Dr. Dalakas has received consulting fees, speaking fees, and/or honoraria from Baxter, Novartis, Octapharma, and Grifols (less than $10,000 each) and Therapath (more than $10,000).
Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis: Quantitative assessment of inflammation and β-amyloid in the muscle
Version of Record online: 28 NOV 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 12, pages 4094–4103, December 2012
How to Cite
Zschüntzsch, J., Voss, J., Creus, K., Sehmisch, S., Raju, R., Dalakas, M. C. and Schmidt, J. (2012), Provision of an explanation for the inefficacy of immunotherapy in sporadic inclusion body myositis: Quantitative assessment of inflammation and β-amyloid in the muscle. Arthritis & Rheumatism, 64: 4094–4103. doi: 10.1002/art.37692
- Issue online: 28 NOV 2012
- Version of Record online: 28 NOV 2012
- Accepted manuscript online: 31 AUG 2012 02:45PM EST
- Manuscript Accepted: 28 AUG 2012
- Manuscript Received: 6 FEB 2012
- DFG. Grant Numbers: Schm 1669-1-1, Schm 1669-2-1
- Fellowship from The Myositis Association
In sporadic inclusion body myositis (IBM), inflammation and accumulation of β-amyloid–associated molecules cause muscle fiber damage. We undertook this study to determine why intravenous immunoglobulin (IVIG) and prednisone are not effective in sporadic IBM despite their effectiveness in other inflammatory myopathies.
Relevant inflammatory and degeneration- associated markers were assessed by quantitative polymerase chain reaction and immunohistochemistry in repeated muscle biopsy specimens from patients with sporadic IBM treated in a controlled study with IVIG and prednisone (n = 5) or with prednisone alone (n = 5). Functional effects were assessed in a muscle cell culture model.
In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-γ (IFNγ), transforming growth factor β, interleukin-10 (IL-10), and IL-1β was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor α, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat-shock protein αB-crystallin was also reduced, but no changes were noted for amyloid precursor protein (APP) or desmin. By immunohistochemistry, a significant down-modulation of chemokines was observed, but not of inducible nitric oxide (NO) synthase, nitrotyrosine, IL-1β, APP, and ubiquitin; β-amyloid was reduced in 6 of 10 patients. Pronounced staining of IgG was observed in the muscle after treatment with IVIG, indicating penetration of infused IgG into the muscle and a possible local effect. In muscle cells exposed to IFNγ plus IL-1β, IgG and/or prednisone down-regulated mRNA expression of IL-1β 2.5-fold. Accumulation of β-amyloid, overexpression of αB-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged.
IVIG and prednisone reduce some inflammatory and degenerative molecules in muscle of patients with sporadic IBM and in vitro, but do not sufficiently suppress myotoxic and cell stress mediators such as NO. The data provide an explanation for the resistance of sporadic IBM to immunotherapy and identify markers that may help to design novel treatment strategies.