Nidhi Sofat

Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease.

Although there have been major advances in the treatment of rheumatoid arthritis with the advent of biological agents, the mechanisms that drive cytokine production and sustain disease chronicity remain unknown. Tenascin-C (encoded by Tnc) is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. Here we show that mice that do not express tenascin-C show rapid resolution of acute joint inflammation and are protected from erosive arthritis. Intra-articular injection of tenascin-C promotes joint inflammation in vivo in mice, and addition of exogenous tenascin-C induces cytokine synthesis in explant cultures from inflamed synovia of individuals with rheumatoid arthritis. Moreover, in human macrophages and fibroblasts from synovia of individuals with rheumatoid arthritis, tenascin-C induces synthesis of proinflammatory cytokines via activation of Toll-like receptor 4 (TLR4). Thus, we have identified tenascin-C as a novel endogenous activator of TLR4-mediated immunity that mediates persistent synovial inflammation and tissue destruction in arthritic joint disease.

Analysing the role of endogenous matrix molecules in the development of osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis worldwide. In this condition, damage to the extracellular matrix (ECM) of cartilage occurs, resulting in joint destruction. Factors mediating cartilage damage include mechanical injury, cytokine and superoxide release on a background of genetic susceptibility and obesity. Studies of arthritic cartilage show increased production of ECM molecules including type II collagen, cartilage oligomeric matrix protein, fibronectin (FN) and fibromodulin. Recent reports suggest that ECM proteins may become endogenous catabolic factors during joint damage. Activation of pro‐inflammatory pathways by ECM proteins has led to their description as damage‐associated molecular patterns (DAMPs). The ECM proteins involved include fibromodulin, which activates the complement pathway and may promote the persistence of joint inflammation. Fragmentation of type II collagen, FN and hyaluronan reveals cryptic epitopes that stimulate proteolytic enzymes including matrix metalloproteinases and aggrecanases (ADAMTSs – a disintegrin and metalloproteinase with thrombospondin type 1 motifs). Proteolytic fragments also stimulate the release of nitric oxide, chemokines and cytokines and activation of the MAP kinases. Reports are emerging that the receptors for the fragments described involve interaction with integrins and toll‐like receptors. In this review the contribution of endogenous ECM molecules to joint destruction will be discussed. A deeper understanding of the pathways stimulated by endogenous ligands could offer potential avenues for novel therapies in the future.

Hand to Mouth: A Systematic Review and Meta-Analysis of the Association between Rheumatoid Arthritis and Periodontitis.

Background Rheumatoid arthritis (RA) and periodontitis are both chronic inflammatory diseases, which demonstrate similarities in terms of mechanism, histopathology, and demography. An association between these conditions has been demonstrated previously but has been called into question more recently. Methods The published databases, such as MEDLINE, EMBASE, and PsycINFO, were searched using search terms related to RA and periodontitis. Articles were selected if they included data on the number of people with RA diagnosed with periodontitis (or periodontal disease parameters) compared to a control comparison group. Review articles, case reports, animal model studies, non-English language, and articles with unavailable abstracts were excluded. Data were extracted, critically appraised using the Downs and Black tool, and a random-effect Mantel–Haenszel meta-analysis was performed. Results Twenty-one papers met the eligibility criteria and provided data for the meta-analysis; 17 studies (including a total of 153,492 participants) comparing RA to healthy controls and 4 (including a total of 1378 participants) comparing RA to osteoarthritis (OA). There was a significantly increased risk of periodontitis in people with RA compared to healthy controls (relative risk: 1.13; 95% CI: 1.04, 1.23; p = 0.006; N = 153,277) with a significantly raised mean probing depth, risk of bleeding on probing (BOP), and absolute value of clinical attachment loss in those with RA. When comparing RA and OA, there was no significant difference in the prevalence of periodontitis; however, the risk of BOP was greater in OA than RA. Conclusion A significant association between RA and periodontitis is supported by the results of our systematic review and meta-analysis of studies comparing RA to healthy controls. In our meta-analysis, however, this is not replicated when comparing RA to OA controls.

Are bisphosphonates effective in the treatment of osteoarthritis pain? A meta-analysis and systematic review.

Objective Osteoarthritis (OA) is the most common form of arthritis worldwide. Pain and reduced function are the main symptoms in this prevalent disease. There are currently no treatments for OA that modify disease progression; therefore analgesic drugs and joint replacement for larger joints are the standard of care. In light of several recent studies reporting the use of bisphosphonates for OA treatment, our work aimed to evaluate published literature to assess the effectiveness of bisphosphonates in OA treatment. Methods Literature databases were searched from inception to the 30th June 2012 for clinical trials of bisphosphonates to treat OA pain. Data was appraised and levels of evidence determined qualitatively using best evidence synthesis from the Cochrane Collaboration. The two largest studies were conducted with risedronate in the treatment of knee OA, for which meta-analyses were performed for pain and functional outcomes. Results Our searches found 13/297 eligible studies, which included a total of 3832 participants. The trials recruited participants with OA of the hand (n = 1), knee (n = 8), knee and spine (n = 3), or hip (n = 1). Our meta-analysis of the two largest knee studies using risedronate 15 mg showed odds ratios favouring placebo interventions for the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain (1.73), WOMAC function (2.03), and WOMAC stiffness (1.82). However, 8 trials (61.5%) reported that bisphosphonates improve pain assessed by VAS scores and 2 (38.5%) reported significant improvement in WOMAC pain scores compared to control groups. Conclusions There is limited evidence that bisphosphonates are effective in the treatment of OA pain. Limitations of the studies we analysed included the differences in duration of bisphosphonate use, the dose and route of administration and the lack of long-term data on OA joint structure modification post-bisphosphonate therapy. Future more targeted studies are required to appreciate the value of bisphosphonates in treating osteoarthritis pain. Trial Registration PROSPERO Register CRD42012002541

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 (R2=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.

New insights into the impact of neuro-inflammation in rheumatoid arthritis

Rheumatoid arthritis (RA) is considered to be, in many respects, an archetypal autoimmune disease that causes activation of pro-inflammatory pathways resulting in joint and systemic inflammation. RA remains a major clinical problem with the development of several new therapies targeted at cytokine inhibition in recent years. In RA, biologic therapies targeted at inhibition of tumor necrosis factor alpha (TNFα) have been shown to reduce joint inflammation, limit erosive change, reduce disability and improve quality of life. The cytokine TNFα has a central role in systemic RA inflammation and has also been shown to have pro-inflammatory effects in the brain. Emerging data suggests there is an important bidirectional communication between the brain and immune system in inflammatory conditions like RA. Recent work has shown how TNF inhibitor therapy in people with RA is protective for Alzheimers disease. Functional MRI studies to measure brain activation in people with RA to stimulus by finger joint compression, have also shown that those who responded to TNF inhibition showed a significantly greater activation volume in thalamic, limbic, and associative areas of the brain than non-responders. Infections are the main risk of therapies with biologic drugs and infections have been shown to be related to disease flares in RA. Recent basic science data has also emerged suggesting that bacterial components including lipopolysaccharide induce pain by directly activating sensory neurons that modulate inflammation, a previously unsuspected role for the nervous system in host-pathogen interactions. In this review, we discuss the current evidence for neuro-inflammation as an important factor that impacts on disease persistence and pain in RA.

Fibronectin III 13-14 Domains Induce Joint Damage via Toll-Like Receptor 4 Activation and Synergize with Interleukin-1 and Tumour Necrosis Factor

Cartilage loss is a feature of chronic arthritis. It results from degradation of the extracellular matrix which is composed predominantly of aggrecan and type II collagen. Extracellular matrix degradation is mediated by aggrecanases and matrix metalloproteinases (MMPs). Recently, a number of endogenous matrix molecules, including fibronectin (FN), have been implicated in mediating cartilage degradation. We were interested in studying the C-terminal heparin-binding region of FN since it mediates aggrecan and type II collagen breakdown in cartilage, but the specific FN domains responsible for proteolytic enzyme activity and their receptors in cartilage are unknown. In this study, the ability of recombinant FN domains to induce cartilage breakdown was tested. We found that the FN III 13-14 domains in the C-terminal heparin-binding region of FN are potent inducers of aggrecanase activity in articular cartilage. In murine studies, the FN III 13-14-induced aggrecanase activity was inhibited in Toll-like receptor 4 (TLR4) knockout mice but not wild-type mice. FN III 13-14 domains also synergized with the known catabolic cytokines interleukin-1α and tumour necrosis factor and induced secretion of MMP-1, MMP-3, gp38 and serum amyloid-like protein A in chondrocytes. Our studies provide a mechanistic link between the innate immune receptor TLR4 and sterile arthritis induced by the FN III 13-14 domains of the endogenous matrix molecule FN.

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.

Functional MRI demonstrates pain perception in hand osteoarthritis has features of central pain processing.

BACKGROUND Hand osteoarthritis (HOA) is typified by pain and reduced function. We hypothesised that people with HOA have enhanced sensitivity and activation of peripheral nociceptors in the hand, thereby potentiating chronic pain. In our study we aimed to assess if central sensitisation mediates pain perception in osteoarthritis of the hand. METHODS Participants with proximal and distal interphalangeal joint (PIP/DIP) HOA and non-OA controls were recruited. Clinical pain scores using the visual analogue scale (VAS) were recorded before and after performing a painful hand task. Central pain processing was evaluated with functional brain neuroimaging (fMRI) using a finger flexion-extension (FFE) task performed over 3 minutes. Data was analysed with FMRIB software (www.fmrib.ox.ac.uk/fsl). Group mean activation of functional MRI signal between hand osteoarthritis and control non-arthritic participants was compared. RESULTS Our group of hand OA participants reported high pain levels compared with non-arthritic controls as demonstrated by the mean VAS in hand OA participants of 59.31± 8.19 mm compared to 4.00 ± 1.89 mm in controls (p < 0.0001), despite all participants reporting analgesic use. Functional MRI analysis showed increased activation in the thalamus, cingulate, frontal and somatosensory cortex in the hand OA group but not in controls (thresholded at p < 0.05). Regions of activation were mapped to Brodmann areas 3, 4, 6, 9, 13, 22, 24 and 44. Activated regions found in our study are recognised higher brain pain processing centres implicated in central sensitisation. CONCLUSIONS People with hand osteoarthritis demonstrated features of central sensitisation that was evident after a finger flexion-extension task using functional MRI. Functional MRI is a useful biomarker in detecting pain in hand osteoarthritis and could be used in future hand osteoarthritis pain studies to evaluate pain modulation strategies.

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.