An interdisciplinary perspective on peripheral drivers of pain in rheumatoid arthritis.

Pain is one of the most debilitating symptoms of rheumatoid arthritis (RA), and yet remains poorly understood, especially when pain occurs in the absence of synovitis. Without active inflammation, experts most often attribute joint pain to central nervous system dysfunction. However, advances in the past 5 years in both immunology and neuroscience research suggest that chronic pain in RA is also driven by a variety of abnormal interactions between peripheral neurons and mediators produced by resident cells in the local joint environment. In this Review, we discuss these novel insights from an interdisciplinary neuro-immune perspective. We outline a potential working model for the peripheral drivers of pain in RA, which includes autoantibodies, resident immune and mesenchymal cells and their interactions with different subtypes of peripheral sensory neurons. We also offer suggestions for how future collaborative research could be designed to accelerate analgesic drug development.

Comparative analysis of centrally mediated and inflammatory pain experiences amongst patients diagnosed with rheumatoid arthritis: A multimethods study.

BACKGROUND: The identification of pain originating from distinct biological processes may lead to individualised pain treatment. In this study, we aimed to explore the pain experiences of patients with rheumatoid arthritis (RA), differentiating between those predominantly exhibiting features of peripheral inflammatory versus centrally mediated pain. METHODS: Through a multimethods approach we (i) quantitatively analysed the differences in pain descriptors between patients diagnosed with RA experiencing peripheral inflammatory and centrally mediated pain, utilising the Short Form-McGill Pain Questionnaire which includes the pain visual analogue scale (VAS) and (ii) qualitatively explored their subjective pain experiences grounded in the biopsychosocial model, commonly applied in chronic pain. RESULTS: Participants with centrally mediated pain reported higher pain scores on the VAS, used a wider range of pain descriptors, and a higher proportion selected each descriptor compared to those with inflammatory pain (p < .001). The qualitative analysis revealed the centrally mediated pain group's experiences were overwhelming and relentless, struggling to precisely articulate the nature of their pain. In contrast, individuals with inflammatory pain expressed their pain in more tangible terms and shared their adaptive and coping strategies. Importantly, both groups revealed the substantial psychological, functional and social impacts of their pain, highlighting the often 'invisible' and misunderstood nature of their symptoms. CONCLUSION: This study has gained a deeper insight into the pain experiences of patients living with RA, particularly in differentiating between centrally mediated and inflammatory types of pain, potentially facilitating a more individualised approach to pain treatment. PATIENT CONTRIBUTION: Patients actively participated in the study conception and design. This engagement includes collaboration with key stakeholders, such as members of the National Rheumatoid Arthritis Society and Patient Research Partners (PRPs), who provided continuous feedback and guidance throughout the research process. Specifically, the qualitative element was coproduced with two PRPs, who were involved in co-leading the focus groups and data analysis.

A randomised controlled trial of the effect of intra-articular lidocaine on pain scores in inflammatory arthritis.

ABSTRACT: Chronic pain in inflammatory arthritis (IA) reflects a complex interplay between active disease in a peripheral joint and central pronociceptive mechanisms. Because intra-articular lidocaine may be used to abolish joint-specific peripheral input to the central nervous system, we aimed to validate its use as a clinical tool to identify those patients with IA whose pain likely incorporates centrally mediated mechanisms. We began by investigating whether there was a placebo response of intra-articular injection in patients with IA 1:1 randomised to receive intra-articular lidocaine or control (0.9% saline). After, in a larger patient cohort not randomized to placebo vs lidocaine groups, we tested whether patients with IA could be stratified into 2 cohorts based on their response to intra-articular lidocaine according to markers of centrally mediated pain. To this end, we evaluated postlidocaine pain numerical rating scale (NRS) scores alongside baseline painDETECT, fibromyalgia criteria fulfillment, and quantitative sensory testing outcomes. Numerical rating scale scores were collected at baseline and 3-, 5-, and 10-minutes postinjection. Firstly, the placebo effect of intra-articular injection was low: compared to baseline, the mean pain NRS score 5-minutes postinjection was reduced by 3.5 points in the lidocaine group vs 1.2 points in the control group. Secondly, postlidocaine NRS scores were significantly higher in those with a high (>18) baseline painDETECT score, fibromyalgia, and low-pressure pain threshold at the trapezius (P = 0.002, P = 0.001, P = 0.005, respectively). Persistent high pain after intra-articular lidocaine injection could be used as an indicator of pronociceptive mechanisms that are centrally mediated, informing centrally targeted analgesic strategies.

Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis.

INTRODUCTION: Despite better therapies and strategies, many people with rheumatoid arthritis (RA) have persistent pain, often from abnormal pain processing, now termed nociplastic pain. However, RA patients with fibromyalgia (FM), a central nociplastic pain syndrome, also have power doppler ultrasound (PDUS+) joint inflammation. To understand the complex causes of pain, we performed clinical examination and patient-reported outcome measures (PROMs) plus comprehensive PDUS evaluation not previously combined. METHODS: In a cross-sectional study of sequential RA patients with at least moderate DAS28 erythrocyte sedimentation rate disease activity, we assessed 66/68 joints for swelling and tenderness, respectively, FM American College of Rheumatology 2010 diagnostic criteria, completed PROMs for function, quality of life and mood, alongside PDUS examination of 44 joints. Statistical analysis included logistic regression modelling and regularised (lasso) logistic regression methods. RESULTS: From 158 patients, 72 (46%) patients met FM criteria, with significantly worse tender joint counts and PROMs, but no differences in PDUS compared with the non-FM group. Categorising patients by PDUS+ joint presence and/or FM criteria, we identified four distinct groups: 43 (27.2%) patients with -FM-PD, 43 (27.2%) with -FM+PD, 42 (26.6%) with +FM-PD and 30 (19%) with +FM+PD. Both FM+ groups had worse PROMs for fatigue, mood and pain, compared with the FM- groups. We were unable to develop algorithms to identify different groups. CONCLUSION: The unexpected group -FM-PD group may have peripheral nociplastic pain, not commonly recognised in rheumatology. Only 46% of patients demonstrated PDUS+ inflammation. However clinical examination and PROMs did not reliably differentiate groups, emphasising PDUS remains an important tool.

A systematic review and meta-analysis of questionnaires to screen for pain sensitisation and neuropathic like pain in inflammatory arthritis.

BACKGROUND: Targeted pain relief is a major unmet medical need for patients with inflammatory arthritis (IA), where approximately 40% of patients experience persistent pain. Self-reported questionnaires which report on pain sensitivity and neuropathic like pain may provide an insight into certain pain types to guide targeted treatment. OBJECTIVE: In this systematic review and meta-analysis we evaluated self-reported pain sensitivity and neuropathic like pain in subjects with IA, as defined by questionnaires. METHODS: MEDLINE, Embase, Web of Science, PsycINFO and google scholar were searched for publications and conference abstracts, reporting on pain sensitivity and neuropathic pain using painDETECT, DN4, LANSS, CSI, PSQ and McGill pain questionnaire in adult patients with IA. Risk of bias was assessed using National Institute of Health Quality Assessment Tool. Meta-analysis according to individual questionnaire criteria, was undertaken. RESULTS: 63 studies (38 full text and 25 conference abstracts) were included in the review, reporting on a total of 13,035 patients. On meta-analysis, prevalence of pain sensitivity/neuropathic like pain in IA was 36% (95% CI 31-41%) according to painDETECT, 31% (95% CI 26-37%) according to the DN4, 40% (95% CI 32-49%) according to the LANSS and 42% (95% CI 34-51%) according to the CSI. On meta-regression, prevalence of pain sensitivity/neuropathic pain in RA was significantly lower than SpA (p = 0.01) and PsA (p = 0.002) using the painDETECT questionnaire. Across all questionnaires, pain sensitivity and neuropathic like pain were significantly associated with worse pain severity, disease activity, disability, quality of life and anxiety and depression measures. Studies reporting on whether neuropathic like pain is a predictor of treatment outcome were inconsistent. CONCLUSION: Pain sensitivity and neuropathic like pain contribute to pain perception in up to 42% of patients with IA. Despite substantial heterogeneity between studies on meta-analysis, this review highlights the large proportion of patients with IA who may experience pain due to underlying mechanisms other than, or in addition to, synovial inflammation.

ANCA-associated vasculitis can present with episodic attacks of joint pain consistent with palindromic rheumatism.

A 64-year-old man with a 2-year history of palindromic rheumatoid arthritis, presented with recurrent flares of arthritis, weight loss, new onset Raynaud's phenomenon and one previous episode of small-volume haemoptysis. Investigations, including renal biopsy, revealed antineutrophil cytoplasmic antibodies-mediated vasculitis. This case highlights the need to consider vasculitis in patients in whom there is an atypical history of arthritis.

Rheumatology care of migrants from sub-Saharan Africa: a literature review and qualitative pilot study of patients' perspectives.

INTRODUCTION: Rheumatologists practising in the UK National Health Service (NHS) are likely to treat migrant patients from sub-Saharan Africa. This study aimed to conduct a literature review about rheumatoid arthritis prevalence in Africa and understand the experiences of patients with rheumatological conditions, about their past healthcare in sub-Saharan Africa and their transition of care to the United Kingdom (UK). METHODS: A systematic search and a pilot study using semi-structured interviews to gain the views of migrants from sub-Saharan Africa with rheumatological conditions was conducted. RESULTS: Thirty-two studies reported on the prevalence of rheumatoid arthritis in Africa. Studies were small and out-of-date, and there was significant heterogeneity in prevalence rates. For the qualitative study, seven participants were recruited. Four themes were highlighted: (i) the physical and emotional impact of rheumatological conditions on participants; (ii) limited rheumatology care in sub-Saharan Africa with high costs, limited access to specialists, lack of investigations and treatments, the use of traditional medicines and poor communication by clinicians; (iii) barriers to rheumatology care in the UK such as migrants' poor understanding of rheumatological conditions and NHS entitlements; (iv) and ways to improve access to care such as patient, public and general practitioner education. CONCLUSION: This study has highlighted the paucity of rheumatoid arthritis prevalence data in Africa and described, for the first time, the migrant's perspective of rheumatology care in sub-Saharan Africa and the transition of care to the UK. This description begins to allow healthcare providers in the UK to tailor management for this migrant population. Key Points • Rheumatological conditions are common in Africa, but there is a paucity of epidemiological data regarding the prevalence of specific conditions such as rheumatoid arthritis. • UK clinicians need to be mindful when treating migrants that access to rheumatologists and specialist investigations and treatment is limited in sub-Saharan Africa and that there is often limited public and patient understanding of rheumatological conditions. • Migrants continue to lack understanding of their NHS entitlements and fear data sharing with immigration services which can be a barrier to seeking care. • This study has exposed the lack of understanding about rheumatological conditions by the public and some general practitioners which needs to be addressed with effective education and awareness campaigns.

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.

Analysis of terms used for the diagnosis and classification of amyotrophic lateral sclerosis and motor neuron disease.

There is no test for amyotrophic lateral sclerosis (ALS) and so attempts have been made to produce standardized diagnostic criteria based on clinical and electrophysiological findings, e.g. El Escorial. However, the phenotypic classification of the subtypes of ALS is also based on clinical features leading to conflation of diagnosis and phenotype. We used a five-question online survey with ALS specialists to explore the range of descriptors and how they are used. Of 101 specialists approached, 72 completed the survey. The most frequently used labels were 'ALS', 'PLS' and 'familial'. Labels other than the El Escorial categories were mainly used as clinical descriptors (83%). Approximately 50% of respondents recorded that the El Escorial criteria had no useful role in patient discussion or in the diagnostic process. Only 31% of respondents rated their current classification system above the median for being logical. A more rational system explicitly distinguishing diagnostic and phenotypic criteria is essential.

Sneddon's syndrome: it is all in the ectoderm.

A 51-year-old man gave a 2-year history of worsening mobility, cognitive decline and headaches. He had a history of thromboembolic stroke, recurrent transient ischaemic attacks and a spontaneous intraventricular haemorrhage. On examination, he had livedo reticularis and perniosis and a systolic murmur. Catheter cerebral angiography showed peripheral small-vessel and medium-vessel vasculopathy resulting in pruning of the distal cortical vessels and tortuous irregular distal collaterals. Skin biopsy showed subtle vasculopathy with ectasia of capillaries and postcapillary venules but no frank vasculitis or arterial thrombosis. Repeated serum antiphospholipid antibody titres were negative. The clinical features, skin biopsy and angiogram findings strongly supported a diagnosis of Sneddon's syndrome. Clinicians should consider Sneddon's syndrome in patients with livedo reticularis and stroke. There are treatment dilemmas in this situation when ischaemic and haemorrhagic cerebral events coexist.

Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury.

AMPK activation during ischemia helps the myocardium to cope with the deficit of energy production. As AMPK activity is considered to be impaired in diabetes, we hypothesized that enhancing AMPK activation during ischemia above physiological levels would protect the ischemic diabetic heart through AMPK activation and subsequent inhibition of mitochondrial permeability transition pore (mPTP) opening. Isolated perfused hearts from normoglycemic Wistar or diabetic Goto-Kakizaki (GK) rats (n ≥ 6/group) were subjected to 35 min of ischemia in the presence of 10, 20, and 40 µM of A-769662, a known activator of AMPK, followed by 120 min of reperfusion with normal buffer. Myocardial infarction and AMPK phosphorylation were assessed. The effect of A-769662 on mPTP opening in adult cardiomyocytes isolated from both strains was also determined. A-769662 at 20 µM reduced infarct size in both Wistar (30.5 ± 2.7 vs. 51.8 ± 3.9% vehicle; P < 0.001) and GK hearts (22.7 ± 3.0 vs. 48.5 ± 4.7% vehicle; P < 0.001). This protection was accompanied by a significant increase in AMPK and GSK-3ß phosphorylation. In addition, A-769662 significantly inhibited mPTP opening in both Wistar and GK cardiomyocytes subjected to oxidative stress. We demonstrate that AMPK activation during ischemia via A-769662 reduces myocardial infarct size in both the nondiabetic and diabetic rat heart. Furthermore, this cardioprotective effect appears to be mediated through inhibition of mPTP opening. Our findings suggest that improving AMPK activation during ischemia can be another mechanism for protecting the ischemic heart.