[Show abstract][Hide abstract] ABSTRACT: A Diagnostic Protocol for Giant Cell Arteritis (GCA) Using Ultrasound Assessment
Jennifer Piper1, Ana Sofia Serafim1, Cristina Ponte1, Surjeet Singh2, Bhaskar Dasgupta3, Wolfgang A. Schmidt4, Eugene McNally5, Andreas P. Diamantopoulos6, Andrew Hutchings7 and Raashid Luqmani8, 1Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom, 2University of Oxford, Sciences, Oxford, England, 3Department of Rheumatology, Southend University Hospital, Essex, United Kingdom, 4Rheumatology, Immanuel Krankenhaus, Berlin, Germany, 5Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, United Kingdom, 6Rheumatology, Hospital of Southern Norway Trust, Kristiansand, Norway, 7Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom, 8Oxford NIHR Musculoskeletal Biomedical Research Unit, Oxford, United Kingdom
Ultrasound (US) has not yet superseded temporal artery biopsy as a diagnostic test. This may reflect poor consistency of the scanning technique, due to the lack of a standardised scanning protocol. We have developed a standardised protocol which was implemented in a prospective study of 857 participants: 439 healthy controls and 418 patients with suspected GCA (Temporal Artery Biopsy versus Ultrasound, TABUL). We assessed each patient for evidence of typical ultrasound features of GCA: the presence of a halo surrounding the vessel wall, stenosis or occlusion of the vessel.
A detailed scanning protocol was developed for all cases and controls. We recorded the presence or absence of ultrasound features of GCA in each segment of each temporal artery (common, parietal, frontal proximal and frontal distal) and both axillary arteries. Sonographers were asked to acquire video and static images for each patient to ensure accuracy of findings. The sonographer measured and documented: halo diameter (based on a normal range of up to 0.3 mm for the temporal artery and up to 1.0 mm in the axillary artery) and length; pulse Doppler measurements prior to and within a stenosis (confirmed if the highest maximum systolic velocity was over twice the lowest maximum systolic velocity) and arterial occlusion. Each study site sonographer was required to be proficient in the protocol by scanning at least 10 healthy controls, passing an online test showing normal and abnormal scans (pass mark >75%) and scanning a patient with ultrasound evidence of active GCA.
The US scanning protocol was started by 33 sites, with only 22 sites completing the training in 6.7 months [range 0.2 – 16.4 months]. A total of 439 controls were scanned across 31 sites (1 sonographer covered 3 sites). The online test was passed by 39 sonographers (multiple sonographers at some sites) with an average of 2 attempts [range 1-4]); 22 sonographers successfully scanned an active GCA patient, validated by the expert panel. The longest delay in completing the training was due to difficulty in recruiting a patient with active GCA (hot case), which was necessary for each site prior to it joining the main study. Common issues encountered were a lack of time away from clinical duties and locating a new suspected GCA case for the hot case assessment.
We have created a bank of 857 sets of consistently recorded US images of temporal and axillary arteries from 418 patients with suspected GCA and 439 healthy controls. Expert review of the first 263 suspected patients has confirmed positive US findings of GCA in 100 patients and no US evidence in 163 cases.
Quality and accuracy are imperative for the clinical use of ultrasound data in the diagnosis of GCA. We have developed an effective training program and scanning protocol which ensures consistency and proficiency. The methodology can be adapted and extended to allow for additional artery assessment, including carotid, vertebral and subclavian arteries, extending the value of a structured approach. We recommend the TABUL study scanning protocol as the standard approach for diagnosis of GCA using ultrasound.
[Show abstract][Hide abstract] ABSTRACT: Early Halo Sign Features on Ultrasound Examination of Treated Patients with Giant Cell Arteritis
Ana Sofia Serafim1, Surjeet Singh1, Jennifer Piper1, Andrew Hutchings2, Mike Bradburn3, Cristina Ponte4, Bhaskar Dasgupta5, Wolfgang A. Schmidt6, Andreas P. Diamantopoulos7, Eugene McNally8 and Raashid Luqmani9, 1Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom, 2Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom, 3Clinical Trials Research Unit (CTRU), Sheffield University, Sheffield, United Kingdom, 4Rheumatology and Metabolic Bone Diseases Department, Rheumatology Research Unit - IMM, Lisbon Academic Medical Centre, Lisbon, Portugal, 5Department of Rheumatology, Southend University Hospital, Essex, United Kingdom, 6Rheumatology, Immanuel Krankenhaus, Berlin, Germany, 7Rheumatology, Hospital of Southern Norway Trust, Kristiansand, Norway, 8Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, United Kingdom, 9Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom
The TABUL study (Temporal Artery Biopsy Vs Ultrasound in diagnosis of Giant Cell Arteritis) is assessing the relative performance of ultrasound and temporal artery biopsy for diagnosing GCA. All patients with newly suspected GCA underwent a single ultrasound scan of both temporal and axillary arteries within 7 days of commencing glucocorticoid therapy. We aimed to examine the ultrasound response to treatment as a potential biomarker in GCA, by measuring differences in the size of the halo around the arteries with different steroid duration within a 7 day period; furthermore we correlated the halo size with ischaemic symptoms of GCA.
All 415 cases with suspected GCA had an ultrasound examination of the temporal and axillary arteries and a biopsy of the temporal artery within 7 days of inclusion. The 301 patients with clinically defined definite or probable GCA at baseline were included in this analysis. Using the IBM SPSS Statistics package v20, we performed a cross-sectional analysis with linear and logistic regression models to determine the relationship of the halo size with days of steroid treatment and with ischaemic symptoms of GCA (jaw and tongue claudication, amaurosis fugax and reduced, lost or double vision).
We included 214 women and 87 men (mean age 72.6 and 71.2 years old respectively) from 20 different recruitment centres. Fifty percent were scanned on the second day of steroid treatment or before. Forty three per cent (131 patients) had one or more temporal segments with a halo, 48.5% (146 patients) had bilateral temporal artery halos and 12.6% (38 patients) had axillary involvement. The linear regression model showed a consistently smaller halo size over the 7 days of steroid treatment (p<0.005) for the temporal arteries. The likelihood of finding a halo diminished with time, which was confirmed in a logistic regression until day 4 of steroid treatment (p<0.005), whereas this trend was not possible to predict after that time. At least one ischaemic symptom was present in 42% of the patients: jaw claudication in 48.2% (146 patients), reduced or lost vision in 36.6% (111 patients), double vision in 8.6% (26 patients), tongue claudication in 6.6% (20 patients) and amaurosis fugax in 4% (12 patients). The presence of jaw claudication was more frequent in patients with a halo (p<0.05). The symptomatic side of temporal arteries correlated significantly with the ipsilateral ultrasound findings (p<0.05 for right and left side findings on physical examination).
In newly diagnosed GCA, ultrasound halo size decreases with steroid treatment and correlates with the presence of ischaemic symptoms, supporting its early use as a diagnostic and potentially prognostic marker. We are exploring the potential value of change in halo size in individual patients over time to determine its value in monitoring response to treatment.
[Show abstract][Hide abstract] ABSTRACT: This study sets out to investigate the relationship between health status [EuroQol five-dimensions questionnaire (EQ-5D)] in primary SS and three of the European League Against Rheumatism (EULAR) SS outcome measures-the disease activity index (ESSDAI), the patient reported index (ESSPRI) and the sicca score. In particular, the goal was to establish whether there is a relationship between the EULAR outcome measures and quality of life.
[Show abstract][Hide abstract] ABSTRACT: Objective: This study investigates the relationship between health status (EQ-5D) in primary Sjögren’s syndrome and three of the EULAR Sjögren’s syndrome outcome measures – the disease activity index (ESSDAI), the patient reported index (ESSPRI) and the sicca score.
Methods: Health status was evaluated using a standardised measure developed by the EuroQol Group - the EQ5D. This permits calculation of two measures of health status: time trade-off values (TTO) and the EQ5D visual analogue scale (VAS) scores. We used Spearman rank correlation analysis to investigate the strength of association between health status and three EULAR measures of physician and patient reported disease activity in 639 patients from the United Kingdom primary Sjögren’s syndrome registry (UKPSSR) cohort.
Results: This study demonstrates that the EULAR Sjögren’s syndrome disease specific outcome measures are significantly correlated with health outcome values (p<0.001). Higher scores on the ESSDAI, EULAR sicca score and ESSPRI are associated with poorer health states – i.e. lower TTO values and lower VAS scores. While all three are significantly correlated with TTO values and EQ5D-VAS scores, the effect is strongest for the ESSPRI index.
Conclusion: This study provides further evidence supporting the use of ESSDAI, EULAR sicca score and ESSPRI measures in the clinic. We also discuss the need for disease-specific measures of health status and their comparison to standardised health outcome measures.
[Show abstract][Hide abstract] ABSTRACT: The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.
Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.
Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1-29.9%, OKZ=32.5-60.7%; ACR50: PBO=1.3-4.9%, OKZ=11.5-33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.
OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.
Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The Diagnostic and Classification Criteria for Vasculitis (DCVAS) Study is a multinational observational study to develop diagnostic criteria and to update classification criteria for the primary systemic vasculitides. By 2015 the database will include clinical, laboratory and radiology data from over 2000 patients with vasculitis and 1500 comparator patients who present with features similar to vasculitis. To avoid the inherent circularity of using the submitting physician diagnosis as the gold standard, a reference diagnosis for
each patient will be established using a combination of expert panel opinion and data-driven methods (e.g. machine learning algorithms).
The aim of this analysis was to evaluate the methodology by which the expert panel will assess individual patient data to establish the reference diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Rationale: Giant-cell arteritis (GCA) is a large vessel vasculitis characterized by immune cell infiltration, yet the potential involvement of neutrophils has been rarely studied. Objective: We investigated whether alterations in neutrophil reactivity occurred in the pathogenesis of GCA, or during its clinical management with a canonical glucocorticoid dose regimen over a 6-month period. Methods and Results: Blood samples were taken within 48h of therapy commencement and at week-1, 4 and 24 post-glucocorticoid. Flow-cytometric analysis revealed three distinct neutrophils populations and phenotypes. Within 48hrs of steroid treatment, neutrophils displayed an AnxA1(hi)CD62L(lo)CD11b(hi) phenotype, whereas week-1 neutrophils were AnxA1(hi)CD62L(lo)CD11b(lo) and displayed minimal adhesion to endothelial monolayers under flow, and week 24 (i.e. lowest glucocorticoid dose) neutrophils were AnxA1(hi)CD62L(hi)CD11b(hi) with increased endothelial adhesion under flow. Week 24 plasma analyses showed high levels of CXCL5, IL-8, IL-17 and IL-6. Importantly, comparison of week-1 and 24 samples revealed a suppressive neutrophil effect on T-cell proliferation at the former time point only. Finally, in vitro incubation of naïve neutrophils with concentrations of IL-6 and IL-17 quantified in GCA plasma at week-1 and 24 replicated this differential modulation of lymphocyte proliferation. Conclusions: This translational study highlights a novel clinical manifestations of GCA, with evidence for a neutrophil component and an 'escaped' pro-inflammatory phenotype when glucocorticoid therapy is tapered. These results indicate potential involvement of neutrophils in GCA pathogenesis.
Circulation Research 10/2013; · 11.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the risk of aortic aneurysm in patients with giant cell arteritis (GCA) compared with age-, gender- and location-matched controls.
A UK General Practice Research Database (GPRD) parallel cohort study of 6999 patients with GCA and 41 994 controls, matched on location, age and gender, was carried out. A competing risk model using aortic aneurysm as the primary outcome and non-aortic-aneurysm-related death as the competing risk was used to determine the relative risk (subhazard ratio) between non-GCA and GCA subjects, after adjustment for cardiovascular risk factors.
Comparing the GCA cohort with the non-GCA cohort, the adjusted subhazard ratio (95% CI) for aortic aneurysm was 1.92 (1.52 to 2.41). Significant predictors of aortic aneurysm were being an ex-smoker (2.64 (2.03 to 3.43)) or a current smoker (3.37 (2.61 to 4.37)), previously taking antihypertensive drugs (1.57 (1.23 to 2.01)) and a history of diabetes (0.32 (0.19 to 0.56)) or cardiovascular disease (1.98 (1.50 to 2.63)). In a multivariate model of the GCA cohort, male gender (2.10 (1.38 to 3.19)), ex-smoker (2.20 (1.22 to 3.98)), current smoker (3.79 (2.20 to 6.53)), previous antihypertensive drugs (1.62 (1.00 to 2.61)) and diabetes (0.19 (0.05 to 0.77)) were significant predictors of aortic aneurysm.
Patients with GCA have a twofold increased risk of aortic aneurysm, and this should be considered within the range of other risk factors including male gender, age and smoking. A separate screening programme is not indicated. The protective effect of diabetes in the development of aortic aneurysms in patients with GCA is also demonstrated.
Annals of the rheumatic diseases 10/2013; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: To evaluate the efficacy and safety of subcutaneous golimumab as add-on therapy in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) treatment. To evaluate an intravenous plus subcutaneous (IV+SC) golimumab strategy in patients who had not attained remission. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active RA in typical clinical practice settings. In part 1, patients received add-on monthly 50-mg subcutaneous golimumab for 6 months. The percentage of patients with good/moderate European League Against Rheumatism (EULAR) 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) response was compared in patient subgroups with various concurrent or previous DMARD treatments. In part 2, patients with EULAR responses but not remission were randomly assigned to receive IV+SC or subcutaneous golimumab to month 12; DAS28-ESR remission was measured. RESULTS: 3366 patients were enrolled. At baseline of part 1, 3280 efficacy-evaluable patients had mean disease duration of 7.6 years and mean DAS28-ESR of 5.97 (SD=1.095). At month 6, 82.1% achieved good/moderate EULAR responses and 23.9% attained remission. When EULAR responses were analysed by the number of previously failed DMARD or the concomitant methotrexate dose, DMARD type, or corticosteroid use, no statistically significant differences were observed. Part 2 patients (N=490) who received IV+SC or subcutaneous golimumab achieved similar remission rates (∼25%). Adverse events were consistent with previous reports of golimumab and other tumour necrosis antagonists in this population. CONCLUSIONS: Add-on monthly subcutaneous golimumab resulted in good/moderate EULAR response in most patients; 25% achieved remission after 6 more months of golimumab, but an IV+SC regimen provided no additional efficacy over the subcutaneous regimen.
Annals of the rheumatic diseases 06/2013; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract
Objectives: EuroQoL-5 dimension (EQ-5D) is a standardised, preference-based tool for measurement of health-related quality of life and EQ-5D utility values can be converted to Quality Adjusted Life Years (QALY) to aid cost-utility analysis. This study aimed to evaluate the EQ-5D utility values of 639 primary Sjögren’s syndrome (PSS) patients from the UK PSS registry.
Methods: Prospective data collected using a standardised pro forma were compared to UK normative data. Relationships between utility values and the clinical and laboratory features of PSS were explored.
Results: The proportion (%) of PSS patients reporting any problem in mobility, self-care, usual activities, pain/discomfort & anxiety/depression were 42.2, 16.7, 56.6, 80.6 & 49.4 respectively, compared to 5.4, 1.6, 7.9, 30.2 & 15.7 for the UK general population. The median EQ-5D utility values was 0.691 (Interquartile range: 0.587-0.796, range: -0.239 to 1.000), with a bi-modal distribution. Bivariate correlation analysis revealed significant correlation between EQ-5D utility values and many clinical features of PSS but most strongly with pain, depression and fatigue (R values >0.5). After adjusting for age and sex differences, multiple regression analysis identified pain and depression asthe two most important predictors of EQ-5D utility values accounting for 48% of the variability. Anxiety, fatigue, and body mass index were other statistically significant predictors but accounting for <5% in variability.
Discussion: This is the first report on the EQ-5D utility values of PSS patients. PSS patients have significantly impaired utility values compared to the UK general population. EQ-5D utility values are significantly related to pain and depression scores in PSS.
Annals of the Rheumatic Diseases 04/2013; · 9.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Giant cell arteritis is the most common vasculitis in Caucasians. Acute visual loss in one or both eyes is by far the most feared and irreversible complication of giant cell arteritis. This article reviews recent guidelines on early recognition of systemic, cranial, and ophthalmic manifestations, and current management and diagnostic strategies and advances in imaging. We share our experience of the fast track pathway and imaging in associated disorders, such as large-vessel vasculitis.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Polymyalgia rheumatica (PMR) is the commonest inflammatory rheumatic disease in the elderly and is a common indication for long-term steroid therapy. We now know that there is a significant overlap with large-vessel vasculitis and inflammatory arthritis and that the polymyalgic syndrome can herald the onset of various inflammatory illnesses in the elderly. The management of PMR is challenging due to heterogeneity in presentation and response to steroids.
Areas covered: This article reviews current treatment options for PMR, strategies for early identification and treatment of relapse, monitoring of disease activity, complications and prevention of adverse effects. Although steroids suppress signs and symptoms of PMR, they are unable to prevent multiple flares and long-term adverse events. The authors review the unmet need for safer and more efficacious treatment of PMR.
Expert opinion: Slow tapering following a low initial prednisone dose results in better outcomes than high starting doses and a quick tapering regimen. Leflunomide and tocilizumab are two promising agents and larger studies are needed to confirm their efficacy in resistant PMR. We propose that improved methods for classification (such as the EULAR-ACR classification criteria) and disease assessment together with standardized treatment approaches will serve to improve the care of PMR patients.