Background. Giant cell arteritis (GCA) is the commonest systemic vasculitis and a medical emergency. High-dose glucocorticoids are started on suspicion, before confirmation, and cause substantial dose-dependent harm in the many patients who prove not to have GCA. Diagnostic confirmation by temporal artery biopsy or ultrasound remains imperfect. The performance of both approaches is influenced by the clinical context and, for ultrasound, operator expertise, creating the potential for both unnecessary treatment and delayed or missed diagnosis. A laboratory-based, multi-analyte proteomic blood test may help, but its intended use and performance requirements are undefined. Objective. To develop, by structured expert consensus, a Target Product Profile (TPP) for a laboratory-based, multi-analyte proteomic blood test to aid the diagnosis of cranial GCA in secondary care, used alongside clinical assessment, imaging and/or biopsy, with the primary objective of reducing unnecessary glucocorticoid exposure without increasing missed cases, from a UK health-system perspective. Methods and analysis. A multidisciplinary committee of approximately 15 to 30 members, including patient and public representatives, will follow a three-phase process: a scoping phase that confirms the intended use and the prioritised list of characteristics; a drafting phase that specifies minimum (acceptable) and preferred (desirable) values across the TPP domains, using outcome-based methods where feasible; and a consensus-building phase using an up-to-three-round modified Delphi (75% consensus threshold) with interim consensus meetings and a 28-day public consultation. Reporting follows ACCORD and CREDES.

Abstract Background/Aims Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are age-associated inflammatory diseases with overlapping features, including a risk of ischaemic complications. Glucocorticoids, the mainstay treatment, are effective but carry risks for adverse effects and relapse is common after discontinuation. Our aim was to identify core genes for PMR and GCA using a novel method of genetic analysis, and to evaluate the effect of identified genes on other vascular disorders. Methods We performed genome-wide aggregated trans-effects (GATE) analysis in two case-control cohorts with genotypic data: the UK Biobank (6,200 cases with a mention of either PMR or GCA and 458,000 controls) and the UKGCA Consortium (1,878 GCA cases and 5,520 controls). GATE scores for predicted protein levels were computed as a weighted sum of an individual’s genotypes at trans-protein quantitative trait loci (trans-pQTLs) extracted from the deCODE study and the UK Biobank Pharma Proteomics Project. GATE scores were tested for association with PMR/GCA, and putative core genes were identified using a Bonferroni-corrected p-value threshold (p < 2 x 10-5). GATE scores for putative core genes were subsequently tested for association with coronary artery disease (53,000 cases, 411,000 controls) and peripheral vascular disease (14,000 cases, 450,000 controls) in the UK Biobank. Results In the UK Biobank, 4,015 GATE scores, comprising at least 5 trans-pQTLs and corresponding to 3,187 unique genes, were evaluated. Five genes (CXCL9, LECT2, PLG, MST1, CXCL10) were identified as putative core genes for PMR/GCA (p < 2 x 10-5). In UKGCA, 3,247 GATE scores, corresponding to 1,993 unique genes and with > 5 trans-pQTLs, were evaluated. LECT2 and four additional genes (FGFBP3, SNAP25, RSPO1, LRRN1) were identified as putative core genes for GCA. Five of the putative core genes (LECT2, CXCL10, CXCL9, PLG, MST1) were associated with coronary artery disease at p < 10-4 and with consistent direction of effect to PMR/GCA. LECT2 and CXCL10 were also associated with peripheral vascular disease at p < 10-4 and consistent effect direction. Conclusion Using GATE analysis, we identified nine putative core genes for PMR and GCA. Four of these (CXCL9, CXCL10, LECT2, MST1) are directly involved in immune regulation and in particular T-cell responses, and two (PLG, FGFBP3) are involved in angiogenesis and tissue remodelling during repair of vascular injury. LECT2 had the strongest evidence in support of a causal role in vascular pathology with robust associations to PMR/GCA, to GCA alone, and to the two cardiovascular outcomes. While LECT2 is a multifunctional protein, a likely mechanism mediating its effect on PMR/GCA is through its involvement in vascular inflammation upon binding to a receptor on endothelial cells. Mechanistic studies of LECT2 in PMR/GCA are warranted to evaluate its potential as a therapeutic target for these diseases. Disclosure A. Nwagbata: None. A. Iakovliev: None. A. Morgan: None. P. McKeigue: None. A. Spiliopoulou: None.

Abstract FcγRIIa, encoded by FCGR2A , is a widely expressed Fc receptor implicated in autoimmunity and infectious disease susceptibility. To fine-map the rheumatoid arthritis (RA) association at the complex FCGR locus, we combined gene-specific resequencing, genetic association studies in UK and Spanish European cohorts, functional genomics, structural biology, biophysical analyses, and cellular assays. We identified a common European FCGR2A haplotype (2A.3), defined by Q27W, H131H, and the RA-associated SNP rs12746613, which showed the strongest association with RA. Multi-omics analyses demonstrated that 2A.3 is associated with reduced expression of the soluble FCGR2A splice variant and lower circulating soluble FcγRIIa levels. Functional studies revealed altered IgG interactions and delayed FcγRIIa signal transduction associated with Q27W, while structural analyses found no evidence for stable ectodomain dimerisation. Together, these findings identify 2A.3 as an important functional contributor to RA susceptibility and provide mechanistic insight into how FCGR2A variation may influence immune regulation and disease risk in Europeans.

CONTEXT:Chronic oral glucocorticoids (GCs) are widely prescribed for multiple diseases. Although long-term GC exposure causes systemic toxicity, the magnitude, dose-response relationship, and causes of GC-associated mortality remain incompletely defined. OBJECTIVE:To quantify overall and cause-specific mortality associated with chronic oral GC exposure and evaluate dose-response relationships across underlying disease groups. METHODS:We conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO CRD42017067530). PubMed/MEDLINE, EMBASE, Cochrane Library, Web of Science, and CINAHL were searched from 1945 to March 2019. Eligible studies reported standardized mortality ratios (SMRs) or absolute deaths among adults receiving chronic oral GCs. Random-effects meta-analysis and mixed-effects meta-regression were used to synthesize mortality and dose-response associations across GC exposure metrics, exposure duration, and disease subgroups. RESULTS:One-hundred and sixteen studies encompassing 128 cohorts and 51 380 patients were included. Chronic GC exposure was associated with excess mortality (pooled SMR 1.87; 95%CI 1.32-2.61; I2 74.0%). The pooled proportion of death was 12.0% (95%CI 10-14%). Mortality risk was highest in inflammatory diseases (30.0%) and the vasculitides (18.0%). Higher cumulative dose (≥5 g prednisolone-equivalent), average daily dose >5 mg/day, and higher initial dose were each independently associated with increased mortality. Cardiovascular disease was the leading causes of death (25.6%), followed by malignancy (15.7%) and infection (13.4%). CONCLUSION:Chronic oral GC exposure was associated with increased mortality across disease groups, with higher cumulative and early-treatment doses correlating with higher risk. However, causal attribution remains uncertain due to confounding by indication, limited disease-severity data, and exposure misclassification. These findings support GC stewardship and targeted cardiovascular and infection risk mitigation, rather than indiscriminate dose reduction.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely related chronic inflammatory conditions. Glucocorticoids remain the cornerstone of treatment for both conditions, as they rapidly control inflammation and also reduce the risk of ischaemic complications in GCA. However, glucocorticoid therapy is often prolonged and associated with substantial treatment-related morbidity. In addition, many patients experience relapses during glucocorticoid maintenance therapy and can accrue vascular damage. Advances in understanding the immunopathology of GCA and PMR have led to the development of targeted therapies, particularly agents inhibiting the IL-6 pathway and, more recently, Janus kinase (JAK) signalling. IL-6 receptor inhibitors reduce the risk of disease relapse and allow for reduction in glucocorticoid use in both GCA and PMR, and JAK inhibition enables glucocorticoid sparing and lowers the risk of relapse in GCA. Optimal management of GCA and PMR requires close monitoring, careful assessment of disease activity and treatment-related toxicity, as well as individualized therapeutic strategies. Ongoing research continues to refine treatment algorithms and could help to define therapeutic targets across GCA and PMR. Emerging therapeutic options and evolving treatment algorithms reflect the dynamic and patient-centred nature of advancements in GCA and PMR management.

OBJECTIVES:Giant cell arteritis (GCA) is a clinically heterogeneous disease, which complicates both diagnosis and management. This study aimed to identify genetic risk factors associated with GCA clinical manifestations and evaluate their utility for defining clinical phenotypes. METHODS:Genome-wide genotype data from 3498 patients with GCA and 15,550 controls were analysed to investigate the genetic architecture of GCA manifestations. Logistic regression was used to compare patients with and without each manifestation, as well as each subgroup of patients vs controls. Gene annotation was conducted based on functional information using Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA GWAS). Latent class analysis (LCA) was applied to evaluate the ability of associated variants to classify patients with GCA into genetic subgroups. RESULTS:We identified 7 human leukocyte antigen (HLA) variants specifically associated with different clinical features. Furthermore, 7 non-HLA associations across 6 clinical manifestations were found. Gene prioritisation highlighted biologically relevant candidate genes for GCA pathogenesis, including IL17A (limb claudication) and IL22RA1 (jaw claudication), both involved in the Th17 pathway, and ATP2A2 (extracranial form), encoding a transporter that promotes aortic aneurysms. Notably, LCA grouped GCA clinical predisposition into 4 classes capturing cranial-predominant, mixed, extracranial, and ischaemic/occlusive patterns, the latter representing a high-risk subgroup for severe ischaemic and ocular complications. CONCLUSIONS:This first genome-wide association study stratified by GCA-specific manifestations deepens our understanding of the genetic basis underlying GCA clinical heterogeneity. Our findings highlight HLA and non-HLA contributors to specific disease phenotypes and support the potential of genetic profiling to guide early diagnosis and personalised management in GCA.

OBJECTIVES:To develop response criteria for rheumatoid arthritis (RA) using the two-component Disease Activity Score in 28 joints (2C-DAS28). METHODS:Data were available for three stages of RA treatment progression, determined by the disease-modifying antirheumatic drug prescribed: early (on methotrexate; n=1051), established (on tumour necrosis factor inhibitors; n=989) and late RA (on second-line or later therapy; n=301). Inflammation response was defined as achieving remission or a clinically meaningful reduction in disease activity after 3 months of treatment. Corresponding 2C-DAS28 thresholds were determined using receiver operating characteristic analysis and Youden's J, based on Boolean V.2.0 remission and clinical disease activity index response. The correlation of the proposed criteria with synovial thickness (ST) and power Doppler (PD) was assessed in an independent cohort (n=161) and compared with conventional response criteria. Finally, 6-month disease activity was compared between 3-month 2C-DAS28 responders and non-responders. RESULTS:Thresholds to define inflammation response were 2C-DAS28<1.8 or a decrease in 2C-DAS28>1.7. In the validation cohort, 3-month 2C-DAS28 response was significantly correlated with lower ST (r=-0.25 (95% CI -0.47 to -0.04), p=0.037) and PD scores (r=-0.28 (95% CI -0.52 to -0.04), p=0.042). By contrast, conventional response criteria showed no significant correlation with synovitis scores. In the discovery cohorts, 3-month 2C-DAS28 responders retained lower disease activity at 6 months than non-responders. CONCLUSION:2C-DAS28 response correlates significantly with ultrasound-detected synovitis and is associated with improved clinical outcomes. This may support identification of biomarkers of treatment efficacy and clinical stratification, to identify patients with ongoing inflammation and those in whom disease activity is driven by non-inflammatory features.

OBJECTIVE:Low copy number (CN) of complement C4 isoforms and high CN of retroviral HERV-K elements are known risk factors for many immune-mediated inflammatory diseases (IMIDs), often showing sex-biased effects. Here, we assessed whether CN variation within the C4 gene contributes to giant cell arteritis (GCA) and IgA vasculitis (IgAV), two complex vasculitides involving complement dysregulation. METHODS:C4A, C4B, and HERV-K CNs were imputed from genotypic data of 3,498 patients with GCA, 284 patients with IgAV, and 16,867 controls. We evaluated their associations with vasculitis risk overall and stratified by sex (inferred from genetic data), alongside classical HLA alleles. RESULTS:Contrary to other IMIDs, we identified higher C4 CN to confer risk to GCA and IgAV. Specifically, in GCA, higher C4B CN conferred risk in male patients (odds ratio (OR) 1.23, 95% confidence interval (CI) 1.07-1.42, P = 4.52 × 10-3, P adjusted by false discovery rate (PFDR) = 1.40 × 10-2). In IgAV, elevated C4A CN was significantly associated with disease susceptibility in the overall cohort (OR 1.68, 95% CI 1.22-2.30, P = 1.49 × 10-3, PFDR = 4.48 × 10-3), whereas C4B CN showed a male-biased trend, as observed in GCA (OR 1.46, 95% CI 1.02-2.08, P = 3.88 × 10-2, PFDR = 5.80 × 10-2). Conditional analyses confirmed that these associations were independent of classical HLA alleles. CONCLUSION:This study reveals sex-dependent variation in C4 CN as a novel genetic risk factor for GCA and IgAV, suggesting shared biologic mechanisms involving complement dysregulation, sustained inflammation, and vascular damage.

Abstract Dysregulated innate immunity contributes to clonal cytopenias and myeloid neoplasms, but its extent across disease stages and clinical relevance remain incompletely defined. We analyzed plasma ASC/NLRP3 double‐positive (DP) specks, ASC single‐positive (SP) specks, and 45 cytokines in 223 patients with idiopathic cytopenias of undetermined significance (ICUS)/clonal cytopenias of undetermined significance (CCUS), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) and 39 matched non‐inflammatory controls using adjusted regression, survival modeling, and paired longitudinal analyses. Inflammasome activation and cytokine perturbations were evident across the disease spectrum. DP‐ASC specks were elevated in MDS and CMML, whereas SP‐ASC specks were increased across all groups, indicating activation of ASC‐containing inflammasomes beyond NLRP3. Cytokines followed a graded ICUS → MDS → CMML pattern, with widespread upregulation of interleukins and chemokines (including IL‐7, IL‐8, IL‐11/CXCL11, and CCL7) alongside suppression of stem and progenitor support factors such as CSF3, FLT3LG, TRAIL, and TWEAK. At baseline, elevated IL‐15 and MMP1 predicted progression to acute myeloid Leukaemia, while higher IL‐10, CXCL8, and IL‐18 were associated with reduced survival; ASC specks were not independently prognostic. Longitudinal increases in selected cytokines distinguished progressors (area under the curve 0.82; 95% CI: 0.49–1.0). Cytokine patterns correlated with mutation categories, with the isolated SF3B1 mutation associated with higher DP‐ASC specks. These findings define early and progressive inflammasome engagement and nominate dynamic cytokine panels and the inflammasome–IL‐1 axis as actionable biomarkers and therapeutic targets.

The search for targeted therapies and biomarkers for immune-mediated systemic vasculitis requires detailed understanding of molecular pathogenesis. Whilst candidate approaches have identified new opportunities for drug repurposing, they also miss novel approaches for targeting critical immunological or stromal pathways. On the other hand, bulk transcriptional profiling may fail to capture differences in cellular composition and, depending on the cell source profiled, miss important changes within inflamed vascular tissue. The past decade has seen major advances in both experimental techniques and analytical tools that enable multi-dimensional molecular profiling. Interrogation of the transcriptome and proteome is now possible at a single cell level, or at levels of spatial resolution within tissue that was previously unimaginable. As demonstrated during the presentations in the breakout session of the 21st International Vasculitis Workshop entitled Transcriptomic approaches to the study of systemic vasculitis, these techniques are revealing greater understanding of molecular underpinnings of the systemic vasculitides.

Routine use of genetic data in healthcare is much-discussed, yet little is known about its performance in epidemiological models including traditional risk factors. Using severe COVID-19 as an exemplar, we explore the integration of polygenic risk scores (PRS) into disease models alongside sociodemographic and clinical variables. PRS were optimized for 23 clinical variables and related traits previously-associated with severe COVID-19 in up to 450,449 UK Biobank participants, and tested in 9,560 individuals diagnosed in the pre-vaccination era. Associations were further adjusted for (i) sociodemographic and (ii) clinical variables. Pathway analyses of PRS were performed to improve biological understanding of disease. In univariate analyses, 17 PRS were associated with increased risk of severe COVID-19 and, of these, four remained associated with COVID-19 outcomes following adjustment for sociodemographic/clinical variables: hypertension PRS (OR = 1.1, 95%CI 1.03–1.18), atrial fibrillation PRS (OR = 1.12, 95%CI 1.03–1.22), peripheral vascular disease PRS (OR = 0.9, 95%CI 0.82–0.99), and Alzheimer’s disease PRS (OR = 1.14, 95%CI 1.05–1.25). Pathway analyses revealed enrichment of genetic variants in pathways for cardiac muscle contraction (genes N = 5; beta[SE] = 3.48[0.60]; adjusted-P = 1.86 × 10−5). These findings underscore the potential for integrating genetic data into epidemiological models and highlight the advantages of utilizing multiple trait PRS rather than a single PRS for a specific outcome of interest.

Objectives:To investigate the clinical use of steroids in established RA. Methods:A cohort of RA patients commencing treatment with biologic or targeted synthetic (b/ts) DMARDs was followed prospectively, with clinical data recorded pre-baseline and at the 3, 6 and 12-month follow-up. Patients were included in this analysis if they had completed the first year of follow-up and had data on steroid use available for at least one follow-up. The proportions of patients receiving steroids at different timepoints were compared and further differentiated between continued (receiving steroids at two consecutive timepoints) and newly started treatment. Lastly, mixed linear effect models were used to assess the relationship between clinical factors and steroid use. Results:The cohort (N = 1846) had a median disease duration of 7 years and, across each timepoint, ≈30% of patients received steroids, up to two-thirds of which continued treatment from a preceding follow-up. At 12 months, the proportion of patients continuing treatment decreased, but more patients started steroid treatment (P < 0.001). Linear mixed effects modelling further showed that steroid use was more common in patients who had required pre-baseline steroids [odds ratio (OR) 1.44 (95% CI 1.38, 1.49)] and in those on later-stage treatments [OR 1.15 (95% CI 1.08, 1.23)]. Conclusion:Despite the introduction of b/tsDMARDs, steroid use in this cohort continued over the first year of follow-up, particularly in patients with more severe RA. Together with previous data, this further highlights the need for future research and trials to better understand the right course of steroid administration to maximize efficacy and limit adverse side effects.

Avacopan is licensed in combination with rituximab or cyclophosphamide for the treatment of severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). However, there is a paucity of real-world data, particularly since patients with severe disease (eGFR<15) were excluded from the ADVOCATE trial and glucocorticoid use was protocolised. Our objectives were to assess the real-world patient population and prescribing pattern of avacopan in ANCA-associated vasculitis (AAV); and its effectiveness and safety compared with a historical cohort. A retrospective observational study was conducted in avacopan-treated AAV patients from seven UK centres. Clinicians could deviate from the ADVOCATE glucocorticoid tapering regimen if deemed appropriate. Effectiveness and safety were compared with a historical cohort in Leeds treated with cyclophosphamide and/or rituximab with non-protocolised glucocorticoid taper between 2017-2019 using inverse probability weighting (IPW) propensity score method. Clinical response at 6 months was defined as BVASv3.0 ≤3 point AND prednisolone dose ≤5mg/day. A total of 123 patients were analysed (avacopan=61; historical=62). Our avacopan cohort differed from the ADVOCATE population in that 11 (18%) had eGFR<15; concomitant immunosuppression was used in 17 (28%); and combination of cyclophosphamide and rituximab was used in 14 (23%) patients. Avacopan was started later than in ADVOCATE, mean (SD) 4.5 (9.6) weeks from remission induction. Of 49/61 patients with 6-month data, clinical response was met in 31/49 (63%). There were significant reductions in BVAS score and oral prednisolone dose from baseline. 18/49 (37%) patients stopped glucocorticoids with only 2/16 experiencing a flare at 12 months. Of 9/11 patients with eGFR<15 and data available, 7 (78%) had eGFR>15 at 6 months. At 6 months, only 7/49 (11.5%) patients would have met the primary endpoint of ADVOCATE (complete remission). Avacopan was discontinued due to toxicity in 9 (14.8%) patients (transaminitis=3, GI intolerance=2, leg swelling, anaemia and breathlessness=1 each); and deaths=2 (chest infection=1 and myocardial infarction=1). Severe infection rate in the avacopan cohort was 19.2/100 PY (11 infections in 9 patients) and 20.8/100 PY (14 in 12 patients) for the historical cohort. Baseline salient characteristics of a historical AAV cohort in Leeds were comparable to the avacopan cohort apart from slightly younger age, longer disease duration, and lower BVAS score and GC dose in the former. After IPW, significantly more of the avacopan cohort met clinical response compared to the historical cohort OR 2.92 (95% CI 1.34-6.35); p = 0.007 (1) Avacopan use in real-world practice differs from ADVOCATE: more patients had eGFR<15, it was started later, more frequently combined with other immunosuppressants, and different glucocorticoid protocols. (2) Complete remission rate was low, but incomplete remission did not appear to lead to clinicians prescribing additional immunosuppression or deaths due to vasculitis. (3) After IPW, avacopan-treated patients were 2.9-times more likely to achieve clinical response than those without avacopan. Future work will analyse longer term outcomes and after avacopan discontinuation. S. Wood: None. F.A. Khan: None. A. Aslam: None. F. Mahmood: None. J. Ellis: None. S. Skeoch: None. B. Aung Din: None. G. Tran: None. H. Reddy: None. L. Bissell: None. J. Freeston: None. A. Barr: None. H. Ford: None. A.W. Morgan: None. E.M. Vital: None. E. Dunn: None. S. Dass: None. S. Dubey: None. T. Bansal: None. J. Heaney: None. M. Md Yusof: Member of speakers’ bureau; Vifor Pharma UK.

Giant cell arteritis (GCA) is a complex inflammatory disease affecting individuals over 50 suggesting a strong link with aging-related immune and vascular changes. However, the precise mechanisms underlying this age-related susceptibility remain poorly understood. Considering the relevance of aging in GCA, genetic factors influencing biological aging markers, such as telomere shortening and epigenetic age acceleration (EAA), might also contribute to its development. This study investigated the shared genetic basis between GCA and these markers to enhance understanding of the role of aging in this vasculitis. Data from approximately 6.6 million variants obtained from previously published genome-wide association studies (GWASs) of GCA (3,498 cases and 15,550 controls), telomere length (472,174 individuals), and EAA (34,710 individuals) were meta-analysed using ASSET. Significant variants (p<5×10-8) were functionally annotated, and causal genes were prioritized using FUMA. Potential therapeutic candidates were identified through drug repurposing. This study identified 21 genetic variants shared between GCA and at least one aging marker. Two pleiotropic signals were annotated at PTPN22 and PLG, known risk factors for GCA, whereas the remainder represent potentially new susceptibility loci for this vasculitis. Several prioritized causal genes, such as SERPING1, SAR1B, SESN1, and SMC4, are involved in both inflammation and senescence, shedding light on the molecular pathways linking aging and GCA. Interestingly, expression levels of some of the prioritized genes PDE1B, ATXN2, and CNEP1R1, were dysregulated in immune cells from active patients. Drug repurposing analysis highlighted promising therapeutic candidates for GCA, including sulfasalazine, an anti-inflammatory agent, and investigational drugs targeting inflammatory pathways like NF-κB. These findings uncover significant genetic overlap between GCA and aging markers, offering insights into shared molecular pathways and potential new therapies targeting both inflammation and cellular senescence.

OBJECTIVE:Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments. METHODS:Plasma proteomic profiling of 184 proteins was performed in two cohorts. Cohort 1 included patients with established TAK (n = 96) and large-vessel GCA (LV-GCA) (n = 35) in addition to healthy control participants (HCs) (n = 35). Cohort 2 comprised patients presenting acutely with possible cranial GCA (C-GCA) in whom the diagnosis was subsequently confirmed (C-GCA, n = 150) or excluded (Not C-GCA, n = 89). Proteomic findings were compared to published transcriptomic data from LVV-affected arteries. RESULTS:In cohort 1, comparison to HCs revealed 52 differentially abundant proteins (DAPs) in TAK and 72 DAPs in LV-GCA. Within-case analyses identified 16 and 18 disease activity-associated proteins in TAK and LV-GCA, respectively. In cohort 2, comparing C-GCA versus not C-GCA revealed 31 DAPs. Analysis within C-GCA cases suggested the presence of distinct endotypes, with more pronounced proteomic changes in the biopsy-proven subgroup. Cross-comparison of TAK, LV-GCA, and biopsy-proven C-GCA revealed highly similar plasma proteomic profiles, with 26 shared DAPs including interleukin 6 (IL-6), monocyte/macrophage-related proteins (CCL7, CSF1), tissue remodeling proteins (TIMP1, TNC), and novel associations (TNFSF14, IL-7R). Plasma proteomic findings reflected LVV arterial phenotype; for 42% of DAPs, the corresponding gene was differentially expressed in tissue. CONCLUSION:These findings suggest shared pathobiology across the LVV spectrum involving innate immunity, lymphocyte homeostasis, and tissue remodeling. Network-based analyses highlighted immune-stromal cross-talk and identified novel therapeutic targets (eg, TNFSF14).

Background: Arterial wall inflammation in giant cell arteritis (GCA) is characterized by T-cell infiltration and granuloma formation. There have been limited studies investigating the diversity of the T-cell receptor (TCR) repertoire in GCA patients. Here we aim to identify disease-relevant TCRs. Methods: We sequenced the TCR beta repertoires in peripheral blood and biopsies from 72 GCA patients and compared them to repertoires of 60 age-matched controls. Applying K-nearest neighbours classification based on tcrdist3, an established TCR similarity measure, we identified GCA-associated TCRs across multiple model hyperparameters and experimental replicates. Results: We observed that species richness and Shannon diversity were significantly lower (P = 0.0003 and P = 0.004, respectively) in GCA peripheral blood TCR repertoires compared with age-matched controls. 1526 TCRs were identified that were consistently associated with GCA, 63 TCRs were also detected in TAB repertoires. Identical GCA-associated TCRs were observed in paired blood and tissue samples from 21/30 GCA cases. 57 % of GCA-associated TCRs were fitted into 10 clusters, which displayed distinct TCR sequences and TCR V and J segment usage. TRBV20-1*01, TRBV4-3*01, TRBV4-2*01 and TRBV4-1*01 segments were over-represented and occurred at least 10 % more often among GCA patients than age-matched controls. Only 27/1526 TCR sequences had matches reported in public databases, reducing the likelihood that these targeted common infectious agents. Conclusions: Our data provide evidence of circulating T-cell clonal expansions in GCA patients. Certain TCR sequence patterns were over-represented in GCA subjects. As more TCR sequences directed at human antigens become available, further analysis may ultimately reveal whether these TCRs bind a common target antigen.

The shared epitope (SE), a genetic sequence coding for a 5-amino acid motif within the peptide-binding groove of HLA-DRβ1, represents the strongest genetic factor associated with both susceptibility and prognosis of rheumatoid arthritis (RA). However, the mechanisms of action underlying its association with clinical outcome measures remain poorly understood, limiting the development of tolerogenic therapies for precision medicine targeting the right autoantigens, the right cell types, at the right time. HLA-DRB1*04:01 is the most common SE allele and its unique structure facilitates the presentation of citrullinated self-peptides to CD4+ T cells. To explore cellular mechanisms of autoimmunity underlying the association between HLA-DRB1*04:01 and RA outcome. The Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate recruits RA patients who have failed to respond to conventional synthetic DMARDs from 53 centres across the UK. Clinical data is collected at baseline (before initiation of biologic drugs) and at 3-, 6- and 12-months post-biologic treatment. Blood samples for the extraction of DNA and peripheral blood mononuclear cells are taken at baseline. In parallel, we also recruited control individuals without any history of rheumatologic conditions into the National Repository of Healthy Volunteers (NRHV). Genotyping was performed using the Illumina Human Core Exome array, followed by imputation of 4-digit HLA alleles (SNP2HLA). Six different fluorophore-labelled HLA-DRβ1*04:01 tetramers loaded with 6 different citrullinated autoantigenic peptides originating from Vimentin, Cartilage Intermediate Layer Protein and α-Enolase were incorporated into a 15-colour flow cytometry panel, in order to quantify and deeply immunophenotype citrulline-specific CD4+ T cells. Anti-citrullinated protein/peptide antibody (ACPA) status and titres were derived from clinical notes and also determined in-house by ELISA. Between January 2015 and December 2021, we recruited 310 subjects (212 RA patients and 98 NRHVs). The SE was strongly associated with RA susceptibility (OR = 2.2, p = 2.9E-05), as was HLA-DRB1*04:01 (OR = 2.8, p = 1.2E-04). The frequency and immunophenotype of citrulline-specific CD4+ T cells was determined in 63 HLA-DRB1*04:01+ participants (46 patients, 17 NRHVs). Citrulline-specific CD4+ T cells were significantly increased in all RA patients (p = 3.xE-04), even in those without humoral immunity against citrulline (ACPA-negative), were associated with disease duration (p = 0.02), CRP (p = 0.03) and disability (HAQ score p = 0.008). At baseline, anti-citrulline cellular immunity was significantly lower in patients treated with methotrexate (p = 0.02). None of these effects were observed for cellular immunity against influenza. Citrulline-specific CD4+ T cells were not autoimmune-associated Tph cells, but displayed a phenotype nearly identical to anti-influenza CD4+ T cells, with a predominance of PD1neg CXCR5neg, HLA-DR+ CD27+ and TEM cells. Cellular autoimmunity against citrulline is present in all HLA-DRB1*04:01+ patients, even in the absence of humoral autoimmunity and associates with multiple outcome measures. The immunophenotype of anti-citrulline CD4+ T cells is similar to an anti-viral phenotype. M.A. Elhafnawy: None. S. Valma: None. M. Christofi: None. N. Nair: None. L. Marshall: None. S. Turcinov: None. J. Bowes: None. A. Mohammad Ariff: None. A. W Morgan: None. J. Isaacs: None. G. Wilson: None. K.L. Hyrich: None. D. Plant: None. W.W. Kwok: None. A. Barton: None. E.A. James: None. V. Malmström: None. S. Viatte: None.

Background Infectious diseases are a major cause of mortality in spite of existing public health, anti-microbial and vaccine interventions. We aimed to define plasma proteomic associates of infection mortality and then apply Mendelian randomisation (MR) to yield biomarkers that may be causally associated. Methods We used UK Biobank plasma proteomic data to associate 2,923 plasma proteins with infection mortality before 31st December 2019 (240 events in 52,520 participants). Since many plasma proteins also predict non-infection mortality, we focussed on those associated with >1.5-fold risk of infection mortality in an analysis excluding survivors. Protein quantitative trait scores (pQTS) were then used to identify whether genetically predicted protein levels also associated with infection mortality. To conduct Two Sample MR, we performed a genome-wide association study (GWAS) of infection mortality using UK Biobank participants without plasma proteomic data (n=363,953 including 984 infection deaths). Findings After adjusting for clinical risk factors, 1,142 plasma proteins were associated with risk of infection mortality (false discovery rate <0.05). 259 proteins were associated with >1.5-fold increased risk of infection versus non-infection mortality. Of these, we identified genetically predicted increasing MERTK concentration was associated with increased risk of infection mortality. MR supported a causal association between increasing plasma MERTK protein and infection mortality (odds ratio 1.46 per unit; 95% CI 1.15- 1.85; p=0.002). Conclusion Plasma MERTK is causally associated with infection mortality and warrants exploration as a potential therapeutic target.