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-1ß, 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.

Immunolocalization of interleukin-1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies.

OBJECTIVE: Interleukin-1 (IL-1) acts via its receptors to induce gene expression that mediates protein synthesis involved in inflammation. Increased expression of IL-1alpha and IL-1beta in muscle tissue from patients with polymyositis and dermatomyositis has been demonstrated. It is not known whether the reciprocal IL-1 receptors are expressed in human muscle tissue. The purpose of this study was to investigate the expression of IL-1 receptors and their ligands in muscle tissue from patients with myositis and from healthy controls. METHODS: Muscle biopsy tissues from 10 patients with polymyositis or dermatomyositis and 7 healthy control subjects were investigated by immunohistochemistry using antibodies against IL-1 receptor type I (IL-1RI), IL-1RII, IL-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1Ra). Quantification was performed by computerized image analysis, and localization of expression was determined by double staining using immunofluorescence and confocal microscopy. RESULTS: In tissue samples from the patients, IL-1RI and IL-1RII were expressed in muscle fibers, inflammatory cells, and endothelial cells. Expression in muscle fibers was localized to the sarcolemma and nuclei. IL-1alpha was expressed in endothelial cells and inflammatory cells, whereas IL-1beta and IL-1Ra were expressed only in inflammatory cells. Expression of the two IL-1 receptors and their ligands was significantly higher in patients than in controls. IL-1 receptor expression on muscle fibers was most pronounced in the vicinity of cells expressing IL-1alpha and IL-1beta. CONCLUSION: The increased expression of IL-1 receptor and the colocalization with reciprocal ligands in patients with myositis but not in healthy controls support the hypothesis of a crucial role of IL-1 in the pathogenesis of polymyositis and dermatomyositis.

Idiopathic inflammatory myopathies - myositis.

The inflammatory myopathies - myositis - encompass a heterogeneous group of chronic muscle disorders of unknown origin and with varying prognoses. New clinical phenotypes of myositis have been identified since the most widely used classification criteria were proposed in 1975. Based on clinical and histopathological features, inclusion body myositis was identified. Furthermore, the myositis-specific autoantibodies may also identify different clinical phenotypes and serve as prognostic markers. The different classifications and inclusion criteria that have been used in different studies make some epidemiological data uncertain. In order to improve our knowledge of causative factors, as well as of pathogenic mechanisms, there is a need for revision and also for an international acceptance of the classification criteria. During recent years, our knowledge has increased regarding the role of some genetic and environmental factors that could affect susceptibility for developing myositis as well as the prognosis. Whether there is an association between myositis and malignancies has been a subject of controversy for many years and recent epidemiological data have brought some clarification on this issue.