Maryam Dastmalchi

Interstitial lung disease, a common manifestation of newly diagnosed polymyositis and dermatomyositis

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.

A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies

Objective: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. Methods: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1α, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon γ (IFNγ), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. Results: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by ⩾20% in three or more variables of the disease activity core set, four were unchanged and two worsened ⩾30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. Conclusions: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.

T Cell Infiltrates in the Muscles of Patients with Dermatomyositis and Polymyositis Are Dominated by CD28null T Cells

Dermatomyositis and polymyositis are disabling rheumatic diseases characterized by an appreciable number of T cells infiltrating muscle tissue. The precise phenotype, function and specificity of these cells remain elusive. In this study, we aimed to characterize T cells in muscle tissue and circulation and to investigate their association to clinical phenotype. Twenty-four patients with dermatomyositis and 42 with polymyositis were screened for frequency of CD4+CD28null and CD8+CD28null T cells in peripheral blood by flow cytometry. Presence of these cells in inflamed muscle tissue from 13 of these patients was analyzed by three-color immunofluorescence microscopy. Effector functions, proliferation and Ag specificity were analyzed by flow cytometry after in vitro stimulation. The clinical relevance of CD28null T cells was analyzed by multiple regression analyses including six separate and combined disease variables. We demonstrate that muscle-infiltrating T cells are predominantly CD4+CD28null and CD8+CD28null T cells in patients with dermatomyositis and polymyositis. Muscle-infiltrating CD28null T cells were found already at time of diagnosis. Disease activity correlated with the frequency of CD8+ T cells in the inflamed muscles of polymyositis patients. Circulating CD4+CD28null and CD8+CD28null T cells were significantly more frequent in human CMV (HCMV) seropositive individuals, responded to HCMV Ag stimulation, and correlated with disease duration. These cells also display a proinflammatory cytokine profile, contain perforin and lack the costimulatory molecule CD28. Our observations imply that CD28null T cells represent clinically important effector cells in dermatomyositis and polymyositis, and that HCMV might play a role in propagating disease in a subset of patients.

Anti-PL-7 (Anti-Threonyl-tRNA synthetase) Antisynthetase syndrome: Clinical manifestations in a series of patients from a european multicenter study (EUMYONET) and review of the literature

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

A longitudinal, integrated, clinical, histological and mRNA profiling study of resistance exercise in myositis.

Polymyositis and dermatomyositis are orphan, chronic skeletal muscle disorders characterized by weakness, infiltrations by mononuclear inflammatory cells, and fibrosis. Until recently, patients were advised to refrain from physical activity because of fears of exacerbation of muscle inflammation. However, recent studies have shown that moderate exercise training in combination with immunosuppressive drugs can improve muscle performance. Despite the positive effects of exercise training, the molecular mechanisms underlying the exercise-associated clinical improvements remain poorly understood. The present study was designed to define, at the molecular level, the effects of resistance exercise training on muscle performance and disease progression in myositis patients. We evaluated changes in muscle strength, histology and genome-wide mRNA profiles to determine the beneficial effects of exercise and determine the possible molecular changes associated with improved muscle performance. A total of 8 myositis patients underwent a 7-wk resistance exercise training program that resulted in improved muscle strength and increased maximal oxygen uptake (VO2max). Training also resulted in marked reductions in gene expression, reflecting reductions in proinflammatory and profibrotic gene networks, changes that were also accompanied by a reduction in tissue fibrosis. Consistent with the exercise-associated increase in VO2max, a subset of transcripts was associated with a shift toward oxidative metabolism. The changes in gene expression reported in the present study are in agreement with the performance improvements induced by exercise and suggest that resistance exercise training can induce a reduction in inflammation and fibrosis in skeletal muscle.

Limited effects of high-dose intravenous immunoglobulin (IVIg) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies

Objectives: The study was conducted with the aim of achieving an improved understanding of the molecular mechanisms of high-dose intravenous immunoglobulin (IVIG) in inflammatory myopathies by investigating the effects on muscle function and immunological molecules in skeletal muscle of polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) patients. Methods: Thirteen treatment-resistant patients, 6 PM, 4 DM, 2 IBM and 1 juvenile DM, were treated with 2 g/kg of IVIG, three times at monthly intervals. Functional Index in Myositis and serum creatinine kinase (CK) levels were determined, and muscle biopsies were performed before treatment and after the third IVIG infusion. Immunological molecules were also studied in biopsies taken 24–48 h after the first infusion. Results: Improved muscle function was observed in three patients (1 PM, 1 DM and 1 IBM) and CK levels decreased in five. T cells, macrophages, major histocompatibility complex (MHC) class I antigen on muscle fibres, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and membranolytic attack complex (MAC) deposits on capillaries were present to an equal degree in biopsies before and after IVIG treatment. No correlation between the clinical response and molecular changes was found. Conclusions: The clinical effects of high-dose IVIG on muscle function in patients with refractory inflammatory active myositis did not correspond to effects on any of the investigated molecules in our study. T cells, macrophages, phenotypical changes in muscle fibres and endothelial cell activation were still present after treatment. These observations question a role for IVIG as an immune-modulating therapy in patients with inflammatory myopathies.

Anakinra treatment in patients with refractory inflammatory myopathies and possible predictive response biomarkers: a mechanistic study with 12 months follow-up

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

Improved exercise performance and increased aerobic capacity after endurance training of patients with stable polymyositis and dermatomyositis

IntroductionThis randomized, controlled study on patients with polymyositis or dermatomyositis was based on three hypotheses: patients display impaired endurance due to reduced aerobic capacity and muscle weakness, endurance training improves their exercise performance by increasing the aerobic capacity, and endurance training has general beneficial effects on their health status.MethodsIn the first part of this study, we compared 23 patients with polymyositis or dermatomyositis with 12 age- and gender-matched healthy controls. A subgroup of patients were randomized to perform a 12-week endurance training program (exercise group, n = 9) or to a non-exercising control group (n = 6). We measured maximal oxygen uptake (VO2 max) and the associated power output during a progressive cycling test. Endurance was assessed as the cycling time to exhaustion at 65% of VO2 max. Lactate levels in the vastus lateralis muscle were measured with microdialysis. Mitochondrial function was assessed by measuring citrate synthase (CS) and β-hydroxyacyl-CoA dehydrogenase (β-HAD) activities in muscle biopsies. Clinical improvement was assessed according to the International Myositis Assessment and Clinical Studies Group (IMACS) improvement criteria. All assessors were blinded to the type of intervention (that is, training or control).ResultsExercise performance and aerobic capacity were lower in patients than in healthy controls, whereas lactate levels at exhaustion were similar. Patients in the exercise group increased their cycling time, aerobic capacity and CS and β-HAD activities, whereas lactate levels at exhaustion decreased. Six of nine patients in the exercise group met the IMACS improvement criteria. Patients in the control group did not show any consistent changes during the 12-week study.ConclusionsPolymyositis and dermatomyositis patients have impaired endurance, which could be improved by 12 weeks of endurance training. The clinical improvement corresponds to increases in aerobic capacity and muscle mitochondrial enzyme activities. The results emphasize the importance of endurance exercise in addition to immunosuppressive treatment of patients with polymyositis or dermatomyositis.Trial registrationClinicalTrials.gov: NCT01184625

Possible pathogenic mechanisms in inflammatory myopathies

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.

Improvement in Health and Possible Reduction in Disease Activity Using Endurance Exercise in Patients With Established Polymyositis and Dermatomyositis : A Multicenter Randomized Controlled Trial With a 1-Year Open Extension Followup

To determine the effects of a 12‐week endurance exercise program on health, disability, VO2 max, and disease activity in a multicenter randomized controlled trial in patients with established polymyositis (PM) and dermatomyositis (DM), and to evaluate health and disability in a 1‐year open extension study.