Studies of immunopathogenic mechanisms and treatment of chronic, inflammatory myopathies, myositis
Author: Dastmalchi, Maryam
Date: 2007-11-02
Location: Föreläsningssalen vid Centrum för Molekylär medicin (CMM, L8:00), Karolinska Universitetssjukhuset
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
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thesis.pdf (1.429Mb)
Abstract
Polymyosit (PM), dermatomyositis (DM) and sporadic inclusion body
myositis (sIBM) are chronic inflammatory myopathies which are
characterized by muscle weakness, fatigue and extra-muscular involvement.
Mononuclear inflammatory cells are typically found in muscle tissue.
Treatment is based on glucocorticoids together with other
immunosuppressive agents. Despite favorable response most patients with
PM and DM develop sustained muscle weakness and some patients do not
respond at all, including sIBM. The explanation for this is unknown.
Aims: The overall aim was to achieve increased understanding of disease mechanisms in myositis by evaluating therapeutic effects on muscle performance and variables in muscle tissue of pharmacological (high dose IVIg treatment and TNF-blockade, infliximab) and of non-pharmacological treatment, endurance and resistance training.
Patients and methods: Clinical outcome measures (disease activity and muscle performance), laboratory tests and muscle biopsies were performed before and after the interventions. Muscle biopsies were investigated for signs of inflammation, fibrosis and muscle fiber characteristics. Patients with chronic, refractory myositis were treated with high dose IVIg for 12 weeks (study I, n= 13) or with infliximab for 16 weeks (study II, n= 12). In studies III and IV patients with chronic, stable and low active inflammatory DM or PM were applied to endurance training for 12 weeks (study III, n = 8) or resistance training for 7 weeks (study IV, n= 8).
Results: After high dose IVIg treatment muscle performance improved in 3 of 13 patients. In two patients there were signs of decreased inflammation in muscle biopsies, but there was no correlation between improved muscle performance and changes of inflammatory markers in muscle tissue. There was still a pronounced expression of inflammatory markers in muscle tissue after treatment. After infliximab treatment 3 patients had decreased, 2 had increased and 5 had unchanged disease activity. Four stopped prematurely due to adverse events. Muscle performance did not improve in any patient. Signs of active inflammation by magnetic resonance imaging were apparent before treatment in two completers and after treatment in five cases. There were minor changes in inflammatory markers in muscle biopsies, but they were still present after treatment with infliximab in all patients.
Before training a low proportion of oxidative, type I fibers (mean 32±10%) and an increased proportion of intermediate type IIC fibers (3± 3%) was apparent in muscle biopsies compared to in healthy individuals. After endurance training type I fibers had increased significantly (42±13%) and type IIC fibers were reduced to 1±1%. Improved muscle performance correlated to an increased proportion of type I fibers and increased type II fiber area. After resistance training improved muscle performance was associated with downregulation of several genes signalling for inflammation and fibrosis. Gene transcripts involved in metabolic regulation were also modified.
Conclusion: Treatment with high dose IVIg or infliximab had limited clinical effects and there was no consistent decrease of inflammatory molecules expressed in muscle tissue. With infliximab treatment some patients even worsened, arguing against TNF as a key molecule in the underlying disease mechanism in chronic, treatment-resistant PM, DM and sIBM. In contrast, endurance as well as resistance training had positive effects on muscle performance and this was associated with changes in muscle characteristics and molecular expression in muscle, supporting the notion that non-immune mechanisms may have a role in causing muscle weakness.
Aims: The overall aim was to achieve increased understanding of disease mechanisms in myositis by evaluating therapeutic effects on muscle performance and variables in muscle tissue of pharmacological (high dose IVIg treatment and TNF-blockade, infliximab) and of non-pharmacological treatment, endurance and resistance training.
Patients and methods: Clinical outcome measures (disease activity and muscle performance), laboratory tests and muscle biopsies were performed before and after the interventions. Muscle biopsies were investigated for signs of inflammation, fibrosis and muscle fiber characteristics. Patients with chronic, refractory myositis were treated with high dose IVIg for 12 weeks (study I, n= 13) or with infliximab for 16 weeks (study II, n= 12). In studies III and IV patients with chronic, stable and low active inflammatory DM or PM were applied to endurance training for 12 weeks (study III, n = 8) or resistance training for 7 weeks (study IV, n= 8).
Results: After high dose IVIg treatment muscle performance improved in 3 of 13 patients. In two patients there were signs of decreased inflammation in muscle biopsies, but there was no correlation between improved muscle performance and changes of inflammatory markers in muscle tissue. There was still a pronounced expression of inflammatory markers in muscle tissue after treatment. After infliximab treatment 3 patients had decreased, 2 had increased and 5 had unchanged disease activity. Four stopped prematurely due to adverse events. Muscle performance did not improve in any patient. Signs of active inflammation by magnetic resonance imaging were apparent before treatment in two completers and after treatment in five cases. There were minor changes in inflammatory markers in muscle biopsies, but they were still present after treatment with infliximab in all patients.
Before training a low proportion of oxidative, type I fibers (mean 32±10%) and an increased proportion of intermediate type IIC fibers (3± 3%) was apparent in muscle biopsies compared to in healthy individuals. After endurance training type I fibers had increased significantly (42±13%) and type IIC fibers were reduced to 1±1%. Improved muscle performance correlated to an increased proportion of type I fibers and increased type II fiber area. After resistance training improved muscle performance was associated with downregulation of several genes signalling for inflammation and fibrosis. Gene transcripts involved in metabolic regulation were also modified.
Conclusion: Treatment with high dose IVIg or infliximab had limited clinical effects and there was no consistent decrease of inflammatory molecules expressed in muscle tissue. With infliximab treatment some patients even worsened, arguing against TNF as a key molecule in the underlying disease mechanism in chronic, treatment-resistant PM, DM and sIBM. In contrast, endurance as well as resistance training had positive effects on muscle performance and this was associated with changes in muscle characteristics and molecular expression in muscle, supporting the notion that non-immune mechanisms may have a role in causing muscle weakness.
List of papers:
I. Helmers SB, Dastmalchi M, Alexanderson H, Nennesmo I, Esbjörnsson M, Lindvall B, Lundberg IE (2007). "Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies." Ann Rheum Dis 66(10): 1276-83. Epub 2007 Feb 2
Pubmed
II. Dastmalchi M, Grundtman C, Alexanderson H, Einarsdottir H, Barbasso Helmers S, Elvin K, Nennesmo I, Lundberg IE (2007). "A high incidence of disease flares in an open study of infliximab in patients with refractory inflammatory myopathies." (Submitted)
III. Dastmalchi M, Alexanderson H, Loell I, Ståhlberg M, Borg K, Lundberg IE, Esbjörnsson M (2007). "Effect of physical training on the proportion of slow-twitch type I muscle fibers, a novel nonimmune-mediated mechanism for muscle impairment in polymyositis or dermatomyositis." Arthritis Rheum 57(7): 1303-1310 [Epub ahead of print]
Pubmed
IV. Nader G, Dastmalchi M, Alexanderson H, Grundtman C, Esbjörnsson M, Rönnelid J, Hoffman E, Nagaraju K, Lundberg IE (2007). "Resistance exercise reduces the expression of inflammation and fibrosis associated genes in autoimmune myositis patients." (Submitted)
I. Helmers SB, Dastmalchi M, Alexanderson H, Nennesmo I, Esbjörnsson M, Lindvall B, Lundberg IE (2007). "Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies." Ann Rheum Dis 66(10): 1276-83. Epub 2007 Feb 2
Pubmed
II. Dastmalchi M, Grundtman C, Alexanderson H, Einarsdottir H, Barbasso Helmers S, Elvin K, Nennesmo I, Lundberg IE (2007). "A high incidence of disease flares in an open study of infliximab in patients with refractory inflammatory myopathies." (Submitted)
III. Dastmalchi M, Alexanderson H, Loell I, Ståhlberg M, Borg K, Lundberg IE, Esbjörnsson M (2007). "Effect of physical training on the proportion of slow-twitch type I muscle fibers, a novel nonimmune-mediated mechanism for muscle impairment in polymyositis or dermatomyositis." Arthritis Rheum 57(7): 1303-1310 [Epub ahead of print]
Pubmed
IV. Nader G, Dastmalchi M, Alexanderson H, Grundtman C, Esbjörnsson M, Rönnelid J, Hoffman E, Nagaraju K, Lundberg IE (2007). "Resistance exercise reduces the expression of inflammation and fibrosis associated genes in autoimmune myositis patients." (Submitted)
Issue date: 2007-10-12
Rights:
Publication year: 2007
ISBN: 978-91-7357-323-8
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