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Objectives GCA can be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used HLA genetic association of TAB-positive GCA as an 'unbiased umpire' test to estimate historic overdiagnosis of GCA. Methods Patients diagnosed with GCA between 1990 and 2014 were genotyped. During this era, vascular imaging alone was rarely used to diagnose GCA. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all HLA variants with P  < 1.0 × 10−5 were compared with population control data to estimate overdiagnosis rates in cases without a positive TAB. Results Genetic data from 663 GCA patients were compared with data from 2619 population controls. TAB-negative GCA (n  = 147) and GCA without TAB result (n  = 160) had variant frequencies intermediate between TAB-positive GCA (n  = 356) and population controls. For example, the allele frequency of HLA-DRB1*04 was 32% for TAB-positive GCA, 29% for GCA without TAB result, 27% for TAB-negative GCA and 20% in population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated as 88%. Conclusions Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Our method for utilizing standard genotyping data as an 'unbiased umpire' might be used as a way of comparing the accuracy of different diagnostic pathways. [ABSTRACT FROM AUTHOR]

Objectives Extracellular vesicles (EVs) are abundant in body fluids, contributing to intercellular signalling by transferring cargo that includes microRNAs (miRs)—themselves implicated in pathobiology. For the first time we evaluated the potential of EV miRs to contribute diagnostic information in early RA, predict methotrexate (MTX) efficacy or shed light on the drug's mechanism of action. Methods Seven hundred and ninety-eight miRs isolated from serum-derived EVs of 46 patients with untreated RA, 23 with untreated polymyalgia rheumatica (PMR; inflammatory disease control group) and 12 in whom significant inflammatory disease had been excluded (non-inflammatory controls; NICs) were profiled (NanoString); the same measurements were made for RA patients after 6 months' MTX treatment. Analyses took multiple testing into account. Results Twenty-eight EV miRs were robustly differentially expressed between early RA (but not PMR) patients and NICs after correction for age and sex, suggesting discriminatory value. Cross-validated partial least squares-discriminant analysis also indicated the predictive potential of a distinct baseline EV miR signature with respect to MTX-induced remission at 6 months. The change in expression of 13 miRs over the course of MTX treatment differed significantly between responders and non-responders, and four of those exhibiting increased relative abundance amongst responders have known roles in regulating the pathogenic potential of synovial fibroblasts, namely miR-212-3p, miR-338-5p, miR-410-3p and miR-537. Conclusion Our data highlight the potential of serum EV miRs as diagnostic and therapeutic biomarkers, highlighting a novel potential mechanism by which MTX may exert its therapeutic effect in early RA that warrants further investigation. [ABSTRACT FROM AUTHOR]

The last British Society for Rheumatology (BSR) guideline on PMR was published in 2009. The guideline needs to be updated to provide a summary of the current evidence for pharmacological and non-pharmacological management of adults with PMR. This guideline is aimed at healthcare professionals in the UK who directly care for people with PMR, including general practitioners, rheumatologists, nurses, physiotherapists, occupational therapists, pharmacists, psychologists and other health professionals. It will also be relevant to people living with PMR and organisations that support them in the public and third sector, including charities and informal patient support groups. This guideline will be developed using the methods and processes outlined in the BSR Guidelines Protocol. Here we provide a brief summary of the scope of the guideline update in development. [ABSTRACT FROM AUTHOR]

Objective Jaw symptoms can be a vital clue to the diagnosis of GCA. Guidelines recommend more intensive treatment if jaw claudication is present. We sought to explore how patients with GCA described their jaw symptoms. Methods We carried out a secondary, qualitative analysis of interview data from 36 participants from the UK (n  = 25) and Australia (n  = 11), originally collected in order to develop a patient-reported outcome measure for GCA. In all cases, GCA had been confirmed by biopsy/imaging. Interview transcripts were organized within QSR NVivo 12 software and analysed using template analysis. Themes were refined through discussion among the research team, including a patient partner. Results Twenty of 36 participants reported jaw symptoms associated with GCA. The median age of these 20 participants was 76.5 years; 60% were female. Five themes were identified: physical sensations; impact on function; impact on diet; symptom response with CSs; and attribution to other causes. Physical sensations included ache, cramp, stiffness and 'lockjaw'. Functional impacts included difficulty in eating/chewing, cleaning teeth, speaking or opening the mouth. Dietary impacts included switching to softer food. Response to CSs was not always immediate. Jaw symptoms were initially mis-attributed by some participants to arthritis, age or viral illnesses; or by health-care professionals to a dental cavity, ear infection or teeth-grinding. Conclusion Jaw symptoms in GCA are diverse and can lead to diagnostic confusion with primary temporomandibular joint disorder, potentially contributing to delay in GCA diagnosis. Further research is needed to determine the relationship of jaw stiffness to jaw claudication. [ABSTRACT FROM AUTHOR]

Objectives To determine whether the halo count (HC) on temporal and axillary artery US (TAUS) predicts time to relapse in giant cell arteritis (GCA). Methods We conducted a single-centre retrospective study of GCA patients. HC, the number of vessels with non-compressible halo on the TAUS at diagnosis, was determined by retrospective review of the US report and images. Relapse was defined as increase in GCA disease activity requiring treatment escalation. Cox proportional hazard regression was used to identify predictors of time to relapse. Results A total of 72 patients with confirmed GCA were followed up for a median of 20.9 months. Thirty-seven of 72 (51.4%) relapsed during follow-up, at a median prednisolone dose of 9 mg (range 0–40 mg). Large-vessel (axillary artery) involvement did not predict relapse. On univariable analysis, a higher HC was associated with shorter time to relapse (per-halo hazard ratio 1.15, 95% CI 1.02, 1.30; P  = 0.028). However, statistical significance was lost when the 10 GCA patients with an HC of zero were excluded from analysis. Conclusion In this real-world setting, relapse occurred at a wide range of glucocorticoid doses and was not predicted by axillary artery involvement. GCA patients with a higher HC at diagnosis were significantly more likely to relapse, but significance was lost on excluding those with HC of zero. HC is feasible in routine care and may be worth incorporating into future prognostic scores. Further research is required to determine whether confirmed GCA patients with negative TAUS represent a qualitatively different subphenotype within the GCA disease spectrum. [ABSTRACT FROM AUTHOR]

Objectives Glucocorticoids (GCs) ('steroids') are used to treat rheumatic diseases but adverse effects are common. We aimed to explore the impact of GC therapy on health-related quality of life (HRQoL), to inform the development of a treatment-specific patient-reported outcome measure (PROM) for use in clinical trials and practice. Methods Semi-structured qualitative interviews were conducted with patients from the UK, USA and Australia, treated for a rheumatic condition with GCs in the last 2 years. Purposive sampling was used to select participants with a range of demographic and disease features. An initial conceptual framework informed interview prompts and cues. Interviews elicited GC-related physical and psychological symptoms and salient aspects of HRQoL in relation to GC therapy. Interview data were analysed inductively to develop initial individual themes and domains. Candidate questionnaire items were developed and refined. Results Sixty semi-structured qualitative interviews were conducted (UK n  = 34, USA n  = 10, Australia n  = 16). The mean age was 58 years; 39/60 were female; and 18 rheumatic diseases were represented. Some 126 individual themes were identified and organized into six domains: physical symptoms; psychological symptoms; psychological impact of steroids; impact of steroids on participation; impact of steroids on relationships; and benefits of steroids. Candidate questionnaire items were tested and refined by piloting with patient research partners, iterative rounds of cognitive interviews and linguistic translatability assessment, informing a draft questionnaire. Conclusion We describe an international qualitative study to develop candidate items for a treatment-specific PROM for patients with rheumatic diseases. A future survey will enable the validation of a final version of the PROM. [ABSTRACT FROM AUTHOR]

Objective The aim was to determine prevalent co-morbidities in cases with PMR or GCA compared with matched controls. Methods This was a nested, cross-sectional case–control study within the UK Biobank, which recruited participants aged 40–69 years. Case status was defined as self-reported prior diagnosis of PMR or GCA. Ten controls per case were matched for age, sex, ethnicity and assessment centre. Associations with selected self-reported co-morbidities were studied using conditional logistic regression. Results Of PMR (n  = 1036) or GCA (n  = 102) cases, 72% were female, 98% White, and 58% reported current use of glucocorticoids. Mean age was 63 years. At the time of the assessment visit, compared with controls, PMR/GCA cases were more likely to report poor general health and at least several days of low mood in the past 2 weeks. PMR was associated with hypothyroidism [odds ratio (OR) = 1.34; 95% CI = 1.07, 1.67] and ever-use of HRT (OR = 1.26; 95% CI = 1.07, 1.47). Regarding common co-morbidities, PMR and GCA were both associated with hypertension (PMR: OR = 1.21; 95% CI = 1.06, 1.39; GCA: OR = 1.86; 95% CI = 1.23, 2.81) and cataract (PMR: OR = 1.51; 95% CI = 1.19, 1.93; GCA: OR = 3.84; 95% CI = 2.23, 6.60). Additionally, GCA was associated with depression (OR = 3.05; 95% CI = 1.59, 5.85). Neither condition was associated with diabetes. Conclusion Participants with a history of PMR/GCA, including those not currently taking glucocorticoids, rated their health as poorer than matched controls. Some previously described disease associations (hypothyroidism and early menopause) were replicated. Hypertension and cataract, both of which can be exacerbated by long-term glucocorticoid therapy, were over-represented in both diseases, particularly GCA. [ABSTRACT FROM AUTHOR]

Objectives Angiotensin II is implicated in GCA pathology. We examined whether the use of angiotensin receptor blockers (ARBs) is associated with GCA risk compared with angiotensin-converting enzyme inhibitors (ACEis) or other antihypertensives. Methods We performed a matched cohort study including adults who were initiators of antihypertensives in UK primary care data between 1995 and 2019. Treatment-naïve individuals without prior GCA or PMR were categorized into three groups—ARB initiators, ACEi initiators, or other antihypertensive initiators (beta-blockers, calcium channel blockers, diuretics or alpha-adrenoceptor blockers)—and followed for up to 5 years. Incident GCA was defined using validated Read codes, with age of onset ≥50 years and two or more glucocorticoid prescriptions. Inverse probability–weighted Cox models were used to model outcome risk, adjusting for lifestyle parameters, comorbidities and comedications. Results Among >1 million new starters of antihypertensives (81 780 ARBs, 422 940 ACEis and 873 066 other antihypertensives), the incidence rate of GCA per 10 000 patient-years was 2.73 (95% CI 2.12, 3.50) in the ARB group, 1.76 (95% CI 1.25, 2.39) in the ACEi group and 1.90 (95% CI 1.37, 2.56) in the other antihypertensives group. The hazard of GCA was higher in ARB initiators [hazard ratio (HR) 1.55; 95% CI 1.16, 2.06] than initiators of ACEis, but similar between initiators of other antihypertensives and ACEis (HR 1.08; 95% CI 0.87, 1.35). Conclusions Initiation of ARBs is associated with a higher risk of GCA compared with ACEis or other antihypertensives. Mechanistic studies of angiotensin receptor biology will provide further clarity for our findings. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop and validate an automated pipeline that could assist the diagnosis of active aortitis using radiomic imaging biomarkers derived from [18F]-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography (FDG PET-CT) images. The aorta was automatically segmented by convolutional neural network (CNN) on FDG PET-CT of aortitis and control patients. The FDG PET-CT dataset was split into training (43 aortitis:21 control), test (12 aortitis:5 control) and validation (24 aortitis:14 control) cohorts. Radiomic features (RF), including SUV metrics, were extracted from the segmented data and harmonized. Three radiomic fingerprints were constructed: A—RFs with high diagnostic utility removing highly correlated RFs; B used principal component analysis (PCA); C—Random Forest intrinsic feature selection. The diagnostic utility was evaluated with accuracy and area under the receiver operating characteristic curve (AUC). Several RFs and Fingerprints had high AUC values (AUC > 0.8), confirmed by balanced accuracy, across training, test and external validation datasets. Good diagnostic performance achieved across several multi-centre datasets suggests that a radiomic pipeline can be generalizable. These findings could be used to build an automated clinical decision tool to facilitate objective and standardized assessment regardless of observer experience. [ABSTRACT FROM AUTHOR]

The Delphi method is a well‐established research tool, used for consensus building across a number of fields. Despite its widespread use, and popularity in many medical specialities, there is a paucity of literature on the use of the Delphi method in Histopathology. This literature review seeks to critique the Delphi methodology and explore its potential applications to histopathology‐based clinical and research questions. We review those published studies that have utilized the Delphi methodology in Histopathology settings and specifically outline the advantages and limitations of this technique, highlighting situations where its application can be most effective. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the potential effect of genetically proxied interleukin-1 (IL-1) receptor antagonist (IL-1Ra) on risk of polymyalgia rheumatica (PMR). Topics include disadvantages of IL-6 inhibition as a therapeutic strategy for PMR compared with glucocorticoids, clinical characteristics of PMR, and genetic evidence that IL-1Ra is associated with reduced risk of PMR.

Clinicians are advised caution in reducing serum urate for gout management due to observational associations with risk of neuropsychiatric diseases. We examined the causal effect of genetically predicted serum urate levels on the risk of major depressive disorder (MDD), anxiety, and related psychiatric disorders using two-sample Mendelian randomization (MR). We identified single-nucleotide polymorphisms (SNPs) associated with serum urate from a genome-wide association study (GWAS) of 110,347 European-descent individuals. The causal effect of serum urate on MDD was tested using summary data from a GWAS of 135,458 cases and 344,901 controls of European descent. MR was performed using random-effects inverse variance-weighted method and a series of sensitivity analyses. This approach was repeated using summary GWAS data for anxiety, bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, schizophrenia, and anorexia nervosa. We identified 30 SNPs associated with serum urate. Genetically predicted urate levels were not causally associated with risk of MDD (OR 0.98; 95% CI 0.94, 1.03), anxiety (OR 0.90; 95% CI 0.80, 1.02), or the other psychiatric conditions (OR range 0.95 to 1.06). Results were similar in sensitivity analyses. We found no evidence that genetically predicted serum urate has a causal effect on risk of MDD, anxiety, or other psychiatric disorders. Key Points • Clinicians are advised to be cautious about reducing the serum urate level too far in gout management, citing observational associations between low serum urate levels and various neuropsychiatric diseases. • In this two-sample Mendelian randomization study, we found no evidence for a causal link between genetically predicted serum urate level and the development of major depressive, anxiety, or other related psychiatric disorders. • Future revisions of clinical guidelines may need to reconsider recommendations regarding lower limits for serum urate levels. [ABSTRACT FROM AUTHOR]

Introduction. Glucocorticoids (GCs) remain widely used. However, the impact of GCs from the perspective of the patient, rather than of the clinician, remains relatively unexplored. Additionally, no general patient reported outcome measure has been developed to assess the effects of GCs across rheumatological conditions. The aim of this literature review was to identify the adverse effects of systemic GC use that are of importance to patients. Methods. OVID EMBASE, OVID MEDLINE, PsycINFO and CINAHL was searched relating to three concepts: GCs, the patient perspective and adverse effects. A meta-synthesis of the qualitative data was performed separately by two independent researchers before qualitative metasummary was utilized to quantitatively aggregate the findings (combining quantitative and qualitative results), including the derivation of frequency and intensity effect sizes to identify those outcomes most prominently featured across all reviewed articles. Results. The initial search retrieved 1,356 articles, of which 25 (18 quantitative, 7 qualitative) were deemed suitable for quality assessment and data extraction. Four major themes emerged amongst the 71 discrete outcomes: physical symptoms (44), psychological symptoms (18), effect on participation (6) and contextual factors (3). Conclusions. Patients with a broad range of inflammatory diseases and demographic features describe key cross-cutting themes in relation to GCs and their impact on health-related quality of life. This work will inform the development of a core domain set for clinical trials involving GCs and a patient reported outcome to measure impact of GCs from the patient's perspective. [ABSTRACT FROM AUTHOR]

Objective: Morning stiffness is a hallmark symptom of rheumatoid arthritis (RA), but its etiology is poorly understood. This study was undertaken to determine whether any histologic features of synovium are associated with this symptom. Methods: Data on patient‐reported morning stiffness duration and severity, and Disease Activity Score in 28 joints (DAS28) were collected from 176 patients with RA undergoing arthroplasty. Synovium was scored for 10 histopathologic features: synovial lining hyperplasia, lymphocytes, plasma cells, Russell bodies, binucleate plasma cells, fibrin, synovial giant cells, detritus, neutrophils, and mucin. Fibrinolysis of clots seeded with various cell types was measured in turbidimetric lysis assays. Results: Stiffness severity and morning stiffness duration were both significantly associated with DAS28 (P = 0.0001 and P = 0.001, respectively). None of the synovial features examined were associated with patient‐reported stiffness severity. The presence of neutrophils and fibrin in RA synovial tissue were significantly associated (P < 0.0001) with patient‐reported morning stiffness of ≥1 hour, such that 73% of patients with both synovial fibrin and neutrophils reported morning stiffness of ≥1 hour. Further, neutrophils and fibrin deposits colocalized along the synovial lining. In in vitro analyses, fibrin clots seeded with necrotic neutrophils were more resistant to fibrinolysis than those seeded with living neutrophils or no cells (P = 0.008). DNase I treatment of necrotic neutrophils abrogated the delay in fibrinolysis. Conclusion: In RA, prolonged morning stiffness may be related to impaired fibrinolysis of neutrophil‐enmeshed fibrin deposits along the synovial membrane. Our findings also suggest that morning stiffness severity and duration may reflect distinct pathophysiologic phenomena. [ABSTRACT FROM AUTHOR]

The article presents the guideline of the British Society for Rheumatology on diagnosis and treatment of giant cell arteritis (GCA). Topics discussed include objectives of the guideline, important stakeholder representation in the guideline, and methods used to formulate the recommendations. Also mentioned are the general principles of the guideline, specific recommendations for diagnostic tests in suspected GCA, and potential organizational barriers to implementation.

Objectives PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. Methods Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. Results In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P =0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P =0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. Conclusion PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk. [ABSTRACT FROM AUTHOR]

We report a patient with chronic lymphocytic leukaemia (CLL) who was treated with idelalisib, a PI3Kδ inhibitor with rituximab. After 20 weeks of treatment, the patient developed classical signs and symptoms of polymyalgia rheumatica (PMR) in association with an elevated C reactive protein of 74 mg/L. After 2 weeks of prednisolone 15 mg daily symptoms had resolved and acute phase markers normalised. To our knowledge, this is the first report of PMR developing as a complication of PI3Kδ inhibitor treatment of CLL. [ABSTRACT FROM AUTHOR]