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.

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.

Anti-arthritic actions of ß-cryptoxanthin against the degradation of articular cartilage in vivo and in vitro.

An inverse correlation between the morbidity of rheumatoid arthritis and daily intake of ß-cryptoxanthin has been epidemiologically shown. In this study, we investigated the effects of ß-cryptoxanthin on the metabolism of cartilage extracellular matrix in vivo and in vitro. Oral administration of ß-cryptoxanthin (0.1-1 mg/kg) to antigen-induced arthritic rats suppressed the loss of glycosaminoglycans in articular cartilage, which is accompanied by the interference of aggrecanase-mediated degradation of aggrecan. Inhibition of the interleukin 1α (IL-1α)-induced aggrecan degradation by ß-cryptoxanthin was also observed with porcine articular cartilage explants in culture. ß-Cryptoxanthin (1-10 µM) dose-dependently down-regulated the IL-1α-induced gene expression of aggrecanase 1 (ADAMTS-4) and aggrecanase 2 (ADAMTS-5) in cultured human chondrocytes. Moreover, ß-cryptoxanthin was found to augment the gene expression of aggrecan core protein in chondrocytes. These results provide novel evidence that ß-cryptoxanthin exerts anti-arthritic actions and suggest that ß-cryptoxanthin may be useful in blocking the progression of rheumatoid arthritis and osteoarthritis.

Rheumatoid meningitis.

Rheumatoid meningitis is a rare, potentially treatable condition that can mimic a wide range of neurological conditions, including vascular syndromes and encephalopathies. Despite a concurrent history of rheumatoid arthritis, patients often have no active synovitis. Here we describe a patient with rheumatoid meningitis who presented to a hyperacute stroke unit with dysarthria on waking and transient facial droop.

Can we achieve pain stratification in musculoskeletal conditions? Implications for clinical practice.

In the last few years there has been an increased appreciation that pain perception in rheumatic and musculoskeletal diseases (RMDs) has several mechanisms which include nociceptive, inflammatory, nociplastic and neuropathic components. Studies in specific patient groups have also demonstrated that the pain experienced by people with specific diagnoses can present with distinctive components over time. For example, the pain observed in rheumatoid arthritis has been widely accepted to be caused by the activation of nociceptors, potentiated by the release of inflammatory mediators, including prostaglandins, leukotrienes and cytokine networks in the joint environment. However, people with RA may also experience nociplastic and neuropathic pain components, particularly when treatments with disease modifying anti-rheumatic drugs (DMARDs) have been implemented and are insufficient to control pain symptoms. In other RMDs, the concept of pain sensitisation or nociplastic pain in driving ongoing pain symptoms e.g. osteoarthritis and fibromyalgia, is becoming increasingly recognised. In this review, we explore the hypothesis that pain has distinct modalities based on clinical, pathophysiological, imaging and genetic factors. The concept of pain stratification in RMD is explored and implications for future management are also discussed.

Assessing the effects of distinct biologic therapies on rheumatoid arthritis pain by nociceptive, neuropathic and nociplastic pain components: a randomised feasibility study.

BACKGROUND: Pain management is a major unmet need in people with rheumatoid arthritis (RA). Although many patients are treated with disease modifying anti-rheumatic drugs (DMARDS), including biologic therapies, many people with RA continue to experience significant pain. We aimed to determine whether performing a comprehensive pain evaluation is feasible in people with active RA receiving conventional DMARDs and biologic therapies. METHODS: The BIORA-PAIN feasibility study was an open-label, randomised trial, which recruited participants suitable for treatment with biologic therapy. The primary feasibility outcomes were recruitment, randomisation and retention of eligible participants. All participants underwent pain assessment for nociceptive, neuropathic and nociplastic pain during the 12-month study period, with quarterly assessments for VAS (Visual Analogue Scale) pain, painDETECT and QST (quantitative sensory testing). This trial was registered in clinicaltrials.gov NCT04255134. RESULTS: During the study period, 93 participants were screened of whom 25 were eligible: 13 were randomised to adalimumab and 12 to abatacept. Participant recruitment was lower than expected due to the COVID-19 pandemic. Pain assessments were practical in the clinical trial setting. An improvement was observed for VAS pain from baseline over 12 months, with a mean (SEM) of 3.7 (0.82) in the abatacept group and 2.3 (1.1) in the adalimumab group. There was a reduction in painDETECT and improvement in QST measures in both treatment groups during the study. Participant feedback included that some of the questionnaire-based pain assessments were lengthy and overlapped in their content. Adverse events were similar in both groups. There was one death due to COVID-19. CONCLUSIONS: This first-ever feasibility study of a randomised controlled trial assessing distinct modalities of pain in RA met its progression criteria. This study demonstrates that it is feasible to recruit and assess participants with active RA for specific modalities of pain, including nociceptive, neuropathic and nociplastic elements. Our data suggests that it is possible to stratify people for RA based on pain features. The differences in pain outcomes between abatacept and adalimumab treated groups warrant further investigation. TRIAL REGISTRATION: NCT04255134, Registered on Feb 5, 2020.

Bone marrow lesions: plugging the holes in our knowledge using animal models.

Bone marrow lesions (BMLs), which are early signs of osteoarthritis (OA) that are associated with the presence, onset and severity of pain, represent an emerging imaging biomarker and clinical target. Little is known, however, regarding their early spatial and temporal development, structural relationships or aetiopathogenesis, because of the sparsity of human early OA imaging and paucity of relevant tissue samples. The use of animal models is a logical approach to fill the gaps in our knowledge, and it can be informed by appraising models in which BMLs and closely related subchondral cysts have already been reported, including in spontaneous OA and pain models. The utility of these models in OA research, their relevance to clinical BMLs and practical considerations for their optimal deployment can also inform medical and veterinary clinicians and researchers alike.

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.

Tocilizumab for relapsing and remitting giant cell arteritis: a case series.

BACKGROUND: Giant cell arteritis is a large vessel vasculitis of the arteries in the head and neck. The mainstay of management is with high-dose corticosteroids, and patients often face difficulties stopping or reducing steroids without recurrence of symptoms. Corticosteroids are well established to have numerous associated side effects, including osteoporosis, weight gain, and diabetes. Therefore, when tocilizumab was approved for up to 1 year for cases of relapsing or refractory giant cell arteritis by the National Institute of Health and Care Excellence (NICE) in April 2018, this offered an opportunity to benefit from new funding and to reduce steroid burden. CASE PRESENTATION: This case series describes the impact of the establishment of a new hub and spoke referral pathway for the use of tocilizumab in refractory or relapsing giant cell arteritis, with case examples from consecutive patients who accessed the funding between August 2018 and April 2021. A total of 16 patients were identified: 11 female and 5 male, with an average age of 72.4 (range 61-82) years, with a majority of 11 ethnically white. The central assessing hub is St George's University Hospitals NHS Foundation Trust Hospital, serving a population of 1.3 million in the south of England. This is the first large case series looking into the impact of the establishment of a regional clinical pathway for the new tocilizumab funding. CONCLUSIONS: The case series demonstrates that the use of tocilizumab has reduced both the duration and the dose of corticosteroids in these 16 cases (mean prednisolone reduction 20.4 mg: 95% CI 13.0-27.8 mg), with 50% of patients continuing on tocilizumab after the initial 12 month funding period. The disease course, patterns of response, and maintenance of remission are discussed, and we describe the benefits of replicating this hub and spoke tocilizumab pathway in other centers.

What makes osteoarthritis painful? The evidence for local and central pain processing.

OA is a chronic arthritic disease characterized by pain, local tissue damage and attempts at tissue repair. Historically, cartilage damage was believed to be the hallmark of OA. However, since cartilage is an avascular, aneural tissue, the mechanisms of pain are likely to be complex and influenced by non-cartilaginous structures in the joint including the synovium, bone and soft tissue. Imaging studies reveal the presence of synovitis and bone marrow lesions that may mediate pain. The presence of local joint inflammation and altered cartilage and bone turnover in OA implicates a potential role for a range of molecular mediators in OA pain. Mechanisms of pain perception may include the activation and release of local pro-inflammatory mediators such as prostaglandins and cytokines accompanied by the destruction of tissue, which is mediated by proteases. However, clinically, there is often disparity between the degree of pain perception and the extent of joint changes in subjects with OA. Such observations have prompted work to investigate the mechanisms of central pain perception in OA. Functional MRI has identified multiple areas of the brain that are involved in OA pain processing. These data demonstrate that pain perception in OA is complex in being influenced by local factors and activation of central pain-processing pathways. In this review, we will discuss current concepts underlying the pathophysiology of pain perception in OA and suggest possible directions for the future management of pain in this condition based on recent clinical studies.

Immunomodulatory Drugs in the Management of SARS-CoV-2.

With the onset of the global pandemic in 2020 of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), there has been increasing research activity around certain disease-modifying drugs that are used for the management of inflammatory disorders such as rheumatoid arthritis, spondyloarthrosis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel disease for managing coronavirus symptoms. In the conditions mentioned, many people are on long-term treatment with agents including hydroxychloroquine, tumor necrosis factor alpha (TNFα) inhibitor drugs, other biologic agents such as monoclonal antibodies to IL-6 and Janus kinase inhibitors including baricitinib and tofacitinib, which are used to control inflammatory responses in their respective auto-immune condition. There is emerging data that immunomodulatory drugs could be protective at reducing certain features of SARS-CoV-2 and improving recovery. In addition, it is important to understand if subjects being treated with the immunomodulatory agents described have a less severe SARS-CoV-2 infection, as they are deemed some protection from their immunomodulatory treatment, or if they develop infections similar to non-immunocompromised patients. There is a huge unmet clinical need to advise patients responsibly about whether they should remain on their immunomodulatory treatment or not in light of Covid-19 infection. In this article we will discuss potential treatment options for SARS-CoV-2 using immunomodulatory drugs and at what stage of the condition they may be beneficial. Viable treatment options during the global coronavirus pandemic are a much-needed and an intensely active area of research.

Risk factors for pain and functional impairment in people with knee and hip osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE: To identify risk factors for pain and functional deterioration in people with knee and hip osteoarthritis (OA) to form the basis of a future 'stratification tool' for OA development or progression. DESIGN: Systematic review and meta-analysis. METHODS: An electronic search of the literature databases, Medline, Embase, CINAHL, and Web of Science (1990-February 2020), was conducted. Studies that identified risk factors for pain and functional deterioration to knee and hip OA were included. Where data and study heterogeneity permitted, meta-analyses presenting mean difference (MD) and ORs with corresponding 95% CIs were undertaken. Where this was not possible, a narrative analysis was undertaken. The Downs & Black tool assessed methodological quality of selected studies before data extraction. Pooled analysis outcomes were assessed and reported using the Grading of Reccomendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: 82 studies (41 810 participants) were included. On meta-analysis: there was moderate quality evidence that knee OA pain was associated with factors including: Kellgren and Lawrence≥2 (MD: 2.04, 95% CI 1.48 to 2.81; p<0.01), increasing age (MD: 1.46, 95% CI 0.26 to 2.66; p=0.02) and whole-organ MRI scoring method (WORMS) knee effusion score ≥1 (OR: 1.35, 95% CI 0.99 to 1.83; p=0.05). On narrative analysis: knee OA pain was associated with factors including WORMS meniscal damage ≥1 (OR: 1.83). Predictors of joint pain in hip OA were large acetabular bone marrow lesions (BML; OR: 5.23), chronic widespread pain (OR: 5.02) and large hip BMLs (OR: 4.43). CONCLUSIONS: Our study identified risk factors for clinical pain in OA by imaging measures that can assist in predicting and stratifying people with knee/hip OA. A 'stratification tool' combining verified risk factors that we have identified would allow selective stratification based on pain and structural outcomes in OA. PROSPERO REGISTRATION NUMBER: CRD42018117643.

The use of technology in the subcategorisation of osteoarthritis: a Delphi study approach.

Objective: This UK-wide OATech Network + consensus study utilised a Delphi approach to discern levels of awareness across an expert panel regarding the role of existing and novel technologies in osteoarthritis research. To direct future cross-disciplinary research it aimed to identify which could be adopted to subcategorise patients with osteoarthritis (OA). Design: An online questionnaire was formulated based on technologies which might aid OA research and subcategorisation. During a two-day face-to-face meeting concordance of expert opinion was established with surveys (23 questions) before, during and at the end of the meeting (Rounds 1, 2 and 3, respectively). Experts spoke on current evidence for imaging, genomics, epigenomics, proteomics, metabolomics, biomarkers, activity monitoring, clinical engineering and machine learning relating to subcategorisation. For each round of voting, ≥80% votes led to consensus and ≤20% to exclusion of a statement. Results: Panel members were unanimous that a combination of novel technological advances have potential to improve OA diagnostics and treatment through subcategorisation, agreeing in Rounds 1 and 2 that epigenetics, genetics, MRI, proteomics, wet biomarkers and machine learning could aid subcategorisation. Expert presentations changed participants' opinions on the value of metabolomics, activity monitoring and clinical engineering, all reaching consensus in Round 2. X-rays lost consensus between Rounds 1 and 2; clinical X-rays reached consensus in Round 3. Conclusion: Consensus identified that 9 of the 11 technologies should be targeted towards OA subcategorisation to address existing OA research technology and knowledge gaps. These novel, rapidly evolving technologies are recommended as a focus for emergent, cross-disciplinary osteoarthritis research programmes.

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.

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.

Association between Systemic Lupus Erythematosus and Periodontitis: A Systematic Review and Meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease, the etiology of which remains only partially characterized. Strong evidence implicates chronic infections in the development and chronicity of autoimmune conditions. Recently, an association has been demonstrated between periodontitis and rheumatoid arthritis. Such observations have led to the investigation of the possible role of periodontitis and oral dysbiosis in other systemic inflammatory conditions, including SLE. The aim of this study was to examine whether there is an association between SLE and periodontitis. METHODS: MEDLINE via OVID, EMBASE via OVID, and PsycINFO via OVID databases were searched to identify eligible studies, screened by two independent authors and verified by a third. Studies comparing presence of periodontitis in SLE cases to controls without SLE were included. Data were extracted using a predefined table and papers were appraised using Down's and Black tool. Mantel-Haenszel meta-analysis was performed using RevMan. RESULTS: Eight case-control studies were included, with 487 SLE cases and a total of 1,383 participants. On meta-analysis of four studies, risk of periodontitis in SLE cases compared to controls was significantly greater with a risk ratio of 1.76 (95% CI 1.29-2.41, p = 0.0004). No statistical difference was found in individual measures of periodontitis, such as probing depth or clinical attachment loss, between SLE cases and controls. CONCLUSION: Our study found a statistically significant increased risk of periodontitis in patients with SLE compared to controls. This finding suggests a possible association between these two conditions. Larger longitudinal studies are needed to confirm this possible association.

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.