Monday, March 23, 2015

Biomarkers of Early Stage Osteoarthritis, Rheumatoid Arthritis

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