According to a recently published study, low expression of
CD39 on regulatory T cells (Tregs) could be used as a biomarker for resistance
to methotrexate (MTX) therapy in rheumatoid arthritis (RA). MTX, an
antimetabolic drug, is the first line of therapy for RA patients. However, up
to 40% of patients are unresponsive to MTX (or UR-MTX resistant). There is a
need to early diagnose MTX resistance as the resistance generally appears after
3 months of therapy and that means worsening of RA symptoms during that time.
The study published in January
issue of PNAS shows that low expression of CD39 on circulating Tregs is a
rapid, reliable and convenient biomarker for MTX resistance.
RA is an inflammatory autoimmune disease associated with
joint destruction and severe morbidity. MTX has been generally used as drug to
treat RA. MTX has two known functions: inhibitor of dihydrofolate
reductase/folic acid metabolism and reducing inflammation by elevation of
extracellular adenosine (ADO). Tregs are regulatory T cells responsible for
keeping the immune system in check by suppressive activation and proliferation
of wide variety of cell types. One of the mechanisms through which Treg
suppress other cells is through production of extracellular ADO by CD39/CD73,
expressed on the surface of Tregs.
Given that the MTX also exerts its effect through generation
of ADO by CD39/CD73 and that CD39/CD73 are also important in Tregs activity,
the authors investigated possible link between MTX unresponsiveness and expression
of CD39 on Tregs in RA patients. The authors first observed that parameters
related to disease severity were significantly higher in UR-MTX patients than
in R-MTX (responsive) patients. Furthermore, the number of circulating Tregs
was lower in UR-MTX than in R-MTX. Encouraged by these findings, the
researchers compared expression of CD39 and CD73 on Tregs from R-MTX and UR-MTX
RA patients. The expression of CD39 on Trges from UR-MTX RA patients was
significantly lower than that in R-MTX patients. To find out if the increase in
number of CD39+Tregs in R-MTX was a result of MTX treatment, the authors
followed some patients and studied CD39+ expression on T regs before and after
treatment. Although there was no difference in percentage of CD39+ tregs in R
and UR-MTX before treatment, their numbers increased much more in R-MTX
patients than in UR-MTX patients following treatment. They further observed
that the density of expression of CD39 was low in UR-MTX patients before and
after treatment in comparison to R-MTX patients.
Various attempts have been made in the past to identify a
biomarker for MTX unresponsiveness. This study provides a unique non-invasive approach
of using CD39 expression on Tregs as biomarker for unresponsiveness.
