Background/Purpose:
Connective tissue degradation and formation is markedly increased in rheumatoid
arthritis (RA). Increased tissue formation may result in fibrosis, whereas
increased degradation may result in joint and tissue destruction. Different interventions
such as anti-TNF-α,
Anti-IL6R and JAK may provide both similar and different responses on key
tissues.

Quantification of circulating levels of specific neo-epitopes of
the extracellular matrix may act as biomarkers of connective tissue turnover
and thereby may be used as objective tools for monitoring treatments effects in
RA. Type II collagen formation (PRO-C3) has been demonstrated to be both a
diagnostic marker for the presence of liver fibrosis and in addition to provide
prognostic information on progression.

The aim of the study was to investigate the effect of fibrogenesis biomarkers in RA patients as an effect of
methotrexate (MTX) combined with either tocilizumab
(TCZ, anti-IL-6R), tofacitinib (TOFA, JAK inhibitor),
adalimumab (ADA, anti-TNF-α) or given as a monotherapy.

Methods:
149 RA patients were included at the time of initiating one of the following
treatments: 1) MTX; 23, 2) ADA+MTX; 49, 3) TOFA+MTX; 27, and 4) TCZ+MTX; 50.
Serum samples were drawn along with Sharp-vdH
score (SHS) and other clinical data at baseline and again 1 year after
initiation of treatment (follow-up). Type III collagen formation, PRO-C3, ASAT,
and ALAT were measured in the serum samples. Wilcoxon matched-paired rank test
was performed. Error bars are shown as SEM.

Results:
Anti-TNF-α,
and anti-IL6-R resulted both in statistical increase in the liver enzymes ASAT
and ALAT, whereas JAK intervention did not. Interestingly, the PRO-C3 marker was
significantly (P<0.05) inhibited by JAK inhibition in the TOFA group from
19.9ng/ml on average at baseline to 16.4ng/ml at follow-up, whereas the other
treatments did not affect PRO-C3 significantly. Also, although serum EGF levels were decreased by
anti-TNF and anti-IL-6, they are increased by TOFA.

Conclusion:
Increased tissue remodeling is a characteristic of rheumatoid arthritis, in
which both formation and degradation is affected. JAK inhibition resulted in a
significant attenuation of a marker of fibrogenesis
and could be involved in mesenchymal-epithelial transition,
which warrant further investigation of the effect if JAK inhibition compared to
that of anti-TNF-α
and anti-IL6R.

Figure
1, Evaluations of ASAT, ALAT and Pro-C3 at baseline and follow-up.
Difference between baseline and Follow-up was evaluated by mean of Wilcoxon
match pairs signed rank test. *p<0.05, **
p<0.01, ***p<0.001. Error bars are illustrated as SEM.