Anti-FHL1 autoantibodies in adult patients with myositis: a longitudinal follow-up analysis.

OBJECTIVES: To determine prevalence and clinical associations of anti-FHL1 autoantibodies in patients with idiopathic inflammatory myopathies (IIM), and to evaluate autoantibody levels over time. METHODS: Sera at the time of diagnosis from patients with IIM (n = 449), autoimmune disease controls (DC, n = 130), neuromuscular diseases (NMD, n = 16) and healthy controls (HC, n = 100) were analyzed for anti-FHL1 autoantibodies by Enzyme-Linked ImmunoSorbent Assay (ELISA). Patients with IIM FHL1+ and FHL1- were included in a longitudinal analysis. Serum levels were correlated to disease activity. RESULTS: Autoantibodies to FHL1 were more frequent in patients with IIM (122/449, 27%) compared with DC (Autoimmune DC and NMD, 13/146, 9%, p< 0.001) and HC (3/100,3%, p< 0.001). Anti-FHL1 levels were higher in IIM [median (IQR)=0.62 (0.15-1.04)] in comparison with DC [0.22 (0.08-0.58)], HC [0.35 (0.23-0.47)] and NMD [0.48 (0.36-0.80)] p< 0.001. Anti-FHL1+ patients with IIM were younger at time of diagnosis compared with the anti-FHL1- group (p= 0.05) and were seronegative for other autoantibodies in 25%.In the first follow-up anti-FHL1+ sample 20/33 (60%) positive at baseline had turned negative for anti-FHL1 autoantibodies. Anti-FHL1 autoantibodies rarely appeared after initiating treatment. Anti-FHL1 autoantibody levels correlated with CK (r = 0.62, p= 0.01), disease activity measure MYOACT (n = 14, p= 0.004) and inversely with manual muscle test-8 (r=-0.59, p= 0.02) at baseline. CONCLUSIONS: Anti-FHL1 autoantibodies were present in 27% of patients with IIM, of these 25% were negative for other autoantibodies. Other autoimmune diseases had lower frequencies and levels. Anti-FHL1 levels often decreased with immunosuppressive treatment, correlated with disease activity measures at diagnosis and rarely appeared after start of treatment.

Extracorporeal Membrane Oxygenation for Acute Lung Injury in Idiopathic Inflammatory Myopathies-A Potential Lifesaving Intervention.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) can present with acute IIM-related lung injury and respiratory failure, leading to a high mortality risk in intensive care units (ICU). Extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome can be lifesaving. We aimed to report a case series of IIM patients that received ECMO. METHODS: Patients with IIM from tertiary care centers in Belgium, Canada, Denmark, United States, and Sweden who underwent ECMO were reviewed to describe clinical characteristics, disease outcomes and hospitalization course. Clinical characteristics at admission and during ICU stay including ECMO complications and mortality causes were summarized. RESULTS: The study included 22 patients (50% female, mean±SD age at admission 47 ± 12 years) with anti-MDA5 positive dermatomyositis (68%), anti-synthetase syndrome (14%), polymyositis (9%), overlap myositis (5%) and non-MDA5 dermatomyositis (5%). Patients had low comorbidity scores and 46% had received immunosuppression before their ICU admission. Eight (36%) patients died in the ICU, six (27%) were bridged to recovery and eight (36%) were bridged to transplant. When comparing patients bridged to recovery and those who died in the ICU, those who died were older (p= 0.03) and had higher median Charlson comorbidity index scores (p= 0.05). Both groups had similar frequencies of ECMO-related complications (33% vs 50%, p= 0.94). CONCLUSION: In the patients exposed to ECMO in this case series, 14 were successfully bridged to recovery or transplant, while 8 died in the ICU. Large studies are needed to collect data on clinical outcomes in patients with IIM-ILD exposed to ECMO to identify the best candidates for the intervention.

Patient global assessment and inflammatory markers in patients with idiopathic inflammatory myopathies - A longitudinal study.

AIM: To explore if patient global assessment (PGA) is associated with inflammation over time and if associations are explained by other measures of disease activity and function in patients with idiopathic inflammatory myopathies (IIM). METHODS: PGA and systemic inflammatory markers prospectively collected over five years were retrieved from the International MyoNet registry for 1200 patients with IIM. Associations between PGA, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and creatine kinase (CK) were analyzed using mixed models. Mediation analysis was used to test if the association between PGA and inflammatory markers during the first year of observation could be explained by measures of disease activity and function. RESULTS: PGA improved, and inflammatory markers decreased during the first year of observation. In the mixed models, high levels of inflammatory markers were associated with worse PGA in both men and women across time points during five years of observation. In men, but not in women, the association between elevated ESR, CRP and poorer PGA was explained by measures of function and disease activity. With a few exceptions, the association between improved PGA and reduced inflammatory markers was partially mediated by improvements in all measures of function and disease activity. CONCLUSION: Increased levels of systemic inflammation are associated with poorer PGA in patients with IIM. In addition to known benefits of lowered inflammation, these findings emphasize the need to reduce systemic inflammation to improve subjective health in patients with IIM. Furthermore, the results demonstrate the importance of incorporating PGA as an outcome measure in clinical practice and clinical trials.

Single-cell profiling of muscle-infiltrating T cells in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM) are rare autoimmune systemic diseases characterized by muscle weakness and the presence of muscle-infiltrating T cells. IIM represent a clinical challenge due to heterogeneity of symptoms and variability of response to immunosuppressive treatment. Here, we performed in-depth single-cell sequencing on muscle-infiltrating T cells and peripheral blood memory T cells in six patients with recently diagnosed IIM. We identified tissue resident memory T-cell (TRM ) signatures including the expression of HOBIT, XCL1 and CXCR6 in the muscle biopsies of all patients with IIM. Clonally expanded T-cell clones were mainly found among cytotoxic and TRM implying their role in the disease pathogenesis. Finally, identical expanded T-cell clones persisting at follow-up in the muscle tissue of two patients suggest their involvement in disease chronicity. Our study reveals a muscle tissue resident memory T-cell signature in patients with IIM and a transcriptomic map to identify novel therapeutic targets in IIM.

[Myositis-related interstitial lung disease - a systemic autoimmune desease often overlooked]. / Interstitiell lungsjukdom med myositantikroppar ofta förbisedd.

Interstitial lung disease can be the first sign of systemic autoimmune disease. If associated with myositis, interstitial lung disease may be the only symptom, with no presence of muscular weakness or other extramuscular manifestations. ANA-testing performed with indirect immune fluorescence may be negative. Testing for myositis antibodies should be considered as a step in the diagnostic process when strong clinical suspicion of interstitial lung disease of unknown origin is present. If interstitial lung disease is suspected, the patients should be referred to a specialist clinic for further investigation and, if possible, for discussion within a multidisciplinary team. Early suspicion of systemic inflammatory disease, rapid diagnosis and early start of treatment are crucial for future prognosis, quality of life and survival.

Screening for Anti-HMGCR Antibodies in a Large Single Myositis Center Reveals Infrequent Exposure to Statins and Diversiform Presentation of the Disease.

Background: The objective of this study is to assess the frequency of autoantibodies against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) in a single center myositis cohort and to analyze associations with statin exposure, clinical features, and outcome of disease course. Methods: A total of 312 patients with idiopathic inflammatory myopathies (IIMs) followed at the rheumatology clinic, Karolinska University Hospital, were identified in the Euromyositis registry between 1988 and 2014 and were classified according to the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) criteria. Available serum samples were analyzed for anti-HMGCR autoantibodies by ELISA. Positive sera were confirmed by immunoprecipitation. Clinical data were extracted from Euromyositis registry and medical records. Muscle samples were examined by two pathologists blinded to the subjects' autoantibody status. Results: Of 312 patients, 13 (4.3%) were positive for anti-HMGCR. Two of the 13 (15%) anti-HMGCR-positive patients had histories of statin use versus 12 (4.2%) in the anti-HMGCR-negative group. In the anti-HMGCR-positive group, five (38%) had a clinical phenotype compatible with dermatomyositis. Muscle biopsies of patients with HMGCR autoantibodies showed findings consistent with immune-mediated necrotizing myopathy in all cases except for one. Five (38%) patients required treatment with intravenous immunoglobulin compared to seven (2.3%) without this antibody. At the last visit, seven patients had chronic, active disease course, and five of 13 patients were in remission, including three without treatment. Conclusions: Patients with IIM related to anti-HMGCR autoantibodies may present with a wide range of symptoms, more than previously anticipated. When a broad approach to screening for these antibodies is applied, only a minority of patients was found to have previous statin exposure. The results of this study justify the addition of anti-HMGCR autoantibodies to routine diagnostic procedures in patients with myositis.

Myositis-specific autoantibodies and QTc changes by ECG in idiopathic inflammatory myopathies.

OBJECTIVES: The aim of this study was to investigate cardiac involvement detected by ECG in patients with idiopathic inflammatory myopathies (IIMs) and to evaluate possible associations between the autoantibody profile and ECG changes in these patients. METHODS: In a Scandinavian cross-sectional study, patients were included from two Danish centres and one Swedish centre. Resting 12-lead ECG was investigated in 261 patients with IIM compared with 102 patients with systemic sclerosis (SSc) and 48 healthy controls (HCs). ECG changes were correlated to clinical manifestations and myositis-specific and myositis-associated autoantibodies (MSAs and MAAs, respectively). RESULTS: Patients with IIM had a longer mean corrected QT (QTc) duration and more frequently presented with prolonged QTc (≥450 ms; P = 0.038) compared with HCs. A longer QTc duration was recorded in SSc compared with IIM [433 ms (s.d. 23) vs 426 (24); P = 0.011], yet there was no significant difference in the fraction with prolonged QTc (SSc: 22%, IIM: 16%; P = 0.19). In multivariable regression analyses, anti-Mi2 (P = 0.01, P = 0.035) and anti-Pl-7 (P = 0.045, P = 0.014) were associated with QTc duration and prolonged QTc in IIM. Elevated CRP was associated with prolonged QTc (P = 0.041). CONCLUSION: The presence of QTc abnormalities was as common in patients with IIM as in patients with SSc, including prolonged QTc seen in almost one-fifth of the patients. Anti-Mi2, anti-Pl-7 and elevated CRP may serve as biomarkers for cardiac disease in IIM, but needs to be confirmed in a larger prospective study.

Factors Associated With Treatment Response in Patients With Idiopathic Inflammatory Myopathies: A Registry-Based Study.

OBJECTIVE: To identify predictors of response to immunosuppressive therapy after 1 year, with a focus on autoantibodies, in patients newly diagnosed with idiopathic inflammatory myopathies (IIM) followed longitudinally in an electronic registry. METHODS: We assessed the association between autoantibody-defined groups and improvement according to American College of Rheumatology/European Alliance of Associations for Rheumatology 2016 response criteria. RESULTS: We identified 156 patients; of those, 111 (71%) were positive for any autoantibody tested, 90% received glucocorticoid treatment at baseline, and 78% received immunosuppressive drugs at some follow-up point. After 1 year from the index date, the overall median improvement score was 27.5 (interquartile range 10-51). No differences were observed in the total improvement score between the autoantibody-defined groups. Overall, 62% of patients (n = 96) showed a minimal response, 38% (n = 60) achieved a moderate response, and 19% (n = 30) achieved a major response. Regarding the different levels of response, dermatomyositis-specific autoantibodies were associated with a moderate response versus the seronegative group (reference), odds ratio 4.12 (95% confidence interval 1.2-16.5). In addition, dysphagia, time from symptom onset to diagnosis, and initial glucocorticoid dose were significant predictors of response after 1 year of follow-up. CONCLUSION: Patients with DM-specific autoantibodies achieved better levels of response compared to other autoantibody-defined groups. Dysphagia, a shorter time span from symptom onset to diagnosis, and intensive initial immunosuppressive treatment were associated with a higher response rate after 1 year of pharmacologic treatment from the index date, regardless of autoantibody status.

Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs. METHODS: Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case-control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant- and gene-level enrichment analyses, was implemented to explore genotype-phenotype relations. RESULTS: Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle-specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants. CONCLUSION: Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.

Performance of the new EULAR/ACR classification criteria for idiopathic inflammatory myopathies (IIM) in a large monocentric IIM cohort.

BACKGROUND: In 2017, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) published new classification criteria for idiopathic inflammatory myopathies (IIM). OBJECTIVES: To [1] assess the performance of the EULAR/ACR criteria in a monocentric cohort of consecutive patients with IIM, compare them with the Bohan and Peter (BP) criteria, and with the physician's diagnosis; and [2] evaluate the effect of including the presence of interstitial lung disease (ILD) as variable in the criteria. METHODS: 439 consecutive patients with a diagnosis of IIM followed at the Rheumatology Clinic, Karolinska University Hospital, Sweden were enrolled. The patients were diagnosed as IIM and subclassified by expert physicians. Clinical, laboratory, serological and histopathological data were collected from existing databases (Euromyositis registry and Swedish Rheumatology quality registry) and clinical charts of the patients. The sensitivity of the EULAR/ACR and the BP criteria was calculated. RESULTS: The EULAR/ACR criteria had a higher sensitivity (87.7%) compared to the BP criteria (80.4%). The concordance between the two sets of criteria was low (k = 0.253 p<0.001). The EULAR/ACR criteria showed a very high specificity (>98%) for the major IIM subgroups polymyositis, dermatomyositis, and inclusion body myositis. The sensitivity was variable and was high in inclusion body myositis (98%), dermatomyositis (90%) and lower in polymyositis (73%). When including ILD in the variables of the criteria, six more patients were classified as IIM cases (1.3%). CONCLUSION: The EULAR/ACR criteria for IIM are applicable with high sensitivity and specificity using data available from existing databases and clinical charts and represent a major step forward from the previous criteria for IIM and its subgroups. Their application will improve the quality of clinical trials and research studies with IIM patients.

Anti-transcriptional intermediary factor 1 gamma antibodies in cancer-associated myositis: a longitudinal study.

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

Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+ T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies.

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

Efficacy and safety of rituximab in anti-synthetase antibody positive and negative subjects with idiopathic inflammatory myopathy: a registry-based study.

OBJECTIVE: Post-hoc analyses of the Rituximab in Myositis trial indicate that specific autoantibodies profiles may influence treatment response. We compared the efficacy and safety of rituximab in anti-synthetase antibody (ARS-ab) positive and negative patients. METHODS: Adult idiopathic inflammatory myopathy (IIM) subjects in the Swedish Rheumatology Quality Register who received ⩾ 1 cycle of rituximab were enrolled. Efficacy assessment was based on the International Myositis Assessment and Clinical Studies (IMACS) core set measures and the 2016 ACR/EULAR definition of improvement for PM and DM. Safety assessment included drug-related adverse event and death during study period. Comparisons were done within and between the ARS-ab defined groups before and after first and last cycles. Associations between selected clinical features and improvement after one rituximab cycle were assessed using logistic regression. RESULTS: Sixty-five subjects were included and 43 had a follow-up visit within 5-10 months. Seventy-eight percent of ARS-ab positive subjects had moderate/major ACR/EULAR improvement after one cycle compared with 50% in the ARS-ab negative group. After several cycles, 79% of the ARS-ab positive and 67% of the ARS-ab negative patients achieved moderate/major improvement. A significant glucocorticoid-sparing effect was only observed in the ARS-ab positive group (P = 0.001). The most frequent adverse events were infections. One ARS-ab positive and two ARS-ab negative patients died during follow-up period. CONCLUSION: Irrespectively of their autoantibody status, a majority of subjects treated with several rituximab cycles had moderate/major improvement. In addition, ARS-ab positive subjects experienced a significant glucocorticoid-sparing effect.

Effect of CTLA4-Ig (abatacept) treatment on T cells and B cells in peripheral blood of patients with polymyositis and dermatomyositis.

We aimed to evaluate in vivo effects of abatacept on phenotypes of T and B cells in the circulation of myositis patients in a sub-study of the ARTEMIS trial. Twelve patients with paired frozen PBMCs before and after 6-month abatacept treatment were included in this sub-study where mass cytometry (CyTOF) was chosen as a technology to be tested for its utility in a real-life clinical immune monitoring setting. Using CyTOF, the peripheral T cell phenotypes demonstrated considerable variation over time and between individuals precluding the identification of treatment-specific changes. We therefore conclude that studies of patient cohorts displaying wide clinical heterogeneity using mass cytometry must be relatively large in order to be suited for discovery research and immune monitoring. Still, we did find some correlations with functional muscle outcome, namely positive correlations between the ratio of CD4+ T cells and CD8+ T cells (CD4/CD8) in peripheral blood samples both at baseline and after treatment with muscle endurance improvement as assessed by the functional index-2 (FI-2) test. Our data suggest that the CD4/CD8 ratio in circulation at time of active disease may be a predictor of treatment efficacy in myositis patients.

Targeted lipidomics analysis identified altered serum lipid profiles in patients with polymyositis and dermatomyositis.

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

Muscle Strength and Muscle Endurance During the First Year of Treatment of Polymyositis and Dermatomyositis: A Prospective Study.

OBJECTIVE: To investigate muscle impairment (isometric and dynamic) and disease activity during the first year after diagnosis of polymyositis (PM) and dermatomyositis (DM), and to study the relationship between muscle impairment, patient-reported health, and disease activity. METHODS: Seventy-two patients enrolled in the Swedish Myositis Register, 2003-2010, were followed prospectively. The Manual Muscle test (MMT-8; isometric muscle strength), the Functional Index of myositis test (FI-2; dynamic, repetitive muscle function), and disease activity (6-item core set) were retrieved at the time of diagnosis, and after 6 and 12 months. Self-reported health (Medical Outcomes Study Short Form-36; SF-36) was retrieved at 12 months. RESULTS: At the time of diagnosis, median (Q1-Q3) for the FI-2 was 27.2% (7.9-60.5%) of maximal score compared to 93.8% (92.5-98.8%) of maximal MMT-8. At 12 months, the FI-2 and the MMT-8 improved to 29.4% (16.5-60.7%; p < 0.05) and 96.1% (88.1-99.4%), respectively (p < 0.01). At 12 months, 45% of patients improved ≥ 20%, and 27% worsened ≥ 20% in FI-2 score, while 10% improved ≥ 20% in MMT-8. Physician's global visual analog scale (VAS), Health Assessment Questionnaire, and creatine phosphokinase levels improved significantly at 12 months (p < 0.05-0.001) while patient's global and extramuscular VAS remained unchanged. The SF-36 physical function correlated strongly with the FI-2 (rs = 0.74; CI 0.55-0.85) and moderately with the MMT (rs = 0.54; CI 0.27-0.73), with lower correlations between muscle function and other SF-36 domains. CONCLUSION: Patients with PM/DM were characterized by impaired dynamic repetitive muscle function (DRMF) that correlated well with patient-reported physical function. Assessment of DRMF adds information regarding muscle impairment in these patients.

Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial.

OBJECTIVES: To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM). METHODS: Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines. RESULTS: 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies. CONCLUSIONS: In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs suggests a positive effect of treatment in muscle tissue.

2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

OBJECTIVE: To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). METHODS: Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. RESULTS: Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001). CONCLUSION: The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

Use of biologic agents in idiopathic inflammatory myopathies in Sweden: a descriptive study of real life treatment.

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