4.0 Article

Provision of an Explanation for the Inefficacy of Immunotherapy in Sporadic Inclusion Body Myositis Quantitative Assessment of Inflammation and β-Amyloid in the Muscle

Journal

ARTHRITIS AND RHEUMATISM
Volume 64, Issue 12, Pages 4094-4103

Publisher

WILEY-BLACKWELL
DOI: 10.1002/art.37692

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Funding

  1. DFG [Schm 1669-1-1, Schm 1669-2-1]
  2. Octapharma
  3. Myositis Association
  4. Baxter
  5. Novartis
  6. Grifols
  7. Therapath
  8. CSL Behring
  9. Biotest

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Objective. In sporadic inclusion body myositis (IBM), inflammation and accumulation of beta-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. Methods. 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. Results. In muscle biopsy specimens, messenger RNA (mRNA) expression of the proinflammatory chemokines CXCL9, CCL3, and CCL4 and of the cytokines interferon-gamma (IFN gamma), transforming growth factor beta, interleukin-10 (IL-10), and IL-1 beta was significantly reduced after treatment in both groups. No consistent changes were observed for tumor necrosis factor alpha, IL-6, inducible costimulator (ICOS), its ligand ICOSL, and perforin. Messenger RNA expression of the degeneration-associated molecule ubiquitin and the heat-shock protein alpha B-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-1 beta, APP, and ubiquitin; beta-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 IFN gamma plus IL-1 beta, IgG and/or prednisone downregulated mRNA expression of IL-1 beta 2.5-fold. Accumulation of beta-amyloid, overexpression of alpha B-crystallin, and cell death were prevented. In contrast, NO-associated cell stress remained unchanged. Conclusion. 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.

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