Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Enhancing current guidance for psoriatic arthritis and its comorbidities: recommendations from an expert consensus panel.

OBJECTIVES: Existing guidelines for psoriatic arthritis (PsA) cover many aspects of management. Some gaps remain relating to routine practice application. An expert group aimed to enhance current guidance and develop recommendations for clinical practice that are complementary to existing guidelines. METHODS: A steering committee comprising experienced, research-active clinicians in rheumatology, dermatology and primary care agreed on themes and relevant questions. A targeted literature review of PubMed and Embase following a PICO framework was conducted. At a second meeting, recommendations were drafted and subsequently an extended faculty comprising rheumatologists, dermatologists, primary care clinicians, specialist nurses, allied health professionals, non-clinical academic participants and members of the Brit-PACT patient group, was recruited. Consensus was achieved via an online voting platform when 75% of respondents agreed in the range of 7-9 on a 9-point scale. RESULTS: The guidance comprised 34 statements covering four PsA themes. Diagnosis focused on strategies to identify PsA early and refer appropriately, assessment of diagnostic indicators, use of screening tools and use of imaging. Disease assessment centred on holistic consideration of disease activity, physical functioning and impact from a patient perspective, and on how to implement shared decision-making. For comorbidities, recommendations included specific guidance for high-impact conditions such as depression and obesity. Management statements (which excluded extant guidance on pharmacological therapies) covered multidisciplinary team working, implementation of lifestyle modifications and treat-to-target strategies. Minimising corticosteroid use was recommended where feasible. CONCLUSION: The consensus group have made evidence-based best practice recommendations for the management of PsA to enhance the existing guidelines.

Partial body fat percentage as a predictor of fragility fractures in a large cohort: a cross-sectional study.

Objectives: BMI is a component of fracture risk calculators; however, it may be too simplistic to predict fracture risk. There is emerging evidence for the role that fat plays as a predictor of fracture. Partial body fat percentage (PBF%) may be a novel way to predict both hip and non-hip fractures. The aim of this study is to evaluate PBF% as a predictor of fragility fractures. Methods: A multivariate logistic regression analysis was conducted looking at PBF% as a predicter of both non-hip and hip fractures in an observational cohort. Our results were adjusted for age, biological sex, gender, smoking status, excess alcohol consumption (>3 units/day), current steroid therapy and the T-scores in both femurs. To allow for comparison, the same model was used with BMI, height and weight as the primary predictor of fracture. A subgroup analysis was conducted stratified by fracture site. A sensitivity analysis using a negative binomial regression was conducted. Results: A total of 31 447 patients were included in our analysis [mean age 64.9 years (s.d. 12.9)]. PBF% was shown to predict all non-hip fractures after adjustment [odds ratio (OR) 22.14 (95% CI 15.08, 32.50)]. Hip fractures were not predicted by our model [OR 4.19 (95% CI 0.43, 41.46)]. Sensitivity analysis demonstrated a lack of predictive capability for hip fracture but not non-hip fractures. Conclusion: PBF% may be a suitable predictor for all non-hip fractures, independent of confounding variables. More research is needed on whether it can predict hip fractures.

Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England.

OBJECTIVES: The National Health Service in England funds 12 months of weekly subcutaneous tocilizumab (qwTCZ) for patients with relapsing or refractory giant cell arteritis (GCA). During the COVID-19 pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. METHODS: Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. RESULTS: 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median (interquartile range, IQR) of 12 (12-17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0-5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6% respectively had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10-40) mg/day. 33.6% of relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017); in those not in remission at qwTCZ cessation (P = 0.0036); and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing, and conventional synthetic DMARD use were not associated with time to relapse. CONCLUSION: Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients.

Bone mineral density in patients diagnosed with giant cell arteritis taking glucocorticoids: a case-control study.

Objective: The standard treatment for GCA is high-dose glucocorticoids (GCs). It is unknown whether GCs are more detrimental to BMD at the spine or the hip. The aim of this study was to investigate the effect of GCs on BMD at the lumbar spine and hip in patients with GCA being treated with GCs. Methods: Patients who were referred for DXA at a hospital in the north-west of England between 2010 and 2019 were included. Two patient groups were identified: patients with GCA on current GC (cases) were matched 1:4 based on age and biological sex to those referred to the scanner with no indication for scanning (controls). Logistic models were fitted looking at the spine and hip BMD, unadjusted and adjusted for height and weight. Results: As would be expected, this gave an adjusted odds ratio (OR) of 0.280 (95% CI 0.071, 1.110) at the lumbar spine, OR of 0.238 (95% CI 0.033, 1.719) at the left femoral neck, OR of 0.187 (95% CI 0.037, 0.948) at the right femoral neck, OR of 0.005 (95% CI 0.001, 0.021) at the left total hip and OR of 0.003 (95% CI 0.001, 0.015) at the right total hip. Conclusion: The study has shown that patients diagnosed with GCA receiving GC treatment have a lower BMD at the right femoral neck, left total hip and right total hip compared with controls in patients of the same age and biological sex after adjusting for height and weight.

Quality standards for the care of people with giant cell arteritis in secondary care.

OBJECTIVE: GCA is the commonest primary systemic vasculitis in adults, with significant health economic costs and societal burden. There is wide variation in access to secondary care GCA services, with 34% of hospitals in England not having any formal clinical pathway. Quality standards provide levers for change to improve services. METHODS: The multidisciplinary steering committee were asked to anonymously put forward up to five aspects of service essential for best practice. Responses were qualitatively analysed to identify common themes, subsequently condensed into domain headings, and ranked in order of importance. Quality standards and metrics for each domain were drafted, requiring a minimum 75% agreement. RESULTS: 13 themes were identified from the initial suggestions. Nine quality standards with auditable metrics were developed from the top 10 themes. Patient Access, glucocorticoid use, pathways, ultrasonography, temporal artery biopsy, PET scan access, rheumatology/ophthalmology expertise, education, multidisciplinary working have all been covered in these quality standards. Access to care is a strand that has run through each of the developed standards. An audit tool was developed as part of this exercise. CONCLUSION: These are the first consensus auditable quality standards developed by clinicians from rheumatology and ophthalmology, nursing representatives and involvement of a patient charity. We hope that these standards will be adopted by commissioning bodies to provide levers for change from the improvement of patient care of individuals with GCA.

Paradoxically protective effect of glucocorticoids on bone mass and fragility fracture in a large cohort: a cross-sectional study.

Objectives: Glucocorticoids (GCs) increase the risk of fracture through reduction in BMD; they may also reduce bone quality, but recent supporting data are scarce. We aimed to confirm these effects in a large population-based cohort. Methods: We used data from patients referred for first hip and lumbar spine BMD estimation by the sole DXA scanner in the north-west of England between June 2004 and September 2016. We compared the history of fractures and BMD between patients currently on GCs and patients never exposed to GC. A logistic model adjusted for possible confounders. Results: More than 20 000 subjects were included, 82% female, with mean age 63 (s.d. 13) years; 19% were currently on GCs. The patients on GCs were more often male, with higher BMI, but their age was similar to those not exposed to GC. Surprisingly, patients receiving GCs had ∼2% higher BMD at both sites (P < 0.001) and lower prevalence of (history of) fractures (22% vs 34%; P < 0.001). The corresponding odds ratio was 0.53 (95% CI: 0.49, 0.58); adjustment for age, sex, BMI and the number of indications for scanning did not alter the association. Conclusion: In this large population-based cohort, current GC use compared with never use was associated with higher bone mass and fewer rather than more fractures after adjusting for confounders. These results might be subject to unmeasured confounding, but for now they do not lend support to a detrimental effect of GCs on bone.

Retrospective Analysis of Factors Associated with Fracture in 714 Patients with Polymyalgia Rheumatica.

INTRODUCTION: Polymyalgia rheumatica (PMR) is a disease of the elderly, associated with increased fracture risk due to glucocorticosteroid (GC) treatment with the additional possible influence of chronic inflammation. Risk factors for fracture in PMR have not been extensively studied. Hip structure analysis (HSA) is a way to measure bone morphology in the hip using dual X-ray absorptiometry (DEXA). It has been used as a predictor of fracture in epidemiological settings. HSA has not been studied in PMR before. OBJECTIVES: The object of this retrospective study was to determine if fracture risk in PMR was associated with densitometry data and to determine the influence, if any, of HSA on that association. METHODS: 714 patients with PMR referred for a bone density estimate at a district general hospital from June 2004 to October 2010 were studied. Demographic data, GC use, alcohol consumption, smoking status, secondary osteoporosis, and fracture history were recorded. Bone mineral density (BMD), Z score, T score, body composition data, and HSA measurements were collected. These were geometric measurements taken from 2-dimensional DEXA images of the hip. Fracture was modelled as an outcome variable using logistic regression models, adjusted for age and sex. And the fit of the model was assessed by comparing the area under the curve (AUC). RESULTS: 714 patients were studied, 532 (75%) were female, and mean age was 70.5 with SD of 8.8. 703 (98%) had been treated with GCs. Lumbar and femoral BMD models were significantly associated with fracture. Right femur OR 0.062 (0.014-0.285), left femur OR 0.098 (0.023-0.412), right femoral neck 0.078 (0.014-0.43), left femoral neck 0.104 (0.022-0.492), L1 0.192 (0.066-0.56), L2 OR 0.138 (0.053-0.358), L3 0.192 (0.079-0.463), and L4 0.243 (0.108-0.544). Cross-sectional area was the only HSA parameter that was associated with fracture OR 0.988 (0.980-0.997). CONCLUSION: L2 association models were strongest. Prospective studies are needed to elucidate whether these factors predict future fracture. GC data were binary, not reflecting dose and duration.

Limb girdle muscular dystrophy R12 (LGMD 2L, anoctaminopathy) mimicking idiopathic inflammatory myopathy: key points to prevent misdiagnosis.

OBJECTIVES: Diagnosing the idiopathic inflammatory myopathies (IIMs) can be challenging as several conditions, including genetic myopathies such as limb girdle muscular dystrophy type R12 (LGMD 2 l, anoctaminopathy) mimic the presentation. Here we describe learning points identified from review of four patients with LGMD 2 l who were initially incorrectly diagnosed with IIM. Our aim is to provide clinicians working in adult rheumatology services with a toolkit to help identify non-inflammatory presentations of myopathy. METHODS: We performed retrospective review of medical notes, laboratory results, muscle imaging and histological findings of four patients with LGMD 2 l who were previously misdiagnosed with IIM. We focussed on clinical presentation and progression, therapeutic agents used and events leading to revision of the diagnosis. RESULTS: Three male patients and one female patient with a mean age of 51 years at presentation were reviewed. In each case, treatment with immunosuppressants, in one case for >15 years, was observed without a clear therapeutic response. All patients were negative for anti-nuclear antibodies and available myositis-associated/specific autoantibodies and associated connective tissue disease features were absent. Prominent fatty infiltration and selective muscle involvement on thigh MRI was found in common. CONCLUSIONS: Adult-onset genetic myopathies, particularly LGMD R12, can mimic IIM. Accurate diagnosis is crucial to avoid the use of potentially harmful immunosuppressive therapies, to allow appropriate genetic counselling and to facilitate involvement in research studies.

Targeted literature review of current treatments and unmet need in moderate rheumatoid arthritis in the United Kingdom.

OBJECTIVES: The burden and treatment landscape of RA is poorly understood. This research aimed to identify evidence on quality of life, caregiver burden, economic burden, treatment patterns and clinical outcomes for patients with moderate RA in the United Kingdom. METHODS: A systematic literature review was performed across multiple databases and screened against pre-defined inclusion criteria. RESULTS: A total of 2610 records were screened; seven studies presenting evidence for moderate RA were included. These patients were found to incur substantial burden, with moderate to severe levels of disability. Compared with patients in remission, moderate RA patients reported higher levels of disability and decreased EQ-5D utility scores. The majority of patients did not feel that their current therapy adequately controlled their disease or provided sufficient symptom relief. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) have not approved advanced therapies (such as biological disease-modifying anti-rheumatic drugs) for patients with moderate disease, which restricts access for these patients. CONCLUSION: The evidence available on the burden of moderate RA is limited. Despite current treatments, moderate RA still has a substantial negative impact, given that a DAS28 disease activity score defined as being in the moderate range does not qualify them for access to advanced therapies in the United Kingdom. For these patients, there is a particular need for further studies that investigate their burden and the impact of treating them earlier. Such information would help guide future treatment decisions and ensure the most effective use of resources to gain the best outcomes for patients with moderate RA.