Physical exercise as a targeted therapy in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies are comprised of polymyositis (PM) and dermatomyositis (DM) with muscle impairment being the primary clinical feature. With the currently recommended treatment regimen, a majority of patients develop sustained impaired muscle performance and poor health for undetermined reasons. The overall aim was to test the hypothesis that sustained muscle impairment and poor health in patients with established PM/DM are consequences of low aerobic capacity and that the use of endurance exercise, as the targeted intervention, will contribute to beneficial systemic and muscle adaptations and to clinical improvement. A further aim was to evaluate the individual priorities (e.g., patient preferences) of patients with established PM/DM. The effect of a 12-week endurance exercise intervention was evaluated in a multicenter, randomized control trial in patients with established PM/DM (Papers II-IV). Exercise performance, aerobic capacity (maximal oxygen uptake (VO2 max)), and lactate levels in skeletal muscle were compared between patients (n = 23) and healthy controls (HC) (n = 12). Patients (n = 21) were randomized into an endurance exercise program or a nonexercise control group. Clinical assessments were performed at 0 and 12 weeks and consisted of: VO2 max, health (SF-36), muscle performance and disease activity (International Myositis Assessment and Clinical Studies Group criteria). Disability assessments were repeated at 52 weeks in an open extension. Associations between changes in clinical outcome measures and muscle properties were studied in vastus lateralis muscles by measuring extracellular lactate levels with microdialysis and by analyzing muscle biopsies for: mitochondrial enzyme activities (citrate synthase and -hydroxyacyl-CoA dehydrogenase); mRNA expression profile; target protein validation by western blot analysis and by immuno-histochemistry (capillary density and inflammatory markers). In Paper I, we describe the patient preference in patients with PM/DM (n = 28) using the MacMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR). Exercise performance and VO2 max were lower in the patients than in the HCs, whereas their lactate levels at exhaustion were similar. 12 weeks of endurance exercise added to the recommended pharmacological treatment in patients with established PM/DM increased capillary density and mitochondrial capacity in skeletal muscle, which could have contributed to the markedly improved muscle performance through increased aerobic capacity. Lactate levels at exhaustion decreased. The improved health and decreased clinical disease activity could potentially be mediated through the demonstrated improved VO2 max from the endurance exercise. 12 weeks of endurance exercise only had a long-term beneficial effect on muscle strength. Changes in gene expression following the endurance exercise program indicate activation of the aerobic phenotype and muscle growth pathways, which overwrites the muscle atrophy process and simultaneously suppresses the inflammatory response. However, other mechanisms, such as muscle weakness, also seem to contribute to impaired muscle performance in patients. The MACTAR revealed disease consequences important to individual patients that were not assessed in the recommended PM/DM outcome measures. Altogether the results of this thesis indicate that endurance exercise is essential to improve aerobic capacity, muscle performance, and health in these patients. LIST OF PUBLICATIONS I. Alemo Munters L, van Vollenhoven R F, Alexanderson H. Patient Preference Assessment Reveals Disease Aspects Not Covered by Recommended Outcomes in Polymyositis and Dermatomyositis. International Scholarly Research Network, ISRN Rheumatology Volume 2011, Article ID 463124, 5 pages II. Alemo Munters L, Dastmalchi M, Andgren V, Emilson C, Bergegård J, Regardt M, Johansson A, Orefelt Tholander I, Hanna B, Lidén M, Esbjörnsson M, Alexanderson H. 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. Arthritis Care Res (Hoboken). 2013 Jul 16. doi: 10.1002/acr.22068. [Epub ahead of print] III. Alemo Munters L, Dastmalchi M, Katz A, Esbjörnsson M, Loell I, Hanna B, Lidén M, Westerblad H, Lundberg IE, Alexanderson H. Improved Exercise Performance and Increased Aerobic Capacity after Endurance Training of Patients with Stable Polymyositis and Dermatomyositis. Arthritis Res Ther. 2013, 15:R83. http://arthritis-research.com/content/15/4/R83 IV. Alemo Munters L*, Loell I*, Raouf J, Dastmalchi M, Lindroos E, Ottosson C, Chen Y-W, Chi R, van Delden AF, Esbjörnsson M, Korotkova M, Alexanderson H, Nagaraju K, Lundberg IE. Effects of Endurance Training on Molecular Expression in Skeletal Muscle from Patients with Polymyositis and Dermatomyositis; A Pilot Study. Manuscript. * = authors contributed equally