Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation.

BACKGROUND: Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored. METHODS: tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM. RESULTS: We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation. CONCLUSIONS: Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM.

Prevalence and characteristics of subclinical giant cell arteritis in polymyalgia rheumatica.

OBJECTIVE: The main objective of this study was to analyse the prevalence and characteristics of subclinical GCA in patients with PMR. METHODS: This was a cross-sectional multicentre international study of consecutive patients with newly diagnosed PMR without symptoms or signs suggestive of GCA. All patients underwent US of the temporal superficial, common carotid, subclavian and axillary arteries. Patients with halo signs in at least one examined artery were considered to have subclinical GCA. The clinical, demographic and laboratory characteristics of the PMR group without subclinical vasculitis were compared with subclinical GCA, and the pattern of vessel involvement was compared with that of a classical single-centre GCA cohort. RESULTS: We included 346 PMR patients, 267 (77.2%) without subclinical GCA and 79 (22.8%) with subclinical GCA. The PMR patients with subclinical GCA were significantly older, had a longer duration of morning stiffness and more frequently reported hip pain than PMR without subclinical GCA. PMR with subclinical GCA showed a predominant extracranial large vessel pattern of vasculitic involvement compared with classical GCA, where the cranial phenotype predominated. The patients with PMR in the classical GCA group showed a pattern of vessel involvement similar to classical GCA without PMR but different from PMR with subclinical involvement. CONCLUSION: More than a fifth of the pure PMR patients had US findings consistent with subclinical GCA. This specific subset of patients showed a predilection for extracranial artery involvement. The optimal screening strategy to assess the presence of vasculitis in PMR remains to be determined.

Treatment of giant cell arteritis with ultra-short glucocorticoids and tocilizumab: the role of imaging in a prospective observational study.

OBJECTIVES: To assess the impact of tocilizumab (TCZ) monotherapy after ultra-short-pulse glucocorticoids (GCs) on clinical manifestations, and vessel inflammation and damage in large vessel-GCA (LV-GCA). METHODS: In this prospective observational study, we enrolled patients with active LV-GCA. All patients received 500 mg per day i.v. methylprednisolone for three consecutive days and weekly s.c. TCZ injections from day 4 until week 52. PET/CT was performed on all patients at baseline and at weeks 24 and 52. The primary end points were the reduction in the PET vascular activity score (PETVAS) at weeks 24 and 52 compared with baseline, and the proportion of patients with relapse-free remission at weeks 24 and 52. The secondary end point was the proportion of patients with new aortic dilation at weeks 24 and 52. RESULTS: A total of 18 patients were included (72% female, mean age 68.5 years). Compared with the baseline value, a significant reduction in the PETVAS was observed at weeks 24 and 52, mean (95% CI) reductions -8.6 (-11.5 to -5.7) and -10.4 (-13.6 to -7.2), P = 0.001 and 0.002, respectively. The proportion of patients with relapse-free remission at weeks 24 and 52 was 10/18 (56%, 95% CI 31-78) and 8/17 (47%, 95% CI 23-72), respectively. At weeks 24 and 52, no patient had shown new aortic dilation. However, 4 patients who had shown aortic dilation at baseline showed a significant increase in aortic diameter (≥5 mm) at week 52. CONCLUSION: TCZ monotherapy after ultra-short-pulse GCs controlled the clinical symptoms of GCA and reduced vascular inflammation. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05394909.

Evidence on treat to target strategies in polymyalgia rheumatica and giant cell arteritis: a systematic literature review.

OBJECTIVES: To inform an international task force about current evidence on Treat to Target (T2T) strategies in PMR and GCA. METHODS: A systematic literature research (SLR) was conducted in Medline, EMBASE, Cochrane Library, clinicaltrials.gov from their inception date to May 2022, and in the EULAR/ACR abstract database (2019-2021). Randomised clinical trials (RCTs) and non-randomised interventional studies published in English and answering at least one of the eleven PICO questions on T2T strategies, treatment targets and outcomes, framed by the taskforce, were identified. Study selection process, data extraction and risk of bias assessment were conducted independently by two investigators. RESULTS: Of 7809 screened abstracts, 397 were selected for detailed review and 76 manuscripts were finally included (31 RCTs, eight subgroup/exploratory analyses of RCTs and 37 non-randomised interventional studies). No study comparing a T2T strategy against standard of care was identified. In PMR RCTs, the most frequently applied outcomes concerned treatment (90.9% of RCTs), particularly the cumulative glucocorticoids (GC) dose and GC tapering, followed by clinical, laboratory and safety outcomes (63.3% each). Conversely, the most commonly reported outcomes in RCTs in GCA were prevention of relapses (72.2%), remission as well as treatment-related and safety outcomes (67.0% each). CONCLUSIONS: This SLR provides evidence and highlights the knowledge gaps on T2T strategies in PMR and GCA, informing the task force developing T2T recommendations for these diseases.

MRVAS Score-introducing a standardized magnetic resonance scoring system for assessing the extent of inflammatory burden in giant cell arteritis.

OBJECTIVES: Our aim was to introduce a standardized system for assessing the extent of giant cell arteritis (GCA) on MRI, titled MRVAS (MR Vasculitis Activity score). To obtain a comprehensive view, we used an extensive MRI protocol including cranial vessels and the aorta with its branches. To test reliability, MRI was assessed by 4 readers with different levels of experience. METHODS: 80 patients with suspected GCA underwent MRI of cranial arteries and the aorta/branches (20 vessel segments). Every vessel was rated dichotomous [inflamed (coded as 1) or not 0], providing a summed score from 0 to 20. Blinded readers (two experienced radiologists [ExR], two inexperienced radiologists [InR]) applied the MRVAS on an individual vessel and an overall level (defined as the highest score of any of the individual vessel scores). To determine interrater agreement, Cohen's kappa was calculated for pairwise comparison of each reader for individual vessel segments. Intraclass correlation coefficients (ICC) were used for the MRVAS score. RESULTS: Concordance rates were excellent for both sub-cohorts on an individual vessel-based (GCA, ICC, 0.95; and non-GCA, ICC, 0.96) and Overall MRVAS score level (GCA, ICC, 0.96; and non-GCA, ICC, 1.0). Interrater agreement yielded significant concordance (p< 0.001) for all pairs (kappa range 0.78-0.98). No significant differences between ERs and IRs were observed (p= 0.38). CONCLUSION: The proposed MRVAS score allows standardized scoring of inflammation in GCA and achieved high agreement rates in a prospective setting.

Validation of a patient-reported outcome measure for giant cell arteritis.

OBJECTIVES: GCA is systemic vasculitis manifesting as cranial, ocular or large vessel vasculitis. A prior qualitative study developed 40 candidate items to assess the impact of GCA on health-related quality of life (HRQoL). This study aimed to determine final scale structure and measurement properties of the GCA patient reported outcome (GCA-PRO) measure. METHODS: Cross-sectional study included UK patients with clinician-confirmed GCA. They completed 40 candidate items for the GCA-PRO at times 1 and 2 (3 days apart), EQ-5D-5L, ICECAP-A, CAT-PROM5 and self-report of disease activity. Rasch and exploratory factor analyses informed item reduction and established structural validity, reliability and unidimensionality of the final GCA-PRO. Evidence of validity was also established with hypothesis testing (GCA-PRO vs other PRO scores, and between participants with 'active disease' vs those 'in remission') and test-retest reliability. RESULTS: The study population consisted of 428 patients: mean (s.d.) age 74.2 (7.2), 285 (67%) female; 327 (76%) cranial GCA, 114 (26.6%) large vessel vasculitis and 142 (33.2%) ocular involvement. Rasch analysis eliminated 10 candidate GCA items and informed restructuring of response categories into four-point Likert scales. Factor analysis confirmed four domains: acute symptoms (eight items), activities of daily living (seven items), psychological (seven items) and participation (eight items). The overall scale had adequate Rasch model fit (χ2 = 25.219, degrees of freedom = 24, P = 0.394). Convergent validity with EQ5D-5L, ICECAP-A and Cat-PROM5 was confirmed through hypothesis testing. Internal consistency and test-retest reliability were excellent. CONCLUSION: The final GCA-PRO is a 30-item, four-domain scale with robust evidence of validity and reliability in measuring HRQoL in people with GCA.

Nitro fatty acids: A comprehensive review on analytical methods and levels in health and disease.

Nitro fatty acids (NO2-FAs) are biologically active compounds produced from the reaction of unsaturated fatty acids with reactive nitrogen species (RNS). Due to their electrophilic nature, these endogenously produced metabolites can react with nucleophilic targets, producing a spectrum of modulatory and protective effects. Determination of NO2-FAs in biological samples is challenging due to their low nanomolar to picomolar endogenous concentrations, indistinct metabolism, and distribution in many tissues and biofluids. Several attempts have been made to develop precise, standardized, and efficient methodologies for assessing physiological and pathophysiological processes to overcome the difficulties associated with their measurement. This review discusses those approaches utilizing liquid chromatography tandem mass spectrometry (LC‒MS/MS) and gas chromatography tandem mass spectrometry (GC‒MS/MS) for the quantification of NO2-FAs, in addition to a summary of their laboratory synthesis and extraction from biological samples. Clinical associations with different pathological conditions, including hyperlipidaemia, cardiac ischemia and herpes simplex type 2 viral infection (HSV-2), are also discussed.

Uncovering spatiotemporal dynamics of the corticothalamic network at ictal onset.

OBJECTIVE: Although the clinical efficacy of deep brain stimulation targeting the anterior nucleus (AN) and centromedian nucleus (CM) of the thalamus has been actively investigated for the treatment of medication-resistant epilepsy, few studies have investigated dynamic ictal changes in corticothalamic connectivity in human electroencephalographic (EEG) recording. This study aims to establish the complex spatiotemporal dynamics of the ictal corticothalamic network associated with various seizure foci. METHODS: We analyzed 10 patients (aged 2.7-28.1 years) with medication-resistant focal epilepsy who underwent stereotactic EEG evaluation with thalamic sampling. We examined both undirected and directed connectivity, incorporating coherence and spectral Granger causality analysis (GCA) between the diverse seizure foci and thalamic nuclei (AN and CM) at ictal onset. RESULTS: In our analysis of 36 seizures, coherence between seizure onset and thalamic nuclei increased across all frequencies, especially in slower bands (delta, theta, alpha). GCA showed increased information flow from seizure onset to the thalamus across all frequency bands, but outflows from the thalamus were mainly in slower frequencies, particularly delta. In the subgroup analysis based on various seizure foci, the delta coherence showed a more pronounced increase at CM than at AN during frontal lobe seizures. Conversely, in limbic seizures, the delta coherence increase was greater at AN compared to CM. SIGNIFICANCE: It appears that the delta frequency plays a pivotal role in modulating the corticothalamic network during seizures. Our results underscore the significance of comprehending the spatiotemporal dynamics of the corticothalamic network at ictal onset, and this knowledge could guide personalized responsive neuromodulation treatment strategies.

Review of phase 2/3 trials in polymyalgia rheumatica and giant cell arteritis.

INTRODUCTION: GCA (giant cell arteritis) and PMR (polymyalgia rheumatica) are two overlapping inflammatory rheumatic conditions that are seen exclusively in older adults, sharing some common features. GCA is a clinical syndrome characterized by inflammation of the medium and large arteries, with both cranial and extracranial symptoms. PMR is a clinical syndrome characterized by stiffness in the neck, shoulder, and pelvic girdle muscles. Both are associated with constitutional symptoms. AREAS COVERED: In this review, we assess the established and upcoming treatments for GCA and PMR. We review the current treatment landscape, completed trials, and upcoming trials in these conditions, to identify new and promising therapies. EXPERT OPINION: Early use of glucocorticoids (GC) remains integral to the immediate management of PMR and GCA but being aware of patient co-morbidities that may influence treatment toxicity is paramount. As such GC sparing agents are required in the treatment of PMR. Currently there are limited treatment options available for PMR and GCA, and significant unmet needs remain. Newer mechanisms of action, and hence therapeutic options being studied include CD4 T cell co-stimulation blockade, IL-17 inhibition, IL-12/23 inhibition, GM-CSF inhibition, IL-1ß inhibition, TNF-α antagonist and Jak inhibition, among others, which will be discussed in this review.

Short-Term Prognostic Effect of Comprehensive Complication Index in Patients With Gastric Cardia Adenocarcinoma.

INTRODUCTION: The Clavien-Dindo Classification (CDC) has been traditionally used for assessing postoperative complications. Recently, the Comprehensive Complication Index (CCI) has been introduced as a new tool. However, its prognostic significance in Gastric Cardia Adenocarcinoma (GCA) is yet to be determined. METHODS: The CCI and CDC of 203 patients who underwent radical surgery for GCA at Jinling Hospital from 2016 to 2023 were evaluated. Primary outcome variables included Hospital Length of Stay, duration of intensive care unit stay postoperatively, time to return to normal activities, and total hospitalization cost. The area under the curve was used to measure the correlation strength of the CCI and CDC for these outcomes. RESULTS: The CCI demonstrated superior association strength, indicated by higher area under the curve values for all primary outcome variables compared to the CDC: Hospital Length of Stay (0.956 versus 0.910), intensive care unit stay duration (0.969 versus 0.954), time to return to normal activities (0.983 versus 0.962), and total hospitalization cost (0.925 versus 0.911). CONCLUSIONS: The CCI showed a stronger positive association than the CDC with short-term postoperative complications in GCA. It has potential implications for improving postoperative patient management.

Predictive Factors for Biopsy-Negative Giant Cell Arteritis and Alternative Diagnoses in a Neuro-Ophthalmology Context.

Giant cell arteritis is a challenging diagnosis for patients given the high prevalence of negative temporal artery biopsies (TAB). Despite the lack of histopathological evidence of giant cell arteritis in the TAB, patients can still have TAB-negative giant cell arteritis. The purpose of this paper is to analyse the predictors for TAB-negative giant cell arteritis and the alternative diagnosis of biopsy-negative patients without a giant cell arteritis diagnosis. A retrospective electronic database review of all TABs performed at the Royal Victorian Eye and Ear Hospital from February 2015 to May 2020. Logistic regression analysis was performed to determine predictive factors for a diagnosis of TAB-negative giant cell arteritis. In all cases, a clinical diagnosis of TAB-negative giant cell arteritis was determined by a neuro-ophthalmologist. Alternative diagnoses for negative TABs were identified and explored. A total of 368 TABs were analysed with 287 (78%) negative for histopathological evidence of GCA. Twenty-seven (9.4%) patients were diagnosed and treated as TAB-negative giant cell arteritis. The clinical predictors of a TAB-negative giant cell arteritis diagnosis were the presence of jaw claudication (OR 2.77, 95% CI 1.10-6.98) and CRP (OR 1.02, 95% CI 1.00-1.03). Alternative diagnoses included non-specific headache, non-arteritic anterior ischaemic optic neuropathy, retinal vessel occlusions, and ocular nerve palsies. Predictive factors for a diagnosis of TAB-negative giant cell arteritis were jaw claudication and an elevated CRP. Several alternative diagnoses can be considered for patients with a negative TAB in a neuro-ophthalmology context.

PET/CT of cranial arteries for a sensitive diagnosis of giant cell arteritis.

OBJECTIVES: To investigate the performance of cranial PET/CT for the diagnosis of GCA. METHODS: All patients with a suspected diagnosis of GCA were prospectively enrolled in this study and had a digital PET/CT with evaluation of cranial arteries if they had not started glucocorticoids >72 h previously. The diagnosis of GCA was retained after at least 6 months of follow-up if no other diagnosis was considered by the clinician and the patient went into remission after at least 6 consecutive months of treatment. Cranial PET/CT was considered positive if at least one arterial segment showed hypermetabolism similar to or greater than liver uptake. RESULTS: For cranial PET/CT, sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were 73.3%, 97.2%, 91.7% and 89.7%, respectively. For extracranial PET/CT, diagnostic performance was lower (Se = 66.7%, Sp = 80.6%, PPV = 58.8%, NPV = 85.3%). The combination of cranial and extracranial PET/CT improved overall sensitivity (Se = 80%) and NPV (NPV = 90.3%) while decreasing overall specificity (Sp = 77.8%) and PPV (PPV = 60%). CONCLUSION: Cranial PET/CT can be easily combined with extracranial PET/CT with a limited increase in examination time. Combined cranial and extracranial PET/CT showed very high diagnostic accuracy for the diagnosis of GCA. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05246540.

Does the halo count on temporal and axillary ultrasound predict time to relapse in giant cell arteritis?

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.

Extended ultrasound examination identifies more large vessel involvement in patients with giant cell arteritis.

OBJECTIVES: To compare limited with a more extended ultrasound examination (anteromedial ultrasound, A2-ultrasound) to detect large vessel (LV) involvement in patients with newly diagnosed GCA. METHODS: Patients with new-onset GCA were included at the time of diagnosis. All patients were examined using limited ultrasound (ultrasound of the axillary artery as visualized in the axilla) and an extended A2-ultrasound method (which also includes the carotid, vertebral, subclavian and proximal axillary arteries), in addition to temporal artery ultrasound. RESULTS: One hundred and thirty-three patients were included in the study. All patients fulfilled the criteria according to a proposed extension of the 1990 ACR classification criteria for GCA and had a positive ultrasound examination at diagnosis. Ninety-three of the 133 GCA patients (69.9%) had LV involvement when examined by extended A2-ultrasound, compared with only 56 patients (42.1%) by limited ultrasound (P < 0.001). Twelve patients (9.0%) had vasculitis of the vertebral arteries as the only LVs involved. Five patients (3.8%) would have been missed as having GCA if only limited ultrasound was performed. Forty patients (30.0%) had isolated cranial GCA, 21 patients (15.8%) had isolated large vessel GCA and 72 patients (54.1%) had mixed-GCA. CONCLUSION: Extended A2-ultrasound examination identified more patients with LV involvement than the limited ultrasound method. However, extended A2-ultrasound requires high expertise and high-end equipment and should be performed by ultrasonographers with adequate training.

Added diagnostic yield of temporal artery magnetic resonance angiography in the evaluation of giant cell arteritis.

OBJECTIVES: Temporal artery magnetic resonance angiography (TAMRA) is a useful tool to investigate possible diagnoses of GCA. As acquired images also reveal other local structures, they may assist in finding alternative diagnoses when assessing for possible GCA. We sought to assess the utility of TAMRA in identifying other significant abnormalities either associated with a diagnosis of GCA or potentially mimicking a clinical presentation of GCA. METHODS: A retrospective cohort study was undertaken at St Joseph's Healthcare in Hamilton, Ontario, Canada between February 2007 and April 2020 and included patients who underwent TAMRA for a possible diagnosis of GCA. Patient demographics, diagnosis and imaging findings were extracted, and descriptive analysis of findings was performed. RESULTS: We included 340 individuals who underwent TAMRA for assessment of a potential diagnosis of GCA and had clinical information available; there were 126 (37.1%) diagnoses of GCA. Fourteen (4.1%) patients had findings on TAMRA that demonstrated an alternative diagnosis, findings were predominantly in the temporomandibular joint, orbit and meninges. Eighteen (14.3%) patients with GCA had intracranial vascular changes that were demonstrative of intracranial vasculitis; one stroke was attributed to intracranial GCA. CONCLUSIONS: TAMRA has proven utility in diagnosing GCA, and these data suggest that it also has utility in identifying alternative diagnoses to rule out the disease. Intracranial vasculitis was also seen in 14.3% of patients; the clinical impact of these findings is currently poorly understood and requires further study.

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.

Analyses of plasma inflammatory proteins reveal biomarkers predictive of subsequent development of giant cell arteritis: a prospective study.

OBJECTIVE: To investigate the relation between biomarkers of inflammation and subsequent development of GCA. METHOD: Participants in the population-based Malmö Diet Cancer Study (MDCS; N = 30 447), established 1991-96, who were subsequently diagnosed with GCA, were identified in a structured process. GCA-free controls, matched for sex, year of birth and year of screening were selected from the study cohort. Baseline plasma samples were analysed using the antibody-based OLINK proteomics inflammation panel (92 inflammatory proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. Within components selected based on eigenvalues, proteins with a factor loading of >0.50 were investigated. RESULTS: Ninety-four cases with a confirmed incident diagnosis of GCA (median 11.9 years after inclusion) were identified. Among biomarkers with a priori hypotheses, IFN-γ was positively associated with GCA [odds ratio (OR) per s.d. 1.52; 95% CI 1.00, 2.30]. Eight biomarkers in the hypothesis-generating analyses were significantly associated with development of GCA. Among these, higher levels of IFN-γ (OR 2.37; 95% CI 1.14, 4.92) and monocyte chemotactic protein 3 (MCP3) (OR 4.27; 95% CI 1.26, 14.53) were particularly associated with increased risk of GCA in the subset sampled <8.5 years before diagnosis. Several other proteins known to be important for T cell function were also associated with GCA in these analyses, e.g. CXCL9, IL-2, CD40 and CCL25. CONCLUSION: Elevated IFN-γ levels were found years prior to diagnosis of GCA. T cell activation may precede the clinical onset of GCA.

Angiotensin receptor blockade is associated with increased risk of giant cell arteritis.

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.

Ultrasonography in the assessment of disease activity in cranial and large-vessel giant cell arteritis: a prospective follow-up study.

OBJECTIVES: We evaluated sensitivity to change and discriminative abilities of vascular US scores in disease monitoring in the follow-up of a prospective cohort of new-onset cranial and large-vessel (LV) GCA patients. METHODS: Baseline and follow-up (8 weeks, 24 weeks and 15 months) US of temporal arteries (TA), carotid and axillary arteries (LV) included assessment of halo and measurement of the intima media complex (IMC). Max IMC, max halo IMC, sum IMC, sum halo IMC, mean IMC, halo count and the Southend halo score were calculated. The provisional OMERACT US score, OGUS, was obtained, taking the average of temporal arteries and axillary arteries IMCs divided by their normal cut-off values. RESULTS: Baseline US was positive in 44/47 patients (72% TA, 72% LV). Sensitivity to change of all composite US scores containing TAs was evident by week 8 onward. LVs responded poorly and new axillary US lesions emerged in six patients despite clinical remission. The OGUS showed a large magnitude of change and is considered the score least prone to potential bias. All TA-based US scores showed moderate-strong correlation with disease activity markers. OGUS, TA halo count, Southend TA halo score, TA sum IMC and TA mean IMC showed potential to discriminate remission and relapse with area under the curve ≥0.8. CONCLUSIONS: The OGUS is suggested as an outcome measurement for the assessment of treatment response in clinical trials. The abilities of US scores to discriminate remission and relapse are encouraging and should be further explored.

Immunosuppressive treatments selectively affect the humoral and cellular response to SARS-CoV-2 in vaccinated patients with vasculitis.

OBJECTIVES: To analyse humoral and cellular immune response to mRNA COVID-19 vaccines in patients with GCA. METHODS: Consecutive patients with a diagnosis of GCA receiving two doses of BNT162b2 vaccine were assessed at baseline and 3 weeks from the second vaccine dose. Healthy subjects (n = 51) were included as controls (HC). Humoral response was assessed with Spike-specific IgG antibody response (S-IgG) and neutralizing antibodies (NtAb). Specific T cell response was assessed by enzyme linked immunosorbent spot (ELISpot). RESULTS: Of 56 included patients with GCA, 44 were eligible after exclusion of previous evidence of COVID-19 and incomplete follow-up. A significant proportion of patients with GCA (91%) demonstrated antibody (S-IgG) response, but this was significantly lower than HCs (100%); P < 0.0001. Neutralizing activity was not detected in 16% of patients with GCA. Antibody titres (S-IgG and NtAb) were significantly lower compared with HCs. Humoral response (S-IgG and NtAb) was significantly hampered by treatment with MTX. Cellular response was lacking in 30% of patients with GCA (vs 0% in HCs; P < 0.0001). Cellular response was significantly influenced by the levels of baseline peripheral T-lymphocytes and by glucocorticoid treatment. Treatment with tocilizumab did not affect any level of the immune response elicited by vaccination. CONCLUSIONS: Although patients with GCA apparently achieve a robust antibody seroconversion, there is a significant impairment of the neutralizing activity. MTX significantly reduced all levels of the humoral response. Up to one-third of patients do not develop a cellular immune protection in response to COVID-19 vaccination.