Biomarkers in Painful Symptomatic Knee OA Demonstrate That MRI Assessed Joint Damage and Type II Collagen Degradation Products Are Linked to Disease Progression.

BACKGROUND: Osteoarthritis (OA) is the most prevalent arthritis worldwide, but the evolution of pain in relation to joint damage and biochemical markers are not well understood. We evaluated the relation between clinical pain measures and evoked pain in relation to structural damage and biochemical biomarkers in knee OA. METHODS: A cross-sectional study in people with knee OA and healthy controls was conducted. A total of 130 participants with advanced OA requiring total knee replacement (TKR) (n = 78), mild OA having standard care (n = 42) and non-OA controls (n = 6), with four drop-outs were assessed. Pain scoring was performed by the Western Ontario and McMaster Universities OA Index (WOMAC_P) and the Visual Analog Scale (VAS). Pain sensitization was assessed by pain pressure thresholds (PPTs). Knee magnetic resonance imaging (MRI) assessed joint damage using the MRI Knee OA Score (MOAKS). Overall MOAKS scores were created for bone marrow lesions (BMLs), cartilage degradation (CD), and effusion/Hoffa synovitis (tSyn). Type II collagen cleavage products (CTX-II) were determined by ELISA. RESULTS: The advanced OA group had a mean age of 68.9 ± 7.7 years and the mild group 63.1 ± 9.6. The advanced OA group had higher levels of pain, with mean WOMAC_P of 58.8 ± 21.7 compared with the mild OA group of 40.6 ± 26.0. All OA subjects had pain sensitization by PPT compared with controls (p < 0.05). WOMAC_P correlated with the total number of regions with cartilage damage (nCD) (R = 0.225, p = 0.033) and total number of BMLs (nBML) (R = 0.195, p = 0.065) using body mass index (BMI), age, and Hospital Anxiety and Depression Scale (HADS) as covariates. Levels of CTX-II correlated with tSyn (R = 0.313, p = 0.03), nBML (R = 0.252, p = 0.019), number of osteophytes (R = 0.33, p = 0.002), and nCD (R = 0.218, p = 0.042), using BMI and age as covariates. A multivariate analysis indicated that BMI and HADS were the most significant predictors of pain scores (p < 0.05). CONCLUSION: People with both mild and advanced OA show features of pain sensitization. We found that increasing MRI-detected joint damage was associated with higher levels of CTX-II, suggesting that increasing disease severity can be assessed by MRI and CTX-II biomarkers to evaluate OA disease progression.

The effect of pregabalin or duloxetine on arthritis pain: a clinical and mechanistic study in people with hand osteoarthritis.

Osteoarthritis (OA) is the most prevalent arthritis worldwide and is characterized by chronic pain and impaired physical function. We hypothesized that heightened pain in hand OA could be reduced with duloxetine or pregabalin. In this prospective, randomized clinical study, we recruited 65 participants, aged 40-75 years, with a Numerical Rating Scale (NRS) for pain of at least 5. Participants were randomized to one of the following three groups: duloxetine, pregabalin, and placebo. The primary endpoint was the NRS pain score, and the secondary endpoints included the Australian and Canadian Hand Osteoarthritis Index (AUSCAN) pain, stiffness, and function scores and quantitative sensory testing by pain pressure algometry. After 13 weeks, compared to placebo, ANOVA found significant differences between the three groups (P=0.0078). In the intention-to-treat analysis, the pregabalin group showed improvement for NRS pain (P=0.023), AUSCAN pain (P=0.008), and AUSCAN function (P=0.009), but no difference between duloxetine and placebo (P>0.05) was observed. In the per protocol analysis, NRS pain was reduced for pregabalin (P<0.0001) and duloxetine (P=0.029) compared to placebo. We conclude that centrally acting analgesics improve pain outcomes in people with hand arthritis, offering new treatment paradigms for OA pain.

Microarray analysis of bone marrow lesions in osteoarthritis demonstrates upregulation of genes implicated in osteochondral turnover, neurogenesis and inflammation.

OBJECTIVE: Bone marrow lesions (BMLs) are well described in osteoarthritis (OA) using MRI and are associated with pain, but little is known about their pathological characteristics and gene expression. We evaluated BMLs using novel tissue analysis tools to gain a deeper understanding of their cellular and molecular expression. METHODS: We recruited 98 participants, 72 with advanced OA requiring total knee replacement (TKR), 12 with mild OA and 14 non-OA controls. Participants were assessed for pain (using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)) and with a knee MRI (using MOAKS). Tissue was then harvested at TKR for BML analysis using histology and tissue microarray. RESULTS: The mean (SD) WOMAC pain scores were significantly increased in advanced OA 59.4 (21.3) and mild OA 30.9 (20.3) compared with controls 0.5 (1.28) (p<0.0001). MOAKS showed all TKR tissue analysed had BMLs, and within these lesions, bone marrow volume was starkly reduced being replaced by dense fibrous connective tissue, new blood vessels, hyaline cartilage and fibrocartilage. Microarray comparing OA BML and normal bone found a significant difference in expression of 218 genes (p<0.05). The most upregulated genes included stathmin 2, thrombospondin 4, matrix metalloproteinase 13 and Wnt/Notch/catenin/chemokine signalling molecules that are known to constitute neuronal, osteogenic and chondrogenic pathways. CONCLUSION: Our study is the first to employ detailed histological analysis and microarray techniques to investigate knee OA BMLs. BMLs demonstrated areas of high metabolic activity expressing pain sensitisation, neuronal, extracellular matrix and proinflammatory signalling genes that may explain their strong association with pain.

Use of the painDETECT tool in rheumatoid arthritis suggests neuropathic and sensitization components in pain reporting.

Rheumatoid arthritis (RA) is an inflammatory autoimmune condition typified by systemic inflammation targeted toward synovial joints. Inhibition of proinflammatory networks by disease-modifying antirheumatic drugs, eg, methotrexate and biologic therapies, including tumor necrosis factor-α inhibitors, often leads to suppression of disease activity observed at the clinical level. However, despite the era of widespread use of disease-modifying treatments, there remain significant groups of patients who continue to experience pain. Our study formulated a pain assessment tool in the arthritis clinic to assess feasibility of measurements including the visual analog scale (VAS) and painDETECT to assess multimodal features of pain in people with established RA (n=100). Clinical measures of disease activity (Disease Activity Score in 28 Joints [DAS28]) were also recorded. Our data showed that despite the majority of subjects on at least one disease-modifying agent, the majority of patients reported severe pain (54%) by VAS, despite well-controlled clinical disease, with mean DAS28 2.07±0.9. Using the painDETECT questionnaire, 67% of patients had unlikely neuropathic pain. A significant proportion of subjects (28%) had possible neuropathic pain and 5% had features of likely neuropathic pain by painDETECT scoring. We found a positive correlation between VAS and painDETECT (R (2)=0.757). Of note, the group who had likely or probable neuropathic pain also showed significantly increased pain reporting by VAS (P<0.01). Subjects who were clinically obese (body mass index >30) also had statistically higher proportions of pain reporting (VAS 89.0±0.7 mm) compared with subjects who had a normal body mass index (VAS 45.2±21.8 mm), P<0.05. Our findings suggest that multimodal features of pain perception exist in RA, including neuropathic and sensitization elements, perhaps explaining why a subgroup of people with RA continue to experience ongoing pain, despite their apparent suppression of inflammation.