Abstract
BackgroundMechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). Recent evidence demonstrated that intravenous immunoglobulin failed to suppress cell-stress mediators in IBM. Here we studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab.MethodsRelevant inflammatory and degeneration-associated markers were assessed by quantitative-PCR and immunohistochemistry in repeated muscle biopsy specimens from patients with IBM, which had been treated in a previously published uncontrolled proof-of-concept trial with alemtuzumab.ResultsThere were no significant changes of the mRNA expression levels of the pro-inflammatory chemokines CXCL-9, CCL-4, and the cytokines IFN-γ, TGF-β, TNF-α, and IL-1β. Similarly, the degeneration-associated molecules ubiquitin, APP and αB-crystallin did not substantially change. Although no overall beneficial treatment effect was noted except for a 6-month stabilization, some patients experienced a transient improvement in muscle strength. In such responders, a trend towards reduced expression of inflammatory markers was noted. In contrast, the expression remained unchanged in the others who did not experience any change. The expression levels of IL-1β and MHC-I correlated with the positive clinical effect. By immunohistochemistry, some inflammatory mediators like CD8, CXCL-9, and MHC-I were downmodulated. However, no consistent changes were noted for ubiquitin, nitrotyrosin and β-amyloid.ConclusionsAlemtuzumab showed a trend towards downregulation of the expression of some inflammatory molecules in skeletal muscle of IBM patients but has no effect on several crucial markers of cell stress and degeneration. The data are helpful to explain the molecular treatment effects of future lymphocyte-targeted immunotherapies in IBM.
Highlights
Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM)
Partial downmodulation of mRNA levels of inflammatory mediators after alemtuzumab The expression levels of several disease-relevant markers of IBM were determined by quantitative PCR (Fig. 1)
The mRNA expression of pro-inflammatory chemokines CXCL-9, CCL-4, IL-1β, IFN-γ, and TNF-α were downmodulated after treatment in several patients, but no statistical significance was observed
Summary
Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). We studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab. Inclusion body myositis (IBM), the most common myopathy in patients over 50 years of age, leads to a progressive muscle weakness and atrophy [1]. Histopathological examination in IBM muscles reveals two major features: inflammation and degeneration [2]. Cytotoxic lymphocytes surround and invade non-necrotic myofibers and Despite the clearly demonstrated inflammatory pathomechanisms, immunosuppressive treatments failed to show a clear benefit in IBM, including methotrexate, mycophenolate-mofetil and the TNF-α blocker etanercept. In an uncontrolled proof-of-concept study with alemtuzumab in 13 IBM patients, a reduction of their disease progression for up to six months was observed [13]. Alemtuzumab is a monoclonal antibody directed against CD52 and leads to a profound depletion of peripheral lymphocytes [14]
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