Circulating Protein Fragments of Cartilage and Connective Tissue Degradation Are Diagnostic and Prognostic Markers of Rheumatoid Arthritis and Ankylosing Spondylitis

Abstract

Inflammation driven connective tissue turnover is key in rheumatic diseases, such as ankylosing spondylitis (AS). Few biomarkers are available for measuring disease prognosis or the efficacy of interventions applied in these tissue-related conditions. Type II collagen is the primary structural protein of cartilage and type III collagen of connective tissues, and obvious targets for the collagenalytic, which increase during tissue inflammation. The objective of the study was to investigate the diagnostic and prognostic utility of cartilage, C2M, and synovial, C3M, turnover biomarkers in AS. Serum samples were retrieved from patients suffering from AS (n = 103), RA (n = 47) and healthy controls (n = 56). AS progressors were defined as having new vertebral syndesmophytes or more that 3 unit change in mSASSS over a two-year period. Type II collagen degradation markers in serum were measured by the C2M ELISA, and type III collagen degradation by the C3M ELISA. Logistic regression and dichotomized decision tree were used to analyze the prognostic value of the markers individually or in combination. Both C2M and C3M levels were significantly higher in RA patients than in healthy controls (p<0.0001). Diagnostic utility was analyzed by ROC and areas under the curve (AUCs) were 72% and 89% for C2M and C3M, respectively. Both C2M and C3M, were significantly higher in serum samples from AS patient than from healthy controls (p<0.0001). The AUCs of C2M and C3M, respectively, were 70% and 81% for AS. A combination of C2M and C3M, dichotomized according to best cut-offs for individual markers, could correctly identify 80% of the progressors and 61% of the non-progressors. The present study is the first to show that specific biomarkers of cartilage and connective tissue degradation facilitate both diagnosis and prediction of progression of RA and AS.

Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis

“…In yet another examination looking at MRI scans in AxSpA patients [61], higher pretreatment MRI inflammation scores for SI joints and/or lumbar spine were associated with higher baseline CTX-II levels, but not with higher levels of other biomarkers of inflammation and bone turnover. Two neo-epitope biomarkers, C2M, which measures a matrix metalloproteinase (MMP)-generated neo-epitope of type II collagen and C3M, a marker of soft tissue turnover associated with inflammation which directly measure tissue remodeling, have been shown to be elevated in AS patients [62], and in one report, a combination of C2M and C3M was dichotomized according to the best cut-offs for individual markers to predict 80 % of the radiographic progressors and 61 % of the non-progressors.…”

Redox proteomics gives insights into the role of oxidative stress in alkaptonuria

“…Several areas of medicine lack biomarkers to follow disease progression and response to therapy. This is not only true for AKU but also for more common human diseases such as inflammatory arthritis [64,65]. In the biomarker discovery process, genomics and transcriptomics are powerful methods; nevertheless, they cannot match the power of proteomics and MS, allowing for the simultaneous identification and quantification of proteins in complex biological mixtures, which provided the researchers with unprecedented and invaluable tools for the discovery of novel biomarkers which may help a predictive and personalized medicine in the future [66].…”

Association between biochemical cartilage markers and clinical symptoms in patients with hip osteoarthritis: cohort study with 2-year follow-up

“…Although serum CIIM levels are reported to be higher in patients with radiographic knee OA than in those without radiographic knee OA, its relationship with pain has not previously been investigated 6 . Serum CIIM levels are reported to be somewhat predictive for structural progression in ankylosing spondylitis 19 and for treatment response in rheumatoid arthritis 20 .…”