Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health

Abstract

There is currently no biochemical test for detection of early-stage osteoarthritis (eOA). Tests for early-stage rheumatoid arthritis (eRA) such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies require refinement to improve clinical utility. We developed robust mass spectrometric methods to quantify citrullinated protein (CP) and free hydroxyproline in body fluids. We detected CP in the plasma of healthy subjects and 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.

Protein oxidation, nitration and glycation biomarkers for early-stage diagnosis of osteoarthritis of the knee and typing and progression of arthritic disease

“…Patient recruitment, characteristics and sampling was as previously described [16]. The recruited study groups are illustrated in Fig.…”

“…The presumed antigen is citrullinated protein (CP), which we recently identified as increased in both eRA and eOA, with only dominant immunogenicity in the former [16]. The anti-CCP antibody test is now considered state-of-the-art in RA diagnosis.…”

“…Plasma levels of oxidized, nitrated and glycated amino acids may thereby provide signatures of protein damage, dysfunction and disease progression in the joint in early and advanced stage arthritis. In combination with the biomarker of bone turnover and resorption - hydroxyproline (Hyp) - and anti-CCP antibody status, the signature may be made specific for arthritic disease [15, 16, 18]. …”

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

“…Joint space narrowing is still the FDA‐approved standard for clinical efficacy and many of the other outcomes are inferred. MRI provides moderate sensitivity and there are few biochemical tests that are prognostic or diagnostic 103, 104. Currently, efforts to validate and qualify new biomarkers are focussed on further imaging and biochemical tests (Osteoarthritis Biomarker Consortium).…”

“…For example, in work from our group38 the Rho GTPase dissociation inhibitor Arhgdib was found to discriminate between healthy and diseased cartilage derived from the RAAK dataset 108. Other machine learning tools have been used for discriminatory analysis of a combination of biochemical markers, including citrullinated protein expression, between individuals with musculoskeletal disorders including early OA 103. As systems approaches bed down in OA research a key objective is to undertake discrimination analysis to establish genetic sub‐populations.…”