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.

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.

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.

Predictors of fragility fracture and low bone mineral density in patients with a history of parental fracture.

OBJECTIVES: Bone mineral density (BMD) and fragility fracture (FF) have high heritability, but few data exist on impact of other factors on families with fracture history. We aimed to evaluate predictors of FF and low BMD, in patients with family history of FF. METHODS: This was a retrospective study on patients undergoing dual energy X-ray absorptiometry at a district general hospital (DGH), 2004-2016. Parameters recorded (in addition to standard dual energy X-ray absorptiometry parameters): age, smoking, alcohol, corticosteroids, aromatase inhibitors, Depo-Provera, hormone replacement therapy, rheumatoid arthritis, polymyalgia rheumatica, breast or prostate cancer, coeliac disease, and fracture site. Logistic regression was used to model fracture risk and site, and linear regression for impact of factors on L1-4 and femoral BMD. Factor analyses with polychoric correlation matrices and calculation of Eigenvalues were applied to determine association between fracture sites and associated risk factors. RESULTS: A total of 6053 patients were included, 91.1% female. 2094 had sustained at least one FF. Smoking, alcoholism, increased age, height, and fat mass increased FF risk. Sites analysed: femur, tibia/fibula, humerus, forearm, ribs, and vertebrae. Alcoholism, and increasing tissue thickness and fat mass significantly increased FF risk. Decreased right femoral and vertebral BMD increased overall FF risk. CONCLUSIONS: Our study confirms the effect of certain factors on vertebral BMD, but suggests a differential effect on the upper and lower spine, as well as in the dominant and nondominant hip. Different sites of fracture are associated with different risk factors, the most common sites of fracture being the peripheral long bones and vertebrae.

Drug-induced rheumatic diseases: a review of published case reports from the last two years.

PURPOSE OF REVIEW: New drugs are continuously being developed and some rheumatic syndromes have been associated with specific drugs. As most of the rheumatic diseases are multisystem, it is worthwhile examining the wider case report literature to see whether any recent studies signify new associations between drugs and the rheumatic diseases. The last 2 years' case reports in English were scrutinized for noninfectious association with the rheumatic diseases. Cross-referencing from MEDLINE was performed using several databases including Google scholar; British Medical Journal (BMJ) case reports were also queried separately. RECENT FINDINGS: Fifty-three articles comprising 56 case reports are included in the review, with 27 (48.2%) associated with the vasculitides, eight (14.3%) associated with lupus and 13 (23.2%) were associated with the myositis syndromes. The commonest four groups of drugs to potentially induce rheumatic diseases were anti-tumour necrosis factor (TNF) drugs, oncology drugs, propylthiouracil and interferons. SUMMARY: It is important to recognise that drugs used in other specialties may induce rheumatic disease and vigilance on making a diagnosis is the key.

Isolated lower limb medium-vessel vasculitis: a new entity?

A 47-year-old female was referred with bilateral ischaemic lesions affecting her toes with associated gangrene. Systemic examination was normal and her medical history was unremarkable. Close examination of the hands revealed splinter haemorrhages. Her feet were dusky in colour and the toes were dark and weeping, each becoming gangrenous, with erythema around the metatarsal phalangeal joint. Dorsalis pedis and posterior tibial pulses were intact with strong Doppler signals. Investigations for surgical pathology and malignancy were all negative as were routine blood tests and tests for autoimmune and viral markers. Vasculitis was diagnosed when her toes showed improvement with steroids, however, attempts to reduce the steroid dose were unsuccessful and azathioprine was introduced. Despite immunosuppression and immunomodulators, her toes deteriorated and were amputated. Histology revealed findings consistent with a medium-vessel vasculitis which antineutrophil cytoplasmic antibody was negative. A similar vasculitis has not been formally reported in the literature.