Helene Alexanderson

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.

Decreased expression of interleukin‐1α, interleukin‐1β, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis

OBJECTIVE To study the effects of immunosuppressive therapy, in particular, corticosteroids, on morphologic signs of inflammation and expression of cytokines, adhesion molecules, and class I major histocompatibility complex (MHC) antigen in muscle tissue from patients with polymyositis (PM) and dermatomyositis (DM) and to correlate the molecular changes with changes in muscle function. METHODS Seven patients with PM and 4 patients with DM underwent muscle biopsy before and after 3-6 months of therapy. Ten of the 11 patients were initially treated with prednisolone 30-60 mg/day. The phenotypes of infiltrating inflammatory cells and the expression of interleukin-1alpha (IL-1alpha) and IL-1beta, adhesion molecules, and class I MHC antigen were studied by immunochemistry. Computerized image analysis was used for quantitation of staining. Muscle function was assessed with a muscle function index score. RESULTS Pronounced improvement of muscle function during the treatment period was noted in 8 of the 11 patients. The changes in muscle function coincided with an almost complete disappearance of inflammatory cells, including CD3+ T cells, in the patients with clinical improvement. These patients also exhibited decreased expression of IL-1alpha, IL-1beta, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), leukocyte function-associated antigen 1alpha, and very late activation antigen 4alpha. Of note, there was persistent expression of IL-1alpha, ICAM-1, and VCAM-1 in capillaries and of class I MHC antigens on muscle fibers in several of the patients who, after corticosteroid treatment, still had muscle weakness despite the disappearance of inflammatory infiltrates. CONCLUSION Changes in the muscle expression of key molecules in the inflammatory process, such as IL-1alpha and IL-1beta, ICAM-1 and class I MHC antigens, showed a consistent but not complete concordance with changes in and status of muscle function in patients with myositis who received the current standard treatment for the disease. These data indicate that it is possible to further evaluate various therapies for myositis using molecular analysis of muscle biopsy specimens obtained on repeated occasions. In addition, the data demonstrate a dissociation between muscle function and degree of inflammatory infiltration in the affected muscles and suggest that the functional defects are more related to the expression of molecules such as IL-1alpha in muscle capillaries than to the mere presence of inflammatory cells in the affected muscles.

The safety of a resistive home exercise program in patients with recent onset active polymyositis or dermatomyositis

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

Sporadic inclusion body myositis: Pilot study on the effects of a home exercise program on muscle function, histopathology and inflammatory reaction

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

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.

The role of exercise in the rehabilitation of idiopathic inflammatory myopathies.

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

Exercise as a therapeutic modality in patients with idiopathic inflammatory myopathies.

Purpose of reviewTo present scientific evidence on clinical and molecular effects of exercise in adult and juvenile idiopathic inflammatory myopathies focusing on recent studies. Recent findingsIn patients with inclusion body myositis (IBM), one small, open study recently for the first time reported on improved muscle strength and functional capacity after a twice-a-day home exercise programme, whereas earlier studies have not been able to show any or only small improvements, mainly in less-affected muscle groups. For patients with polymyositis and dermatomyositis a few studies have reported reduced clinical disease activity after resistance training in patients with chronic phase of disease. These observations are supported by downregulation of genes regulating inflammation and fibrosis in muscle tissue following this type of training. These results may indicate that resistance exercise might reduce muscle inflammation in adult polymyositis and dermatomyositis. A first case report has described safety and benefits of an exercise programme in a child with dermatomyositis, and a few studies support the safety of single exercise bouts or exercise tolerance tests in juvenile dermatomyositis. SummaryAccumulated evidence supports safety and efficacy of exercise in polymyositis and dermatomyositis, although data are more inconclusive for efficacy in patients with IBM. There is a need for larger studies to further ensure efficacy in IBM and juvenile dermatomyositis.

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