Expression of interleukin-18 in muscle tissue of patients with polymyositis or dermatomyositis and effects of conventional immunosuppressive treatment.

Objectives: To investigate the expression of IL-18 in symptomatic and asymptomatic muscle tissues of patients with PM and DM and the effects of conventional immunosuppressive treatment on such expression. Methods: Two cohorts of patients were included in this study. The first cohort consisted of 10 new-onset myositis patients. IL-18 expression was compared between symptomatic and asymptomatic muscle biopsies that were taken prior to treatment. The second cohort consisted of another 10 patients with repeated muscle biopsies before and after 8 months with conventional immunosuppressive treatment. Using immunohistochemistry, IL-18 expression in muscle tissues was compared before and after treatment. Biopsies from seven healthy individuals were included as controls. Results: IL-18 expression was predominantly localized to inflammatory cells and capillaries in patients and mostly to capillaries in healthy controls. Total IL-18 expression in muscle tissues from the new-onset patients, at both symptomatic and asymptomatic sites, was significantly higher compared with healthy controls (P = 0.007 and P = 0.002) with no statistical difference in appearances between symptomatic and asymptomatic sites. The number of IL-18 positive capillaries was not different among symptomatic, asymptomatic and healthy muscles. Total IL-18 expression appeared lower in biopsies from patients receiving and improving with immunosuppressive treatment, particularly the number of IL-18 positive inflammatory cells but not the number of IL-18 positive capillaries, which was consistent with significantly decreased expression of CD68+ macrophages (P = 0.04). Conclusion: IL-18 is highly expressed in muscle tissue in the context of inflammatory myopathies and based on its plausible effector functions could provide a novel therapeutic target in future.

Inflammatory lung disease a potential risk factor for onset of idiopathic inflammatory myopathies: results from a pilot study.

OBJECTIVES: To assess the association between inflammatory lung disease and the risk of developing idiopathic inflammatory myopathies. METHODS: A population-based case-control study was conducted. Adult myositis cases, identified from the Swedish inpatient registry (diagnosed between 1995 and 1997), and randomly selected controls matched to cases on the date of birth, gender and residency, were asked to fill out a questionnaire with questions on lifestyle, environmental exposures and health. Eventually, 100 cases and 402 controls responded to the questionnaire and were included in the analyses. Exposure was defined as self-reported preceding inflammatory lung diseases (pneumonia, tuberculosis or sarcoidosis). The association between the exposure and risk of developing myositis was evaluated by calculating OR together with 95% CIs in logistic regressions. RESULTS: 42 (42%) cases and 112 (28%) controls reported preceding inflammatory lung disease. Median duration between inflammatory lung disease and first symptom of myositis was 30 years. We observed a significant association between self-reported history of lung disease at study inclusion and diagnosis of myositis (crude OR=1.8 (1.1 to 2.9); smoking adjusted OR=1.9 (1.2 to 3.1)). We further identified a modestly increased, yet non-significant, association between preceding inflammatory lung disease (prior to index year) and diagnosis of myositis (smoking adjusted OR=1.6 (0.9 to 2.8)). The association was more pronounced among the cases of myositis with concurrent interstitial lung disease (OR=3.8 (1.0 to 14.5)). CONCLUSIONS: Patients with preceding inflammatory lung disease tend to have an increased risk of developing myositis compared to those without. The effect was more pronounced among patients with myositis with concurrent interstitial lung disease. Thus inflammatory lung disease may constitute a risk factor for myositis.

Intravenous immune globulin suppresses angiogenesis in mice and humans.

Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~ 60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.

The type I interferon system in idiopathic inflammatory myopathies.

Polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) are chronic inflammatory diseases that are characterized by muscle weakness and inflammatory cells in muscle tissue. Autoantibodies are common, some of them are specific for myositis, the most frequent being the anti-Jo-1 antibody which is associated not only with myositis but also with interstitial lung disease and arthritis. A role of type I interferons in disease mechanisms of myositis was first supported by the reported onset of PM and DM during treatment with type I interferon. More recently an interferon signature has been reported in muscle tissue of DM and PM patients both as gene and protein expression, and type I IFN expression in peripheral blood cells seems to correlate with disease activity. Different mechanisms could induce type I interferon in PM and DM like viral infections or endogenous factors as suggested by the observation that sera from myositis patients with anti-Jo-1 antibodies as well as anti-SSA and anti-SSB antibodies have an interferon inducible capacity. Accumulating data indicate a role of the type I interferon in myositis, particularly in juvenile and adult DM and in anti-Jo-1 or anti-SSA positive PM.