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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.)

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.)

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.)

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.)

Background: Effective and safe therapies are needed for the treatment of patients with giant cell arteritis (GCA). Emerging as a key cytokine in inflammation, granulocyte-macrophage colony stimulating factor (GM-CSF) may play a role in promoting inflammation in GCA., Objectives: To investigate expression of GM-CSF and its receptor in arterial lesions from patients with GCA. To analyse activation of GM-CSF receptor-associated signalling pathways and expression of target genes. To evaluate the effects of blocking GM-CSF receptor α with mavrilimumab in ex vivo cultured arteries from patients with GCA., Methods: Quantitative real time PCR, in situ RNA hybridisation, immunohistochemistry, immunofluorescence and confocal microscopy, immunoassay, western blot and ex vivo temporal artery culture., Results: GM-CSF and GM-CSF receptor α mRNA and protein were increased in GCA lesions; enhanced JAK2/STAT5A expression/phosphorylation as well as increased expression of target genes CD83 and Spi1/PU.1 were observed. Treatment of ex vivo cultured GCA arteries with mavrilimumab resulted in decreased transcripts of CD3ε, CD20, CD14 and CD16 cell markers, and reduction of infiltrating CD16 and CD3ε cells was observed by immunofluorescence. Mavrilimumab reduced expression of molecules relevant to T cell activation (human leukocyte antigen-DR [HLA-DR]) and Th1 differentiation (interferon-γ), the pro-inflammatory cytokines: interleukin 6 (IL-6), tumour necrosis factor α (TNFα) and IL-1β, as well as molecules related to vascular injury (matrix metalloprotease 9, lipid peroxidation products and inducible nitric oxide synthase [iNOS]). Mavrilimumab reduced CD34 + cells and neoangiogenesis in GCA lesions., Conclusion: The inhibitory effects of mavrilimumab on multiple steps in the GCA pathogenesis cascade in vitro are consistent with the clinical observation of reduced GCA flares in a phase 2 trial and support its development as a therapeutic option for patients with GCA., Competing Interests: Competing interests: SM, AJ and AD’A report employment by Kiniksa Pharmaceuticals Corp. during development of the manuscript. KB and JFP report current employment by Kiniksa Pharmaceuticals Corp. MCC reports consulting fees from GSK, Abbvie, Vifor and Janssen, and a research grant from Kiniksa Pharmaceuticals Corp. GE-F reports consulting fees from Janssen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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.)

Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B-T-cell synapses, leading to an inefficient cross talk between FL cells and the supportive T-follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T-regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling, we uncovered that FL-FDC and FL-macrophage cocultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials., (© 2020 by The American Society of Hematology.)

Background: Giant-cell arteritis (GCA) is considered a T helper (Th)1- and Th17-mediated disease. Interleukin (IL)-12 is a heterodimeric cytokine (p35/p40) involved in Th1 differentiation. When combining with p19 subunit, p40 compose IL-23, a powerful pro-inflammatory cytokine that maintains Th17 response., Objectives: The aims of this study were to investigate p40, p35, and p19 subunit expression in GCA lesions and their combinations to conform different cytokines, to assess the effect of glucocorticoid treatment on subunit expression, and to explore functional roles of p40 by culturing temporal artery sections with a neutralizing anti-human IL-12/IL-23p40 antibody., Methods and Results: p40 and p19 mRNA concentrations measured by real-time RT-PCR were significantly higher in temporal arteries from 50 patients compared to 20 controls (4.35 ± 4.06 vs 0.51 ± 0.75; p  < 0.0001 and 20.32 ± 21.78 vs 4.17 ± 4.43 relative units; p  < 0.0001, respectively). No differences were found in constitutively expressed p35 mRNA. Contrarily, p40 and p19 mRNAs were decreased in temporal arteries from 16 treated GCA patients vs those from 34 treatment-naïve GCA patients. Accordingly, dexamethasone reduced p40 and p19 expression in cultured arteries. Subunit associations to conform IL-12 and IL-23 were confirmed by proximity-ligation assay in GCA lesions. Immunofluorescence revealed widespread p19 and p35 expression by inflammatory cells, independent from p40. Blocking IL-12/IL-23p40 tended to reduce IFNγ and IL-17 mRNA production by cultured GCA arteries and tended to increase Th17 inducers IL-1β and IL-6., Conclusion: IL-12 and IL-23 heterodimers are increased in GCA lesions and decrease with glucocorticoid treatment. p19 and p35 subunits are much more abundant than p40, indicating an independent role for these subunits or their potential association with alternative subunits. The modest effect of IL-12/IL-23p40 neutralization may indicate compensation by redundant cytokines or cytokines resulting from alternative combinations.

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the two main large vessel vasculitides. They share some similarities regarding their clinical, radiological and histological presentations but some pathogenic processes in GCA and TAK are activated differently, thus explaining their different sensitivity to biological therapies. The treatment of GCA and TAK essentially relies on glucocorticoids. However, thanks to major progress in our understanding of their pathogenesis, the role of biological therapies in the treatment of these two vasculitides is expanding, especially in relapsing or refractory diseases. In this review, the efficacy, the safety and the limits of the main biological therapies ever tested in GCA and TAK are discussed. Briefly, anti TNF-α agents appear to be effective in treating TAK but not GCA. Recent randomized placebo-controlled trials have reported on the efficacy and safety of abatacept and mostly tocilizumab in inducing and maintaining remission of GCA. Abatacept was not effective in TAK and robust data are still lacking to draw any conclusions concerning the use of tocilizumab in TAK. Furthermore, ustekinumab appears promising in relapsing/refractory GCA whereas rituximab has been reported to be effective in only a few cases of refractory TAK patients. If a biological therapy is indicated, and in light of the data discussed in this review, the first choice would be tocilizumab in GCA and anti-TNF-α agents (mainly infliximab) in TAK., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, tissue inflammation and remodelling. We explored the role of serum OPN (sOPN) as a biomarker in patients with giant cell arteritis (GCA)., Methods: sOPN was measured by immunoassay in 76 treatment-naïve patients with GCA and 25 age-matched and sex-matched controls. In 36 patients, a second measurement was performed after 1 year of glucocorticoid treatment. Baseline clinical and laboratory findings, as well as relapses and glucocorticoid requirements during follow-up, were prospectively recorded. sOPN and C reactive protein (CRP) were measured in 32 additional patients in remission treated with glucocorticoids or tocilizumab (interleukin 6 (IL-6) receptor antagonist). In cultured temporal arteries exposed and unexposed to tocilizumab, OPN mRNA expression and protein production were measured by reverse transcription polymerase chain reaction (RT-PCR) and immunoassay, respectively., Results: sOPN concentration (ng/mL; mean±SD) was significantly elevated in patients with active disease (116.75±65.61) compared with controls (41.10±22.65; p<0.001). A significant decline in sOPN was observed in paired samples as patients entered disease remission (active disease 102.45±57.72, remission 46.47±23.49; p<0.001). sOPN correlated with serum IL-6 (r=0.55; p<0.001). Baseline sOPN concentrations were significantly higher in relapsing versus non-relapsing patients (relapsers 129.08±74.24, non-relapsers 90.63±41.02; p=0.03). OPN mRNA expression and protein production in cultured arteries were not significantly modified by tocilizumab. In tocilizumab-treated patients, CRP became undetectable, whereas sOPN was similar in patients in tocilizumab-maintained (51.91±36.25) or glucocorticoid-maintained remission (50.65±23.59; p=0.49)., Conclusions: sOPN is a marker of disease activity and a predictor of relapse in GCA. Since OPN is not exclusively IL-6-dependent, sOPN might be a suitable disease activity biomarker in tocilizumab-treated patients., Competing Interests: Competing interests: GE-F, SP-G, JH-R, SHU and MCC have participated in the GiACTA trial sponsored by Hoffmann-La Roche. MCC has received consultation fees from Hoffman-La Roche.

Background: Giant-cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries, frequently involving the temporal arteries (TA). Inflammation-induced vascular remodelling leads to vaso-occlusive events. Circulating endothelin-1 (ET-1) is increased in patients with GCA with ischaemic complications suggesting a role for ET-1 in vascular occlusion beyond its vasoactive function., Objective: To investigate whether ET-1 induces a migratory myofibroblastic phenotype in human TA-derived vascular smooth muscle cells (VSMC) leading to intimal hyperplasia and vascular occlusion in GCA., Methods and Results: Immunofluorescence/confocal microscopy showed increased ET-1 expression in GCA lesions compared with control arteries. In inflamed arteries, ET-1 was predominantly expressed by infiltrating mononuclear cells whereas ET receptors, particularly ET-1 receptor B (ET B R), were expressed by both mononuclear cells and VSMC. ET-1 increased TA-derived VSMC migration in vitro and α-smooth muscle actin (αSMA) expression and migration from the media to the intima in cultured TA explants. ET-1 promoted VSMC motility by increasing activation of focal adhesion kinase (FAK), a crucial molecule in the turnover of focal adhesions during cell migration. FAK activation resulted in Y397 autophosphorylation creating binding sites for Src kinases and the p85 subunit of PI3kinases which, upon ET-1 exposure, colocalised with FAK at the focal adhesions of migrating VSMC. Accordingly, FAK or PI3K inhibition abrogated ET-1-induced migration in vitro. Consistently, ET-1 receptor A and ET B R antagonists reduced αSMA expression and delayed VSMC outgrowth from cultured GCA-involved artery explants., Conclusions: ET-1 is upregulated in GCA lesions and, by promoting VSMC migration towards the intimal layer, may contribute to intimal hyperplasia and vascular occlusion in GCA., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Giant cell arteritis (GCA) is a granulomatous vasculitis affecting large arteries, especially the aorta and the extracranial branches of the external carotid artery. Its exact pathogenesis is not fully understood but major progress has been made in recent years, leading to new therapeutic targets like inhibition of the interleukin-6 pathway or the modulation of immune checkpoints. The cause of GCA has not been clearly identified but it is thought that GCA occurs on a genetic background and is triggered by unknown environmental factors that could activate and lead to the maturation of dendritic cells localized in the adventitia of normal arteries. These activated dendritic cells then produce chemokines which trigger the recruitment of CD4 + T cells, which in turn become activated, proliferate and polarize into Th1 and Th17 cells, which produce IFN-γ and IL-17, respectively. Exposed to IFN-γ, endothelial cells and vascular smooth muscle cells produce chemokines leading to the recruitment of further Th1 cells, CD8 + T cells and monocytes. The latter differentiate into macrophages, which, when persistently exposed to IFN-γ, form giant cells, the histological hallmark of GCA. With the contribution of vascular smooth muscle cells, immune cells then trigger the destruction and remodeling of the arterial wall, thus leading to the formation of a neo-intima resulting in progressive occlusion of the arterial lumen, which is responsible for the ischemic symptoms of GCA. In this paper, we review recent progress in our understanding of GCA pathogenesis in the fields of genetics, epigenetics, infections, immunology and vascular remodeling., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Interferon γ (IFNγ) is considered a seminal cytokine in the pathogenesis of giant cell arteritis (GCA), but its functional role has not been investigated. We explored changes in infiltrating cells and biomarkers elicited by blocking IFNγ with a neutralising monoclonal antibody, A6, in temporal arteries from patients with GCA., Methods: Temporal arteries from 34 patients with GCA (positive histology) and 21 controls were cultured on 3D matrix (Matrigel) and exposed to A6 or recombinant IFNγ. Changes in gene/protein expression were measured by qRT-PCR/western blot or immunoassay. Changes in infiltrating cells were assessed by immunohistochemistry/immunofluorescence. Chemotaxis/adhesion assays were performed with temporal artery-derived vascular smooth muscle cells (VSMCs) and peripheral blood mononuclear cells (PBMCs)., Results: Blocking endogenous IFNγ with A6 abrogated STAT-1 phosphorylation in cultured GCA arteries. Furthermore, selective reduction in CXCL9, CXCL10 and CXCL11 chemokine expression was observed along with reduction in infiltrating CD68 macrophages. Adding IFNγ elicited consistent opposite effects. IFNγ induced CXCL9, CXCL10, CXCL11, CCL2 and intracellular adhesion molecule-1 expression by cultured VSMC, resulting in increased PBMC chemotaxis/adhesion. Spontaneous expression of chemokines was higher in VSMC isolated from GCA-involved arteries than in those obtained from controls. Incubation of IFNγ-treated control arteries with PBMC resulted in adhesion/infiltration by CD68 macrophages, which did not occur in untreated arteries., Conclusions: Our ex vivo system suggests that IFNγ may play an important role in the recruitment of macrophages in GCA by inducing production of specific chemokines and adhesion molecules. Vascular wall components (ie, VSMC) are mediators of these functions and may facilitate progression of inflammatory infiltrates through the vessel wall., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Giant cell arteritis (GCA) is a relapsing disease. However, the nature, chronology, therapeutic impact, and clinical consequences of relapses have been scarcely addressed. We conducted the present study to investigate the prevalence, timing, and characteristics of relapses in patients with GCA and to analyze whether a relapsing course is associated with disease-related complications, increased glucocorticoid (GC) doses, and GC-related adverse effects. The study cohort included 106 patients, longitudinally followed by the authors for 7.8 ± 3.3 years. Relapses were defined as reappearance of disease-related symptoms requiring treatment adjustment. Relapses were classified into 4 categories: polymyalgia rheumatica (PMR), cranial symptoms (including ischemic complications), systemic disease, or symptomatic large vessel involvement. Cumulated GC dose during the first year of treatment, time required to achieve a maintenance prednisone dose <10 mg/d (T10), <5 mg/d (T5), or complete prednisone discontinuation (T0), and GC-related side effects were recorded. Sixty-eight patients (64%) experienced at least 1 relapse, and 38 (36%) experienced 2 or more. First relapse consisted of PMR in 51%, cranial symptoms in 31%, and systemic complaints in 18%. Relapses appeared predominantly, but not exclusively, within the first 2 years of treatment, and only 1 patient developed visual loss. T10, T5, and T0 were significantly longer in patients with relapses than in patients without relapse (median, 40 vs 27 wk, p  < 0.0001; 163 vs 89.5 wk, p = 0.004; and 340 vs 190 wk, p = 0.001, respectively). Cumulated prednisone dose during the first year was significantly higher in relapsing patients (6.2 ± 1.7 g vs 5.4 ± 0.78 g, p = 0.015). Osteoporosis was more common in patients with relapses compared to those without (65% vs 32%, p = 0.001). In conclusion, the results of the present study provide evidence that a relapsing course is associated with higher and prolonged GC requirements and a higher frequency of osteoporosis in GCA.

Background: Search for therapeutic targets in giant-cell arteritis (GCA) is hampered by the scarcity of functional systems. We developed a new model consisting of temporal artery culture in tri-dimensional matrix and assessed changes in biomarkers induced by glucocorticoid treatment., Methods: Temporal artery sections from 28 patients with GCA and 22 controls were cultured in Matrigel for 5 days in the presence or the absence of dexamethasone. Tissue mRNA concentrations of pro-inflammatory mediators and vascular remodelling molecules was assessed by real-time RT-PCR. Soluble molecules were measured in the supernatant fluid by immunoassay., Results: Histopathological features were exquisitely preserved in cultured arteries. mRNA concentrations of pro-inflammatory cytokines (particularly IL-1β and IFNγ), chemokines (CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES) and MMP-9 as well as IL-1β and MMP-9 protein concentrations in the supernatants were significantly higher in cultured arteries from patients compared with control arteries. The culture system itself upregulated expression of cytokines and vascular remodelling factors in control arteries. This minimised differences between patients and controls but underlines the relevance of changes observed. Dexamethasone downregulated pro-inflammatory mediator (IL-1β, IL-6, TNFα, IFNγ, MMP-9, TIMP-1, CCL3 and CXCL8) mRNAs but did not modify expression of vascular remodelling factors (platelet derived growth factor, MMP-2 and collagens I and III)., Conclusions: Differences in gene expression in temporal arteries from patients and controls are preserved during temporal artery culture in tri-dimensional matrix. Changes in biomarkers elicited by glucocorticoid treatment satisfactorily parallel results obtained in vivo. This may be a suitable model to explore pathogenetic pathways and to perform preclinical studies with new therapeutic agents.

Background: Interleukin 17A (IL-17A) exerts pivotal proinflammatory functions in chronic inflammatory and autoimmune diseases., Objective: To investigate IL-17A expression in temporal artery lesions from patients with giant-cell arteritis (GCA), and its relationship with disease outcome., Methods: Fifty-seven patients with biopsy-proven GCA were prospectively evaluated, treated and followed for 4.5 years (52-464 weeks). Relapses, time (weeks) required to achieve a maintenance prednisone dose <10 mg/day, and time (weeks) to complete prednisone withdrawal were prospectively recorded. IL-17A mRNA was measured by real-time quantitative RT-PCR in temporal arteries from all patients and 19 controls. IL-17 protein expression was assessed by immunohistochemistry/immunofluorescence., Results: IL-17A expression was significantly increased in temporal artery samples from GCA patients compared with controls (6.22±8.61 vs 2.50±3.9 relative units, p=0.016). Surprisingly, patients with strong IL-17A expression tended to experience less relapses, and required significantly shorter treatment periods (median 25 vs 44 weeks to achieve <10 mg prednisone/day, p=0.0079). There was no correlation between IL-17A and RORc or RORα expression suggesting that these transcription factors may not exclusively reflect Th17 differentiation, and that cells other than Th17 cells might contribute to IL-17 expression in active patients. Accordingly, FoxP3(+)IL-17A(+) cells were identified in lesions by confocal microscopy and were dramatically reduced in specimens from treated patients., Conclusions: IL-17A expression is increased in GCA lesions, and is a predictor of response to glucocorticoid treatment. The contribution of FoxP3+ cells to IL-17A production in untreated patients suggests that induced-Tregs may facilitate disease remission when proinflammatory cytokine production is downregulated by glucocorticosteroids.

Objective: To assess local expression and plasma levels of pentraxin 3 (PTX3) in patients with giant cell arteritis (GCA)., Methods: Plasma and serum samples were obtained from 75 patients with GCA (20 of whom had experienced optic nerve ischemia in the previous 3 weeks and 24 of whom had experienced symptom onset in the previous 6 months and had no history of optic nerve ischemia) and 63 controls (35 age-matched healthy subjects, 15 patients with rheumatoid arthritis, and 13 patients with chronic stable angina). In 9 patients in whom GCA was recently diagnosed, circulating levels of interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12p70, CCL2/monocyte chemotactic protein 1, CCL3/macrophage inflammatory protein 1α (MIP-1α), CCL4/MIP-1β, CCL11/eotaxin, CXCL9/monokine induced by interferon-γ, CXCL10/interferon-γ-inducible 10-kd protein, tumor necrosis factor α (TNFα), interferon-γ, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor, and FasL were measured via a multiplexed cytometric assay. PTX3 and VEGF concentrations were assessed by enzyme-linked immunosorbent assay. PTX3 and CD68 expression were determined by immunohistochemistry and immunofluorescence on temporal artery samples., Results: GCA patients with very recent optic nerve ischemia had significantly higher PTX3 and VEGF levels compared to other GCA patients and controls. GCA patients with a disease duration of <6 months had significantly higher PTX3 levels compared to other GCA patients and controls. Immunohistochemistry revealed selective PTX3 expression in the wall of inflamed arteries., Conclusion: Our findings indicate that local expression of PTX3 is a feature of vascular inflammation in GCA; elevated circulating levels of PTX3 identify patients with very recent optic nerve ischemia or a recent diagnosis. Optic nerve ischemia is also associated with increased circulating VEGF levels., (Copyright © 2012 by the American College of Rheumatology.)

Background: Thalidomide and its analogs are effective agents in the treatment of multiple myeloma. Since gelatinases (matrix metalloproteinases-2 and -9) play a crucial role in tumor progression, we explored the effect of thalidomide on gelatinase production by malignant B lymphoid cell lines., Design and Methods: We investigated the effect of therapeutic doses of thalidomide on integrin-mediated production of gelatinases by malignant B lymphoid cell lines by gelatin zymography, western-blot, reverse transcriptase polymerase chain reaction and invasive capacity through Matrigel-coated Boyden chambers. We also explored the effect of thalidomide on the activation status of the main signaling pathways involved in this process., Results: Thalidomide strongly inhibited gelatinase production by B-cell lines and primary myeloma cells in response to fibronectin, the most efficient gelatinase inducer identified in lymphoid cells. Thalidomide disrupted integrin-mediated signaling pathways involved in gelatinase induction and release, such as Src and MAP-kinase ERK activation, resulting in decreased cell motility and invasiveness. Unexpectedly, treatment with thalidomide elicited an increase in fibronectin-induced Akt phosphorylation through phosphoinositide 3-kinase-independent pathways since thalidomide decreased fibronectin-induced phosphoinositide 3-kinase phosphorylation and reversed the inhibition of Akt phosphorylation achieved by the phosphoinositide 3-kinase inhibitors wortmannin and LY294002., Conclusions: Disruption of integrin-mediated signaling may be an important mechanism through which thalidomide and its analogs impair tumor cell interactions with the microenvironment. The unexpected effects of thalidomide on Akt activation indicate the need for further studies to elucidate whether the interference with Akt downstream effects would synergize with the anti-tumor activity of thalidomide.

Hyperkinetic movements in amyotrophic lateral sclerosis (ALS) are extremely rare. We present clinical, neuropathological, and genetic data for a 53-year-old woman with spinal onset ALS presenting chorea affecting the face, mouth, neck, and hands, and ballism in both arms 31 months after leg weakness onset. Her father and older sister had ALS, but had no movement disorders. As well as the typical neuropathological findings of ALS (marked upper and lower motor neuron loss), post-mortem examination showed prominent neuronal loss and gliosis in the subthalamus, and in the internal globus pallidus, substantia nigra pars compacta, and red nucleus. No abnormalities were found in the caudate, putamen, and thalamus. No defects were found in the SOD1, HD, and DRPLA genes. These data support the idea that choreo-ballism in ALS Plus may be the result of pallido-luyso-rubro-nigral atrophy, despite not being the result of concomitant DRPLA based on neuropathological and genetic criteria., (2007 Movement Disorder Society)

Objective: The effect of the number of copies in the SMN1 and SMN2 genes - the most extensively studied susceptibility and modifying genetic factors in adult onset motor neuron diseases - as a genetic risk factor for Hirayama's disease (HirD) has never been studied. The purpose of this study was to investigate the influence of the number of copies of the SMN1/SMN2 genes on the resulting phenotype in 13 HirD Spanish patients., Patients and Methods: We performed a qualitative and quantitative SMN1/SMN2 gene analysis in 13 unrelated HirD patients. The phenotype-genotype correlation was investigated, paying particular attention to the effect of the SMN1/SMN2 copy number on the disease's phenotype., Results: No patient had a homozygous deletion of the SMN1 or SMN2. No differences were found when comparing the SMN1 and SMN2 copy number distributions of the healthy population and HirD patients, and they do not therefore appear to be a susceptibility factor. There was also no correlation found between the number of copies of the SMN1 and SMN2 and the severity of the resulting phenotype., Conclusion: Our results suggest that SMN1 and SMN2 are not predisposing factors for HirD and therefore support a lack of association between these genes and the resulting phenotype.

Background: SOD1 gene mutations are the most common identified cause of ALS, accounting for approximately 20% of familial ALS cases and around 4% of sporadic ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No previous epidemiological studies have been carried out in Catalonia., Objective: To determine the prevalence of SOD1 gene mutations in a Catalan ALS population, and to analyze the genotype-phenotype relationship., Materials and Methods: 30 different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1 mutations using direct sequence analysis., Results: Five of the 30 FALS pedigrees (16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R, D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1 mutations in our series was 6.45%. In the SALS group, D90A was identified in a patient presenting the typical Scandinavian phenotype. A 53-year-old woman with no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS cases carried the A140A SOD1 mutant., Conclusions: The prevalence of the SOD1 mutation in FALS in Catalonia is similar to levels in other Mediterranean countries, but lower than those in reports studying the Belgian, Japanese, and Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients with no family history of ALS. These results may have significant repercussions on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases must therefore be considered.