Studies on interleukin-1 in idiopathic inflammatory myopathies
Author: Dorph, Christina
Date: 2009-02-20
Location: Föreläsningssalen, Centrum för Molekylär Medicin (CMM), Karolinska Universitetssjukhuset, Solna
Time: 09.30
Department: Institutionen för medicin / Department of Medicine
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Thesis (437.3Kb)
Abstract
The idiopathic inflammatory myopathies (IIM): polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) are chronic rheumatic muscle diseases of unknown origin that are characterized by muscle weakness and by inflammatory infiltrates in the skeletal muscle. Treatment with glucocorticoids and other immunosuppressive agents has improved outcome but not all patients respond to this treatment and most patients have only a partial response and side effects are common. Thus insights into the disease mechanisms of the IIMs are strongly needed and subsequently new therapies could emerge.
Aims: The main aim of this thesis has been to gain more insight into the pathogenesis of IIMs by studying inflammation, with particular focus on the proinflammatory cytokine, interleukin-1 (IL-1), in the muscle tissue and at the clinical level as IL-1 is one of the most consistently found cytokines in muscle tissue of IIMs. Muscle biopsies from patients with IIMs and healthy controls were studied using immunohistochemistry and immunofluoresence. Clinical outcome measures included disease activity and muscle performance using the functional index (FI) of myositis.
Results: As a prerequisite for studies on muscle tissue, we confirmed that muscle biopsy with the percutaneous conchotome technique is simple, safe and gives adequate yield to study inflammation and cytokine expression on the molecular level. The most important observation was that inflammation in muscle tissue in patients with relatively new onset PM or DM is general and not restricted to proximal muscles. We also found expression of the IL-1 receptors, IL-1RI and IL-1RII, on muscle fibers and a higher expression of the receptors and their ligand IL-1 in muscle tissue from PM and DM patients than in healthy individuals. Drug intervention with IL-blockade, anakinra, in 15 patients with refractory PM, DM and IBM revealed beneficial effects on clinical outcome including disease activity in 7 responders and muscle performance measured by FI in 4/7 responders. Notably, one of the responders had IBM, a disease which currently has no effective treatment. We could, however, not explain the clinical improvement by reduced inflammation or IL-1 expression in muscle tissue. Nevertheless, IL-1Ra expression was observed in more patients in post-treatment than in pre-treatment biopsies, all being responders.
Conclusions: The expression of IL-1 receptors on muscle fiber membrane and their colocalization with IL-1 support the hypothesis that IL-1 has an important role in the pathogenesis of PM and DM. This is further supported by the beneficial clinical effects of IL-1 blockade, at least in a subgroup of patients, but this needs to be confirmed in a larger, controlled, trial. However, it is likely that different molecular pathways are predominating in different subsets of myositis patients and this needs further investigations. The mechanisms for improvement could not be explained in our study. In addition, the observation that muscle inflammation in IIMs is general and not restricted to muscles with clinical symptoms implies that other disease mechanisms than can be explained by signs of inflammation in muscle tissue should be searched for. Finally, muscle biopsy with the percutaneous conchotome technique is a method that gives sufficient yield to analyze muscle tissue for diagnostic evaluation and for research and based on the observations of the general muscle inflammation, the range of muscles available for biopsy is not dependent on clinical symptoms.
Aims: The main aim of this thesis has been to gain more insight into the pathogenesis of IIMs by studying inflammation, with particular focus on the proinflammatory cytokine, interleukin-1 (IL-1), in the muscle tissue and at the clinical level as IL-1 is one of the most consistently found cytokines in muscle tissue of IIMs. Muscle biopsies from patients with IIMs and healthy controls were studied using immunohistochemistry and immunofluoresence. Clinical outcome measures included disease activity and muscle performance using the functional index (FI) of myositis.
Results: As a prerequisite for studies on muscle tissue, we confirmed that muscle biopsy with the percutaneous conchotome technique is simple, safe and gives adequate yield to study inflammation and cytokine expression on the molecular level. The most important observation was that inflammation in muscle tissue in patients with relatively new onset PM or DM is general and not restricted to proximal muscles. We also found expression of the IL-1 receptors, IL-1RI and IL-1RII, on muscle fibers and a higher expression of the receptors and their ligand IL-1 in muscle tissue from PM and DM patients than in healthy individuals. Drug intervention with IL-blockade, anakinra, in 15 patients with refractory PM, DM and IBM revealed beneficial effects on clinical outcome including disease activity in 7 responders and muscle performance measured by FI in 4/7 responders. Notably, one of the responders had IBM, a disease which currently has no effective treatment. We could, however, not explain the clinical improvement by reduced inflammation or IL-1 expression in muscle tissue. Nevertheless, IL-1Ra expression was observed in more patients in post-treatment than in pre-treatment biopsies, all being responders.
Conclusions: The expression of IL-1 receptors on muscle fiber membrane and their colocalization with IL-1 support the hypothesis that IL-1 has an important role in the pathogenesis of PM and DM. This is further supported by the beneficial clinical effects of IL-1 blockade, at least in a subgroup of patients, but this needs to be confirmed in a larger, controlled, trial. However, it is likely that different molecular pathways are predominating in different subsets of myositis patients and this needs further investigations. The mechanisms for improvement could not be explained in our study. In addition, the observation that muscle inflammation in IIMs is general and not restricted to muscles with clinical symptoms implies that other disease mechanisms than can be explained by signs of inflammation in muscle tissue should be searched for. Finally, muscle biopsy with the percutaneous conchotome technique is a method that gives sufficient yield to analyze muscle tissue for diagnostic evaluation and for research and based on the observations of the general muscle inflammation, the range of muscles available for biopsy is not dependent on clinical symptoms.
List of papers:
I. Dorph C, Nennesmo I, Lundberg IE (2001). Percutaneous conchotome muscle biopsy. A useful diagnostic and assessment tool. J Rheumatol. 28(7): 1591-9
Pubmed
II. Dorph C, Englund P, Nennesmo I, Lundberg IE (2006). Signs of inflammation in both symptomatic and asymptomatic muscles from patients with polymyositis and dermatomyositis. Ann Rheum Dis. 65(12): 1565-71. Epub 2006 Jul 10
Pubmed
III. Grundtman C, Salomonsson S, Dorph C, Bruton J, Andersson U, Lundberg IE (2007). Immunolocalization of interleukin-1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies. Arthritis Rheum. 56(2): 674-87
Pubmed
IV. Dorph C, Dastmalchi M, Alexanderson H, Nennesmo I, Lundberg IE (2009). Anakinra in patients with refractory idiopathic inflammatory myopathies. [Manuscript]
I. Dorph C, Nennesmo I, Lundberg IE (2001). Percutaneous conchotome muscle biopsy. A useful diagnostic and assessment tool. J Rheumatol. 28(7): 1591-9
Pubmed
II. Dorph C, Englund P, Nennesmo I, Lundberg IE (2006). Signs of inflammation in both symptomatic and asymptomatic muscles from patients with polymyositis and dermatomyositis. Ann Rheum Dis. 65(12): 1565-71. Epub 2006 Jul 10
Pubmed
III. Grundtman C, Salomonsson S, Dorph C, Bruton J, Andersson U, Lundberg IE (2007). Immunolocalization of interleukin-1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies. Arthritis Rheum. 56(2): 674-87
Pubmed
IV. Dorph C, Dastmalchi M, Alexanderson H, Nennesmo I, Lundberg IE (2009). Anakinra in patients with refractory idiopathic inflammatory myopathies. [Manuscript]
Issue date: 2009-01-30
Rights:
Publication year: 2009
ISBN: 978-91-7409-340-7
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