Rheumatoid arthritis (RA)
is a chronic disease that causes pain, stiffness, swelling, and
limitation in the motion and function of multiple joints. Though joints
are the principal body parts affected by RA, inflammation can develop in
other organs as well. An estimated 1.3 million Americans have RA, and
the disease typically affects women twice as often as men.
Early diagnosis and initiation of effective therapy is an important
strategy in RA management. Researchers at the Mayo Clinic in Rochester,
Minn., drew on their recent findings that showed that RA patients'
pre-treatment serum type-1 interferon (IFN)-β/α ratio could predict
their response to tumor necrosis factor-alpha inhibitors (TNFi). They
conducted a new study to look for the cellular mechanisms involved in
‘Distinct gene expression signatures in rheumatoid arthritis patients could help predict how these individuals will respond to tumor necrosis factor inhibitors.’
Distinct gene expression signatures in rheumatoid arthritis patients
could help rheumatologists predict how these individuals will respond to
tumor necrosis factor inhibitors, and may one day enable a more
personalized approach to RA therapy, revealed new research findings
presented this week at the 2016 ACR/ARHP Annual Meeting in Washington.
"The aim of this study was to better understand the impact of the
type-I interferon ratio that predicts non-response to TNFi therapy on a
major inflammatory cell type involved in RA," said Theresa L. Wampler
Muskardin,a rheumatologist in the Department of Pediatric and
Adolescent Medicine, and a lead author of the study. "Effects of type-I
interferon on single cells and immune cell subtypes may be missed when
we analyze whole blood or mixed cell populations. Using single cell gene
expression technology, we hoped to find differences in expression of
select genes between treatment responders and non-responders, which
could ultimately lead to a blood test that we can use to guide treatment
decisions in RA patients prior to starting biologic therapy."
The researchers used single cell expression analysis to study
whether monocyte gene expression was significantly different among RA
patients based on their pre-treatment blood serum IFN- β/α ratio. They
isolated single classical (CL) and single non-classical (NC)
blood-derived monocytes from 15 seropositive RA patients before TNFi
therapy. The patients were divided into two groups according to their
pre-TNFi serum ratio: six patients in IFN-β/α>1.3 and nine patients
in IFN-β/α<1.3. The researchers performed unsupervised hierarchical
clustering of 87 target genes on the single monocytes.
Results of the testing showed that JAK1 and IL1A strongly
differentiated between the two groups. In NC cells only, expression of
STAT2, ILT7, PKR, TLR7 and IRAK1 were more likely in the non-response
patient group. In CL cells only, expression of IFIT2 and CD36 was more
likely. In a multivariate logistic regression, IL1A, CD32a, IL-8, TYK2
and IRAK1 in NC plus CL monocytes aligned with the treatment response
groups. In comparison with that mixed monocyte model, IL-8 and IRAK1 in
NC, and CXCR3 in CL showed even stronger alignment with the treatment
response groups. STAT2 strongly predicted the response group in NC cells
alone. CXCL9 strongly predicted the response group in CL cells alone.
Their previous work showed that an IFN- β/α ratio>1.3 is
predictive of non-response to anti-TNF therapy in RA patients. In this
study, their findings show that gene expression in monocyte subsets
differ in RA patients who have an IFN-β/α ratio>1.3, the ratio of
type-I IFNs that predicts non-response to anti-TNF therapy.
"Difference between therapy response groups was strongest when the
monocyte subsets were analyzed separately, rather than together, and
distinct expression signatures were identified in the subsets," said Dr.
Muskardin. "This suggests that investigating these biological pathways
in monocyte subsets will provide further insight into the biology that
determines TNFi treatment response in RA, and may identify other targets
for therapy or other markers predictive of TNFi response that may be
easier to measure."
Future studies should focus on monocyte subsets to identify possible
molecular differences that could also determine treatment response to
TNFi biologics. In the future, rheumatologists may be able to tailor
therapy to an RA patient based on his or her underlying disease biology,
Dr. Muskardin concluded.