The Impact of Weight-bearing Exercise, Non-Weight-bearing Exercise, and Cardiovascular Stress on Biochemical Markers of Cartilage Turnover in Patients With Mild to Moderate Knee Osteoarthritis: A Sequential, Cross-Over, Clinical Study.

OBJECTIVE: To investigate how running, cycling, and sedentary cardiovascular stress impact biomarkers of cartilage turnover acutely in subjects with knee osteoarthritis (OA). DESIGN: This was a sequential, cross-over, clinical study. Forty subjects with primary knee OA underwent moderate-to-high-intensity cycling, running, and adrenaline infusion on separate days. Blood was sampled before, during, and at 6-time points after intervention. On a control day, similar samples were taken. Biomarkers of type II collagen degradation (C2M, T2CM, Coll2-1, Coll2-1NO2), formation (PRO-C2), and aggrecan degradation (ARGS) were measured. RESULTS: Mean age was 60.4 years, 40% were male, 45% had cumulated Kellgren-Lawrence (KL)-grade (Right + Left knee) of 2 to 3 and 55% had 4 to 6. Analyzing overall changes, area under the curve was significantly lower compared with resting values for ARGS and C2M after cycling and for ARGS after running. Considering individual time points, peak changes in biomarker levels showed reduction in C2M shortly following cycling (T20min = -12.3%, 95% confidence interval [CI]: -19.3% to -5.2%). PRO-C2 increased during cycling (T10min = 14.0%, 95% CI = 4.1% to 23.8%) and running (T20min = 16.5%, 95% CI = 4.3% to 28.6%). T2CM decreased after cycling (T50min = -19.9%, 95% CI = -29.2% to -10.6%), running (T50min = -22.8%, 95% CI = -32.1% to -13.5%), and infusion of adrenaline (peak, T50min = -9.8%, 95% CI = -20.0% to 0.4%). A latent increase was seen in Coll2-1 240 minutes after running (T260min = 21.7%, 95% CI = -1.6% to 45.1%). CONCLUSION: Exercise had an impact on cartilage markers, but it did not suggest any detrimental effect on cartilage. Changes following adrenaline infusion suggest a sympathomimetic influence on the serological composition of biomarkers.

The fibroid phenotype of biological naïve patients with rheumatoid arthritis are less likely to respond to anti-IL-6R treatment.

Type III collagen gene expression is upregulated in the synovium of patients with rheumatoid arthritis (RA) presenting the fibroid phenotype. The soluble type III collagen formation biomarker, PRO-C3, is known to measure fibrogenesis in fibrotic diseases. In this exploratory study, we aimed to investigate the association between fibrogenesis (PRO-C3) and the disease- and treatment response in patients with RA. We measured PRO-C3 in subsets of two clinical trials assessing the effect of the anti-interleukin-6 (IL-6) receptor treatment tocilizumab (TCZ) as monotherapy or polytherapy with methotrexate. PRO-C3 levels had weak or very weak correlations with the clinical parameters (Spearman's). However, when the patients were divided into Disease Activity Score-28 groups characterized by the erythrocyte sedimentation rate (DAS28-ESR), there was a statistical difference between the PRO-C3 levels of the different groups (p < 0.05). To determine the response in relation to PRO-C3, a cut-off based on PRO-C3 levels and patients in remission (DAS28-ESR ≤ 2.6) was identified. This showed that a reduction in PRO-C3 after treatment initiation was associated with decreased DAS28-ESR and a higher response rate in patients with low PRO-C3 levels than in those with high PRO-C3 levels. This indicates that a fibrotic component affects the responsiveness of patients.

From biochemical markers to molecular endotypes of osteoarthritis: a review on validated biomarkers.

INTRODUCTION: Osteoarthritis (OA) affects over 500 million people worldwide. OA patients are symptomatically treated, and current therapies exhibit marginal efficacy and frequently carry safety-risks associated with chronic use. No disease-modifying therapies have been approved to date leaving surgical joint replacement as a last resort. To enable effective patient care and successful drug development there is an urgent need to uncover the pathobiological drivers of OA and how these translate into disease endotypes. Endotypes provide a more precise and mechanistic definition of disease subgroups than observable phenotypes, and a panel of tissue- and pathology-specific biochemical markers may uncover treatable endotypes of OA. AREAS COVERED: We have searched PubMed for full-text articles written in English to provide an in-depth narrative review of a panel of validated biochemical markers utilized for endotyping of OA and their association to key OA pathologies. EXPERT OPINION: As utilized in IMI-APPROACH and validated in OAI-FNIH, a panel of biochemical markers may uncover disease subgroups and facilitate the enrichment of treatable molecular endotypes for recruitment in therapeutic clinical trials. Understanding the link between biochemical markers and patient-reported outcomes and treatable endotypes that may respond to given therapies will pave the way for new drug development in OA.

Changes in type VI collagen degradation reflect clinical response to treatment in rheumatoid arthritis patients treated with tocilizumab.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation in multiple articular joints, causing pain, joint damage, and loss of joint function. Despite the successful development of disease-modifying therapies, the heterogeneity of RA means that a significant proportion of patients respond poorly to treatment. This highlights the need for personalized medicine and predictive biomarkers to optimize treatment efficacy, safety, and cost. This study aimed to explore the relationship between type VI collagen (Col VI) remodeling and clinical response to anti-IL-6 receptor treatment. METHODS: Type VI collagen degradation was quantified using the C6M biomarker, a fragment of type VI collagen degraded by MMPs. Longitudinal differences in average biomarker levels between placebo and treatment groups were estimated using linear mixed models. The predictive capacity of the marker based on change from baseline to 4 weeks was analyzed using logistic regression. RESULTS: Both 4 mg and 8 mg doses of Tocilizumab (TCZ) reduced serum C6M concentrations compared to the placebo. Furthermore, C6M levels were more reduced in patients responding to treatment compared to early non-responders. A lower early reduction in C6M was associated with reduced odds of ACR treatment response and lowered disease activity. CONCLUSION: These findings suggest that quantifying type VI collagen turnover may aid in identifying patients less likely to respond to treatment, indicating a new path towards optimizing patient care. Further studies are needed to validate these findings and explore the underlying mechanisms driving the observed relationships.

Evaluating the inhibition of IL-17A and TNFα in a cartilage explant model cultured with Th17-derived cytokines.

Introduction: T-helper 17 (Th17) cells produce IL-17A playing a critical role in activating the pathogenic chain leading to joint tissue inflammation and destruction. Elevated levels of Th17 cells and IL-17A have been detected in skin lesions, blood, and synovial fluid from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Moreover, IL-17A inhibitors suppress disease activity in psoriasis, PsA and AS, supporting the evidence of IL-17A contributing to the disease pathogenesis. Although, IL-17A inhibitors are widely approved, it remains unclear how the inhibitory effect of IL-17A alters the extracellular matrix (ECM) of the joint in a Th17-conditioned inflammatory milieu. Therefore, the aim of this study was to establish a cartilage model cultured with conditioned medium from Th17 cells and inhibitors to explore the effect of IL-17A inhibition on joint tissue remodeling. Methods: Naïve CD4+ T cells from healthy human buffy coat were differentiated into Th17 cells, followed by Th17 cell activation to secrete Th17-related cytokines and molecules into media. The activated Th17 cells were isolated from the conditioned media (CM) and analyzed using flow cytometry to verify Th17 cell differentiation. The CM were assessed with ELISA to quantify the concentrations of cytokines secreted into the media by the Th17 cells. Healthy bovine cartilage explants were cultured with the Th17-CM and treated with IL-17A and TNFα inhibitors for 21 days. In harvested supernatant from the cartilage cultures, MMP- and ADAMTS-mediated biomarker fragments of type II collagen, aggrecan, and fibronectin were measured by ELISA to investigate the ECM remodeling within the cartilage tissue. Results: Th17-CM stimulated a catabolic response in the cartilage. Markers of type II collagen and aggrecan degradation were upregulated, while anabolic marker of type II collagen formation remained on similar levels as the untreated explants. The addition of IL-17A inhibitor to Th17-CM decreased the elevated type II collagen and aggrecan degradation, however, degenerative levels were still elevated compared to untreated group. The addition of TNFα inhibitor completely reduced both type II collagen and aggrecan degradation compared to untreated explants. Moreover, the TNFα inhibitor treatment did not alter the type II collagen formation compared to untreated group. Conclusion: This study suggests that inhibition of IL-17A in Th17-conditioned cartilage tissue only partially reduced the MMP-mediated type II collagen degradation and ADAMTS-mediated aggrecan degradation, while the TNFα inhibitor treatment fully reduced both MMP- and ADAMTS-mediated ECM degradation. This exploratory study where ECM biomarkers are combined with Th17-conditioned ex vivo model may hold great potential as output for describing joint disease mechanisms and predicting structural effects of treatment on joint tissue.