Researchers
have identified previously undetectable biomarkers that could help diagnose and
direct the treatment of a rare autoimmune disease.
Autoimmune conditions are a class of disease in which a person's
immune system produces antibodies to attack tissues in the body.
There are many types of autoimmune disease, and in a recent
study, researchers focused specifically on myasthenia
gravis (MG).
MG is a rare condition characterized by weakness and rapid fatigue of voluntary
muscles. Symptoms often get worse after exertion.
MG is a chronic illness, and it can be debilitating and, in some
cases, fatal. It affects between 14–40 people per 100,000 in the United States,
and there is no known cure.
Treatment usually involves medications to increase levels of the
organic chemical acetylcholine available to stimulate receptors and improve
muscle strength, as well as drugs to suppress the immune system.
Historically, diagnosing MG has been difficult because symptoms
often mimic those of other neurological conditions, such as stroke.
Now, a team of researchers — based at the University of Alberta,
Edmonton, in Canada — has shown that MG can not only be detected, but its
disease progression can be predicted by the presence of certain metabolic
biomarkers in blood serum.
The researchers hope that their findings, which appear in the
journal Metabolomics,
will help clinicians diagnose this difficult-to-identify disease. Dr. Zaeem
Siddiqi, a neurologist, and graduate student Derrick Blackmore, Ph.D., co-led
the new research.
Why are biomarkers useful?
A biomarker is a small biological compound defined by its
pathological significance in identifying certain diseases. Many diseases can be
detected by the presence of biomarkers in blood serum, and these markers can
help indicate the type of treatment that a person may respond best to.
"Biomarker discovery is an important step in individualized
medicine," explains Dr. Siddiqi.
Currently, MG is diagnosed via the detection of acetylcholine
receptor and anti-MuSK, or muscle-specific kinase, antibodies.
However, previous research has shown that these do not correlate
with disease severity or clinical response. The identification of biomarkers to
detect the severity of MG has remained elusive — until now.
The new study focused on three subject groups. The first
consisted of 46 participants with MG, the second consisted of 23 participants
with rheumatoid arthritis (a
reference autoimmune disease), and the third comprised 49 healthy control
participants.
The study was a two-control approach for metabolomics profiling.
People with rheumatoid arthritis displayed physically identical symptoms to
those with MG, and all participants were age- and gender-matched as closely as
possible.
The researchers extracted serum from each person and analyzed
its principal components. They then filtered the metabolites to remove those
common to both disease cohorts, leaving just the unique markers, of which there
were 12.
Metabolomics profiling helps detect MG
Metabolomics profiling is the study of chemical processes and
molecules — including intermediates and byproducts — involved in metabolism,
which is vital for cell and organism survival.
Changes in metabolomics can have disastrous consequences and often lead to disease. Metabolite markers offer the possibility of identifying specific problems in metabolism associated with specific conditions, such as MG.
Changes in metabolomics can have disastrous consequences and often lead to disease. Metabolite markers offer the possibility of identifying specific problems in metabolism associated with specific conditions, such as MG.
The researchers found a clear distinction in
metabolite markers among all three study cohorts. In addition, there was a
clear separation between different stages of the disease, allowing for analysis
of disease progression.
There was specific upregulation of short-chain keto acids in
participants with MG, compared with controls. This included compounds such as
α-ketobutyric acid, a key regulator of metabolic pathways.
The upregulation of α-ketobutyric acid suggests that there is
enhanced metabolic activity in the cells of people with MG. The majority of
metabolites that the researchers identified also have significant roles in
energy production pathways.
Interestingly, researchers have also observed upregulation
of some metabolites in the blood serum of people with MS, suggesting that both
of these disorders are linked to energy shift in metabolic pathways.
Impaired glycolysis leads to reduced adenosine triphosphate synthesis, and in turn,
this can result in cell death and degeneration, symptomatic of MG.
Strengths and limitations of the study
This study demonstrates a rapid identification of metabolites
present in people who are showing symptoms of MG. This would give a huge
advantage to clinicians treating the disease and allow for quicker diagnosis.
"Right now we don't have the ability to manage [MG] in a
more specific way; we treat all patients the same," explains Dr. Siddiqi.
But the new findings might change this.
"Now we have a unique
fingerprint or map of metabolites that can easily separate healthy individuals
from those with [MG] and a path to the discovery of more accurate and specific
treatments."
Dr. Zaeem Siddiqi
"What we're trying
to do with this biomarker discovery is develop treatments specific to the needs
of the patient, to have more precise management, and to be able to more
accurately predict the effects of the treatments," continues the
researcher.
Although this study paves
the way for more detailed analysis of the metabolic profile of MG, there are
limitations to the work.
These include the fact
that some of the cohort had previously been treated with drugs that could have
altered their metabolic profile, and the participants were not required to fast
before the study.
Both of these factors
could have contributed to the identification of false positives. The analysis
would also benefit from a much larger sampling pool. This would also help
correlate work from previous studies.
Despite the limitations,
it is clear that the results could benefit those currently living with MG or
similar conditions.
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