Drilling down to the bone: Evaluating Bone Marrow Lesions in Osteoarthritis

Osteoarthritis (OA) is the most prevalent form of arthritis worldwide and affects the whole joint. Changes in cartilage integrity, subchondral bone, and synovitis are recognised during OA progression. Although advances have been made in our understanding of OA pathophysiology, there are no current treatments that halt the progression of the disease. Treatments are largely based on physical therapies to improve joint function, anti-inflammatory agents to manage pain, and joint replacement surgery for late-stage disease in large weight-bearing joints. There is, therefore, an urgent need to better understand OA pathophysiology, which could help in the development of new treatments. The aim of this article is to review the evidence for structural correlates of pain and reduced joint function in OA; the data available for different joint compartments, including cartilage, bone, and the synovium, and their association with symptoms of OA are summarised and the use of imaging tools in assisting the understanding of OA pathophysiology is discussed. In recent years, more advanced imaging techniques, including MRI, have led to an improved understanding of changes at the bone–cartilage interface in OA, with a recognition that loss of integrity at this junction and development of bone marrow lesions (BML) in the subchondral bone are associated with OA pain in large epidemiological studies. One of the main challenges in OA BML research has been identifying the structural characteristics and patterns of gene and protein expression. Gene analyses of BML have demonstrated that they are highly metabolically active structures, providing evidence of angiogenesis, new bone and cartilage formation, and expression of neurotrophic factors. Findings from genomic and proteomic studies of BML, which are discussed in this review, have contributed to the identification of new molecular targets and an increase in our understanding of OA pathophysiology

Understanding the Mechanisms of Pain in Rheumatoid Arthritis

Pain is a debilitating feature of rheumatoid arthritis (RA) and is often described by patients as their most important symptom. Rheumatoid arthritis pain has traditionally been attributed solely to joint inflammation, however despite the advent of increasingly effective disease modifying agents, patients continue to report pain at long term follow up. The cause for ongoing pain is multifactorial and includes joint damage and pain sensitisation. In this book chapter, we will describe the mechanisms underlying the distinct components of pain which are manifest in rheumatoid arthritis and discuss why a thorough assessment of pain is vital to target treatments appropriately

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 (P30) 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

Quantitative sensory testing in painful hand osteoarthritis demonstrates features of peripheral sensitisation.

Hand osteoarthritis (HOA) is a prevalent condition for which treatments are based on analgesia and physical therapies. Our primary objective was to evaluate pain perception in participants with HOA by assessing the characteristics of nodal involvement, pain threshold in each hand joint, and radiological severity. We hypothesised that inflammation in hand osteoarthritis joints enhances sensitivity and firing of peripheral nociceptors, thereby causing chronic pain. Participants with proximal and distal interphalangeal (PIP and DIP) joint HOA and non-OA controls were recruited. Clinical parameters of joint involvement were measured including clinical nodes, VAS (visual analogue score) for pain (0-100 mm scale), HAQ (health assessment questionnaire), and Kellgren-Lawrence scores for radiological severity and pain threshold measurement were performed. The mean VAS in HOA participants was 59.3 mm ± 8.19 compared with 4.0 mm ± 1.89 in the control group (P < 0.0001). Quantitative sensory testing (QST) demonstrated lower pain thresholds in DIP/PIP joints and other subgroups in the OA group including the thumb, metacarpophalangeal (MCPs), joints, and wrists (P < 0.008) but not in controls (P = 0.348). Our data demonstrate that HOA subjects are sensitised to pain due to increased firing of peripheral nociceptors. Future work to evaluate mechanisms of peripheral sensitisation warrants further investigation

Tenascin-C fragments are endogenous inducers of cartilage matrix degradation

Cartilage destruction is a hallmark of osteoarthritis (OA) and is characterized by increased protease activity resulting in the degradation of critical extracellular matrix (ECM) proteins essential for maintaining cartilage integrity. Tenascin-C (TN-C) is an ECM glycoprotein, and its expression is upregulated in OA cartilage. We aimed to investigate the presence of TN-C fragments in arthritic cartilage and establish whether they promote cartilage degradation. Expression of TN-C and its fragments was evaluated in cartilage from subjects undergoing joint replacement surgery for OA and RA compared with normal subjects by western blotting. The localization of TN-C in arthritic cartilage was also established by immunohistochemistry. Recombinant TN-C fragments were then tested to evaluate which regions of TN-C are responsible for cartilage-degrading activity in an ex vivo cartilage explant assay measuring glycosaminoglycan (GAG) release, aggrecanase and matrix metalloproteinase (MMP) activity. We found that specific TN-C fragments are highly upregulated in arthritic cartilage. Recombinant TN-C fragments containing the same regions as those identified from OA cartilage mediate cartilage degradation by the induction of aggrecanase activity. TN-C fragments mapping to the EGF-L and FN type III domains 3-8 of TN-C had the highest levels of aggrecan-degrading ability that was not observed either with full-length TN-C or with other domains of TN-C. TN-C fragments represent a novel mechanism for cartilage degradation in arthritis and may present new therapeutic targets for the inhibition of cartilage degradation

Reduced anterior cingulate grey matter volume in painful hand osteoarthritis

Objective Increasing evidence supports the role of central sensitisation in osteoarthritis (OA) pain. In this study, we used neuroimaging to compare pain-processing regions of the brain in participants with and without hand OA. We then assessed for volumetric changes in these brain regions following treatment with centrally acting analgesics. Methods Participants with hand OA (n = 28) underwent T1-weighted MRI of the brain before and after 12 weeks of treatment with pregabalin, duloxetine or placebo. Grey matter volume in the anterior cingulate cortex (ACC), insular cortex and thalamus was compared to non-OA control subjects (n = 11) using FreeSurfer regional volumetric analysis and voxel-based morphometry, and evaluated for differences pre- and post-treatment. Results Relative to non-OA controls, hand OA participants had areas of reduced grey matter volume in the ACC at baseline (p = 0.007). Regional volumetric differences in the ACC persisted after 13 weeks’ treatment with pregabalin or duloxetine (p = 0.004) with no significant differences between treatment cohorts, despite improvements in NRS pain scores for pregabalin (p = 0.005) and duloxetine (p = 0.050). The ACC grey matter changes persisted despite a significant improvement in pain in the pregabalin and duloxetine groups vs. placebo. No structural differences were observed in the insular cortex or thalamus at baseline or following treatment. Conclusion Our study found evidence of reduced ACC grey matter volume in participants with hand arthritis that persisted after treatment with centrally acting analgesics pregabalin and duloxetine, respectively. The sustained changes observed in the ACC in our study could reflect the relatively short duration of treatment, or that the differences observed are irreversible volume changes due to chronic pain that are established over time