-specific or -associated autoantibodies (P = 0.05), and high cardiac (99m) Tc-PYP uptake (P = 0.006). In multivariate analysis of the pooled data for patients and HCs, a diagnosis of PM/DM (P < 0.0001) was associated with LVDD. CONCLUSION: Patients with PM or DM had an increased prevalence of cardiac abnormalities compared to HCs. LVDD was a common occurrence in PM/DM patients and correlated to disease duration. In addition, the association of LVDD with myositis-specific or -associated autoantibodies and high cardiac (99m) Tc-PYP uptake supports the notion of underlying autoimmunity and myocardial inflammation in patients with PM/DM.

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

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

Determination of the minimal clinically important difference for seven measures of fatigue in Swedish patients with systemic lupus erythematosus.

OBJECTIVE: To estimate the minimal clinically important difference (MCID) in seven self-administered measures assessing fatigue in Swedish patients with systemic lupus erythematosus (SLE). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

The autoimmune spectrum of myasthenia gravis: a Swedish population-based study.

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.

Correlation between serum levels of IL-15 and IL-17 in patients with idiopathic inflammatory myopathies.

OBJECTIVES: 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-1ß. Possible correlations with disease activity parameters were also evaluated. METHOD: 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. RESULTS: At baseline, serum levels of IL-15, IL-17, MCP-1, and MIP-1ß 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). CONCLUSIONS: 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.

Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study.

OBJECTIVES: HLA-DRB1*03 is strongly associated with anti-Jo-1-positive idiopathic inflammatory myopathies (IIM) and there is now increasing evidence that Jo-1 antigen is preferentially expressed in lung tissue. This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive IIM. METHODS: IIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specific oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation. RESULTS: 557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1-positive IIM cases, and reached statistical significance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p<0.0001). A strong association between HLA-DRB1*03 and anti-Jo-1 status was observed across all four cohorts (DRB1*03 frequency: 74% Jo-1-positive vs 35% Jo-1-negative, OR 5.55, 95% CI 3.42 to 9.14, p<0.0001). The frequency of HLA-DRB1*03 was increased in smokers. The frequency of anti-Jo-1 was increased in DRB1*03-positive smokers vs DRB1*03-negative non-smokers (42% vs 8%, OR 7.75, 95% CI 4.21 to 14.28, p<0.0001) and DRB1*03-positive non-smokers (42% vs 31%, p=0.08). In DRB1*03-negative patients, anti-Jo-1 status between smokers and non-smokers was not significantly different. No significant interaction was noted between smoking and DRB1*03 status using anti-Jo-1 as the outcome measure. CONCLUSION: Smoking appears to be associated with an increased risk of possession of anti-Jo-1 in HLA-DRB1*03-positive IIM cases. The authors hypothesise that an interaction between HLA-DRB1*03 and smoking may prime the development of anti-Jo-1 antibodies.

KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis.

OBJECTIVES: To investigate whether Caucasian patients with polymyositis (PM) or dermatomyositis (DM) and interstitial lung disease (ILD) have elevated serum levels of KL-6 compared with patients without ILD and whether KL-6 could be used as a marker for ILD activity and treatment efficacy of ILD in PM/DM. DESIGN AND METHODS: Thirty patients with PM/DM (seven with ILD) and 17 age- and sex-matched healthy controls were included in a retrospective, cross-sectional analysis. Twelve patients were followed for longitudinal evaluation. ILD was defined as restrictive lung function impairment with radiographic signs of ILD. Serum KL-6 levels were measured using a sandwich enzyme immunoassay kit. Groups were compared by Mann-Whitney U-test. RESULTS: PM/DM patients with ILD had significantly higher median serum KL-6 levels compared with those without ILD: 995 (range 533-2318) versus 322 (range 132-1225) U mL(-1) (P = 0.0002). Median serum levels of healthy controls were 225 (range 136-519) U mL(-1) . Serum levels of KL-6 were inversely correlated with percentages of forced expiratory volume in 1 s (FEV1), vital capacity (VC), total lung capacity (TLC), forced VC, diffusing capacity of carbon monoxide (DLco), maximal voluntary ventilation at 40 breaths min(-1) and residual volume (RV). Changes in KL-6 levels showed a significant inverse correlation with changes in percentage FEV1, TLC, DLco and RV. At a cut-off level of 549 U mL(-1) (mean ± 2.5 SD for controls), the sensitivity and specificity for diagnosis of ILD were 83% and 100%, respectively. CONCLUSION: The level of serum KL-6 may serve as measure of ILD in patients with PM/DM and is a promising biomarker for use in clinical practice to assess clinical response to treatment.

Can muscle regeneration fail in chronic inflammation: a weakness in inflammatory myopathies?

Idiopathic inflammatory myopathies (IIMs), collectively termed myositis, include three major subgroups: polymyositis, dermatomyositis and inclusion body myositis. IIMs are characterized clinically by muscle weakness and reduced muscle endurance preferentially affecting the proximal skeletal muscle. In typical cases, inflammatory cell infiltrates and proinflammatory cytokines, alarmins and eicosanoids are present in muscle tissue. Treatment with glucocorticoids and other immunosuppressants results in improved performance, but complete recovery is rarely seen. The mechanisms that cause muscle weakness and reduced muscle endurance are multi-factorial, and different mechanisms predominate in different phases of disease. It is likely that a combination of immune-mediated and nonimmune-mediated mechanisms contributes to clinical muscle symptoms. Immune-mediated mechanisms include immune cell-mediated muscle fibre necrosis as well as direct effects of various cytokines on muscle fibre contractility. Among the nonimmune-mediated mechanisms, an acquired metabolic myopathy and so-called endoplasmic reticulum stress may be important. There is also a possibility of defective repair mechanisms, with an influence of both disease-related factors and glucocorticoid treatment. Several proinflammatory molecules observed in muscle tissue of myositis patients, including interleukin (IL)-1, IL-15, tumour necrosis factor, high-mobility group box-1 and eicosanoids, have a role in muscle fibre regeneration, and blocking these molecule may impair muscle repair and recovery. The delicate balance between immunosuppressive treatment to downregulate proinflammatory molecules and an inhibitory effect on muscle fibre regeneration needs to be further understood. This would also be relevant for other chronic inflammatory diseases.

Higher proportion of fast-twitch (type II) muscle fibres in idiopathic inflammatory myopathies - evident in chronic but not in untreated newly diagnosed patients.

OBJECTIVE: Polymyositis and dermatomyositis are idiopathic, inflammatory myopathies characterized by proximal muscle fatigue. Conventional immunosuppressive treatment gives a variable response. Biopsies from chronic patients display a low proportion type I and a high proportion of type II muscle fibres. This raised a suspicion that the low proportion of type I fibres might play a role in the muscle fatigue. AIM: To investigate whether the muscle fibre attributes evident in chronic myositis are characteristic for the polymyositis and dermatomyosistis diseases themselves. METHODS: Muscle biopsies were obtained from thigh muscle from untreated patients (n = 18), treated responders (n = 14) and non-responders (n = 6) and from healthy controls (n = 11), respectively. For clinical evaluations, creatine kinase, functional index of myositis and cumulative dose of cortisone were established. RESULTS: Chronic patients had a lower proportion of type I fibres and a higher proportion of type II fibres compared to untreated myositis patients and healthy controls. Fibre cross-sectional area (CSA) did not differ between patients and healthy individuals but all women had a 20% smaller type II fibre CSA compared to men. CONCLUSIONS: Untreated polymyositis and dermatomyositis patients and healthy controls have a different fibre type composition than chronic polymyositis and dermatomyositis patients. Fibre CSA did not differ between healthy controls or any of the patient groups. A low proportion of oxidative muscle fibres can therefore be excluded as a contributing factor causing muscle fatigue at disease onset and the gender difference should be taken into consideration when evaluating fibre CSA in myositis.