Background/Purpose: Osteoarthritis (OA) is a chronic disease characterized by pain and disability. Central to the revised FDA guidelines for the approval of a disease modifying OA drug are patient reported outcomes (PROs). There is a need in drug development to understand how biomarkers of tissue remodeling objectively relate to PROs, or even predict changes in PROs. Recently, it was shown that levels of the CRP metabolite (CRPM), but not CRP, with concentrations of above 9 ng/mL were prognostic of knee OA progression assessed by X-ray. Moreover, that 1/3 of OA patients had levels of CRPM like that of RA patients. While several biomarkers of tissue modeling correlate to disease activity score in RA, this information is missing in OA. The joint comprises of multiple connective tissues which consist of collagen such as type I, II, III and IV. Biomarkers have been developed which measures the remodeling of collagens. We hypothesis that such markers may provide the missing link between OA pathology and PROs. We differentiated an OA population in high and low CRPM and investigate the relationship to PROS to serological biomarker of tissue turnover.

Methods: 111 knee OA patients, 62% women, from the placebo arm of a phase III study with knee OA were included: mean (SD) age, 32(10); mean (SD) BMI, 27(4); NSAID users, 32%; and radiographic OA (KL≥2) 68%. PROs were: VAS_pain and WOMAC total, pain, stiffness, and function at baseline (BL). 19 healthy individuals were included as reference. Median (IQR) were 39 (13-69) and 37 (13-52) for BL VAS_pain and WOMAC_pain. Eight serum biomarkers of type I, II, III and IV collagen degradation (C1M, C2M, C3M, C4M) and formation (PRO-C1, PRO-C2, PRO-C3 and PRO-C4) as well as two inflammatory biomarkers CRPM and hsCRP, were assessed. Log2 transformed data was adjusted for race, gender, age, and BMI.

Results: None of the collagen formation or degradation markers were on average higher or lower in OA than healthy controls (adjusted for age, gender, race, and BMI). No correlations between collagen markers and PROs were observed. We confirmed the previous identified cut-off and found an AUC of 0.61 (p=0.078, cut-off of 8.7). In patients with low CRPM: PRO-C2 was positively correlated with VASpain (r=0.53) WOMAC total and pain (r=0.22) and PRO-C4 negatively with WOMACpain (r=-0.26). In patients with high CRPM: PRO-C4 was positively correlated with VASpain (r=0.29), WOMACtotal, pain and stiffness (r=0.28, 0.3 and 0.22). C1M was correlated with VASpain (r=0.20), WOMACtotal, pain, stiffness and function (r=0.32, 0.24, 0.29, 0.30). C2M was negatively correlated with VASpain (r=-0.28), WOMACtotal, pain, stiffness and function (r=-0.49, -0.43, 0.44, -0.43). C3M was also negatively correlated with VASpain (r=-0.44), WOMACtotal, pain, stiffness and function (r=-0.51, -0.42, -0.55, -0.49).

Conclusion: Biomarkers of tissue remodeling did not correlate to PROs in the undifferentiated OA population. In contrast, the two distinct subpopulations of ether low or high CRPM had multiple correlation between tissue turnover and PROs. The data provide the first insights into objective tissue turnover biomarkers and PROs, which is essential for successful drug development, and in the understanding of the processes in the OA joint causing pain.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/osteoarthritis-patients-feel-their-tissue-remodeling/