The protocol of a clinical effectiveness trial comparing standard step-up care, early combination DMARD therapy and early use of TNF inhibitors for the treatment of moderate to severe psoriatic arthritis: the 3-arm parallel group SPEED randomized controlled trial.

Objectives: The aim of the Severe Psoriatic arthritis - Early intervEntion to control Disease trial is to compare outcomes in psoriatic arthritis (PsA) patients with poor prognostic factors treated with standard step-up conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), combination csDMARDs or a course of early biologics. Design: This multicentre UK trial was embedded within the MONITOR-PsA cohort, which uses a trial within cohort design. Methods and analysis: Patients with newly diagnosed PsA and at least one poor prognostic factor (polyarthritis, C-reactive protein >5 mg/dL, health assessment questionnaire >1, radiographic erosions) were randomized equally and open-label to either standard care with 'step-up' csDMARD therapy, initial therapy with combination csDMARDs (methotrexate with either sulfasalazine or leflunomide) or to early biologics induction therapy (adalimumab plus methotrexate). The primary outcome is the PsA disease activity score at week 24. Ethics: Ethical approval for the study was granted by the South Central Research Ethics Committee (ref 18/SC/0107). Discussion: Treatment recommendations for PsA suggest more intensive therapy for those with poor prognostic factors but there are no studies that have previously used prognostic factors to guide therapy. Applying initial intensive therapy has shown improved outcomes in other inflammatory arthritides but has never been tried in PsA. Combination csDMARDs have shown some superiority over single therapies but there are limited data and concerns about side effects. Early use of biologics has also been shown to be superior to methotrexate but these drugs are costly and not usually funded first line. However, if a short course of biologics can rapidly suppress inflammation allowing treatment to be withdrawn and response maintained on methotrexate, this may be a cost-effective model for early use. Trial registration: ClinicalTrials.gov (NCT03739853) and EudraCT (2017-004542-24).

Clinical effectiveness of symptomatic therapy compared with standard step-up care for the treatment of low-impact psoriatic oligoarthritis: the two-arm parallel group randomised POISE feasibility study.

INTRODUCTION: In psoriatic arthritis (PsA), treatment recommendations support first-line use of disease-modifying antirheumatic drugs (DMARDs). There are few treatment strategy trials, and no previous studies have investigated tailored treatment choice by disease severity. Studies in oligoarthritis (<5 inflamed joints) are limited but have suggested that some can be managed without DMARDs, preventing unnecessary side effects. This study aimed to assess the feasibility and acceptability of a study comparing standard DMARD treatment against symptomatic therapy in patients with mild psoriatic oligoarthritis. METHODS: This trial was embedded within the MONITOR-PsA cohort, which uses a Trials Within Cohorts (TWiCs) design. Patients with newly diagnosed psoriatic oligoarthritis, with low disease activity (PASDAS ⩽ 3.2) and the absence of poor prognostic factors [C reactive protein (CRP) < 5 mg/dL, HAQ < 1, no radiographic erosions] were randomised open-label to either standard care with 'step-up' DMARD therapy or to symptomatic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections to inflamed joints. Key outcomes were the proportion of eligible cohort patients, consent and study completion rate. RESULTS: Over the 15-month study period, only one eligible patient was randomised. Although oligoarthritis patients represented 45% of patients in this early PsA cohort, the majority did not have mild disease (24% raised CRP, 51% moderate disease activity, 13% radiographic damage and/or poor function). Of those meeting trial inclusion criteria, many patients refused treatment in the observational cohort prior to an invitation into the trial as they did not wish to be treated with DMARDs. CONCLUSION: The study was not feasible as designed. Oligoarthritis represents around half of initial PsA presentations, but the majority starting therapy have high-impact disease. A small proportion have mild oligoarticular disease but many are not keen on treatment with DMARDs, given the potential side effects of these medications. Further research is needed to support evidence-based treatment in this subgroup. TRIAL REGISTRATION NUMBER: - ClinicalTrials.gov (NCT03797872) and EudraCT (2018-001085-42).

Treating to target in psoriatic arthritis: assessing real-world outcomes and optimising therapeutic strategy for adults with psoriatic arthritis-study protocol for the MONITOR-PsA study, a trials within cohorts study design.

BACKGROUND: The Tight Control of psoriatic arthritis (TICOPA) trial confirmed improved clinical outcomes with a treat to target (T2T) strategy in psoriatic arthritis (PsA). This consisted of 4-weekly review and escalation of 'step up' therapy (single disease modifying therapy (DMARD), combination DMARDs and then biologics) based on remission criteria. Based on this, a T2T approach is supported by European PsA treatment recommendations. However, it is not commonly implemented in routine care primarily due to feasibility and cost concerns. In the TICOPA trial, the same treatment regime was used for all participants regardless of their disease profile. Despite the recognition of PsA as a highly heterogeneous condition, no studies have tailored which drugs are used depending on disease severity. The cohort will establish real world outcomes for the T2T approach in PsA and also form the basis of a trials within cohorts (TWiCs) design to test alternative therapeutic approaches within embedded clinical trials providing an evidence base for treatment strategy in PsA. METHODS: The Multicentre Observational Initiative in Treat to target Outcomes in Psoriatic Arthritis (MONITOR-PsA) cohort will apply a T2T approach within routine care. It will recruit newly diagnosed adult patients with PsA starting systemic therapies. The cohort is observational allowing routine therapeutic care within NHS clinics but a T2T approach will be supported when monitoring treatment within the cohort. Eligible participants will be adults (≥18 years) with active PsA with ≥ 1 tender or swollen joints or enthesis who have not previously had treatment with DMARDs for articular disease. DISCUSSION: This study is the first TWiC designed to support a fully powered randomised drug trial. The results from the observational cohort will be compared with those observed in the TICOPA trial investigating the clinical effectiveness and health care costs of the pragmatic T2T approach. Nested trials will provide definitive RCT evidence establishing the optimal management of PsA within the T2T approach. The TWiCs design allows robust generalizability to routine healthcare, avoids disappointment bias, aids recruitment and in future will allow assessment of longer-term outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03531073 . Retrospectively registered on 21 May 2018.

Hand Osteoarthritis: investigating Pain Effects of estrogen-containing therapy (HOPE-e): a protocol for a feasibility randomised placebo-controlled trial.

BACKGROUND: Hand osteoarthritis (OA) is a common condition, causing pain, stiffness and reduced quality of life. Incidence is higher amongst women, particularly around the age of the menopause. Whilst the relationship between sex hormones and OA has been studied in vitro, in epidemiological studies and in clinical trials of hormone replacement therapy (HRT), this study is the first to investigate the effect of estrogen-containing therapy on hand pain in post-menopausal women with symptomatic hand OA in a randomised study design. METHODS: This is a feasibility study of a double-blinded placebo-controlled intervention with 1:1 randomisation to either a combination of conjugated estrogens 0.45 mg and bazedoxifene acetate 20 mg (Duavive) or placebo. The target population is post-menopausal women with symptomatic hand OA, aiming to recruit 60-90 study participants. The primary objective is to assess the feasibility of a future fully powered randomised controlled trial (RCT). Participants will take the study medication for 24 weeks and be followed up for 28 weeks after randomisation. The primary outcomes used to determine feasibility are eligible participant identification rates and routes; recruitment, randomisation and retention rates of eligible participants; study medication compliance; and the likelihood of unintentional unblinding. Secondary outcomes include measures of hand pain, function, appearance and menopausal symptoms. An end of study questionnaire and focus groups will help to refine the final protocol for a full study. DISCUSSION: Identifying new treatments for symptomatic hand OA is a recognised research priority. The study will help us to understand whether there are sufficient interested and eligible individuals in this target population who would consider HRT for their hand symptoms. It will provide proof-of-concept RCT data on the effects of HRT on hand pain and other clinically relevant outcomes in this population. The study will gain valuable information on the feasibility of a full RCT and how best to run this. The findings will be published in a peer-reviewed journal and presented at a relevant conference. TRIAL REGISTRATION: ISRCTN12196200 registered on 15 January 2019.

Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.

More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.

T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5,6). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.

Extremity CT and ultrasound in the assessment of ankle injuries: occult fractures and ligament injuries.

OBJECTIVE: To assess the rates of fractures and ligament injuries in patients with an acute ankle injury and a normal radiographic examination, and to consider the most appropriate examination protocol. METHODS: Patients with an acute ankle injury who presented to the John Radcliffe Hospital Emergency Department with a normal radiographic examination were eligible for the study. They were invited to receive a cone beam CT and ultrasound examination at a local radiology department within 5 days of their ankle injury. RESULTS: Of the 100 patients recruited to the study, 19 patients were found to have major fractures and 42 patients had small avulsion fractures. Additionally, 42 patients had ankle effusions and there were a large number of soft tissue injuries. There were 83 acute injuries of the anterior talofibular ligament, 19 of the anterior tibiofibular ligaments, 26 of the calcaneofibular ligament, 39 of the deltoid ligament complex, 21 of the talonavicular ligament, 14 of the spring ligament and 3 of the calcaneocuboid ligament. CONCLUSION: Conventional radiographic examination misses significant fractures of the foot and ankle and the presence of an ankle effusion does not relate to the severity of injury. Ultrasound is a useful imaging technique that can supplement clinical practice, but it is unlikely to replace current protocols alone. Cone beam CT is an appropriate alternative to plain radiography, being more sensitive in detecting fractures and delivering a similar dose of radiation. However, neither CT or ultrasound examination can detect all avulsion fractures. Simple anterior process fractures of the calcaneus are associated with talonavicular ligament injuries and the medial ligaments are injured in almost 50% of cases when there is a lateral ligament injury. ADVANCES IN KNOWLEDGE: Fractures in the foot and ankle are detected more precisely with cone beam CT compared to radiographs. Cone beam CT delivers similar doses of to conventional radiographs which is around 10% of that resulting from conventional CT. Ultrasound examination is an effective assessment tool to detect ligamentous injuries. The absence of an ankle effusion does not exclude a major fracture.

Meta-analysis of the association of the Taq1A polymorphism with the risk of alcohol dependency: a HuGE gene-disease association review.

The human dopamine 2 receptor Taq1A allele has been implicated as a vulnerability factor for alcohol dependence in a number of studies and reviews. To determine whether this allele is associated with alcoholism, the authors conducted a Human Genome Epidemiology review and meta-analysis. Forty-four studies with 9,382 participants were included. An odds ratio of 1.38 (95% confidence interval: 1.20, 1.58; heterogeneity, 50.5%) was found for the A1A1 + A1A2 versus the A2A2 genotype. Sensitivity analyses suggested lack of ethnic matching as a possible source of heterogeneity; a small, significant association was detected in studies with ethnic-matched controls (odds ratio = 1.26, 95% confidence interval: 1.02, 1.56; heterogeneity, 37%). Significant associations were also found in analyses restricted to studies reporting use of blinding and those with adequate screening of controls for alcohol dependency. For the A1A1 versus the A1A2 + A2A2 genotype, the odds ratio was 1.22 (95% confidence interval: 1.05, 1.43; heterogeneity, 0%). Sensitivity analyses on groups of studies reporting use of ethnic-matched controls and those that screened controls for alcohol dependency still showed significant associations. The relatively small effect for the association of the A1 allele, or another genetic variant linked to it, with alcohol dependence indicates a multigene causality for this complex disorder.

Predicting poor outcome from simple ankle injuries: a prospective cohort study.

BACKGROUND: Sprained ankles are common and when there are no signs or evidence of a fracture, conventional management is conservative. At present, there are no clinical markers to identify those that may develop persisting instability and disability that would require rehabilitation or surgery. OBJECTIVES: To investigate the nature and extent of soft tissue ankle injuries, and to consider whether the anatomical severity of injury can predict functional outcome. METHODS: Patients attending a local Accident and Emergency Department in Oxford with an acute ankle injury with no clinical requirement for radiographs, or where radiographs were normal, were invited into the study. Within 5 days, patients underwent a diagnostic ultrasound examination, a cone beam CT study and a disability assessment. Ultrasound and physiotherapy assessments were repeated at 3 and 6 months. RESULTS: 100 patients were recruited and grouped based upon injuries. 58 had simple ankle injuries, 21 complex, 19 had significant fractures and 2 were excluded from further follow up analysis. There were no clinically significant differences in pain, disability or functional outcomes between the groups at all points of the study. CONCLUSION: Medium to long term clinical outcomes were not solely determined by the severity of injury. Some patients with simple injuries were seen to have ongoing problems, whereas some with complex injuries recovered completely in a shorter period. Advances in knowledge: The severity of an ankle injury determined by radiological imaging does not necessarily dictate the severity of a patient's symptoms and the trajectory of their recovery.

Patients' experiences when accessing their on-line electronic patient records in primary care.

BACKGROUND: Patient access to on-line primary care electronic patient records is being developed nationally. Knowledge of what happens when patients access their electronic records is poor. AIM: To enable 100 patients to access their electronic records for the first time to elicit patients' views and to understand their requirements. DESIGN OF STUDY: In-depth interviews using semi-structured questionnaires as patients accessed their electronic records, plus a series of focus groups. SETTING: Secure facilities for patients to view their primary care records privately. METHOD: One hundred patients from a randomised group viewed their on-line electronic records for the first time. The questionnaire and focus groups addressed patients' views on the following topics: ease of use; confidentiality and security; consent to access; accuracy; printing records; expectations regarding content; exploitation of electronic records; receiving new information and bad news. RESULTS: Most patients found the computer technology used acceptable. The majority found viewing their record useful and understood most of the content, although medical terms and abbreviations required explanation. Patients were concerned about security and confidentiality, including potential exploitation of records. They wanted the facility to give informed consent regarding access and use of data. Many found errors, although most were not medically significant. Many expected more detail and more information. Patients wanted to add personal information. CONCLUSION: Patients have strong views on what they find acceptable regarding access to electronic records. Working in partnership with patients to develop systems is essential to their success. Further work is required to address legal and ethical issues of electronic records and to evaluate their impact on patients, health professionals and service provision.

Patients' access to their online electronic health records.

We surveyed a randomized group of 1050 adult patients stratified for age and sex, from a general practice in Oxfordshire, to find out their attitudes to electronic health records (EHRs). Eighty-six per cent thought that patients should have the right to see their records. While 72% knew that they had the right to see their records, only 4% had done so. Private EHR viewing booths with a computer and fingerprint identification system were installed in the primary care centre. Patients were randomly selected from those who responded to the questionnaire and wished to view their EHR. Of the 100 patients who saw their online EHR, 99 found the session useful and 84 found their records easy to understand. Three focus groups were held with 14 patients who said that they did not want to access their EHRs. The reasons patients gave during the focus groups included that they trusted their general practitioner and thought it would imply a lack of confidence. After the focus groups, 11 patients changed their minds and accessed their records. We believe that patient-accessed EHRs will offer substantial benefits to patients, health professionals and the National Health Service as a whole.

Changes in shoulder muscle size and activity following treatment for breast cancer.

BACKGROUND: Morbidity of the shoulder after breast cancer is a well-known phenomenon. MRI studies have shown muscle morbidity in cervical cancer and prostate cancer. In breast cancer clinical observations and patient reports include muscle morbidity in a number of muscles acting at the shoulder. Several of these muscles lie in the field of surgery and radiotherapy. Timed interaction between muscles that stabilise the shoulder and those acting as prime movers is essential to achieve a smooth scapulohumeral rthythm during functional elevation of the arm. METHOD: CROSS-SECTIONAL STUDY: Seventy-four women treated for unilateral carcinoma of the breast were included in the study. All patients filled out the Shoulder Pain and Disability Index (SPADI). EMG activity of four muscles was recorded during scaption on the affected and unaffected side. Muscle cross sectional area and signal intensity was determined from MRI scans. The association between EMG and covariates was determined using multiple linear regression techniques. RESULTS: Three of the 4 muscles on the affected side demonstrated significantly less EMG activity, particularly when lowering the arm. Upper trapezius demonstrated the greatest loss in activity. Decreased activity in both upper trapezius and rhomboid were significantly associated with an increase in SPADI score and increased time since surgery. Pectoralis major and minor were significantly smaller on the affected side. CONCLUSION: Muscles affected in the long term are the muscles associated with pain and disability yet are not in the direct field of surgery or radiotherapy. Primary muscle shortening and secondary loss of muscle activity may be producing a movement disorder similar to the 'Dropped Shoulder Syndrome'. Exercise programmes should aim not only for range of movement but also for posture correction and education of potential long-term effects.

Access to electronic health records in primary care-a survey of patients' views.

BACKGROUND: The NHS is moving towards electronic access to health records for patients from 2004 and needs to involve patients in the development process. The aim of the study was to explore the views of a large sample of patients about online access to EPRs and health information in primary care. Areas covered included: accuracy rights of access; security; confidentiality and smart cards. MATERIAL/METHODS: The questionnaire was sent to 1050 patients selected at random from the practice list after stratification for age and sex. RESULTS: 66% of patients aged over 20 years old responded. Patients know they have the right to see their records although few have done so. Overall they feel the advantages of electronic health records outweigh the disadvantages. They have concerns about security, confidentiality, understanding their records, their accuracy and completeness. The patients recognised the potential benefits to their healthcare and relationships with health professionals. There was a majority view that parents / guardians and carers should have access to their dependants' records. CONCLUSIONS: Patients need to be confident that access is limited to those who have the right to see the records. The majority were confident they would understand their records and about half were familiar with computer use. However these are major issues for older patients who will require assistance in order to benefit from accessing their EPRs. It is essential that patient involvement takes place at every stage of the development of EPRs and that their views are taken into account.