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Introduction: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are frequently overlapping conditions. Unlike in GCA, vascular inflammation is absent in PMR. Therefore, serum biomarkers reflecting vascular remodelling could be used to identify GCA in cases of apparently isolated PMR., Materials and Methods: 45 patients with isolated PMR and 29 patients with PMR/GCA overlap were included. Blood samples were collected before starting glucocorticoids for all patients. Serum biomarkers reflecting systemic inflammation (interleukin-6 (IL-6), CXCL9), vascular remodelling (MMP-2, MMP-3, MMP-9) and endothelial function (sCD141, sCD146, ICAM-1, VCAM-1, vWFA2) were measured by Luminex assays., Results: Patients with GCA had higher serum levels of sCD141 (p=0.002) and CXCL9 (p=0.002) than isolated PMR. By contrast, serum levels of MMP-3 (p=0.01) and IL-6 (p=0.004) were lower in GCA than isolated PMR. The area under the curve (AUC) was calculated for sCD141, CXCL9, IL-6 and MMP-3. Separately, none of them were >0.7, but combinations revealed higher diagnostic accuracy. The CXCL9/IL-6 ratio was significantly increased in patients with GCA (p=0.0001; cut-off >32.8, AUC 0.76), while the MMP-3/sCD141 ratio was significantly lower in patients with GCA (p<0.0001; cut-off <5.3, AUC 0.79). In patients with subclinical GCA, which is the most difficult to diagnose, sCD141 and MMP-3/sCD141 ratio demonstrated high diagnostic accuracy with AUC of 0.81 and 0.77, respectively., Conclusion: Combined serum biomarkers such as CXCL9/IL-6 and MMP-3/sCD141 could help identify GCA in patients with isolated PMR. It could allow to select patients with PMR in whom complementary examinations are needed., Competing Interests: Competing interests: MS: AbbVie consulting, Argenx consulting, Boehringer Ingelheim consulting, GSK consulting, Novartis consulting and research grant, Roche–Chugai consulting, CSL Vifor consulting, Fresenius consulting. BB: Roche–Chugai personal fees for consulting, Boehringer Ingelheim consulting. AR: Novartis research grant, Novartis consulting, AbbVie consulting, Boehringer Ingelheim consulting, Chugai consulting., (© 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.)

Objectives: To evaluate the ability of 18 FDG PET/CT, at diagnosis of giant cell arteritis (GCA) and during follow-up, to predict occurrence of relapse in large-vessel GCA (LV-GCA)., Methods: We conducted a retrospective study using the French Study Group for Large-Vessel Vasculitis (GEFA) network. Data from patients with LV-GCA diagnosed by PET/CT and who had PET/CT in the following year were collected. For each PET/CT, PET vascular activity score (PETVAS) and total vascular score (TVS) were assessed, and their ability to predict the occurrence of subsequent relapse was assessed., Results: A total of 65 LV-GCA patients were included, of whom 55 had undergone a follow-up PET/CT 3 to 12 months after the diagnosis of GCA. Patients for whom the second PET/CT (PET2) was performed during active GCA were excluded. PETVAS and TVS decreased between PET1 and PET2 in all patients (p < 0.001). There was no correlation between vascular activity scores in PET2 and time to prednisone taper. For relapse prediction, at PET1, the AUC of the TVS and PETVAS were respectively 51.9 and 41.9 at 6 months, 55.3 and 49.7 at 1 year, 55 and 55.7 at 2 years. For PET2, the AUC were respectively 46.1 and 46.7 at 6 months, 52.1 and 48.9 at 1 year, 58.4 and 52.3 at 2 years., Conclusion: PET vascular activity scores at diagnosis and at follow-up PET/CT performed outside a period of GCA activity do not display high performance to predict the occurrence of subsequent relapse in LV-GCA patients., Competing Interests: Disclosures Maxime Samson: Argenx (consulting), Boerhinger Ingelheim (consulting), Chugai (consulting), CSL Vifor (consulting), Fresenius Kabi (consulting), GSK (consulting), Novartis (consulting and research grant), (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Warm autoimmune hemolytic anemia (wAIHA) is a rare acquired autoimmune disease mediated by antibodies targeting red blood cells. The involvement of CD4 T-helper cells has been scarcely explored, with most findings extrapolated from animal models. Here, we performed quantification of both effector T lymphocytes (Teff) and regulatory T cells (Treg), associated with functional and transcriptomic analyses of Treg in human wAIHA. We observed a shift of Teff toward a Th17 polarization concordant with an increase in serum interleukin-17 concentration that correlates with red blood cell destruction parameters, namely lactate dehydrogenase and bilirubin levels. A decrease in circulating Treg, notably effector Treg, associated with a functional deficiency, as represented by their decrease capability to inhibit Teff proliferation, were also observed. Treg deficiency was associated with a reduced expression of Foxp3, the master transcription factor known to maintain the Treg phenotype stability and suppressive functions. Transcriptomic profiling of Treg revealed activation of the tumor necrosis facto (TNF)-α pathway, which was linked to increased serum TNF-α concentrations that were twice as high as in controls. Treg transcriptomic profiling also suggested that post-translational mechanisms possibly accounted for Foxp3 downregulation and Treg dysfunctions. Since TNF-α participates in the rupture of immune tolerance during wAIHA, its inhibition could be of interest. To this end, the effects of fostamatinib, a SYK inhibitor, were investigated in vitro, and we showed that besides the inhibition of erythrocyte phagocytosis by monocytes, fostamatinib is also able to dampen TNF-α production, thus appearing as a promising multitargeting therapy in wAIHA (clinicaltrials gov. Identifier: NCT02158195).

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.)

Hereditary hemorrhagic telangiectasia (HHT) is a rare inherited disease due to heterozygous loss-of-function mutations on the BMP9/10 pathway ( ENG, ACVRL1 or MADH4 mainly). HHT endothelial cells are prone to lose their quiescence, leading to progressive appearance of numerous telangiectases on skin and mucosa (complicated by epistaxis and anemia), and to larger arteriovenous malformations in lungs, liver and brain. HHT is also associated with T lymphocyte abnormalities, which are currently poorly understood. We quantified by flow-cytometry the main T lymphocyte circulating subsets in 40 HHT patients and 20 matched healthy controls. Immunostaining was done on 2 HHT skin telangiectases. Disruptions in T lymphocyte homeostasis was observed, characterized by increases in subsets known to promote angiogenesis: Th2 (1.38% vs 1.15%, p=0.021), Th17 (0.32% vs 0.22%, p=0.019 2) and Treg (4.94% vs 3.51%, p= 0.027). T angiogenic lymphocytes (Tang), defined as CD3+CD31+CXCR4+ T cells, were at similar levels in both groups, but the proportion of VEGF-A+ Tang after stimulation was higher in the HHT group compared to controls (68.2% vs 44.9%, p=0.012). The global HHT T lymphopenia predominantly affected the effector memory T-helper cells (200 vs 270 cells/mm 3 , p=0.017), and the lymphocytic infiltrate around HHT telangiectases consisted of memory T-helper cells. The Th17 circulating subset was positively correlated with the monthly epistaxis duration (r coefficient: +0,431, p=0.042), prospectively assessed. HHT T-helper lymphocytes are affected by several pro-angiogenic changes, potentially resulting from their recruitment by abnormal endothelial cells. They could constitute a biologically relevant source of VEGF-A and a valuable therapeutic target in HHT., 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 © 2023 Guilhem, Ciudad, Aubriot-Lorton, Greigert, Cladière, Leguy-Seguin, Audia, Samson and Bonnotte.)

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients., Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707)., Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034)., Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens., Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole., Competing Interests: Dr. Zuily reports grants from French Ministry of Health, grants from The Grand Est Regional Council, grants from The Grand Nancy Métropole, grants from The Comité ad hoc de pilotage national des essais thérapeutiques et autres recherches sur le COVID-19 (CAPNET, label Priorité Nationale de Recherche–National Research Priority), during the conduct of the study; personal fees from Leo Pharma, personal fees from Bristol Myers Squibb, personal fees from Pfizer, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Viatris, personal fees from Sanofi, grants from Boehringer Ingelheim, grants from Bayer, outside the submitted work; Dr. Lefevre reports grants from Gilead, grants from ViiV, outside the submitted work; Dr. Sanchez reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from Boehringer Ingelheim, personal fees from Inari, personal fees from Boston Scientific, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Chiesi, grants from Oxyvie, outside the submitted work; Dr. Empis De Vendin has nothing to disclose; Dr. De Ciancio has nothing to disclose; Dr. Arlet reports grants from Addmedical, grants and other from Novartis, outside the submitted work; Dr. Khider has nothing to disclose; Dr. Terriat has nothing to disclose; Dr. Greigert has nothing to disclose; Dr. Robert has nothing to disclose; Dr. Louis has nothing to disclose; Dr. Trinh-Duc has nothing to disclose; Dr. Rispal has nothing to disclose; Dr. Accassat reports other from Leo Pharma, other from Janssen, other from MSD, outside the submitted work; Dr. Thiery has nothing to disclose; Dr. Montani reports grants and personal fees from Acceleron, grants and personal fees from Janssen, grants and personal fees from Merck, personal fees from Bayer, outside the submitted work; Dr. Azarian has nothing to disclose; Dr. Meneveau reports grants, personal fees and other from Bayer, grants, personal fees and other from Bristol Myers Squibb, grants, personal fees and other from Pfizer, grants from Medtronic, grants and personal fees from Boston Scientific, grants, personal fees and other from Abbott, personal fees from Inari, personal fees from Terumo, outside the submitted work; Dr. Soudet reports grants and personal fees from Leo Pharma, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, outside the submitted work; Dr. Le Mao has nothing to disclose; Dr. Maurier has nothing to disclose; Dr. Le Moing has nothing to disclose; Dr. Quéré reports other from Leo Pharma, outside the submitted work; Dr. Yelnik has nothing to disclose; Dr. Lefebvre reports personal fees and other from Pfizer, other from Eumedica, outside the submitted work; Dr. Martinot reports other from Menarini, other from Overcome, outside the submitted work; Dr. Delrue has nothing to disclose; Dr. Benhamou has nothing to disclose; Dr. Parent reports grants from Oxyvie, personal fees from MSD, outside the submitted work; Dr. Roy reports personal fees and other from Bayer, personal fees and other from Boehringer Ingelheim, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, personal fees and other from Aspen, personal fees and other from Sanofi, outside the submitted work; Ms. Presles has nothing to disclose; Dr. Goehringer has nothing to disclose; Dr. Mismetti reports personal fees from Bayer Healthcare, personal fees from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Aspen, personal fees from Pfizer, outside the submitted work; Dr. Bertoletti reports grants from Bayer, grants and personal fees from MSD, personal fees and other from Leo Pharma, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, outside the submitted work; Dr. Rossignol reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Boehringer-Ingelheim, personal fees from Cincor, personal fees from KBP, personal fees from Novartis, personal fees from NovoNordisk, personal fees from Roche, personal fees from Vifor/Relypsa, personal fees from Fresenius, personal fees and other from CardioRenal, personal fees from Idorsia, personal fees from Sequana, personal fees from Vifor, non-financial support from G3P, outside the submitted work; Dr. Couturaud reports grants and personal fees (board memberships, symposia or travel) from Bayer, grants and personal fees (board memberships, symposia or travel) from Bristol-Myers Squibb/Pfizer, personal fees (board memberships, symposia or travel) from Merck Sharp and Dohme, personal fees (board memberships, symposia or travel) from Astra Zeneca, personal fees (board memberships or symposia) from Sanofi, personal fees (board memberships or symposia) from Janssen, personal fees (board memberships, symposia or travel) from Leo Pharma, outside the submitted work; Dr. Wahl has nothing to disclose; Dr. Thilly has nothing to disclose; Dr. Laporte reports personal fees from Lilly/Boehringer Ingelheim, personal fees from Bristol Myers Squibb/Pfizer, personal fees from Merck, personal fees from Leo-Pharma, outside the submitted work., (© 2023 The Authors.)

Objectives: To investigate the performance of cranial PET/CT for the diagnosis of GCA., Methods: All patients with a suspected diagnosis of GCA were prospectively enrolled in this study and had a digital PET/CT with evaluation of cranial arteries if they had not started glucocorticoids >72 h previously. The diagnosis of GCA was retained after at least 6 months of follow-up if no other diagnosis was considered by the clinician and the patient went into remission after at least 6 consecutive months of treatment. Cranial PET/CT was considered positive if at least one arterial segment showed hypermetabolism similar to or greater than liver uptake., Results: For cranial PET/CT, sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were 73.3%, 97.2%, 91.7% and 89.7%, respectively. For extracranial PET/CT, diagnostic performance was lower (Se = 66.7%, Sp = 80.6%, PPV = 58.8%, NPV = 85.3%). The combination of cranial and extracranial PET/CT improved overall sensitivity (Se = 80%) and NPV (NPV = 90.3%) while decreasing overall specificity (Sp = 77.8%) and PPV (PPV = 60%)., Conclusion: Cranial PET/CT can be easily combined with extracranial PET/CT with a limited increase in examination time. Combined cranial and extracranial PET/CT showed very high diagnostic accuracy for the diagnosis of GCA., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05246540., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

DIAGNOSIS OF GIANT CELL ARTERITIS. The diagnosis of giant cell arteritis (GCA) must be made promptly in order to initiate appropriate treatment aimed at relieving symptoms and avoiding ischemic complications, particularly visual ones. The diagnosis of GCA is based on the occurrence, in a patient over 50, of clinical signs of GCA, primarily recent headaches, or polymyalgia rheumatica, as «evidence» of large-vessel vasculitis, which is provided by histological analysis of an arterial fragment, usually the temporal artery, or by imaging of the cephalic arteries, the aorta and/ or its main branches by Doppler US scan, angio-CT, 18fluorodeoxyglucose PET scan or more rarely by MRI angiography. In addition, in more than 95% of cases, patients have an elevation in markers of inflammatory syndrome. This is less marked in the case of visual or neurological ischemic complications. Two main GCA phenotypes can be distinguished: on the one hand, cephalic GCA, in which cephalic vessel involvement predominates and which identifies patients at the greatest risk of ischemic complications; on the other hand, extracephalic GCA concerns younger patients with a lower ischemic risk but with more aortic complications and more frequent relapses. The establishment «fast track» type structures in specialized centers allows for rapid management in order to identify patients to be treated in order to avoid ischemic complications and to quickly perform the necessary examinations to confirm the diagnosis and ensure that the patient receives appropriate management., Competing Interests: H. Greigert déclare n’avoir aucun lien d’intérêts. B. Bonotte déclare des interventions ponctuelles pour Roche Chugai, Amgen, Novartis, LFB, Boehringer Ingelheim, Eusa Pharma et avoir été pris en charge à l’occasion de déplacement pour congrès par Novartis, Otsuka, AstraZeneca. M. Samson déclare des interventions ponctuelles pour Roche Chugai, Novartis, Vifor Pharma, AbbVie, Argenx, GSK et avoir été pris en charge à l’occasion de déplacement pour congrès par Roche Chugai, AbbVie, Novartis, Vifor Pharma, GSK.

Competing Interests: M. Samson déclare des interventions ponctuelles pour Roche Chugai, Novartis, Vifor Pharma, AbbVie, Argenx, GSK et avoir été pris en charge à l’occasion de déplacement pour congrès par Roche Chugai, AbbVie, Novartis, Vifor Pharma, GSK. H. Greigert déclare n’avoir aucun lien d’intérêts. B. Bonotte déclare des interventions ponctuelles pour Roche Chugai, Amgen, Novartis, LFB, Boehringer Ingelheim, Eusa Pharma et avoir été pris en charge à l’occasion de déplacement pour congrès par Novartis, Otsuka, AstraZeneca.

EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF GIANT CELL ARTERITIS. Giant cell arteritis (GCA) is a granulomatous vasculitis. It affects patients over 50 years of age, predominantly women. The pathophysiology of GCA involves genetic and environmental factors leading to the development of inflammation and subsequent large artery wall remodelling, the mechanisms of which are increasingly understood. The process is thought to begin with the activation of dendritic cells in the vessel wall. These then recruit and activate CD4 T cells, inducing their proliferation and polarisation into Th1 and Th17 cells, which produce interferon-gamma (IFN-γ) and interleukin-17 (IL-17) respectively. IFN-γ activates vascular smooth muscle cells, which produce chemokines that induce the recruitment of other mononuclear cells (CD4 and CD8 T cells and monocytes). This inflammatory infiltrate, the differentiation of monocytes into macrophages induce the production of other mediators that cause remodeling of the vascular wall based on destruction of the arterial wall, neoangiogenesis and intimal hyperplasia. This remodelling leads to the ischaemic manifestations of GCA by causing stenosis or even occlusion of the affected vessels. More recently, mechanisms have been identified that allow the perpetuation of inflammation and vascular remodelling, explaining the chronic evolution of GCA., Competing Interests: H. Greigert déclare n’avoir aucun lien d’intérêts. B. Bonotte déclare des interventions ponctuelles pour Roche Chugai, Amgen, Novartis, LFB, Boehringer Ingelheim, Eusa Pharma et avoir été pris en charge à l’occasion de déplacement pour congrès par Novartis, Otsuka, AstraZeneca. M. Samson déclare des interventions ponctuelles pour Roche Chugai, Novartis, Vifor Pharma, AbbVie, Argenx, GSK et avoir été pris en charge à l’occasion de déplacement pour congrès par Roche Chugai, AbbVie, Novartis, Vifor Pharma, GSK.

TREATMENT OF GIANT CELL ARTERITIS. The treatment of giant cell arteritis (GCA) is based on glucocorticoids. This treatment significantly reduces the risk of ischemic complications, especially those of a visual nature, rapidly relieves the symptoms of the disease, and eliminates the inflammatory syndrome. The diagnosis of GCA must be able to question if corticosteroid therapy is ineffective. Once the symptoms have resolved and the inflammatory syndrome has normalized, glucocorticosteroids are tapered very gradually. The goal is to discontinue glucocorticosteroids in 12 to 18 months. Nearly half of patients experience flares during the glucocorticoid taper. These are usually benign, not visually life-threatening, and easily controlled by increasing glucocorticoids. However, these relapses contribute to prolonging the treatment duration and thus the cumulative dose of glucocorticoids received by patients, which leads to the occurrence of adverse effects of glucocorticoids in almost all patients. For this reason, it is sometimes necessary to prescribe glucocorticoid-sparing treatments, particularly methotrexate and tocilizumab. The efficacy of these treatments and others in development is essential and to be discussed. In addition, the management of patients with GCA should include preventive measures to reduce cardiovascular, infectious and osteoporosis risks., Competing Interests: M. Samson déclare des interventions ponctuelles pour Roche Chugai, Novartis, Vifor Pharma, AbbVie, Argenx, GSK et avoir été pris en charge à l’occasion de déplacement pour congrès, par Roche Chugai, AbbVie, Novartis, Vifor Pharma, GSK. H. Greigert déclare n’avoir aucun lien d’intérêts. B. Bonotte déclare des interventions ponctuelles pour Roche Chugai, Amgen, Novartis, LFB, Boehringer Ingelheim, Eusa Pharma et avoir été pris en charge à l’occasion de déplacement pour congrès par Novartis, Otsuka, AstraZeneca.

Introduction: The pathogenesis of Giant Cell Arteritis (GCA) relies on vascular inflammation and vascular remodeling, the latter being poorly controlled by current treatments., Methods: This study aimed to evaluate the effect of a novel cell therapy, Human Monocyte-derived Suppressor Cells (HuMoSC), on inflammation and vascular remodeling to improve GCA treatment. Fragments of temporal arteries (TAs) from GCA patients were cultured alone or in the presence of HuMoSCs or their supernatant. After five days, mRNA expression was measured in the TAs and proteins were measured in culture supernatant. The proliferation and migration capacity of vascular smooth muscle cells (VSMCs) were also analyzed with or without HuMoSC supernatant., Results: Transcripts of genes implicated in vascular inflammation ( CCL2 , CCR2 , CXCR3 , HLADR ), vascular remodeling ( PDGF , PDGFR ), angiogenesis (VEGF) and extracellular matrix composition ( COL1A1 , COL3A1 and FN1 ) were decreased in arteries treated with HuMoSCs or their supernatant. Likewise, concentrations of collagen-1 and VEGF were lower in the supernatants of TAs cultivated with HuMoSCs. In the presence of PDGF, the proliferation and migration of VSMCs were both decreased after treatment with HuMoSC supernatant. Study of the PDGF pathway suggests that HuMoSCs act through inhibition of mTOR activity. Finally, we show that HuMoSCs could be recruited in the arterial wall through the implication of CCR5 and its ligands., Conclusion: Altogether, our results suggest that HuMoSCs or their supernatant could be useful to decrease vascular in flammation and remodeling in GCA, the latter being an unmet need in GCA treatment., Competing Interests: MS: Roche–Chugai consulting, AbbVie consulting, Boehringer Ingelheim consulting, Novartis consulting and research grant, VIFOR Pharma consulting; BB: Roche–Chugai personal fees for consulting, Boehringer Ingelheim consulting; CC-G: Horus and Bayer grant, Novartis and Bayer honoraria and Novartis, Bayer, Thea, Horus, Alcon and Allergan medical advisory board; P-HG: Allergan, Bayer and Novartis travel expenses, Novartis and Bayer honoraria; MCC: GlaxoSmithKline consulting, CSL Vifor consulting, AbbVie consulting, Janssen consulting, Astrazeneca consulting, Kiniksa Pharmaceuticals research grant; GE-F: GlaxoSmithKline consulting, Janssen consulting. The remaining 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 © 2023 Samson, Genet, Corbera-Bellalta, Greigert, Espígol-Frigolé, Gérard, Cladière, Alba-Rovira, Ciudad, Gabrielle, Creuzot-Garcher, Tarris, Martin, Saas, Audia, Bonnotte and Cid.)

Polymyalgia rheumatica (PMR) is an inflammatory rheumatism of the shoulder and pelvic girdles. In 16 to 21% of cases, PMR is associated with giant cell arteritis (GCA) that can lead to severe vascular complications. Ruling out GCA in patients with PMR is currently a critical challenge for clinicians. Two GCA phenotypes can be distinguished: cranial GCA (C-GCA) and large vessel GCA (LV-GCA). C-GCA is usually suspected when cranial manifestations (temporal headaches, jaw claudication, scalp tenderness, or visual disturbances) occur. Isolated LV-GCA is more difficult to diagnose, due to the lack of specificity of clinical features which can be limited to constitutional symptoms and/or unexplained fever. Furthermore, many studies have demonstrated the existence-in varying proportions-of subclinical GCA in patients with apparently isolated PMR features. In PMR patients, the occurrence of clinical features of C-GCA (new onset temporal headaches, jaw claudication, or abnormality of temporal arteries) are highly predictive of C-GCA. Additionally, glucocorticoids' resistance occurring during follow-up of PMR patients, the occurrence of constitutional symptoms, or acute phase reactants elevation are suggestive of associated GCA. Research into the predictive biomarkers of GCA in PMR patients is critical for selecting PMR patients for whom imaging and/or temporal artery biopsy is necessary. To date, Angiopoietin-2 and MMP-3 are powerful for predicting GCA in PMR patients, but these results need to be confirmed in further cohorts. In this review, we discuss the diagnostic challenges of subclinical GCA in PMR patients and will review the predictive factors of GCA in PMR patients.

Introduction: This study aimed to identify markers of disease worsening in patients hospitalized for SARS-Cov2 infection., Patients and Methods: Patients hospitalized for severe recent-onset (<1 week) SARS-Cov2 infection were prospectively included. The percentage of T-cell subsets and plasma IL-6 at admission (before any steroid therapy) were compared between patients who progressed to a critical infection and those who did not., Results: Thirty-seven patients (18 men, 19 women) were included; 11 (30%) progressed to critical infection. At admission, the critical infection patients were older (P = 0.021), had higher creatinine levels (P = 0.003), and decreased percentages of circulating B cells (P = 0.04), T cells (P = 0.009), and CD4+ T cells (P = 0.004) than those with a favorable course. Among T cell subsets, there was no significant difference between the two groups except for the percentage of Th17 cells, which was two-fold higher in patients who progressed to critical infection (P = 0.028). Plasma IL-6 at admission was also higher in this group (P = 0.018). In multivariate analysis, the percentage of circulating Th17 cells at admission was the only variable associated with higher risk of progression to critical SARS-Cov2 infection (P = 0.021)., Conclusion: This study suggests that an elevated percentage of Th17 cells in patients hospitalized for SARS-Cov2 infection is associated with an increased risk of progression to critical disease. If these data are confirmed in a larger study, this marker could be used to better target the population of patients in whom tocilizumab could decrease the risk of progression to critical COVID-19., (Copyright © 2022. Published by Elsevier B.V.)

The giant cell arteritis (GCA) pathophysiology is complex and multifactorial, involving a predisposing genetic background, the role of immune aging and the activation of vascular dendritic cells by an unknown trigger. Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ and GM-CSF induce the differentiation of macrophage subpopulations, which play a role in the destruction of the arterial wall, in neoangiogenesis or intimal hyperplasia. Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis. In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells.

Recently developed cell-based therapies have shown potential for graft-versus-host disease (GvHD) mitigation. Our team previously developed a protocol to generate human monocyte-derived suppressor Cells (HuMoSC), a subpopulation of CD33+ suppressor cells of monocytic origin. CD33+HuMoSC successfully reduced xenoGvHD severity in NOD/SCID/IL-2Rγc -/- (NSG) mice. While CD33+ HuMoSC culture supernatant inhibits T cell activation and proliferation, the recovery of CD33+ HuMoSC immunosuppressive cells and the subsequent production of their supernatant is limited. An attractive solution would be to use both the CD33+ and the large number of CD14+ cells derived from our protocol. Here, we assessed the immunoregulatory properties of the CD14+HuMoSC supernatant and demonstrated that it inhibited both CD4 and CD8 T cell proliferation and decreased CD8 cytotoxicity. In vivo , injection of CD14+HuMoSC supernatant reduced xenoGvHD in NSG mice. Furthermore, CD14+HuMoSC supernatant maintained its immunoregulatory properties in an inflammatory environment. Proteomic and multiplex analyses revealed the presence of immunosuppressive proteins such as GPNMB, galectin-3 and IL-1R(A) Finally, CD14+HuMoSC supernatant can be produced using good manufacturing practices and be used as complement to current immunosuppressive drugs. CD14+HuMoSC supernatant is thus a promising therapy for preventing GvHD. ., 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 © 2022 Gérard, Thébault, Lamarthée, Genet, Cattin, Brazdova, Janikashvili, Cladière, Ciudad, Ouandji, Ghesquière, Greigert, Tinel, Adotevi, Saas, Samson, Audia and Bonnotte.)

In this prospective study on patients with acute myocarditis (AM), we aimed to describe the new concept of AMAF (AM with autoimmune features) similar to the previously described interstitial pneumonia with autoimmune features (IPAF). IPAF has recently emerged as a new entity, and IPAF patients appear to have fewer episodes of exacerbation and better survival than patients with idiopathic pulmonary fibrosis. Consecutive patients with infarct-like CMR-confirmed AM were classified AMAF if their serologic status measured from blood sampled at presentation was positive (antinuclear antibodies (ANA) ≥ 1:320), but without meeting established classification criteria for connective tissue disease (CTD). The myocardial tissue abnormalities and their progression were assessed on cardiac magnetic resonance (CMR) within 7 days following symptom onset and at 1 year according to their seropositivity. Among the 64 AM patients included, seven presented AMAF (11%). At baseline CMR, patients with AMAF had half as much late gadolinium enhancement (LGE) as seronegative AM patients (4.41% (1.47-4.41) of myocardial volume versus 8.82% (5.88-14.71), p = 0.01, respectively). At 1-year of follow-up, persistent myocardial scarring was less frequent in AMAF patients (n = 2 (28.6%) than seronegative AM patients (n = 38 (66.7%) (p = 0.021). AMAF, diagnosed as seropositive AM without a specific autoimmune disease, is not rare and is associated with less extensive LGE in the acute phase. In addition, AMAF patients had more favorable outcomes on 12-month CMR. Prospective studies are needed to address the clinical significance of this new concept and its long-term cardiovascular impact., (© 2021. Springer Japan KK, part of Springer Nature.)

Giant cell arteritis (GCA) is a large-vessel granulomatous vasculitis occurring in patients over 50-year-old. Diagnosis can be challenging because there is no specific biological test or other diagnoses to consider. Two main phenotypes of GCA are distinguished and can be associated. First, cranial GCA, whose diagnosis is usually confirmed by the evidence of a non-necrotizing granulomatous panarteritis on temporal artery biopsy. Second, large-vessel GCA, whose related symptoms are less specific (fever, asthenia, and weight loss) and for which other diagnoses must be implemented if there is neither cephalic GCA nor associated polymyalgia rheumatica (PMR) features chronic infection (tuberculosis, Coxiella burnetti ), IgG4-related disease, Erdheim Chester disease, and other primary vasculitis (Behçet disease, relapsing polychondritis, or VEXAS syndrome). Herein, we propose a review of the main differential diagnoses to be considered regarding large vessel vasculitis.

In the presence of temporal arteritis, clinicians often refer to the diagnosis of giant cell arteritis (GCA). However, differential diagnoses should also be evoked because other types of vascular diseases, vasculitis or not, may affect the temporal artery. Among vasculitis, Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is probably the most common, and typically affects the peri-adventitial small vessel of the temporal artery and sometimes mimics giant cell arteritis, however, other symptoms are frequently associated and more specific of ANCA-associated vasculitis prompt a search for ANCA. The Immunoglobulin G4-related disease (IgG4-RD) can cause temporal arteritis as well. Some infections can also affect the temporal artery, primarily an infection caused by the varicella-zoster virus (VZV), which has an arterial tropism that may play a role in triggering giant cell arteritis. Drugs, mainly checkpoint inhibitors that are used to treat cancer, can also trigger giant cell arteritis. Furthermore, the temporal artery can be affected by diseases other than vasculitis such as atherosclerosis, calcyphilaxis, aneurysm, or arteriovenous fistula. In this review, these different diseases affecting the temporal artery are described.

Objectives: An increased risk of haematological malignancies (HM) has been reported in GCA patients. Our study aimed to investigate the incidence and the type of HM occurring in GCA., Methods: All patients with GCA and HM living in Côte d'Or (France) were identified by crossing data from the RHEMCO (Registre des Hémopathies Malignes de Côte d'Or) and those having a positive temporal artery biopsy between 1 January 2001 and 31 December 2018., Results: Among 276 biopsy-proven GCA patients, 14 HM were identified in 12 patients (4.3%). In comparison with the general population aged >50 y, the incidence of myeloid HM and myeloproliferative syndromes were increased in GCA patients [standardized incidence ratios (SIR) = 2.71 and 5.16, respectively], with a specific increase in men with GCA (SIR = 4.82 and 9.04, respectively) but not in women. In addition, the study of SIR depending on the chronology between GCA and HM diagnoses suggests that there was an increased risk of developing GCA in men but not in women, after a diagnosis of myeloid HM (SIR = 9.56), especially if it was a MPS (SIR = 17.56)., Conclusions: Our study shows a particular epidemiology of HM in GCA patients, which is characterized by an increased incidence of myeloid HM, especially MPS, in male GCA patients. The chronology of the diagnoses of GCA and HM raises the hypothesis that clonal hematopoiesis may be implicated in some cases of GCA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To study the percentage, suppressive function and plasticity of Treg in giant cell arteritis (GCA), and the effects of glucocorticoids and tocilizumab., Methods: Blood samples were obtained from 40 controls and 43 GCA patients at baseline and after treatment with glucocorticoids + IV tocilizumab ( n  = 20) or glucocorticoids ( n  = 23). Treg percentage and phenotype were assessed by flow cytometry. Suppressive function of Treg was assessed by measuring their ability to inhibit effector T-cell (Teff) proliferation and polarisation into Th1 and Th17 cells., Results: Treg (CD4 + CD25 high FoxP3 + ) frequency in total CD4 + T cells was decreased in active GCA patients when compared to controls (2.5% vs. 4.7%, P  < 0.001) and increased after treatment with tocilizumab but worsened after treatment with glucocorticoids alone. Treg lacking exon 2 of FoxP3 were increased in GCA patients when compared to controls (23% vs. 10% of total Treg, P  = 0.0096) and normalised after treatment with tocilizumab + glucocorticoids but not glucocorticoids alone. In GCA patients, Treg were unable to control Teff proliferation and induced ˜50% increase in the amount of IL-17 + Teff, which was improved after in vitro blockade of the IL-6 pathway by tocilizumab., Conclusion: This study reports quantitative and functional disruptions in the regulatory immune response of GCA patients and demonstrates that, unlike glucocorticoids, tocilizumab improves Treg immune response., Competing Interests: Maxime Samson has received travel fees and personnel fees for symposium and boards from Roche–Chugaï, and consulting fees from AbbVie. Bernard Bonnotte serves as a board member for Roche–Chugaï. Catherine CREUZOT‐GARCHER has received a grant from Horus and Bayer, honoraria from Novartis and Bayer and serves as a medical advisory board member for Novartis, Bayer, Thea, Horus, Alcon and Allergan. Pierre‐Henry Gabrielle has received travel expenses from Allergan, Bayer and Novartis, and honoraria from Novartis and Bayer., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Cardiovascular risk is increased in giant cell arteritis (GCA). We aimed to characterize myocardial infarction (MI) in a GCA cohort, and to compare the GCA and non-GCA population affected by MI., Methods: In patients with a biopsy-proven diagnosis of GCA between 1 January 2001 and 31 December 2016 in Côte D'Or (France), we identified patients with MI by crossing data from the territorial myocardial infarction registry (Observatoire des Infarctus de Côte d'Or) database. Five controls (non-GCA + MI) were paired with one case (GCA + MI) after matching for age, sex, cardiovascular risk factors and prior cardiovascular disease. MI were characterized as type 1 MI (T1MI), resulting from thrombus formation due to atherothrombotic disease, or type 2 MI (T2MI), due to a myocardial supply/demand mismatch. GCA-related MI was defined as MI occurring within 3 months of a GCA flare (before or after)., Results: Among 251 biopsy-proven GCA patients, 13 MI cases were identified and paired with 65 controls. MI was GCA-related in 6/13 cases, accounting for 2.4% (6/251) of our cohort. T2MI was more frequently GCA-related than GCA-unrelated (80% vs. 16.7%, p = 0.080), and GCA diagnosis was the only identified triggering factor in 75% of GCA-related T2MI. GCA-unrelated MI were more frequently T1MI and occurred in patients who had received a higher cumulative dose of prednisone (p = 0.032). GCA was not associated with poorer one-year survival., Conclusions: GCA-related MI are mainly T2MI probably caused by systemic inflammation rather than coronaritis. GCA-unrelated MI are predominantly T1MI associated with atherothrombotic coronary artery disease., (Copyright © 2021. Published by Elsevier B.V.)

This study aimed to assess the implication of mucosal-associated invariant T (MAIT) cells in GCA. Blood samples were obtained from 34 GCA patients (before and after 3 months of treatment with glucocorticoids (GC) alone) and compared with 20 controls aged >50 years. MAIT cells, defined by a CD3 + CD4 - TCRγδ - TCRVα7.2 + CD161 + phenotype, were analyzed by flow cytometry. After sorting, we assessed the ability of MAIT cells to proliferate and produce cytokines after stimulation with anti CD3/CD28 microbeads or IL-12 and IL-18. MAIT were stained in temporal artery biopsies (TAB) by confocal microscopy. MAIT cells were found in the arterial wall of positive TABs but was absent in negative TAB. MAIT frequency among total αβ-T cells was similar in the blood of patients and controls (0.52 vs. 0.57%; P = 0.43) and not modified after GC treatment (P = 0.82). Expression of IFN-γ was increased in MAIT cells from GCA patients compared to controls (44.49 vs. 32.9%; P = 0.029), and not modified after 3 months of GC therapy (P = 0.82). When they were stimulated with IL-12 and IL-18, MAIT from GCA patients produced very high levels of IFN-γ and displayed a stronger proliferation compared with MAIT from controls (proliferation index 3.39 vs. 1.4; P = 0.032). In GCA, the functional characteristics of MAIT cells are modified toward a pro-inflammatory phenotype and a stronger proliferation capability in response to IL-12 and IL-18, suggesting that MAIT might play a role in GCA pathogenesis. Our results support the use of treatments targeting IL-12/IL-18 to inhibit the IFN-γ pathway in GCA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Immunosuppressive cell-based therapy is a recent strategy for controlling Graft- versus -Host Disease (GvHD). Such cells ought to maintain their suppressive function in inflammatory conditions and in the presence of immunosuppressive agents currently used in allogeneic hematopoietic cell transplantation (allo-HCT). Moreover, these therapies should not diminish the benefits of allo-HCT, the Graft- versus -Leukemia (GvL) effect. We have previously reported on a novel subset of human monocyte-derived suppressor cells (HuMoSC) as a prospective approach for controlling GvHD.Objective., The objective of this study was to explore the therapeutic relevance of the HuMoSC in clinical conditions., Methods: Immune regulatory functions of HuMoSC were assessed in inflammatory conditions and in the presence of immunosuppressants. The therapeutic efficiency of the association of HuMoSC with immunosuppressants was evaluated in an experimental model of GvHD induced by human PBMC in NOD/SCID/IL2-Rγ c -/- (NSG) mice., Interestingly, the inhibitory functions of HuMoSC against T lymphocytes and their ability to polarize Treg are preserved, in vitro , in inflammatory environments and are not affected by immunosuppressive agents. In vivo , the association of HuMoSC-based treatment with an immunosuppressive drug showed a synergistic effect for controlling GvHD. Furthermore, HuMoSC control GvHD while preserving GvL effect in a xeno-GvHD conditioned mouse model with cell neoplasm (CAL-1). HuMoSC are generated according to good manufacturing practices (GMP) and we demonstrated that these cells tolerate long-term preservation with unaltered phenotype and function.Conclusion., HuMoSC-based therapy represents a promising approach for controlling GvHD and could be quickly implemented in clinical practice., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Histopathological examination of temporal artery biopsy (TAB) remains the gold standard for the diagnosis of giant cell arteritis (GCA) but is associated with essential limitations that emphasize the need for an upgraded pathological process. This study pioneered the use of full-field optical coherence tomography (FF-OCT) for rapid and automated on-site pathological diagnosis of GCA. Sixteen TABs (12 negative and 4 positive for GCA) were selected according to major histopathological criteria of GCA following hematoxylin-eosin-saffron-staining for subsequent acquisition with FF-OCT to compare structural modifications of the artery cell wall and thickness of each tunica. Gabor filtering of FF-OCT images was then used to compute TAB orientation maps and validate a potential automated analysis of TAB sections. FF-OCT allowed both qualitative and quantitative visualization of the main structures of the temporal artery wall, from the internal elastic lamina to the vasa vasorum and red blood cells, unveiling a significant correlation with conventional histology. FF-OCT imaging of GCA TABs revealed destruction of the media with distinct remodeling of the whole arterial wall into a denser reticular fibrous neo-intima, which is distinctive of GCA pathogenesis and accessible through automated Gabor filtering. Rapid on-site FF-OCT TAB acquisition makes it possible to identify some characteristic pathological lesions of GCA within a few minutes, paving the way for potential machine intelligence-based or even non-invasive diagnosis of GCA., Competing Interests: We declare the paid employment of LLTech SAS (E. B.) to provide additional FF-OCT images acquisition and analysis. Besides, the commercial affiliation with LLTech SAS does not alter our adherence to PLOS ONE policies on sharing data and materials.

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to autoantibodies targeting platelet glycoproteins (GP). The mechanism of platelet destruction could differ depending on the specificity of antiplatelet antibodies: anti-GPIIb/IIIa antibodies lead to phagocytosis by splenic macrophages, in a Fcγ receptor (FcγR)-dependent manner while anti-GPIb/IX antibodies induce platelet desialylation leading to their destruction by hepatocytes after binding to the Ashwell-Morell receptor, in a FcγR-independent manner. Considering the FcγR-dependent mechanism of action of intravenous immunoglobulins (IVIg), we assumed that the response to IVIg could be less efficient in the presence of anti-GPIb/IX antibodies. We conducted a multicentric, retrospective study including all adult ITP patients treated with IVIg who had antiplatelet antibodies detected between January 2013 and October 2017. Among the 609 identified, 69 patients were included: 17 had anti-GPIb/IX antibodies and 33 had anti-GPIIb/IIIa antibodies. The response to IVIg was not different between the patients with or without anti-GPIb/IX (88.2% vs. 73.1%). The response to IVIg was better in the case of newly diagnosed ITP (odds ratio (OR) = 5.4 (1.2-24.7)) and in presence of anti-GPIIb/IIIa (OR = 4.82 (1.08-21.5)), while secondary ITP had a poor response (OR = 0.1 (0.02-0.64)). In clinical practice, the determination of antiplatelet antibodies is therefore of little value to predict the response to IVIg.

Glucocorticoids (GC) remain the gold standard of the treatment of giant cell arteritis provided objectives of GC-tapering are accurately followed: 15 to 20mg/day at 3 months, 10mg/day at 6 months, 5mg/day at 9-12 months and withdrawal between 12 and 18 months. In case of corticodependance at ≥7.5 mg/day of prednisone or intolerance to GC, a GCsparing therapy has to be introduced, mainly methotrexate or tocilizumab. Individual characteristics of each patient, data about the efficacy of the treatment, its cost and how easy the follow-up under this treatment is are important factors to consider for choosing the right GC-sparing therapy. For all these reasons, except particular situations, we prefer using methotrexate before tocilizumab. Prevention of cardiovascular events is an important aspect of the treatment of GCA. We recommend using aspirin (75-100mg/day) during the first month of treatment or longer in case of occurrence of an ischemic complication. Each patient treated for GCA should receive a prevention of osteoporosis with respect of usual recommendations., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)