Fibroblasts Promote Inflammation and Pain via IL-1α Induction of the Monocyte Chemoattractant Chemokine (C-C Motif) Ligand 2.

Fibroblasts persist within fibrotic scar tissue and exhibit considerable phenotypic and functional plasticity. Herein, we hypothesized that scar-associated fibroblasts may be a source of stress-induced inflammatory exacerbations and pain. To test this idea, we used a human model of surgery-induced fibrosis, total knee arthroplasty (TKA). Using a combination of tissue protein expression profiling and bioinformatics, we discovered that many months after TKA, the fibrotic joint exists in a state of unresolved chronic inflammation. Moreover, the infrapatellar fat pad, a soft tissue that becomes highly fibrotic in the post-TKA joint, expresses multiple inflammatory mediators, including the monocyte chemoattractant, chemokine (C-C motif) ligand (CCL) 2, and the innate immune trigger, IL-1α. Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the IL-1 receptor and on exposure to IL-1α polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-κB prevented IL-1α-induced monocyte recruitment. Clinical investigations discovered that levels of patient-reported pain in the post-TKA joint correlated with concentrations of CCL2 in the joint tissue, such that the chemokine is effectively a pain biomarker in the TKA patient. We propose that an IL-1α-NF-κB-CCL2 signaling pathway, operating within scar-associated fibroblasts, may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues.

Correction to: The WOMAC score can be reliably used to classify patient satisfaction after total knee arthroplasty.

Unfortunately, Fig. 1 in the original article contained incorrect information. Hereby, the correct figure is published and we apologise for the inconvenience.

What is the Minimum Clinically Important Difference for the WOMAC Index After TKA?

BACKGROUND: The WOMAC score is a validated outcome measure for use in patients undergoing TKA. Defining meaningful changes in the WOMAC score is important for sample-size calculations in clinical research and for interpreting published studies. However, inconsistencies among published studies regarding key definitions for changes in the WOMAC score after TKA potentially could result in incorrectly powered studies and the misinterpretation of clinical research results. QUESTIONS/PURPOSES: (1) To identify the minimum clinically important difference (MCID) for the total WOMAC score and its components 1 year after TKA using an anchor-based methodology. (2) To define the minimum important change (MIC) and the minimum detectable change with 95% confidence (MDC95) for the total WOMAC score and its components 1 year after TKA. METHODS: Between 2003 and 2013, 3641 patients underwent primary TKA at one center. Of those, 460 patients (13%) were excluded from this retrospective study for prespecified reasons (mainly secondary OA and bilateral surgery), and 592 patients (16%) were either lost to followup or could not be included because of incomplete questionnaires. WOMAC scores were recorded preoperatively and at 1 year postoperatively. Patient demographics and preoperative Short Form-12 and WOMAC scores were no different for the 16% of patients who were lost to followup or failed to complete 1-year questionnaires and the study cohort (n = 2589). At 1 year, patients were asked "How much did the knee replacement surgery improve the quality of your life?" Their responses were recorded as: a great improvement, moderate improvement, little improvement, no improvement at all, or the quality of my life is worse. The MCID was defined as the difference in the mean change in the WOMAC score between patients with no improvement compared with those with little improvement according to the anchor question. The MIC was defined as the change in the WOMAC score relative to the baseline score for patients who reported a little improvement in their quality of life. The MDC is the smallest change for an individual who is likely to be beyond the measurement error of the scoring tool and represents true change rather than variability in the scoring measure; we report it with 95% confidence bounds defining real change rather than variability in the scoring measure (MDC95). We calculated this with distribution-based methods for the whole cohort. Patients recording a little improvement (n = 211) and no improvement (n = 115) were used as anchor responses to calculate the MCID (using regression analysis to adjust for potential confounding variables such as age, gender, BMI and preoperative Short Form-12 or WOMAC scores) and the MIC (using receiver operative characteristics curves). RESULTS: After adjusting for confounding variables such as age, gender, BMI as well as preoperative Short Form-12 and WOMAC scores, the MCID was 11 for pain, 9 for function, 8 for stiffness and 10 for the total WOMAC score. The MIC was 21 for pain, 16 for function, 13 for stiffness and 17 for the total WOMAC score. The MDC95 was 23 for pain, 11 for function, 27 for stiffness and 12 for the total WOMAC score. CONCLUSIONS: The MCID and MIC for the WOMAC score represent the smallest meaningful effect sizes when comparing the outcome of two groups (difference in mean change between the groups) or when assessing a cohort (a change in score for the group) after TKA, respectively, helping the reader to distinguish between a clinically important effect size and a mere statistical difference. We determined that the error in measurement (based on the MDC95) for the function component and total WOMAC scores were less than the MIC, which suggests changes beyond the MIC are clinically real and not due to uncertainty in the score. These parameters are essential to interpret TKA outcomes research and to ensure clinical research studies are amply powered to detect meaningful differences. Future studies using the WOMAC score to assess TKA outcomes should report not only the statistical significance (a p value) but also the clinical importance using the reported MCID and MIC values. LEVEL OF EVIDENCE: Level III, diagnostic study.

The WOMAC score can be reliably used to classify patient satisfaction after total knee arthroplasty.

PURPOSE: The primary aim of this study was to define a classification in the WOMAC score after total knee arthroplasty (TKA) according to patient satisfaction. The secondary aims were to describe patient demographics for each level of satisfaction. METHODS: A retrospective cohort consisting of 2589 patients undergoing a primary TKA were identified from an established arthroplasty database. Patient demographics, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and short form (SF) 12 scores were collected pre-operatively and 1 year post-operatively. In addition, patient satisfaction was assessed at 1 year with four responses: very satisfied, satisfied, dissatisfied or very dissatisfied. Receiver operating characteristic (ROC) curves were used to identify values in the components and total WOMAC scores that were predictive of each level of satisfaction, which were used to define the categories of excellent, good, fair and poor. RESULTS: At 1 year, there were 1740 (67.5%) very satisfied, 572 (22.2%) satisfied, 190 (7.4%) dissatisfied and 76 (2.9%) very dissatisfied patients. ROC curve analysis identified excellent, good, fair and poor categories for the pain (> 78, 59-78, 44-58, < 44), function (> 72, 54-72, 41-53, < 41), stiffness (> 69, 56-69, 43-55, < 43) and total (> 75, 56-75, 43-55, < 43) WOMAC scores, respectively. Patients with lung disease, diabetes, gastric ulcer, kidney disease, liver disease, depression, back pain, with worse pre-operative functional scores (WOMAC and SF-12) and those with less of an improvement in the scores, had a significantly lower level of satisfaction. CONCLUSION: This study has defined a post-operative classification of excellent, good, fair and poor for the components and total WOMAC scores after TKA. The predictors of level of satisfaction should be recognised in clinical practice and patients at risk of a lower level of satisfaction should be made aware in the pre-operative consent process. LEVEL OF EVIDENCE: III.

Inadequate pre-operative glycaemic control in patients with diabetes mellitus adversely influences functional recovery after total knee arthroplasty : Patients with impaired glycaemic control exhibit poorer functional outcomes at 1-year post-arthroplasty.

PURPOSE: Whilst inadequate glycaemic control is associated with an increase in perioperative complications following total knee arthroplasty, the impact of glycaemic control in this at-risk patient group remains ill-defined. Identification of at-risk patients would allow targeted pre-operative glycaemic control intervention. METHODS: One hundred consecutive patients with a diagnosis of diabetes mellitus and one hundred age, sex and BMI matched patients without diabetes undergoing total knee arthroplasty in a single institution were analysed between 2008 and 2013. Inadequate glycaemic control was defined as having an HbA1c of greater than 64 mmol/mol (8.0 % NGSP) measured within the 3 months before surgery. Patient demographics, diabetes management and complications of diabetes were recorded and used as explanatory variables to deliver a generalised linear model. This allows for relationships to be defined between change in patient-reported function (SF-36, WOMAC) and these explanatory variables. RESULTS: The patient group with concomitant diabetes exhibited smaller improvements in WOMAC and SF-36 physical component summary at 1 year after knee arthroplasty. This effect was most pronounced in the subset of patients with inadequate glycaemic control recorded in the early pre-operative period. CONCLUSION: Patients with diabetes, particularly those with inadequate glycaemic control, exhibit less improvement at 1 year following knee arthroplasty than patients without diabetes mellitus. Clinical focus on modulating this factor in this at-risk group is warranted. LEVEL OF EVIDENCE: III.

Length of stay and its impact upon functional outcomes following lower limb arthroplasty.

PURPOSE: The aim was to investigate the interplay between patient characteristics and (1) length of hospital stay and (2) one-year patient-reported outcome following total knee and hip arthroplasty. METHODS: Event (survival) analysis and structural equation modelling were performed for 1001 patients undergoing knee (n = 566) and hip (n = 435) arthroplasty in a single institution. RESULTS: Age, body mass index and co-morbidities were independent predictors of length of stay in both event analysis and structural equation modelling. These patient characteristics and type of arthroplasty had both small direct and indirect effects on patient-reported outcome measures at one year. Length of stay had a small effect (<2 %) in SF-36 scores at one year. CONCLUSION: Predictors that influence length of stay also impact on one-year post-operative outcome and therefore should be taken into account during patient selection and discharge planning. LEVEL OF EVIDENCE: Retrospective cohort study, Level III.

Operational complexities in international clinical trials: a systematic review of challenges and proposed solutions.

OBJECTIVE: International trials can be challenging to operationalise due to incompatibilities between country-specific policies and infrastructures. The aim of this systematic review was to identify the operational complexities of conducting international trials and identify potential solutions for overcoming them. DESIGN: Systematic review. DATA SOURCES: Medline, Embase and Health Management Information Consortium were searched from 2006 to 30 January 2023. ELIGIBILITY CRITERIA: All studies reporting operational challenges (eg, site selection, trial management, intervention management, data management) of conducting international trials were included. DATA EXTRACTION AND SYNTHESIS: Search results were independently screened by at least two reviewers and data were extracted into a proforma. RESULTS: 38 studies (35 RCTs, 2 reports and 1 qualitative study) fulfilled the inclusion criteria. The median sample size was 1202 (IQR 332-4056) and median number of sites was 40 (IQR 13-78). 88.6% of studies had an academic sponsor and 80% were funded through government sources. Operational complexities were particularly reported during trial set-up due to lack of harmonisation in regulatory approvals and in relation to sponsorship structure, with associated budgetary impacts. Additional challenges included site selection, staff training, lengthy contract negotiations, site monitoring, communication, trial oversight, recruitment, data management, drug procurement and distribution, pharmacy involvement and biospecimen processing and transport. CONCLUSIONS: International collaborative trials are valuable in cases where recruitment may be difficult, diversifying participation and applicability. However, multiple operational and regulatory challenges are encountered when implementing a trial in multiple countries. Careful planning and communication between trials units and investigators, with an emphasis on establishing adequately resourced cross-border sponsorship structures and regulatory approvals, may help to overcome these barriers and realise the benefits of the approach. OPEN SCIENCE FRAMEWORK REGISTRATION NUMBER: osf-registrations-yvtjb-v1.

Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK).

BACKGROUND: Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone. METHODS AND ANALYSIS: E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials. ETHICS AND DISSEMINATION: The East Midlands-Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number 2022-002659-20; ISRCTN 10615985.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Prehabilitation in elective patients undergoing cardiac surgery: a randomised control trial (THE PrEPS TRIAL) - a study protocol.

INTRODUCTION: Prehabilitation prior to surgery has been shown to reduce postoperative complications, reduce length of hospital stay and improve quality of life after cancer and limb reconstruction surgery. However, there are minimal data on the impact of prehabilitation in patients undergoing cardiac surgery, despite the fact these patients are generally older and have more comorbidities and frailty. This trial will assess the feasibility and impact of a prehabilitation intervention consisting of exercise and inspiratory muscle training on preoperative functional exercise capacity in adult patients awaiting elective cardiac surgery, and determine any impact on clinical outcomes after surgery. METHODS AND ANALYSIS: PrEPS is a randomised controlled single-centre trial recruiting 180 participants undergoing elective cardiac surgery. Participants will be randomised in a 1:1 ratio to standard presurgical care or standard care plus a prehabilitation intervention. The primary outcome will be change in functional exercise capacity measured as change in the 6 min walk test distance from baseline. Secondary outcomes will evaluate the impact of prehabilitation on preoperative and postoperative outcomes including; respiratory function, health-related quality of life, anxiety and depression, frailty, and postoperative complications and resource use. This trial will evaluate if a prehabilitation intervention can improve preoperative physical function, inspiratory muscle function, frailty and quality of life prior to surgery in elective patients awaiting cardiac surgery, and impact postoperative outcomes. ETHICS AND DISSEMINATION: A favourable opinion was given by the Sheffield Research Ethics Committee in 2019. Trial findings will be disseminated to patients, clinicians, commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: ISRCTN13860094.

Robotic- and orthosensor-assisted versus manual (ROAM) total knee replacement: a study protocol for a randomised controlled trial.

BACKGROUND: Robotic-arm-assisted knee arthroplasty allows for more accurate component positioning and alignment and is associated with better patient-reported outcomes compared to manually performed jig-based knee arthroplasty. However, what is not known is whether the addition of an intra-articular sensor (VerasenseTM) to aid intraoperative balancing of the total knee replacement (TKR) offers improved functional outcomes for the patient. The purpose of this research is to compare the outcomes of patients undergoing a conventional manual knee replacement to those undergoing TKR using robotic-assisted surgery and the VerasenseTM to optimise alignment and balance the knee joint, respectively, and assess the associated cost economics of such technology. METHODS AND ANALYSIS: This randomised controlled trial will include 90 patients with end-stage osteoarthritis of the knee undergoing primary TKR. Patients meeting the inclusion/exclusion criteria that consent to be in the study will be randomised at a ratio of 1:1 to either manual TKR (standard of care) or robotic-arm-assisted TKR with VerasenseTM to aid balancing of the knee. The primary objective will be functional improvement at 6 months following surgery between the two groups. The secondary objectives are to compare changes in knee-specific function, joint awareness, patient expectation and fulfilment, satisfaction, pain, stiffness and functional ability, health-related quality of life, cost-effectiveness, and gait patterns between the two groups. Ethical approval was obtained by the Tyne & Wear South Research Ethics Committee, UK. The study is sponsored by the Newcastle Hospitals NHS Foundation Trust. DISCUSSION: This study will assess whether the improved accuracy of component positioning using the robotic-arm-assisted surgery and the VerasenseTM to aid balancing of the TKR offers improved outcome relative to standard manual jig-based systems that are currently the standard of care. This will be assessed primarily according to knee-specific function, but several other measures will also be assessed including whether these are cost-effective interventions. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN47889316 https://doi.org/10.1186/ISRCTN47889316 . Registered on 25 November 2019 DATE AND VERSION FOR PROTOCOL: ROAM Protocol V1.0 (13-12-2018).

Synovectomy during total knee arthroplasty: a pilot single-centre randomised controlled trial.

BACKGROUND: Total knee arthroplasty (TKA) is an effective procedure for late-stage osteoarthritis (OA) of the knee; however, up to 20% of patients remain dissatisfied. In some patients, this may be due to residual inflammation of the synovium. Our aim was to perform the first randomised controlled trial (RCT) of synovectomy during TKA for patients with macroscopically inflamed synovium. The main objectives were to assess recruitment rates, protocol adherence and outcomes relating to safety such as haemoglobin decrease and adverse events. We also collected data on patient-reported outcomes. METHODS: We performed a single-centre pilot RCT. Patients with a macroscopically inflamed synovium were randomised to receive synovectomy versus a control group that did not undergo synovectomy. We determined feasibility by measuring patient enrolment, completeness of follow-up, and safety via haemoglobin decrease and documentation of adverse events. RESULTS: We screened 360 patients with 260 deemed ineligible or could not be recruited. From the 100 eligible patients, 54 were enrolled and 40 progressed through to randomisation. All made it to the 12-month follow-up, indicating good protocol adherence. There were no major differences in adverse events or haemoglobin decrease demonstrating acceptable safety. Outcomes relating to satisfaction were reliably obtained. CONCLUSIONS: Patients with macroscopically inflamed synovium of the knee who are due to undergo TKA can be reliably recruited to a randomised trial and synovectomy can be performed safely. A large number is needed to be screened to identify eligible participants, and therefore, a multi-centre trial would be required to assess whether routine synovectomy would improve outcomes in these patients. TRIAL REGISTRATION: ISRCTN, ISRCTN31010214. Registered 6 October 2016-retrospectively registered.

Return to work after knee replacement: a qualitative study of patient experiences.

OBJECTIVE: An increasing number of patients in the working population are undergoing total knee replacement (TKR) for end-stage osteoarthritis. The timing and success of return to work is becoming increasingly important for this group of patients with social and economic implications for patients, employers and society. There is limited understanding of the patient variables that determine the ability to return to work. Our objective was (from the patient's perspective) to gain an insight into the factors influencing return to work following knee replacement. SETTING AND PARTICIPANTS: This qualitative study was undertaken in a secondary-care setting in a large teaching hospital in the north of England. Semistructured interviews were carried out with 10 patients regarding their experiences of returning to work following TKR. OUTCOMES: Interviews were transcribed and analysed using a qualitative thematic approach to identify the factors influencing return to work from the patient's perspective. RESULTS: Three themes were identified that influenced the process of return to work, from the patient's perspective. These were delays in surgical intervention, limited and often inconsistent advice from healthcare professionals regarding return to work, and finally the absence of rehabilitation to optimise patient's recovery and facilitate return to work. CONCLUSIONS: There is currently no consistent process to optimise return to work for patients of working age after TKR. The impact of delayed surgical intervention, limited advice regarding return to work, and a lack of work-focused rehabilitation, all contribute to potential delays in successful return to work. There is a need to change the focus of healthcare provision for this cohort of patients, and provide a tailored healthcare intervention to optimise patient outcomes.