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Background: Tumor necrosis factor-alpha is present in arteries in giant cell arteritis.Objective: To evaluate the efficacy of infliximab, an anti-tumor necrosis factor-alpha agent, in giant cell arteritis.Design: Randomized, controlled trial.Setting: 22 sites in the United States, the United Kingdom, Belgium, Italy, and Spain.Patients: 44 patients with newly diagnosed giant cell arteritis that was in glucocorticosteroid-induced remission.Intervention: Participants were randomly assigned in a 2:1 ratio to receive infliximab (5 mg/kg of body weight) or placebo. Sixteen patients were assigned to glucocorticosteroid plus placebo, and 28 patients to glucocorticosteroid plus infliximab.Measurements: End points were measured through week 22, when an interim analysis resulted in early stopping of the planned 54-week trial. Primary end points were the number of patients who remained free of relapse through week 22 and adverse events. Secondary end points were time to first relapse, biomarkers, cumulative glucocorticosteroid dose, and the number of patients who remained relapse-free while the glucocorticosteroid dosage was tapered to 10 mg/d.Results: Infliximab therapy did not increase the proportion of patients without relapse at week 22 compared with placebo (43% vs. 50%, respectively; difference, -7 percentage points [95% CI, -38 to 23 percentage points; P = 0.65), nor did it increase the proportion of patients whose glucocorticosteroid dosages were tapered to 10 mg/d without relapse (61% vs. 75%, respectively; difference, -14 percentage points [CI, -42 to 14 percentage points]; P = 0.31). The incidence of infection was 71% with infliximab and 56% with placebo (difference, 15 percentage points [CI, -14 to 45 percentage points]).Limitations: The sample was too small to rule out modest effects of infliximab and included only patients with a new diagnosis. Only one dose of infliximab was evaluated, and the study was terminated early.Conclusions: This trial is too small to draw definitive conclusions, but it provides evidence that using infliximab as maintenance therapy in patients in glucocorticoid-induced remission of newly diagnosed giant cell arteritis is of no benefit and may be harmful. If infliximab has benefit, it is unlikely to be great. ClinicalTrials.gov registration number: NCT00076726. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Neovascularization, with an increased number of synovial vessels with a characteristic morphology, seems to contribute to the progression of psoriatic arthritis (PsA). Accordingly, angiogenesis may be an important therapeutic target in PsA. The aim of this study was to analyze the effects of infliximab on angiogenesis in the synovial membrane of patients with PsA who responded to this therapy. METHODS: The study group comprised 9 patients with PsA who were selected for the presence of active polyarthritis (including knee synovitis) despite methotrexate therapy. Clinical and biologic evaluations were performed at each visit. Arthroscopy and synovial biopsies were performed at week 0, before infliximab therapy was initiated, and at week 8, after administration of 3 intravenous infusions of infliximab (5 mg/kg). We used immunohistochemistry to identify changes in infiltrating cells and in the angiogenesis modulators alphavbeta3 integrin, vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang-2), flt-1 (VEGF receptor 1 [VEGFR-1]), kinase insert domain receptor [KDR]/flk-1 (VEGFR-2), and stromal cell-derived factor 1 (SDF-1). Neovascularization was assessed by automated histomorphometry of CD31+ vessels and by measuring alphavbeta3 expression. RESULTS: Rapid and significant clinical and biological improvement were observed after treatment in all patients. In the synovium, infliximab therapy induced a significant reduction in macrophages, the CD31+ vascular area, alphavbeta3+ neovessels/Ulex europaeus agglutinin+ vessels, VEGF and its receptor KDR/flk-1 (VEGFR-2), and SDF-1+ vessels. Expression of flt-1 (VEGFR-1), and SDF-1 in lining cells showed a nonsignificant reduction, whereas expression of Ang-2 increased. In 3 patients, reverse transcription-polymerase chain reaction confirmed the changes in some of these markers at the messenger RNA level. CONCLUSION: These results show consistent changes in several factors involved in angiogenesis regulation, in parallel with the clinical response to infliximab in patients with PsA. The pattern of reduced VEGF with increased Ang-2 suggests vascular regression as a potential mechanism underlying the antiangiogenic effect of infliximab. [ABSTRACT FROM AUTHOR]

Objectives: To study the health-related quality of life (HRQoL) and its possible determinant factors in Spanish children with eosinophilic esophagitis (EoE) and their parents., Methods: Multicenter observational cross-sectional study. The Spanish version of the Pediatric Quality of Life Eosinophilic Esophagitis Module was filled out by EoE patients aged 8-18 and their parents. Demographic, psychosocial, and clinical variables were studied. Multiple linear regression was performed to identify related factors of HRQoL., Results: A total of 279 children and their parents participated (72.7% males). 39.1% received swallowed corticosteroids, 35.5% proton pump inhibitors and 16.8% diet. 1.1% received other treatments and 7.5% received no treatment. Poor compliance to treatment was observed in 11.5% and 6.5% of patients were referred to mental health. The Total Scale Scores were 72.71 ± 17.50 and 75.62 ± 16.73 for children and parents, respectively. "Communication" was the dimension with the highest scores (82.14 ± 21.65 and 81.59 ± 24.13) while "Food and Eating" (48.92 ± 32.94 and 62.85 ± 28.78), and "Food Feelings" (53.55 ± 29.96 and 53.95 ± 27.78) had the lower scores. Patients and parents under dietary treatment showed lower scores than those under pharmacological treatment, 65.77 ± 16.96 versus 74.28 ± 16.96, p = 0.001 and 68.33 ± 17.32 versus 77.24 ± 15.97, p = 0.001, respectively. Factors associated with worse HRQoL scores were symptom frequency, diet, food allergies, and the need for mental health assistance., Conclusions: The HRQoL of children and their parents was "good." However, diet, frequency of symptoms, food allergies, and the need for mental health care were the factors that had a negative impact on HRQoL of children with EoE., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Giant cell arteritis (GCA) is a chronic inflammatory vasculitis with a significant impact on vascular and patient health. It may present with non-specific symptoms and can lead to severe complications if not managed effectively. This narrative review explores the treatment of GCA with interleukin-6 (IL-6) pathway inhibitors, focusing on key studies from selected databases published between 2018 and 2024. The findings reveal that the current treatment primarily involves glucocorticoids (GCs), but their long-term use is associated with adverse effects. Targeting the IL-6 pathway offers therapeutic benefits by reducing inflammation and sparing GC use. Tocilizumab, a humanized immunoglobulin G1κ monoclonal antibody that blocks the IL-6 receptor, has demonstrated efficacy in achieving sustained remission and improving quality of life in people with GCA. However, challenges remain in understanding the optimal duration of therapy, managing relapse upon discontinuation, and addressing long-term structural vascular outcomes. Additional research is needed to further elucidate the complex pathogenesis of GCA and to optimize treatment strategies to achieve sustained remission both clinically and histologically while minimizing adverse effects. This review provides a comprehensive overview of the evidence of IL-6 inhibition in GCA management, highlighting both its therapeutic benefits and the challenges associated with its use., Competing Interests: Declaration of competing interest Maxime Samson has received remuneration from Chugai (invitation to congresses, remuneration for symposium and consulting payments), AstraZeneca (invitations to congresses, consulting payments), Novartis (research grant, consulting payments, invitation to congresses, remuneration for symposium), CSL Vifor (invitation to congresses, remuneration for symposium and consulting payments), Boehringer Ingelheim (invitation to congresses, consulting payments), Argenx (consulting payments), Fresenius Kabi (consulting payments, invitation to congresses, remuneration for symposium), and GSK (consulting payments, invitation to congresses, remuneration for symposium). Maria C. Cid has acted as a consultant for Glaxo Smith Kline, AbbVie, AstraZeneca, CSL-Vifor, Boehringer Ingelheim, Alexion, and Novartis; received a research grant from Kiniksa Pharmaceuticals Ltd.; and has received funding from Ministerio de Ciencia, Innovación y Universidades, AEI (PID2023-152265OB-I00). Christian Pagnoux reports receiving fees for serving on advisory boards from ChemoCentryx, Otsuka, GlaxoSmithKline, AstraZeneca, Sanofi, and Hoffman-LaRoche; lecture fees from Hoffman-La Roche, GlaxoSmithKline, Otsuka, and CSL Vifor; and educational grant support from Hoffman-La Roche, Otsuka, Pfizer, TEVA, Amgen, and GlaxoSmithKline. Wolfgang A. Schmidt has received consultant fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Fresenius Kabi, GlaxoSmithKline, Novartis, and Sanofi; speaker's bureau fees from AbbVie, Amgen, Bristol Myers Squibb, Chugai, GlaxoSmithKline, Lilly, Johnson & Johnson, Medac, Novartis, Pfizer, Roche, Sanofi, and UCB. He is the principal investigator in trials sponsored by AbbVie, GlaxoSmithKline, Novartis, and Sanofi. Rula A. Hajj-Ali has acted as a consultant for Amgen and GlaxoSmithKline and has received royalties from UpToDate, outside the submitted work. Bhaskar Dasgupta reports grants and personal fees from Roche, and personal fees from GSK, BMS, Sanofi, and AbbVie, outside the submitted work. Anthony Sammel and Carlo Salvarani report no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA) is an immune-mediated, inflammatory, multisystemic disease that is considered a form of ANCA-associated vasculitis and whose association with asthma and blood and tissue eosinophilia differentiate it from other types of vasculitis. Nevertheless, diagnosis of EGPA may be difficult or delayed not only because of the rarity of the disease, but also because other diseases can present with similar manifestations., Areas Covered: We review a series of key areas in EGPA, namely, laboratory and clinical indicators of disease, diagnosis, role of biomarkers, induction and maintenance therapy, and use of traditional and novel drugs. This narrative review was based on a thorough search of PubMed., Expert Opinion: Clinicians should be aware of the limitations of available tools for diagnosing EGPA, and more efforts should be made to identify clinical and laboratory red flags, with the purpose of achieving an early diagnosis before irreversible damage occurs. New effective therapies are available, although future research should target an approach that spares glucocorticoids, reduces the risk of flares and organ damage, and maintains long-term remission with minimum adverse effects.

Objectives: ANCA-associated vasculitis (AAV) are chronic diseases with relapses that associate organic damage because of the disease and its treatment. Avacopan is a new treatment indicated for AAV. We present the first experiences with avacopan in Spain as part of an Early Access program., Methods: Patients with AAV who started avacopan between June 2022-September 2023 were included. For comparison, a historical cohort of patients diagnosed with AAV around the same time and treated without avacopan was also included., Results: 29 patients treated with avacopan were analyzed. Twelve patients (41.4%) were male, median age was 56 years. Most of patients were ANCA MPO positive (21/29, 72.4%). The most frequently affected organ was the kidney (23/29, 79.31%), with a mean eGFR of 23.2 ml/minMedian follow-up was 456.8 ± 181.7 days with a remission rate of 86.2%. eGFR increased from 23.2 ± 11.2-38.38 ± 18.55 ml/min after 12 months of diagnosis.2 patients had Adverse Events related to avacopan as severe neutropenia and a gastrointestinal affectation , 13 infections were reported and 1 death.Patients treated with avacopan received a significantly lower cumulative dose of prednisone at 6 and 12 months (p-values of 0.02 and <0.01, respectively) compared with historical controls. The evolution of GFR at 1 year of follow-up and the incidence of relapse were similar in both groups., Conclusion: The combination of avacopan in clinical practice presents a good safety profile and provides added value by contributing to the control of AAV activity, increase GFR, and removal of steroids., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA), is a rare ANCA-associated systemic vasculitis. Its overlapping features with other vasculitic or eosinophilic diseases, and the wide and heterogeneous range of clinical manifestations, often result in a delay to diagnosis., Objective: To identify red flags that raise a suspicion of EGPA to prompt diagnostic testing and to present an evidence-based clinical checklist tool for use in routine clinical practice., Methods: Systematic literature review and expert consensus to identify a list of red flags based on clinical judgement. GRADE applied to generate a strength of recommendation for each red flag and to develop a checklist tool., Results: 86 studies were included. 40 red flags were identified as relevant to raise a suspicion of EGPA and assessed by the experts as being clinically significant. Experts agreed that a diagnosis of EGPA should be considered in a patient aged ≥6 years with a blood eosinophil level >1000 cells/µL if untreated and >500 cells/µL if previously treated with any medication likely to have altered the blood eosinophil count. The presence of asthma and/or nasal polyposis should reinforce a suspicion of EGPA. Red flags of asthma, lung infiltrates, pericarditis, cardiomyopathy, polyneuropathy, biopsy with inflammatory eosinophilic infiltrates, palpable purpura, digital ischaemia and ANCA positivity, usually anti-myeloperoxidase, among others, were identified., Conclusion: The identification of a comprehensive set of red flags could be used to raise a suspicion of EGPA in patients with eosinophilia, providing clinicians with an evidence-based checklist tool that can be integrated into their practice., Competing Interests: Declaration of competing interest Iñigo Rúa-Figueroa: Lectures and advisors boards for GSK. No other conflicts of interest. Roser Solans Laqué: Honoraria for consultancy and conferences from GSK, and conferences from CSL- Vifor. Marina Blanco Aparicio declares to have received payment or honoraria for lectures, presentations, speakers’ bureaus, or educational events and support for attending meetings and/or travel for AstraZeneca, GSK, Sanofi, Chiesi, TEVA and Faes. Ismael García Moguel: Consultant and speaker: Novartis, AstraZeneca, Teva, Novartis, GSK, Sanofi Genzyme, Chiesi, Allergy therapeutics, Leti, Stallergenes, ALK-Abelló, Mundipharma, Pfizer, and Orion Pharma. PI clinical trials: Novartis, GSK, AstraZeneca, Sanofi Genzyme. Ricardo Blanco: Grants/research support from AbbVie, MSD, and Roche, and had consultation fees/participation in a company-sponsored speaker's bureau from AbbVie, Pfizer, Roche, Lilly, UCB, Bristol-Myers, GSK, Janssen, Novartis and MSD. Francisco Pérez Grimaldi: Honoraria for conferences from AstraZeneca, GSK, Sanofi, Novartis, Chiesi, Teva, Esteve, Menarini y Boehringer-Ingelheim. Ana Noblejas Mozo: Colaboration with CSL Vifor, Gebro Pharma, Astra Zeneca. Colaboration in a vasculitis meeting with patients: CSL Vifor. Honoraria for consultancy from GSK. Moises Labrador Horrillo: Payment for lectures including service on speakers’ bureaus from: AstraZeneca, GSK, Novartis and Sanofi. Consultancy from: AstraZeneca, Novartis and GSK. J.M. Álvaro-Gracia: Honoraria for lecturing, advisories and Congress attendance from AbbVie, AstraZeneca, Galapagos, Gilead, Pfizer, Novartis, GSK, Lilly, MSD y UCB. Christian Domingo Ribas. CDR has acted as consultant for GSK, AstraZeneca and Sanofi and has received funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, MSD, Novartis, Stallergenes and Pfizer. Georgina Espígol-Frigolé: Honoraria for consultancy from Janssen, GSK and CSL-Vifor. Congress attendance from Boehringer-Ingelheim. Fernando Sánchez Toril. I have received personal fees (payments for presentations, advisory boards, etc.) from: ALK, AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, FAES, Gebro Pharma, GSK, Menarini, Novartis, Pfeizer, TEVA and Sanofi. I have participated in clinical trials and received research grants from: AstraZeneca, Chiesi, GSK, Novartis, TEVA, Sanofi. I am not employed (including part-time) in any pharmaceutical industry. I do not maintain any relationship with the tobacco industry. Francisco Ortiz Sanjuán: Advisor, Review Panel member or Consultant fee from GSK, Grünenthal and received financial aid for attendance at medical conferences from Lilly. Ebymar Arismendi: Honoraria for consultancy, advisory board and/or conferences from GSK, AstraZeneca, MSD, Novartis, Chiesi, Gebro Pharma and Sanofi-Genzyme. Maria C Cid: Consulting fees from GSK, AbbVie, CSL- Vifor and AstraZeneca; royalties from UpToDate, and a research grant from Kiniksa Pharmaceuticals Corp., (Copyright © 2024. Published by Elsevier B.V.)

The photo-Fenton process is effective for pathogen removal, and its low-cost versions can be applied in resource-poor contexts. Herein, a photo-Fenton-like system was proposed using low concentrations of iron oxides (hematite and magnetite) and persulfates (peroxymonosulfate - PMS, and peroxydisulfate - PDS), which exhibited excellent inactivation performance towards MS2 bacteriophages. In the presence of bacteria, MS2 inactivation was inhibited in H 2 O 2 and PDS systems but promoted in PMS-involved systems. The inactivation efficacy of all the proposed systems for mixed bacteria and viruses was greater than that of the sole bacteria, showing potential practical applications. The inactivation performance of humic acid-incorporated iron oxides mediating photo-Fenton-like processes was also studied; except for the PMS-involved system, the inactivation efficacy of the H 2 O 2 - and PDS-involved systems was inhibited, but the PDS-involved system was still acceptable (< 2 h). Reactive species exploration experiments indicated that ·OH was the main radical in the H 2 O 2 and PDS systems, whereas 1 O 2 played a key role in the PMS-involved system. In summary, hematite- and magnetite-mediated persulfate-assisted photo-Fenton-like systems at low concentrations can be used as alternatives to the photo-Fenton process for virus inactivation in sunny areas, providing more possibilities for point-of-use drinking water treatment in developing countries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: To analyze pregnancy outcomes of patients with primary systemic vasculitis followed in a third-level referral center., Methods: Retrospective cohort study of all pregnant women with systemic vasculitis followed between 2009 and 2022 at the High-Risk Pregnancy Clinic of the Department of Systemic Autoimmune Diseases of the Hospital Clínic, Barcelona., Results: Twenty women with primary vasculitis were identified, with a total of 30 pregnancies. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (n = 7) and Behçet disease (n = 4) were the most frequent types of vasculitis. All women had the diagnosis of vasculitis before pregnancy, with a median time between disease diagnosis and pregnancy of 5.8 years (range: 2 months-29 years). Most were in remission at conception (76.7 %). During pregnancy, a vasculitis flare occurred in 4 (13.3 %) patients (one each with Takayasu arteritis, eosinophilic granulomatosis with polyangiitis [EGPA], IgA vasculitis [IgAV], and Behçet disease [BD]). Four (16.7 %) of the successful pregnancies had post-partum relapses (one each with EGPA, granulomatosis with polyangiitis, IgAV, and BD). Eighty percent of pregnancies resulted in live babies. In four cases (13.3 %), medical termination of pregnancy was decided, considering the mother or baby health risk. There were two spontaneous miscarriages, and no stillbirths or neonatal deaths. Preeclampsia was the most frequent maternal complication (25 %). Newborns were preterm in 24 % and low birthweight in 20 % of cases. No maternal deaths occurred., Conclusions: This cohort study shows that vasculitis relapses during pregnancy and post-partum, together with other pregnancy complications, occur in a considerable number of patients with systemic vasculitides, although a final good pregnancy outcome can be expected in most cases. These findings emphasize the convenience of managing these special situations in expert reference centers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests MCC reports support from the Spanish Ministry of Science and Innovation (PID2020-114909RB-I00), Vasculitis Foundation, Agency for the Management of University and Research Grants (2021 SGR 01561), and Kiniksa Pharmaceuticals; consulting fees or honoraria from GSK, CSL Vifor, AbbVie, and AstraZeneca; support for attending meetings from Kiniksa Pharmaceuticals; and participation on a data safety monitoring board or advisory board for GSK, CSL Vifor, and AstraZeneca. GE has acted as a consultant for GSK, AstraZeneca, Sobi, Novartis, Boehringer, and CSL Vifor. AWM reports support from the UK Medical Research Council (MRC), National Institute for Health and Care Research (NIHR), Leeds Care, and Roche Products; and consulting fees or honoraria from CSL Vifor and AstraZeneca. PL reports grants or contracts from the Federal Ministry of Education and Research, German Research Society, German Society for Rheumatology, John Grube Foundation, and CSL Vifor; consulting fees or honoraria from GSK, CSL Vifor, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Forum für medizinische Fortbildung, Janssen, Rheumaakademie, and UCB; support for attending meetings from CSL Vifor; and participation on a data safety monitoring board or advisory board for GSK, CSL Vifor, AbbVie, and Novartis. TW reports consulting fees or honoraria from AbbVie, AstraZeneca, Lilly, UCB, and Novartis; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Lilly, UCB, Novartis, and Fresenius. MAG-G reports honoraria from GSK. NK reports grants or contracts from Bristol Myers Squibb, AbbVie, and Sanofi; and consulting fees or honoraria from Roche, Otsuka, GSK, and Mallinckrodt. CAL reports grants or contracts from Bristol Myers Squibb and support from the National Institutes of Health. PAM reports grants, contracts, or consulting fees from AbbVie, Amgen, AstraZeneca, ArGenx, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, CSL Behring, Eicos, Electra, Forbius, Genentech–Roche, GSK, HiBio, InflaRx, Janssen, Jubilant, Kyverna, MiroBio, Neutrolis, Novartis, NS Pharma, Q32, Regeneron, Sanofi, Sparrow, Takeda, and Vistera; royalties or licenses from UpToDate; and stock or stock options from Kyverna, Q32, and Sparrow. SLM reports grants or contracts from MRC, NIHR, and CSL Vifor; consulting fees from Roche, Sanofi, AbbVie, AstraZeneca, and Pfizer; payment or honoraria for lectures or educational events from Roche, Pfizer, UCB, CSL Vifor, Fresenius Kabi, and Novartis; support for attending meetings from Pfizer; participation on a data safety monitoring board or advisory board for Collaboration for Leadership in Applied Health Research and Care, Haywood Foundation, and GC-SheaLD; a leadership or fiduciary role in the British Society for Rheumatology Clinical Affairs Committee; participation as an investigator on industry-sponsored clinical trials for Sanofi; and infrastructure support from MRC. LB reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Instrumentation Laboratory SPA and AbbVie; and support for attending meetings from AbbVie and Novartis. EB reports payments or honoraria from EULAR and received grants from the Dutch Arthritis Society DAS and the EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking Immune-Image grant no 831514. EB is member of the board of the non-profit organisation, Auto-immune Research Hub, in the Netherlands. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Large-vessel vasculitides (LVV) comprise a group of chronic inflammatory diseases of the aorta and its major branches. The most common forms of LVV are giant cell arteritis (GCA) and Takayasu arteritis (TAK). Both GCA and TAK are characterized by granulomatous inflammation of the vessel wall accompanied by a maladaptive immune and vascular response that promotes vascular damage and remodeling. The inflammatory process in LVV starts in the adventitia where fibroblasts constitute the dominant cell population. Fibroblasts are traditionally recognized for synthesizing and renewing the extracellular matrix thereby being major players in maintenance of normal tissue architecture and in tissue repair. More recently, fibroblasts have emerged as a highly plastic cell population exerting various functions, including the regulation of local immune processes and organization of immune cells at the site of inflammation through production of cytokines, chemokines and growth factors as well as cell-cell interaction. In this review, we summarize and discuss the current knowledge on fibroblasts in LVV. Furthermore, we identify key questions that need to be addressed to fully understand the role of fibroblasts in the pathogenesis of LVV., Competing Interests: Declaration of competing interest Kornelis S.M. van der Geest received speaking fee from Roche, and research support from AbbVie and Siemens Healthineers. Other authors had no conflicts of interest to declare. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Kornelis S.M. van der Geest reports a relationship with Roche that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Since its first clinical description in 1890, extensive research has advanced our understanding of giant cell arteritis, leading to improvements in both diagnosis and management for affected patients. Imaging studies have shown that the disease frequently extends beyond the typical cranial arteries, also affecting large vessels such as the aorta and its proximal branches. Meanwhile, advances in comprehending the underlying pathophysiology of giant cell arteritis have given rise to numerous potential therapeutic agents, which aim to minimise the need for glucocorticoid treatment and prevent flares. Classification criteria for giant cell arteritis, as well as recommendations for management, imaging, and treat-to-target have been developed or updated in the last 5 years, and current research encompasses a broad spectrum covering basic, translational, and clinical research. In this Series paper, we aim to discuss the current understanding of giant cell arteritis with cranial manifestations, describe the clinical approach to this condition, and explore future directions in research and patient care., Competing Interests: Declaration of interests PB has received speaker fees from Janssen and AbbVie; meeting travel support from Janssen, Merck, Sharp & Dohme, and Lilly; and project grants from Pfizer. GEF has received advisory board fees from GSK, SCL-Vifor, and Janssen, and speaker fees and a research grant from GSK. MCC reports consulting fees from GSK, AbbVie, CSL-Vifor, and AstraZeneca; royalties from UpToDate; lecturing fees from GSK, AbbVie, and CSL-Vifor; participation in advisory boards for GSK, CSL-Vifor, AbbVie, and AstraZeneca; and a research grant and meeting travel support from Kiniksa Pharmaceuticals. SPM reports consultancy fees from Invex Therapeutics, Neurodiem, Ocular Therapeutix, and GenSight; advisory board fees from Invex Therapeutics; speaker fees from Invex therapeutics, Gensight, Heidelberg Engineering, and Chiesi; royalties from Springer Publishing; a grant from the UK Space Agency (NIHR131211); travel grants from AbbVie; and equipment funding from Heidelberg Engineering. WAS has received speaker fees from AbbVie, Amgen, Bristol Myers Squibb, Chugai, GSK, Johnson & Johnson, Medac, Novartis, Roche, and Union Chimique Belge; advisory board fees from AbbVie, Amgen, Fresenius Kabi, GSK, Novartis, and Sanofi; and is principal investigator of trials sponsored by AbbVie, GSK, Novartis, and Sanofi. MCC was funded by Ministerio de Ciencia e Innovación (AEI//10·13039/501100011033 [PID2020–114909RB-I00])., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4 + T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4 + T cells will yield new insights into its pathogenesis., Methods: Transcriptome analysis was conducted on CD4 + T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14 + monocytes., Results: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4 + T cells in GCA. Specifically, CD4 + T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4 + T cells and monocytes that could have pathogenic relevance in GCA., Conclusions: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To update the EULAR recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV)., Methods: A systematic literature review update was performed to retrieve new evidence on ultrasound, MRI, CT and [ 18 F]-fluorodeoxyglucose positron emission tomography (FDG-PET) for diagnosis, monitoring and outcome prediction in LVV. The task force consisted of 24 physicians, health professionals and patients from 14 countries. The recommendations were updated based on evidence and expert opinion, iterating until voting indicated consensus. The level of agreement was determined by anonymous votes., Results: Three overarching principles and eight recommendations were agreed. Compared to the 2018 version, ultrasound is now recommended as first-line imaging test in all patients with suspected giant cell arteritis, and axillary arteries should be included in the standard examination. As an alternative to ultrasound, cranial and extracranial arteries can be examined by FDG-PET or MRI. For Takayasu arteritis, MRI is the preferred imaging modality; FDG-PET, CT or ultrasound are alternatives. Although imaging is not routinely recommended for follow-up, ultrasound, FDG-PET or MRI may be used for assessing vessel abnormalities in LVV patients with suspected relapse, particularly when laboratory markers of inflammation are unreliable. MR-angiography, CT-angiography or ultrasound may be used for long-term monitoring of structural damage, particularly at sites of preceding vascular inflammation., Conclusions: The 2023 EULAR recommendations provide up-to-date guidance for the role of imaging in the diagnosis and assessment of patients with LVV., Competing Interests: Competing interests: CDejaco has received consulting/speaker’s fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Galapagos, Sparrow and Sanofi; grant support from AbbVie and Novartis, all unrelated to this manuscript. He is an editorial board member of ARD. SR has received research grants and/or consultancy fees From AbbVie, Eli Lilly, Galapagos, MSD, Novartis, Pfizer, Sanofi, UCB. MB: consultancy fees from AbbVie PB has received speaker fees by Janssen and project grants by Pfizer. CP has received research grants and/or consultancy fees from AbbVie, Vifor, Roche, GlaxoSmithKline and AstraZeneca, all unrelated to this manuscript. SLM reports: Consultancy on behalf of her institution for Roche/Chugai, Sanofi, AbbVie, AstraZeneca; Investigator on clinical trials for Sanofi, GSK, Sparrow; speaking/lecturing on behalf of her institution for Roche/Chugai, Vifor, Pfizer and Novartis; chief investigator on STERLING-PMR trial, funded by NIHR; patron of the charity PMRGCAuk. No personal remuneration was received for any of the above activities. Support from Roche/Chugai to attend EULAR2019 in person and from Pfizer to attend ACR Convergence 2021 virtually. SLM is supported in part by the NIHR Leeds Biomedical Research Centre. TAB reports research grants from Deutsche Forschungsgemeinschaft (DFG) and Siemens Healthineers on behalf of his Department. He has received consulting/speaker’s fees from BioTel Research, Chugai, Guerbet, Novartis, Roche, Sanofi and Siemens Healthineers. DB consultancy fees from Roche and GSKSara Brolin: Grant from Novartis. MCC has received consulting fees from GSK, SCL-Vifor, AbbVie, AstraZeneca and Janssen, and a research grant form Kiniksa Pharmaceuticals. JM-C has received consulting/speaker’s fees from Abbvie, Lilly, Janssen, Novartis, Pfizer, UCB, MSD, all unrelated to this manuscript. BD has received consultancies and educational grants from Novartis, Abbvie, Roche, Chugai, Sanofi. BDN has received consulting/speaker’s fees from Roche and Novartis all unrelated to this manuscript. EDM Research funding/consulting and conferences fees from: Abbvie, Novartis, Pfizer, Roche, Janssen, Lilly, MSD, BMS, UCB, Grunental and Sanofi. CDuftner has received consulting/speaker’s fees from Abbvie, AOP Orphan, Astra-Zeneca, Bristol-Myers-Squibb, Eli-Lilly, Janssen, Galapagos, Merck-Sharp-Dohme, Novartis, Pfizer, Roche, Sandoz, UCB, Vifor, and grant/research support from Eli-Lilly, Pfizer, UCBHaner Direskeneli is investigator in clinical trials for Abbvie and Novartis, had educational support from Pfizer, Amgene, Celltrion, UCB and Roche unrelated to this manuscript. AM has received research grants and/or consultancy fees From AbbVie, BMS, Biogen, Eli Lilly, Galapagos, Janssen, MSD, Novartis and UCB. LS has received grant support from the Swiss Society of Rheumatology, iQone and Sandoz and support for travel expenses from Sanofi; all unrelated to this manuscript. RHJAS has received independent research grants of Siemens Healtineers and WAS has received consultancy fees, honoraria and travel expenses from Abbvie, Chugai, GlaxoSmithKline, Medac, Novartis, Roche, and Sanofi and is principal investigator in trials sponsored by Abbvie, GlaxoSmithKline, Novartis and Sanofi., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Objectives: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated., Results: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients., Conclusions: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Giant cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries. MiRNAs are small, non-coding RNAs that inhibit gene expression at post-transcriptional level. Several miRNAs have been shown to be dysregulated in temporal artery biopsies (TABs) from GCA patients, but their role is unknown. The aims of the present work were: to gain insight into the link between inflammation and miRNA up-regulation in GCA; to identify the role of miR-146a and miR-146b. Primary cultures from TABs were treated with IL-1β, IL-6, soluble IL-6R (sIL6R), IL-17, IL-22, IFNγ, LPS and PolyIC. Correlations between cytokine mRNA and miRNA levels were determined in inflamed TABs. Primary cultures from TABs, human aortic endothelial and smooth muscle cells and ex-vivo TAB sections were transfected with synthetic miR-146a and miR-146b to mimic miRNA activities. Cell viability, target gene expression, cytokine levels in culture supernatants were assayed. Treatment of primary cultures from TABs with IL-1β and IL-17 increased miR-146a expression while IL-1β, IL-6+sIL6R and IFNγ increased miR-146b expression. IFNγ and IL-1β mRNA levels correlated with miR-146a/b levels. Following transfection, cell viability decreased only in primary cultures from TABs. Moreover, transfection of miR-146a/b mimics increased ICAM-1 gene expression and production of the soluble form of ICAM-1 by primary cultures from TABs and by ex-vivo TABs. ICAM-1 expression was higher in inflamed than normal TABs and ICAM-1 levels correlated with miR-146a/b levels. Expression of miR-146a and miR-146b in GCA appeared to be driven by inflammatory cytokines (e.g. IL-1β, IFNγ). miR-146a and miR-146b seem responsible for the increase of soluble ICAM-1., Competing Interests: Declaration of competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update., Methods: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations., Results: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV., Conclusions: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance., Competing Interests: Competing interests: AB received honoraria for consulting from GSK. AJM received speaker fees and/or consultancies from Amgen, Lilly, Vifor, Roche and GSK. AJM received speaker fees and/or consultancies from Amgen, Celgene, Chugai, Novartis, Roche and Vifor. AK received speaker fees and/or consultancies from Catalyst Biosciences, Walden Bioscience, Delta4, Otsuka, UriSalt and Vifor. BH received speaker fees and/or consultancies from AbbVie, Amgen, AstraZeneca, BMS, Boehringer, Chugai, GSK, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, Roche and Vifor. BT received consulting fees from AstraZeneca, GlaxoSmithKline, Vifor and Pharma. DB received consultancies from Roche. DJ received speaker fees and/or consultancies from Amgen, AstraZeneca, BMS, Boehringer, Chemocentryx, Chugai, GSK, Novartis, Roche, Takeda and Vifor. DV received speaker fees and/or consultancies and/or grants from AbbVie, Genesis-Pharma, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB. The work is supported by the Greek Rheumatology Society and Professional Association of Rheumatologists (ERE-EPERE) and the Special Account for Research Grants (SARG), National and Kapodistrian University of Athens, Greece. JHS received research grants from the John Grube Foundation and the Deutsche Gesellschaft für Rheumatologie (German Society for Rheumatology). MAL received unrestricted research funding and consultancy fees from Vifor with Chemocentryx. MCC received consulting fees from GSK, Vifor, AbbVie and Janssen, and a research grant from Kiniksa Pharmaceuticals. MS has received consultancy fees from Hansa Biopharma, Vifor, AstraZeneca, Toleranzia and Chemocentryx. PM reports receiving funds for the following activities in the past 2 years: consulting: AbbVie, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chemocentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Mitsubishi, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sparrow, Takeda and Talaris; research support: AbbVie, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chemocentryx, Eicos, Electra, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi and Takeda; stock options: Kyverna. OK reports receiving speaking fees and/or consultancies from Amgen, AbbVie, Lilly, UCB-Pharma, Novartis, Celltrion; and research support from AbbVie, Viela-Bio, Roche and Novartis. RAL received speaker fees and/or consultancies and/or grants from AbbVie, BMS/Celgene, Chemocentryx, Chugai, GSK, InflaRx, Pfizer Global, Roche and Vifor. The LUMC received on behalf of YKOT an unrestricted research grant from CSL Vifor, GlaxoSmithKline, Aurinia Pharmaceuticals. The LUMC received consulting fees from Aurinia Pharmaceuticals, Novartis, GSK, KezarBio, Vifor Pharma and Otsuka Pharmaceuticals on consultancies delivered by YKOT. The work of YKOT is supported by the Dutch Kidney Foundation (17OKG04) and by the Arthritis Research and Collaboration Hub (ARCH) foundation. ARCH is funded by Dutch Arthritis Foundation (ReumaNederland). AV, BS-A, CBM, FP-K, GT, JH, JM, NH, PV and SM reported no conflicts of interest., (© 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.)

Vascular smooth muscle cells (VSMCs) have been shown to play a role in the pathogenesis of giant cell arteritis (GCA) through their capacity to produce chemokines recruiting T cells and monocytes in the arterial wall and their ability to migrate and proliferate in the neointima where they acquire a myofibroblast (MF) phenotype, leading to vascular stenosis. This study aimed to investigate if MFs could also impact T-cell polarization. Confocal microscopy was used to analyze fresh fragments of temporal artery biopsies (TABs). Healthy TAB sections were cultured to obtain MFs, which were then treated or not with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and analyzed by immunofluorescence and RT-PCR. After peripheral blood mononuclear cells and MFs were co-cultured for seven days, T-cell polarization was analyzed by flow cytometry. In the neointima of GCA arteries, we observed a phenotypic heterogeneity among VSMCs that was consistent with a MF phenotype (α-SMA + CD90 + desmin + MYH11 + ) with a high level of STAT1 phosphorylation. Co-culture experiments showed that MFs sustain Th1/Tc1 and Th17/Tc17 polarizations. The increased Th1 and Tc1 polarization was further enhanced following the stimulation of MFs with IFN-γ and TNF-α, which induced STAT1 phosphorylation in MFs. These findings correlated with increases in the production of IL-1β, IL-6, IL-12 and IL-23 by MFs. Our study showed that MFs play an additional role in the pathogenesis of GCA through their ability to maintain Th17/Tc17 and Th1/Tc1 polarizations, the latter being further enhanced in case of stimulation of MF with IFN-γ and TNF-α., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4 + T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4 + T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4 + T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4 + T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4 + T cells in GCA and suggest targeting CTLs as a potential therapeutic option., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)