Search

Objective Tofacitinib is an oral Janus kinase ( JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. Methods A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Results Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 ( p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses ( p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Conclusions Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. Trial registration number NCT00976599. [ABSTRACT FROM AUTHOR]

Background Rheumatoid arthritis is an inflammatory disease marked by intra-articular decreases in pH, aberrant hyaluronan regulation and destruction of bone and cartilage. Acid-sensing ion channels (ASICs) are the primary acid sensors in the nervous system, particularly in sensory neurons and are important in nociception. ASIC3 was recently discovered in synoviocytes, non-neuronal joint cells critical to the inflammatory process. Objectives To investigate the role of ASIC3 in joint tissue, specifically the relationship between ASIC3 and hyaluronan and the response to decreased pH. Methods Histochemical methods were used to compare morphology, hyaluronan expression and ASIC3 expression in and mouse knee joints. Isolated fibroblast-like synoviocytes (FLS) were used to examine hyaluronan release and intracellular calcium in response to decreases in pH. Results In tissue sections from mice, ASIC3 localised to articular cartilage, growth plate, meniscus and type B synoviocytes. In cultured FLS, mRNA and protein was also expressed. In FLS cultures, pH 5.5 increased hyaluronan release in FLS, but not FLS. In FLS from mice, approximately 50% of cells (25/53) increased intracellular calcium while only 24% (14/59) showed an increase in FLS. Of the cells that responded to pH 5.5, there was significantly less intracellular calcium increases in FLS compared to FLS. Conclusion ASIC3 may serve as a pH sensor in synoviocytes and be important for modulation of expression of hyaluronan within joint tissue. [ABSTRACT FROM PUBLISHER]

Objectives: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFα) blocking therapy. Methods: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. Results: Sixteen patients (13 women) were studied; all had previously failed TNFα-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNγ of −52% (95% CI −73 to −15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE–MRI showed a reduction of 15–40% in MRI parameters. Conclusion: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA. [ABSTRACT FROM PUBLISHER]

Objectives: The I kappaB kinase (IKK)-related kinase IKKepsilon regulates type I interferon expression and responses as well as proinflammatory mediator production. We examined the role of IKKepsilon in arthritis and its ability to enhance the therapeutic response to systemic interferon (IFN) beta therapy in passive murine K/BxN arthritis.Methods: IKKepsilon(-/-), IFN alpha(approximately)beta R(-/-) and wild type mice were given K/BxN serum and treated with polyinosinic polycytidylic acid (poly(I:C)), IFN beta, or normal saline. Clinical response and histological scores were assessed. Gene expression in the paws was measured by quantitative PCR. Serum interleukin 1a receptor agonist (IL1Ra) and IL10 were measured by ELISA and multiplex bead array.Results: Arthritis was almost completely blocked in wild type mice if arthritogenic K/BxN serum and the Toll-like receptor (TLR)3 ligand, poly(I:C), were coadministered at the onset of the model, but not in established disease. Mice deficient in IFN alpha(approximately)beta R had an accelerated course of arthritis, and did not respond to poly(I:C). IKKepsilon null mice had a modest decrease in clinical arthritis compared with heterozygous mice. Low doses of IFN beta that were ineffective in wild type mice significantly decreased clinical arthritis in IKKepsilon null mice. Articular chemokine gene expression was reduced in the IKKepsilon(-/-) mice with arthritis and secreted IL1Ra (sIL1Ra) mRNA was significantly increased. Serum levels of IL1Ra were increased in low dose IFN beta-treated IKKepsilon(-/-) mice.Conclusions: Subtherapeutic doses of IFN beta enhance the anti-inflammatory effects of IKKepsilon deficiency, possibly by increasing production of IL1Ra and unmasking the antichemokine effects. Combination therapy with low dose IFN beta and an IKKepsilon inhibitor might improve efficacy of either agent alone and offers a novel approach to RA. [ABSTRACT FROM AUTHOR]

Objective: Treatment with the anti-CD20 monoclonal antibody (mAb) rituximab is effective in rheumatoid arthritis (RA). Marked depletion of circulating B cells, seen in almost all patients, does not correlate with efficacy. The potential synovial immunomodulatory effects of rituximab have not been fully defined.Methods: The ARISE trial is an open label, serial synovial biopsy (pre-treatment and 8 weeks) study of rituximab, given 1 g intravenously on days 0 and 14 without peri-infusional steroids, in active RA patients on concomitant methotrexate (MTX). Synovial tissue was analysed by immunohistochemistry with digital image analysis and gene expression by real-time PCR.Results: The mean (SD) baseline DAS28 score was 6.5 (0.4), and mean MTX dose 17.3 mg/week. Of 13 patients, 11 had failed prior tumour necrosis factor (TNF) inhibitor therapy. With treatment, all patients experienced near complete depletion of circulating B cell numbers. During the 6 months after treatment, 7/13 patients achieved an American College of Rheumatology (ACR) 20% improvement (ACR20) response, 3/13 an ACR50 response and 2/13 an ACR70 response. There was a significant decrease in synovial B cells after treatment, but only a small trend towards greater reduction among clinical responders. Among the three patients with ACR50 responses there was a significant decrease in synovial immunoglobulin synthesis.Conclusions: These data suggest that unlike those in circulation, synovial B cells are decreased but are not eliminated by rituximab therapy. Patients with higher levels of response may have more consistent depletion of synovial B cells, and may also have an alteration in synovial B cell function, as indicated by decreases in synovial immunoglobulin synthesis. Thus, effects on synovial B cells may be necessary but not sufficient for inducing clinical efficacy. Other effects, such as on primary lymph organ B cell antigen presentation or cytokine production, may be operative. [ABSTRACT FROM AUTHOR]

The Eighth Survey of Staffing in Cardiology was conducted with an index date of 30 September 1992. The total number of cardiologists in England and Wales, defined as individuals trained in the specialty and spending at least 40% of their professional time working in it, was 358. Of these 11 were part time, defined as six sessions or less, giving a number in whole time (or near whole time) equivalents of 352.5. The number of individuals increased from 1991 by 18 (5.3%). There were 71 cardiologists in Scotland and Northern Ireland, making a total for the United Kingdom of 429 individuals (423.5 whole time equivalents), which is 7.3 per million population. A total of 44 Districts serving 8.8 million people have no resident cardiologist. There has been little improvement since the 1991 survey. An additional 34 Districts with populations greater than 250,000 have only one cardiologist: we have clear evidence of inadequate provision of care in most of these, a situation that is inevitable within the resources provided. A wider threat to the provision of a satisfactory level of cardiological care throughout the United Kingdom will follow from changes in the organisation of the National Health Service and in the new requirements for training of future cardiologists because these changes will make major new demands on consultant time which cannot be met within existing resources. A crisis will be averted only if a rapid and major expansion of the consultant grade can be achieved. [ABSTRACT FROM PUBLISHER]

The Sixth Biennial Survey of Staffing in Cardiology was conducted in July 1990. This report summarises the data that were collected, together with the results of a survey of facilities in cardiology made in 1989. The total number of cardiologists in the United Kingdom, defined as individuals trained in the specialty and spending at least 40% of their time working in it, is now 323. Six individuals work part time only, making 320 whole time posts. This number has increased over the two years from 1988 to 1990 by 32, of which 23 work only in the specialty and nine as general physicians with a major interest in cardiology. The rate of increase in numbers over the past decade has been reasonably consistent with an average of approximately 4.4% per year. Thirty one districts in England and Wales still have no cardiologist and 13 other districts have little provision with an average of three (visiting) sessions each per week. The population in these 44 districts is 8.3 million. Scotland also has an inadequate distribution of service in the specialty. If recommendations for cardiac surgery and angioplasty made in the Fourth Report of a Joint Cardiology Committee of the Royal College of Physicians of London and the Royal College of Surgeons of England are to be met, we calculate that we need 63 more cardiologists in our major centres. To provide one cardiologist in every district hospital and two for larger districts would require 94 more specialists, making a total shortfall of 157 individuals. We have no excess of senior registrars to provide for a major expansion at consultant level. Time spent within the senior registrar (or academic equivalent) grade has tended steadily to decline and very few now reach the end of their contracts. The need for more individuals to pass through the senior registrar grade will be met in part by a planned reduction in the training period to three years. This will be inadequate, however, because projected retirements show that the number of consultant vacancies will increase sharply from 1997. We believe that additional senior registrar posts must be created if a serious shortfall in service provision by consultants is to be avoided. The provision of non-invasive facilities in cardiology is reasonable. The need for additional equipment for invasive cardiology has not been assessed. The number of physiological measurement technicians varies considerably between regions and is generally inadequate. [ABSTRACT FROM PUBLISHER]

This is the fifth survey of staffing (consultants and senior registrars) in cardiology in the United Kingdom. Data from previous years--including the fourth survey (1986) that was not published separately--are used to show the trends over the past decade. In 1988 there were less than six cardiologists per million population. The United Kingdom, with Ireland, has fewer cardiologists than all other European countries with reliable figures. The ratio for Europe as a whole is approximately 45 per million population; the recommended figure for the United States of America is 60 per million. The distribution of cardiologists in England and Wales is still very uneven. Seven million people--nearly 15% of the population--have no immediate access to special expertise in cardiology. Women are particularly poorly represented in the specialty. This survey indicates that the crisis in staffing for cardiology continues. It will worsen as the possibilities grow for effective management of heart disease and as needs increase with the greater average age of the population. Resolution of this crisis should be a major priority in policies aimed at countering the ravages of heart disease. [ABSTRACT FROM PUBLISHER]

All patients with a presumptive diagnosis of myocardial infarction, who were seen within six hours of the onset of symptoms and had no reason for exclusion, were considered for entry into a trial to compare the effects of metoprolol and placebo on creatine kinase MB isoenzyme release. The trial was randomised and double blind. The median time from onset of symptoms to receiving trial drug was just under two hours. Two hundred and four patients (of whom 120 had myocardial infarction) received metoprolol and 187 (of whom 105 had myocardial infarction) received placebo. Infarct size was estimated semiquantitatively using cumulative release of the cardiospecific isoenzyme, creatine kinase MB. Mean creatine kinase MB isoenzyme was less in patients who received metoprolol, but the reduction did not achieve statistical significance. Clinical problems related to early intravenous metoprolol were uncommon. [ABSTRACT FROM PUBLISHER]

A cardiovascular study of a group of 90 newly diagnosed diabetic women aged 35 to 75 years was begun in 1965 and a repeat examination was carried out on the same patients in 1968. A high prevalence of ischaemic heart disease was found in these patients at the time of diagnosis, and this finding had some predictive value as regards prognosis over the three-year period. A comparative study with general medical outpatients and long-established diabetics (greater than 10 years' duration of disease) confirmed the high prevalence of ischaemic heart disease in late-onset mild diabetics controlled by diet or oral drugs. It is suggested that this type of milder diabetic patient contributes in undue proportion to the high prevalence of ischaemic heart disease in diabetes. [ABSTRACT FROM PUBLISHER]

A simple combined intravenous/intramuscular regimen is described for lignocaine administration in the early vulnerable stage of myocardial infarction. Plasma levels in the therapeutic range are attained. This allows adequate drug protection during transport to hospital when an intravenous regimen may be impractical or impossible. [ABSTRACT FROM PUBLISHER]

Abstract Introduction/aims Oxaliplatin chemotherapy-induced peripheral neuropathy (OxCIPN) is a common post-treatment toxicity. Many patients are left with long-term pain and disability. Available systemic agents have limited efficacy, cause significant side-effects and take several weeks/months to work. Colleagues' preclinical work showed analgesic effects of topical transient receptor potential melastatin receptor activators in neuropathic pain. We therefore conducted a proof-of-concept study using menthol in patients with OxCIPN. Methods 21 patients a median of 19 months post-treatment (range 3–35) applied 1% topical menthol, twice daily to affected areas and skin overlying corresponding dorsal root ganglia. At baseline, 2 and 6 weeks, patients completed: Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale and underwent objective assessments of gait (electronic walkway), hand dexterity (peg-board) and Quantitative Sensory Testing. Analysis: Wilcoxon signed-rank test and Pearson product-moment correlation. Results Between baseline and 6 weeks, total BPI scores decreased (median 3.6 (range 1.1–7.9) versus 0.7 (0–8.3), p=0.002). 83% described less pain and 52% had ≤30% BPI decrease (deemed clinically significant). There were corresponding improvements in mood (r=0.442, p=0.045), walking velocity (r=-0.797, p=0.026) and cadence (r=-0.823, p=0.012) and trends for improved hand dexterity (r=0.487, p=0.065) and mechanical pain thresholds (r=0.447, p=0.072). Four patients discontinued treatment after 2 weeks: two had difficulty applying the cream, two described worse pain. BPI changes were predicted by pre-treatment mechanical detection thresholds (r=0.534, p=0.027). Conclusion Topical menthol appeared to improve OxCIPN pain and physical function. It also seems to be well tolerated, have minimal side-effects, works relatively quickly and warrants further study. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article by E. Morris, P. Quirke, J. D. Thomas, L. Fairley, B. Cottier, and D. Forman on variation in abdominoperineal excision rates for rectal cancer that was published in the previous issue.

Objectives: This study aimed to perform a meta-analysis of the short-term impact of ischaemic postconditioning (IPoC) on myocardial injury in ST elevation myocardial infarction (STEMI) using surrogate cardiac biomarkers., Methods: Eligible studies were identified using several article databases. Randomised controlled trials published between 1 January 2000 and 1 December 2021 comparing IPoC to standard of therapy in STEMI patients were included in the search. Outcomes included surrogates of myocardial injury, specifically peak troponin, creatine-kinase (CK) and CK myoglobin binding (CK-MB) enzyme levels., Results: 11 articles involving 1273 patients reported on CK-MB and 8 studies involving 505 patients reported on CK. Few studies used troponin as an outcome, thus, a subanalysis of troponin dynamics was not performed. Meta-regression analysis demonstrated no significant effect of IPoC on peak CK-MB (effect size -0.41, 95% CI -1.15 to 0.34) or peak CK (effect size -0.42, 95% CI -1.20 to 0.36). Linear regression analysis demonstrated a significant correlation between a history of smoking and CK-MB in the IPoC group (p=0.038)., Conclusions: IPoC does not seem to protect against myocardial injury in STEMI, except possibly in smokers. These results resonate with some studies using imaging techniques to ascertain myocardial damage. More research using troponin and cardiac imaging should be pursued to better assess the effects of IPoC on cardiovascular outcomes in STEMI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine whether characterisation of patients' metabolic profiles, utilising nuclear magnetic resonance (NMR) and mass spectrometry (MS), could predict response to rituximab therapy. 23 patients with active, seropositive rheumatoid arthritis (RA) on concomitant methotrexate were treated with rituximab. Patients were grouped into responders and non-responders according to the American College of Rheumatology improvement criteria, at a 20% level at 6 months. A Bruker Avance 700 MHz spectrometer and a Thermo Scientific Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer were used to acquire (1)H-NMR and ultra high pressure liquid chromatography (UPLC)-MS/MS spectra, respectively, of serum samples before and after rituximab therapy. Data processing and statistical analysis were performed in MATLAB. 14 patients were characterised as responders, and 9 patients were considered non-responders. 7 polar metabolites (phenylalanine, 2-hydroxyvalerate, succinate, choline, glycine, acetoacetate and tyrosine) and 15 lipid species were different between responders and non-responders at baseline. Phosphatidylethanolamines, phosphatidyserines and phosphatidylglycerols were downregulated in responders. An opposite trend was observed in phosphatidylinositols. At 6 months, 5 polar metabolites (succinate, taurine, lactate, pyruvate and aspartate) and 37 lipids were different between groups. The relationship between serum metabolic profiles and clinical response to rituximab suggests that (1)H-NMR and UPLC-MS/MS may be promising tools for predicting response to rituximab.