Biomarkers of Early Stage Osteoarthritis, Rheumatoid Arthritis
Musculoskeletal disease including osteoarthritis (OA) and
rheumatoid arthritis (RA) is the most common cause of chronic disability
worldwide and is increasingly important in current ageing populations. Severe
life impairment may be prevented if decline in musculoskeletal health and
development of OA and RA are identified and treated in the early stages.
An inexpensive, minimally invasive biochemical test which
preferably detects and distinguishes common types of arthritis at the early
stage is required. Magnetic resonance imaging (MRI) techniques have been developed
for early-stage evaluation of cartilage damage in OA. MRI is an expensive
technique and also not favoured by all. Early biochemical tests for detection
of established RA were based on measurement of rheumatoid factor (RF) which in
current form have reported sensitivity and specificity of 63% and 94%
respectively for established or advanced disease. RF is often negative with
eRA. The anti-cyclic citrullinated peptide (CCP) antibody test is used for
early-stage detection of RA and has sensitivity of 61%.
There is currently no
simple biochemical test to detect early-stage osteoarthritis (eOA) and to
discriminate different types of early-stage arthritis.
Tests for early-stage rheumatoid arthritis (eRA) such as RF and CCP antibodies
require refinement to improve clinical utility. Researchers have developed robust mass spectrometric methods
to quantify citrullinated protein (CP) and free hydroxyproline (Hyp) in body
fluids. On correlating CP in the plasma of healthy subjects it was surprisingly
found that CP was increased in both patients with eOA and eRA whereas anti-CCP
antibodies were predominantly present in eRA.
A 4-class diagnostic algorithm combining plasma/serum CP,
anti-CCP antibody and hydroxyproline applied to a cohort gave specific and
sensitive detection and discrimination of eOA, eRA, other non-RA inflammatory
joint diseases and good skeletal health. This provides a first-in-class
plasma/serum-based biochemical assay for diagnosis and type discrimination of
early-stage arthritis to facilitate improved treatment and patient outcomes,
exploiting citrullinated protein and related differential autoimmunity.
The clinical presence of anti-CCP antibodies, antibodies
which bind to synthetic cyclic citrullinated peptide, are considered to reflect
immunogenicity of endogenous citrullinated proteins (CPs) but the diagnostic
utility of CPs has hitherto been little explored.
The researchers hypothesized that changes in plasma CP and Hyp, combined with anti-CCP antibody test, would
provide improved diagnostic power over current standard techniques for
diagnosis of early-stage arthritis.
The surprising and remarkable biochemical finding of this
study is increased levels of plasma CP in eOA. Increased CP was found in serum
of eRA but this was suspected with regard to the high prevalence of anti-CCP
antibody positivity in eRA. Also remarkable was the higher CP concentration in
plasma than in synovial fluid of patients with eOA and reversal of this in
patients with aOA. Autoimmunity to CP is important in the pathogenesis of RA
and underlies the diagnostic utility of anti-CCP antibody measurement for eRA5.
We found high levels of serum CP in patients with eRA and association of this
with anti-CCP antibodies, consistent with formation and immunogenicity of CPs.
Article citation: Ahmed, U.; et. al. Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health. Scientific Reports, 2015, 5, Article number: 9259 doi:10.1038/srep09259
