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Selected annotated bibliography 2015 on sIBM.
This is a highly selected sampling of the research that I felt was
significant annotated with direct quotations and figures from the
articles.
Key points for patients:
Respiratory involvement is a critical factor that should be investigated
as soon as an sIBM diagnosis is made. Respiratory dysfunction can be
identified, treated and monitored. The most common causes of death in sIBM
patients are complications due to respiratory failure and aspiration
pneumonia (associated with both weak respiration and dysphagia –
weakness in swallowing). Therefore, ongoing monitoring and awareness of
these issues is highly recommended to both the patient and his or her
physicians.
The basic cause of sIBM is still unclear and until a cause can be isolated
direct treatments are effectively stymied.
The defective mechanisms that are being discovered associated with sIBM
involve the very fundamental, basic mechanisms of the cell’s
functions (for example, mitochondrial dysfunction).
Again this year, the literature is divided between the ideas that sIBM is
caused by protein abnormalities that trigger the immune system versus an
abnormal immune response that then triggers muscle protein damage.
A possible link to genetics – isolating a genetic susceptibility
– continues to be researched.
A blood test is in the pipeline but faces a number of obstacles among
them, as of yet, there is no consistent and standard method agreed on for
measuring the exact chemical they are looking for (anti-cN-1A
auto-anti-bodies).
An indirect treatment is being investigated and looks somewhat promising.
This drug, Bimagrumab, increases overall muscle mass with the idea that
having more muscle produced may help increase function in spite of the
ongoing harm done by sIBM mechanisms.
Alfano, L., & Lowes, L. P. (2015). Emerging therapeutic options for
sporadic inclusion body myositis. Therapeutics and Clinical Risk
Management, 1459. http://doi.org/10.2147/TCRM.S65368
In a subset of patients with sIBM, insidious onset dysphagia creates
swallowing difficulties and choking. As with the initial muscle wasting,
early signs of dysphagia can be overlooked as aging related choking or
coughing associated with eating or drinking. In 40%–50% of patients,
however, dysphagia becomes quite debilitating later in disease
progression. Interestingly, although sIBM is more common in men, there is
some evidence suggesting that dysphagia is more commonly the initial
presenting symptom in women.
Cardiac function appears to be spared in sIBM, although case studies have
been published reporting various cardio-myopathies coexisting in patients
with sIBM. While heart function may be preserved, there are reports of
sleep disordered breathing being identified primarily later in disease
progression, although not necessarily correlated to severity of peripheral
muscle weakness. Respiratory decline has also been reported as the most
common cause of death in a long-term follow-up of patients with sIBM.
Bimagrumab acts to inhibit activin type II receptors in the myostatin
pathway to potentially increase muscle size in patients with sIBM. . . . A
pivotal trial in 240 subjects with sIBM is currently ongoing to evaluate
changes in the distance walked on the 6MWT after 52 weeks.
Askanas, V., Engel, W. K., & Nogalska, A. (2015). Sporadic
inclusion-body myositis: A degenerative muscle disease associated with
aging, impaired muscle protein homeostasis and abnormal mitophagy.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1852(4),
633–643. http://doi.org/10.1016/j.bbadis.2014.09.005
We propose that in older h-IBM patients, the “aging”
muscle-fiber environment, and perhaps other individual intrinsic muscle
fiber abnormalities, make some of the accumulated proteins interpreted as
“foreign” by the immune system, thereby inducing the component
of T-cell lymphocytic inflammation.
In conclusion, s-IBM is a degenerative muscle disease in which aging
appears to be a key risk factor. Several molecular mechanisms responsible
for multiprotein aggregation and accumulation within s-IBM muscle fibers
were reviewed. Since anti-dysimmune treatments are generally not
effective, and were even reported to be detrimental for s-IBM patients
[12], it is not likely that s-IBM is a primary dysimmune/inflammatory
disease. But as we have been proposing, accumulation of
posttranslationally modified, misfolded proteins in the aging milieu of
s-IBM muscle fibers might be perceived by the patient's immune system as
“foreign” (not “self”) and be responsible for
inducing T-cell inflammation in the s-IBM muscle. Accordingly, we feel
that therapeutic approaches should be directed toward decreasing
degenerative components of the s-IBM pathogenesis. Unfortunately, thus far
the source of a Fountain of Myo-Youth has not yet been identified.
Benveniste, O., Stenzel, W., Hilton-Jones, D., Sandri, M., Boyer, O.,
& van Engelen, B. G. M. (2015). Amyloid deposits and inflammatory
infiltrates in sporadic inclusion body myositis: the inflammatory egg
comes before the degenerative chicken. Acta Neuropathologica, 129(5),
611–624. http://doi.org/10.1007/s00401-015-1384-5
Controversy reigns as to whether sIBM is primarily an inflammatory or a
degenerative myopathy, the distinction being vitally important in terms of
directing research for effective specific therapies. We review here the
pros and the cons for the respective hypotheses. A possible scenario,
which our experience leads us to favour, is that sIBM may start with
inflammation within muscle. The rush of leukocytes attracted by chemokines
and cytokines may induce fibre injury and HLA-I overexpression. If the
protein degradation systems are overloaded (possibly due to genetic
predisposition, particular HLA-I subtypes or ageing), amyloid and other
protein deposits may appear within muscle fibres, reinforcing the
myopathic process in a vicious circle.
Pneumonia, secondary to immobility, respiratory muscle weakness and
aspiration due to dysphagia, is a common terminal event.
Two major aspects to pathology:
1). Amyloid component of sIBM.
[Amyloids are insoluble fibrous protein aggregates sharing specific
structural traits. They are insoluble and arise from at least 18
inappropriately folded versions of proteins and polypeptides present
naturally in the body. These misfolded structures alter their proper
configuration such that they erroneously interact with one another or
other cell components forming insoluble fibrils. They have been associated
with the pathology of more than 20 serious human diseases. . . Amyloid.
(2015, December 16). In Wikipedia, The Free Encyclopedia. Retrieved 22:28,
December 18, 2015, from
https://en.wikipedia.org/w/index.php?title=Amyloid&oldid=695491308]
Accumulation of [abnormal protein] aggregates seems to be related to
proteasome and autophagy dysfunctions, but with what pathophysiological
consequences?
2). Inflammatory component of sIBM
The second pathological hallmark of sIBM is the presence of inflammatory
infiltrates. These infiltrates are rich in lymphocytes (mostly CD8+ T
cells) and macrophages, while CD4+ T cells and B lymphocytes are less
abundant. CD8+ T cell- and macrophage-rich infiltrates are regularly
observed invading non-necrotic fibres.
A possible scenario for the pathogenesis of sIBM, and one that we favour,
is that it may start with inflammation within muscle (of unknown aetiology
but postulates include viral infections and muscle micro-trauma by
eccentric exercise) with the histological features long considered the
hall-mark of polymyositis (inflammatory cells, invasion of non-necrotic
muscle fibres, necrotic and regenerating muscle fibres, but without
vacuoles or amyloid). . . . The rush of leukocytes, attracted by
chemokines and cytokines, may induce fibre injury, mitochondrial
dysfunction and HLA class I overexpression through, presumably, components
of pro-inflammatory cell stress mechanisms such as nitric oxide
production. If the protein degradation systems are overloaded (perhaps
failing to cope because of genetic predisposition, particular HLA class I
subtypes or ageing), amyloid and other protein deposits may appear within
muscle fibres, reinforcing the myopathy in a vicious circle, which is
clinically manifest as progressive muscle weakness. Figure 5 tries to
summarize these hypothetical physiological pathways starting from
inflammation: the egg, if we accept that it came first! The opposite
scenario, where amyloid deposits come first, leading to a secondary
inflammatory reaction, is in our opinion, less probable since (apart some
rare exceptions) neither hereditary inclusion body myopathy nor animal
models of forced amyloid deposits (with proteasomal and/ or autophagosomal
pathway deficiencies) are accompanied by by inflammation.
Gang, Q., Bettencourt, C., Houlden, H., Hanna, M. G., & Machado, P. M.
(2015). Genetic advances in sporadic inclusion body myositis. Current
Opinion in Rheumatology, 27(6), 586–594.
http://doi.org/10.1097/BOR.0000000000000213
Genes located within the MHC region remain the strongest genetic
association with sIBM. Some candidate genes/geno types have also been
evaluated, building on previous studies, including the APOE-TOMM40
genotypes, mtDNA rearrangement and mitochondrial-related nuclear DNA.
Genes related to hIBM and diseases with clinico-pathological features
resembling sIBM are providing important clues to sIBM genetic research. Of
note, rare variants in the VCP and SQSTM1 genes have for the first time
been identified in sIBM patients.
Gang, Q., Bettencourt, C., Machado, P. M., Fox, Z., Brady, S., Healy, E.,
… Houlden, H. (2015). The effects of an intronic polymorphism in
TOMM40 and APOE genotypes in sporadic inclusion body myositis.
Neurobiology of Aging, 44, 2014–2016.
http://doi.org/10.1016/j.neurobiolaging.2014.12.039
This is the largest cohort where the influence of the APOE and TOMM40
genes in sIBM disease risk and features has been investigated. Concerning
APOE, our findings confirmed that the APOE ε4 allele is not a
susceptibility factor for developing sIBM, which is consistent with the
previous studies (Needham et al., 2008). APOE alleles were also not
significantly associated with the age of onset of the disease. In
addition, our findings did not replicate a previously reported association
between APOE-TOMM40 and risk of developing sIBM (Mastaglia et al., 2013).
However, we observed that carriage of a VL repeat allele was significantly
associated with a later age of onset of symptoms. This effect was even
more pronounced among those also with the APOE ε3/ε3
genotype. This suggests that the TOMM40 VL polyT repeat has a
disease-modifying effect on sIBM by delaying the onset of symptoms, and
the APOE ε3/ ε3 genotype enhances this effect. Although
the association between APOE and TOMM40 and sIBM risk was not confirmed in
our study, the finding of an association between the TOMM40 VL polyT
repeat and a later age of onset of sIBM may justify further gene
expression studies in the future.
Goyal, N., Cash, T. M., Alam, U., Enam, S., Tierney, P., Araujo, N.,
… Mozaffar, T. (2015). Seropositivity for NT5c1A antibody in
sporadic inclusion body myositis predicts more severe motor, bulbar and
respiratory involvement. Journal of Neurology, Neurosurgery &
Psychiatry, 1–6. http://doi.org/10.1136/jnnp-2014-310008
In this cross-sectional analysis of patients with sIBM we asked whether
patients with seropositive and seronegative sIBM have different disease
phenotype. Our data suggests that seropositive sIBM with antibodies to
NT5c1A may represent a more aggressive disease, with more severe motor and
functional deficits and a higher incidence of bulbar and respiratory
involvement.
Dysphagia is a known complication in sIBM: reported in 10% of patients
with sIBM at onset and in 40% at the time of diagnosis.
Respiratory dysfunction in sIBM has been reported previously in the
context of aspiration pneumonia and primary respiratory failure. It
remains the predominant cause of mortality in long-term follow-up of
patients with sIBM.
• Females have higher odds of being seropositive. • Participants
with seropositive sIBM took significantly longer to get up and stand.
• There were no significant differences between the two groups in
terms of distance covered on a six minute walk. • Seropositive
participants were more likely to require assistive devices such as a
walker or wheelchair for mobility. • Participants with the NT5c1A
antibody were significantly more likely to have symptoms of dysphagia.
• Facial weakness occurred in 50% of seropositive participants while
it was only seen in 14% of seronegative participants. Researchers
concluded that even the small sample showed those positive to the NT5c1A
antibody are likely to have greater motor and functional disability. [from
The Outlook, Summer, 2015]
Herbert, M. K., & Pruijn, G. J. M. (2015). Novel serology testing for
sporadic inclusion body myositis. Current Opinion in Rheumatology, 27(6),
595–600. http://doi.org/10.1097/BOR.0000000000000216
Anti-cN-1A auto-antibodies represent the only serum biomarker for sIBM and
highlight a potential role for adaptive immunity in sIBM pathogenesis. . .
. the presence of anti-cN-1A auto-antibodies could be detected in up to
72% of sIBM sera, [blood] but in less than 5% of polymyositis and
dermatomyositis sera. . . . they are not specific for sIBM. Rather, we
also frequently detected anti-cN- 1A auto-antibodies in the sera of
patients with Sjogren’s syndrome (SjS; 37%) and systemic lupus
erythematosus (SLE; 20%).
Musculoskeletal Diseases and Conditions: Studies from Sir Charles Gairdner
Hospital Further Understanding of Inclusion Body Myositis (Sleep
disordered breathing and subclinical impairment of respiratory function
are common in sporadic inclusion body myositis). (2015 Feb. 23).
Gastroenterology Week, p. 307. Retrieved from
http://go.galegroup.com/ps/i.do?id=GALE%7CA406465309&v=2.1&u=ucalgary&it=r&p=AONE&sw=w&asid=83b078ac683217a8a1bb60d3c9e708ef
This is a medical news article reporting on this: Rodríguez Cruz,
P. M., Needham, M., Hollingsworth, P., Mastaglia, F. L., & Hillman, D.
R. (2014). Sleep disordered breathing and subclinical impairment of
respiratory function are common in sporadic inclusion body myositis.
Neuromuscular Disorders : NMD. http://doi.org/10.1016/j.nmd.2014.08.003
According to the news editors, the research concluded: "This suggests
respiratory function testing, including sleep study, should be performed
routinely in sIBM, irrespective of peripheral muscle function or other
disease severity parameters."
Muth, I. E., Zschüntzsch, J., Kleinschnitz, K., Wrede, A., Gerhardt,
E., Balcarek, P., … Schmidt, J. (2015). HMGB1 and RAGE in skeletal
muscle inflammation: Implications for protein accumulation in inclusion
body myositis. Experimental Neurology, 271, 189–197.
http://doi.org/10.1016/j.expneurol.2015.05.023
HMGB1 [high mobility group box 1 protein released by necrotic cells]
RAGE [(receptor for advanced glycation end products] the receptor of
HMGB1, is crucial for β-amyloid-associated neurodegeneration.
mRNA-expression levels of HMGB1 and RAGE were upregulated [increased] in
muscle biopsies of patients with sIBM and PM, but not in muscular
dystrophy or non-myopathic controls.
Upregulation of RAGE on the cell surface was [also seen].
The findings strengthen the concept of unique interactions between
degenerative and inflammatory mechanisms and suggest that HMGB1 / RAGE
signaling is a critical pathway in sIBM pathology.
Collectively, our results indicate that HMGB1 uniquely contributes to the
interplay of inflammation and degeneration in sIBM. In spite of beneficial
effects of the HMGB1 antagonist BoxA in animal models of sepsis and
arthritis (Yang et al., 2004; Kokkola et al., 2003), the HMGB1-RAGE- axis
could be an interesting target for future therapeutic strategies in
diseases with chronic inflammatory cell stress in conjunction with
accumulation of β-amyloid such as in sIBM and several
neurodegenerative disorders.
Nogalska, A., D’Agostino, C., Engel, W. K., Cacciottolo, M., Asada,
S., Mori, K., & Askanas, V. (2015). Activation of the Unfolded Protein
Response in Sporadic Inclusion-Body Myositis but Not in Hereditary GNE
Inclusion-Body Myopathy. Journal of Neuropathology and Experimental
Neurology, 74(6), 538–46.
http://doi.org/10.1097/NEN.0000000000000196
Endoplasmic reticulum (ER) plays a critical role in processing, folding,
and exporting newly synthesized normal and unfolded/misfolded proteins
into the secretory pathway. Accumulation of the unfolded/misfolded
proteins in the ER lumen leads to ER stress, which subsequently elicits
the unfolded protein response (UPR), a mechanism by which cells attempt to
both protect themselves against the ER stress and restore their folding
capacity.
Here we demonstrate for the first time that UPR [unfolded protein
response] is activated in s-IBM muscle biopsies . . . In contrast, we did
not find similar evidence of the UPR induction in GNE-h-IBM patient muscle
In summary, our results demonstrate a coordinated activation of 3 branches
of the UPR in s-IBM muscle fibers. The lack of UPR, implying no ER stress,
in GNE-h-IBM suggests that different intracellular mechanisms might be
associated with very similar pathologic phenotypes.
[3 branches of the UPR: (a) protein kinase RNA (PKR)-like ER protein
kinase (PERK); (b) activating transcription factor 6 (ATF6); and (c)
inositol-requiring enzyme 1 (IRE1)]
Rygiel, K. Miller, J., Grady, J. P., Rocha, M. C., Taylor, R. W., &
Turnbull, D. M. (2015). Mitochondrial and inflammatory changes in sporadic
inclusion body myositis. Neuropathology and Applied Neurobiology, 41(3),
288–303. http://doi.org/10.1111/nan.12149
We identified respiratory-deficient fibres at different stages of
mitochondrial dysfunction, with downregulated [decreased] expression of
complex I of mitochondrial respiratory chain being the initial feature. We
detected mitochondrial DNA rearrangements in the majority of individual
respiratory-deficient muscle fibres. There was a strong correlation
between number of T lymphocytes and macrophages residing in muscle tissue
and the abundance of respiratory-deficient fibres. Moreover, we found that
respiratory-deficient muscle fibres were more likely to be atrophic
compared with respiratory-normal counterparts. Conclusions: Our findings
suggest that mitochondrial dysfunction has a role in sIBM progression.
Discussion
Mitochondrial dysfunction is common and often very prominent in muscle
from sIBM patients. We demonstrate that there are abnormalities in the
expression of individual mitochondrial respiratory complexes, and propose
that a protocol combining mitochondrial respiratory subunit expression and
COX/SDH activity provides a clearer picture of the mitochondrial changes
in sIBM. We have explored the nature of the mitochondrial defect in
individual muscle fibres and, in accordance with previous reports, we show
that some of them accumulate high level of clonally expanded mtDNA
deletions. We also show that respiratory-deficient fibres are more prone
to atrophy indicating that the mitochondrial defect has a direct effect on
muscle wasting. In addition, there is a clear correlation between the
overall percentage of respiratory-deficient fibres and the degree of T
lymphocyte infiltrate. Thus there seems to be a direct link between the
inflammation present in muscle environment and the mitochondrial defect.
[The eukaryotic cell's most efficient path for production of ATP is
aerobic respiration that takes place in mitochondria. Cellular respiration
is the set of metabolic reactions and processes that take place in the
cells of organisms to convert biochemical energy from nutrients into
adenosine triphosphate (ATP), and then release waste products.
Glucose + Oxygen -> ->-> Water + Carbon dioxide + Chemical energy
(ATP)
The reactions involved in respiration are catabolic reactions, which break
large molecules into smaller ones, releasing energy in the process, as
weak so-called "high-energy" bonds are replaced by stronger bonds in the
products. Respiration is one of the key ways a cell gains useful energy to
fuel cellular activity. Cellular respiration is considered an exothermic
redox reaction which releases heat. The overall reaction occurs in a
series of biochemical steps, most of which are redox reactions themselves.
[[redox: a process in which one substance or molecule is reduced and
another oxidized; oxidation and reduction considered together as
complimentary processes: redox reactions involve electron transfer.]]
Although technically, cellular respiration is a combustion reaction, it
clearly does not resemble one when it occurs in a living cell due to slow
release of energy from the series of reactions. Nutrients that are
commonly used by animal and plant cells in respiration include sugar,
amino acids and fatty acids, and the most common oxidizing agent (electron
acceptor) is molecular oxygen (O2). The chemical energy stored in ATP (its
third phosphate group is weakly bonded to the rest of the molecule and is
easily broken allowing stronger bonds to form, thereby transferring energy
for use by the cell) can then be used to drive processes requiring energy,
including biosynthesis, locomotion or transportation of molecules across
cell membranes. Cellular respiration. (2015, December 14). In Wikipedia,
The Free Encyclopedia. Retrieved 01:16, December 20, 2015, from
https://en.wikipedia.org/w/index.php?title=Cellular_respiration&oldid=695161884]
Saltychev, M., Mikkelsson, M., & Laimi, K. (2015). Medication of
inclusion body myositis: a systematic review. Acta Neurologica
Scandinavica, (5), n/a–n/a. http://doi.org/10.1111/ane.12455
Our findings reflect the rareness of the disease and the existing
uncertainty in understanding the causes and pathogenesis of sIBM. Only a
few controlled trials have focused exclusively on the treatment of sIBM.
So far, there is no evidence indicating that any specific treatment for
sIBM is effective, and further high-quality research is needed on the
topic. Acknowledgements
van de Vlekkert, J., Hoogendijk, J. E., & de Visser, M. (2015).
Myositis with endomysial cell invasion indicates inclusion body myositis
even if other criteria are not fulfilled. Neuromuscular Disorders, 25(6),
451–456. http://doi.org/10.1016/j.nmd.2015.02.014
In conclusion, patients with a muscle biopsy showing endomysial cell
infiltration with invasion of non-necrotic muscle fibers most probably
have sIBM, regardless of clinical and other pathological features. Women
lack typical features more often than men.
Weihl, C. C., Baloh, R. H., Lee, Y., Chou, T., Pittman, S. K., Lopate, G.,
… Harms, M. B. (2015). Targeted sequencing and identification of
genetic variants in sporadic inclusion body myositis. Neuromuscular
Disorders, 25 , Issue 4 , 289 - 296
http://doi.org/10.1016/j.nmd.2014.12.009
We performed targeted sequencing of 38 “high probability”
genes associated with clinical syndromes having phenotypic and pathogenic
similarities to sIBM, in 78 patients with sIBM; making it the largest
genetic study performed to date for sIBM.
The future of research and clinical treatment for acquired muscle diseases
such as sIBM is rapidly evolving and will dramatically change with the
advent of inexpensive and comprehensive genetic testing. Moreover,
clinical trials and therapeutic interventions for sIBM are currently in
development. The identification of potential genetic risk factors, genetic
modifiers or genetic elements associated with treatment response for sIBM
will be of equal value to that of properly genetically diagnosing sIBM
patients. Our study offers an initial glimpse into the genetic variation
seen in clinically reported sIBM patients.