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Objectives: Ageing and inflammation are associated with clonal haematopoiesis (CH), the emergence of somatic mutations in haematopoietic cells. This study details CH in patients with systemic vasculitis in association with clinical, haematological and immunological parameters., Methods: Patients with three forms of vasculitis were screened for CH in peripheral blood by error-corrected sequencing. Relative contributions of age and vasculitis on CH prevalence were calculated using multivariable logistic regression. Clonal hierarchies were assessed by proteogenomic single-cell DNA sequencing, and functional experiments were performed in association with CH status., Results: Patients with Takayasu's arteritis (TAK; n=70; mean age=33.2 years), antineutrophil cytoplasmic antibody-associated vasculitis (AAV; n=47; mean age=55.3 years) and giant cell arteritis (GCA; n=59; mean age=71.2 years) were studied. CH, most commonly in DNMT3A and TET2, was detected in 34% (60/176) of patients versus 18% (28/151) of age-matched controls (p<0.01). Prevalence of CH was independently associated with age (standardised B=0.96, p<0.01) and vasculitis (standardised B=0.46, p<0.01), occurring in 61%, 32% and 13% of patients with GCA, AAV and TAK, respectively. Both branched and linear clonal trajectories showed myeloid-lineage bias, and CH was associated with markers of cellular activation. In GCA, mutations were detected in temporal artery biopsies, and clinical relapse correlated with CH in a dose-dependent relationship with clone size., Conclusions: Age was more strongly associated with CH prevalence than inflammation in systemic vasculitis. Clonal profile was dominated by DNMT3A mutations which were associated with relapse in GCA. CH is not likely a primary causal factor in systemic vasculitis but may contribute to inflammation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown aetiology. The objective of this study was to examine the contribution of rare genetic variations to RP., Methods: We performed a case-control exome-wide rare variant association analysis that included 66 unrelated European American cases with RP and 2923 healthy controls (HC). Gene-level collapsing analysis was performed using Firth's logistics regression. Exploratory pathway analysis was performed using three different methods: Gene Set Enrichment Analysis, sequence kernel association test and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and HC using ELISA., Results: In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted OR=79.8, p=2.93×10 -7 ). Plasma DCBLD2 protein levels were significantly higher in RP than in HC (median 4.06 ng/µL vs 0.05 ng/µL, p<0.001). The pathway analysis revealed a statistically significant enrichment of genes in the tumour necrosis factor signalling pathway driven by rare damaging variants in RELB , RELA and REL using higher criticism test weighted by eigenvector centrality., Conclusions: This study identified specific rare variants in the DCBLD2 gene as a putative genetic risk factor for RP. These findings should be validated in additional patients with RP and supported by future functional experiments., Competing Interests: Competing interests: MZ is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)., Methods: A systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously., Results: Five overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment., Conclusion: These are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research., Competing Interests: Competing interests: CDe has received consulting/speaker’s fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, Sparrow, Roche, Galapagos and Sanofi, all unrelated to this manuscript. He is an editorial board member of ARD. AK has received consultancy fees, honoraria and travel expenses from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB and Pfizer, all unrelated to this manuscript. He is an editorial board member of ARD. DA received grants, speaker fees, and/or consultancy fees from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi. He is an editorial board member of ARD. MB has received consulting fees from AbbVie. DC has received speaker fees from Abiogen, BMS and GSK. MCC received consultancy and/or speaker fees from GSK, Vifor, Abbvie, Astra Zeneca and Janssen and a research grant form Kiniksa Pharmaceuticals. BD has received consultancies from Novartis, Abbvie, Roche and speaker agreements from Chugai. CDu has received consultancy or speaker fees and travel expenses from Abbvie, AOP Orphan, Astra-Zeneca, Bristol-Myers-Squibb, Eli-Lilly, Janssen, Galapagos, Merck-Sharp-Dohme, Novartis, Pfizer, Roche, Sandoz, UCB, Vifor and research support by Eli-Lilly, Pfizer, UCB, all unrelated to this manuscript. BH received speaker fees and/or consultancies from Abbvie, Amgen, Astra-Zeneca, BMS, Boehringer, Chugai, GSK, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, Roche and Vifor. ELM has received consulting fees from Boehringer-Ingelheim, Horizon Therapeutics, Alvotech Inc; speaker fees from Boehringer-Ingelheim; royalties from UpToDate. SPM has received consultancy fees (Invex Therapeutics); advisory board fees (Invex therapeutics; Gensight) and speaker fees (Heidelberg engineering; Chugai-Roche Ltd; Allergan; Santen; Teva UK; Chiesi; and Santhera). All unrelated to this manuscript. LN has received consulting fees from AbbVie. CP is or has been the principal investigator of studies by AbbVie, Sanofi and Novartis and has received consulting/speaker’s fees from Vifor, AstraZeneca, GlaxoSmithKline and Roche, all unrelated to this manuscript. CS has received consultancy fees from Abbvie, Boehringer-Ingelheim, Eli Lilly, Galapagos, Novartis, Pfizer and Roche and royalties from UpToDate. All unrelated to this manuscript. SES has received research support by Astra-Zeneca and has done provided unpaid consultancy for Sanofi. SES is supported by the Rheumatology Research Foundation RISE pilot award and Bristol Myers Squibb Foundation Robert A Winn Diversity in Clinical Trials Career Development Award, outside of the submitted work. WAS has received consultancy fees, honoraria and travel expenses from Abbvie, Amgen, Bristol-Myers Squibb, Chugai, GlaxoSmithKline, Johnson & Johnson, Medac, Novartis, Roche, and Sanofi and is principal investigator in trials sponsored by Abbvie, Amgen, GlaxoSmithKline, Novartis, Roche and Sanofi. PS has received consultancy fees from Amgen and Janssen and royalties from UpToDate, all unrelated to this manuscript. JSS received grants to his institution from Abbvie, AstraZeneca, Lilly, Novartis and Roche and provided expert advice for, or had symposia speaking engagements with, AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celltrion, Chugai, Gilead, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharm, Roche, Samsung, Sanofi and UCB. He is the editor in chief of ARD. JT has received consultancy or speaker fees Bristol-Myers-Squibb, Novartis, Glaxo-Smith-Kline, Astra-Zeneca, Janssen, Abbvie, Eli-Lilly. All unrelated to this manuscript. CET-G has received consultancy fees, honoraria and travel expenses from Abbvie, BMS, Boehringer Ingelheim, Biopas, Janssen, Pfizer, Pharmalab, Roche, all unrelated to this manuscript. FB has received consultancy fees, honoraria and travel expenses from Abbvie, Novartis, Pfizer, Roche and Sanofi, all unrelated to this manuscript. He is an editorial board member of ARD. EH, LE, AA, SA, PCG, AH, TAK and MW declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare the presence of head, neck and upper extremity symptoms in patients with Takayasu's (TAK) and giant cell arteritis (GCA) and their association with vascular inflammation assessed by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) or arterial damage assessed by magnetic resonance angiography (MRA)., Methods: Patients with TAK and GCA underwent clinical and imaging assessments within 24 hours, blinded to each other. Vascular inflammation was defined as arterial FDG-PET uptake greater than liver by visual assessment. Arterial damage was defined as stenosis, occlusion, or aneurysm by MRA. Clinically reported symptoms were compared with corresponding imaging findings using generalised mixed model regression. Cranial symptoms were studied in association with burden of arterial disease in the neck using ordinal regression., Results: Participants with TAK (n=56) and GCA (n=54) contributed data from 270 visits. Carotidynia was reported only in patients with TAK (21%) and was associated with vascular inflammation (p<0.01) but not damage (p=0.33) in the corresponding carotid artery. Posterior headache was reported in TAK (16%) and GCA (20%) but was only associated with corresponding vertebral artery inflammation and damage in GCA (p<0.01). Arm claudication was associated with subclavian artery damage (p<0.01) and inflammation (p=0.04) in TAK and with damage in GCA (p<0.01). Patients with an increased burden of damaged neck arteries were more likely to experience positional lightheadedness (p<0.01) or a major central nervous system event (p=0.01)., Conclusion: The distribution of symptoms and association with imaging abnormalities differs in patients with TAK and GCA. These findings may help clinicians predict associated FDG-PET and MRA findings based on a specific clinical symptom., Clinical Trial Registration Number: NCT02257866., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess agreement between interpretation of magnetic resonance angiography (MRA) and 18 F-fluorodeoxyglucose positron emission tomography (PET) for disease extent and disease activity in large-vessel vasculitis (LVV) and determine associations between imaging and clinical assessments., Methods: Patients with giant cell arteritis (GCA), Takayasu's arteritis (TAK) and comparators were recruited into a prospective, observational cohort. Imaging and clinical assessments were performed concurrently, blinded to each other. Agreement was assessed by per cent agreement, Cohen's kappa and McNemar's test. Multivariable logistic regression identified MRA features associated with PET scan activity., Results: Eighty-four patients (GCA=35; TAK=30; comparator=19) contributed 133 paired studies. Agreement for disease extent between MRA and PET was 580 out of 966 (60%) arterial territories with Cohen's kappa=0.22. Of 386 territories with disagreement, MRA demonstrated disease in more territories than PET (304vs82, p<0.01). Agreement for disease activity between MRA and PET was 90 studies (68%) with Cohen's kappa=0.30. In studies with disagreement, MRA demonstrated activity in 23 studies and PET in 20 studies (p=0.76). Oedema and wall thickness on MRA were independently associated with PET scan activity. Clinical status was associated with disease activity by PET (p<0.01) but not MRA (p=0.70), yet 35/69 (51%) patients with LVV in clinical remission had active disease by both MRA and PET., Conclusions: In assessment of LVV, MRA and PET contribute unique and complementary information. MRA better captures disease extent, and PET scan is better suited to assess vascular activity. Clinical and imaging-based assessments often do not correlate over the disease course in LVV., Trial Registration Number: NCT02257866., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Alterations in the immune system and infections are suspected to increase susceptibility to giant cell arteritis (GCA). Recently herpes zoster has been directly implicated in the pathogenesis of GCA. We examined the association between prior infections, in particular herpes zoster, and incident GCA in a population-based cohort., Methods: A nested case-control study was performed using an electronic database from the UK. Cases with newly diagnosed GCA were identified using a validated algorithm and compared with age-matched, sex-matched and practice-matched controls. Conditional logistic regression was used to examine the relationship between any infection or herpes zoster infection on the development of GCA after adjusting for potential confounders; results were expressed as incidence rate ratios (IRRs)., Results: There were 4559 cases of GCA and 22 795 controls. Any prior infection and herpes zoster were associated with incident GCA (IRR 1.26 (95% CI 1.16 to 1.36), p<0.01; and 1.17 (95% CI 1.04 to 1.32), p<0.01, respectively). A greater number of infections was associated with a higher risk of developing GCA (IRR for 1, 2-4 and ≥5 infections was 1.28, 1.60 and 2.18, respectively)., Conclusions: Antecedent infections and, to a lesser extent, herpes zoster infections are modestly associated with incident GCA. These data provide population-level support for the hypothesis that long-standing alterations of the immune system are associated with susceptibility to GCA and suggest that herpes zoster is unlikely to play a major causal role in the pathogenesis of GCA., Competing Interests: Competing interests: Intercontinental Marketing Services (IMS) Health Real World Evidence Solutions is an UK-based expert in anonymous patient data for the healthcare industry. IMS Health is a commercial organisation that supplies data and trains and supports researchers in the use of primary care patient data. Data are available for us in medical research in the academic setting as well as in industry for a fee which varies depending on the type of data requested. Aside from undergoing ethical review by The Health Improvement Network (THIN) Scientific Review Committee, independent academic groups who voluntarily act as an ethical review body, this protocol was not in any way discussed with IMS Health nor were any changes made by the company. We did not receive financial support or other forms of computational or analytical support from IMS/THIN. The data were collected by IMS and the general practitioners without knowledge of the study objectives and hypotheses., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)