TY - JOUR
TI - Provision of an Explanation for the Inefficacy of Immunotherapy in
Sporadic Inclusion Body Myositis Quantitative Assessment of Inflammation
and beta-Amyloid in the Muscle
AU - Zschuentzsch, Jana
AU - Voss, Joachim
AU - Creus, Kim
AU - Sehmisch,
AU - Stephan
AU - Raju, Raghavan
AU - Dalakas, Marinos C.
AU - Schmidt, Jens
JO - Seminars in Arthritis and Rheumatism
PY - 2012
VL - 64
TODO - 12
SP - 4094-4103
PB - Wiley-Blackwell
SN - 0049-0172
TODO - 10.1002/art.37692
TODO - null
TODO - 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.
ER -