Inclusion body myositis
Date de creation: April 2000
Last up-date: March 2003
Epidemiology
Sporadic IBM most frequently affect men (M/F ratio: 3/1), usually adults
over 50 years old. Sporadic IBM represent, depending on the series,
15–30% of all idiopathic inflammatory myopathies. Sporadic IBM must be
differentiated from familial (non inflammatory) inclusion body myopathie.
Clinical manifestations
The motor defect of IBM is myogenic, predominantly affecting proximal
muscles, notably the shoulder and especially pelvic girdles, and cervical
muscles. Certain clinical manifestations can orient the diagnosis
towards this myopathy. The clinical picture typically associates
bilateral muscle deficits and atrophy of insidious or progressive onset,
often asymmetrical, proximal and distal deficits from the start, but generally
late distal deficit during the course of PM and DM. The asymmetrical
nature of the distribution and selective involvement of certain muscles
are sometimes suggestive of the diagnosis: anterior tibial and quadriceps
in the legs; flexors of the wrist and fingers; palmar, biceps and triceps
in the arms. Myalgias and dysphagia are seen in 15–20% of the patients.
Visceral manifestations, other than deglutition pneumopathies caused by
pharyngeolaryngeal muscle involvement and rare cardiomyopathies , seem
to be unusual.
Complementary examinations
Muscle enzymes, especially creatine phosphokinase (CPK), are normal
or, more frequently, moderately elevated. An inflammatory syndrome
is usually (70%) absent or moderate. No specific manifestations of
immune dysfunction have been identified. Electromyography tracings
show myogenic or, more rarely, mixed patterns attesting to an associated
neurogenic process. Nerve conduction velocities are normal.
Histology and immunohistochemistry
The diagnosis is based on light microscopy of muscle biopsies, which
detects rimmed vacuoles, 3–30 microns in diameter, within normal or atrophic
muscle fibers. These rimmed vacuoles contain eosinophilic granules
and are located in the cytoplasm of muscle cells. Inflammatory infiltrates,
comprised mainly of macrophages and CD8+ T lymphocytes, are associated
only in the sporadic forms and predominantly invade the endomysium and
perivascular regions of non-necrotic muscle fibers. Other anomalies
are also present: muscle fibers of abnormal size with hypertrophic
fibers and increased numbers of muscle capillaries. Unlike PM and
DM, necrotic and regenerating foci are rarely seen in IBM. These
anomalies might not be found in routine histological examination.
New sections must be cut or a new biopsy taken. Electron microscopy
can detect inside these vacuoles tubulofilamentous structures, 15–20 nm
in diameter, rectilinear, curvilinear and corresponding to eosinophilic
granulations. These intracytoplasmic and/or intranuclear filamentous
inclusions are sufficient to confirm the diagnosis.
Immunohistochemical labeling of the mononuclear cells forming
the inflammatory infiltrates shows them to be mainly macrophages and CD8+
T lymphocytes, attesting to a predominantly cell-mediated immune reaction.
Major histocompatibility complex (MHC) HLA class I antigens are also abnormally
expressed on the sarcolemma of non-necrotic infiltrated muscle fibers.
This possible cytotoxic T-cell origin restricted to MHC class I makes IBM
more reminiscent of chronic PM. These immunological abnormalities
tend to favor an immune dysfunction but do not prove the autoimmune nature
of IBM.
Immunohistochemistry is able to specify the possible composition
of cytoplasmic and nuclear inclusions. The contents of rimmed vacuoles
exhibit positive yellow–green birefringence, characteristic of deposits
of beta-folded amyloid proteins, notably beta-amyloid (or A4 protein).
These deposits are not always strictly intracellular, but also found adjacent
to the sarcolemma or even outside the muscle fiber. Amyloid is usually
deposited in the extracellular spaces after abnormal enzymatic cleavage
from its precursor, a transmembrane protein, which releases A4 protein.
Beta-amyloid and the protein precursor accumulate in the vacuolated fibers,
under the sarcolemma or outside the fiber in the form of amorphous, flocular
beads. In addition, ubiquitin, a physiological protein involved in
transport and regulation of proteolysis, is abnormally present in muscles
of IBM patients. Ubiquitin assures the transport of abnormal cell
proteins, notably filamentous cytoskeletal proteins, towards the ATPase-dependent
proteolytic lysosome system, which degrades them. This protein is
abnormally abundant in cytoplasmic vacuoles, in the amorphous flocular
substance and monocyte nuclei. An anomaly of cellular proteolysis,
notably of ubiquitin, could induce amyloidogenesis and an immune reaction.
Cytoplasmic inclusions could also correspond to deposits of a protein associated
with microtubules, which constitute, along with actin and intermediary
filaments, the protein network of the cytoskeleton of eukaryote cells.
The microtubules are composed of tubulin and microtubule-associated proteins
(MAP). The inclusions could correspond to a MAP, either its normally
phosphorylated form, the protein tau, or its abnormally phosphorylated
form, the ALZ 50 protein. Other proteins, precursors or not of beta-amyloid,
notably apolipoprotein E, alpha-1-antichymotrypsin and the prion protein,
have been found in excess in muscle cells of IBM patients, making this
disease reminiscent of Alzheimer’s disease.
Prognosis
Spontaneously, IBM generally worsens progressively and slowly.
Some observations of stabilizations and remissions, spontaneous or under
treatment, have been reported, but are usually only transient.
Treatment
At present, no treatment has been shown to be effective against the
different forms of IBM, be it corticosteroids, plasma exchanges, immunosuppressants
or total body irradiation. Some moderate success has sometimes been
obtained with the combination of corticosteroids and methotrexate or human
intravenous immunoglobulins (IVIg). New therapeutic protocols are
currently being tested. Symptomatic treatments – prevention of inhalation
pneumopathies, physical therapy, ergotherapy – are systematically prescribed.
Key-words
Inclusion body myositis, inflammatory myopathy, motor deficiency, muscle
biopsy, immunomodulating agents, rimmed vacuoles
References