Central Nervous System Vasculitis: Still More Questions than Answers

The central nervous system (CNS) may be involved by a variety of inflammatory diseases of blood vessels. These include primary angiitis of the central nervous system (PACNS), a rare disorder specifically targeting the CNS vasculature, and the systemic vasculitides which may affect the CNS among other organs and systems. Both situations are severe and convey a guarded prognosis. PACNS usually presents with headache and cognitive impairment. Focal symptoms are infrequent at disease onset but are common in more advanced stages. The diagnosis of PACNS is difficult because, although magnetic resonance imaging is almost invariably abnormal, findings are non specific. Angiography has limited sensitivity and specificity. Brain and leptomeningeal biopsy may provide a definitive diagnosis when disclosing blood vessel inflammation and are also useful to exclude other conditions presenting with similar findings. However, since lesions are segmental, a normal biopsy does not completely exclude PACNS. Secondary CNS involvement by systemic vasculitis occurs in less than one fifth of patients but may be devastating. A prompt recognition and aggressive treatment is crucial to avoid permanent damage and dysfunction. Glucocorticoids and cyclophosphamide are recommended for patients with PACNS and for patients with secondary CNS involvement by small-medium-sized systemic vasculitis. CNS involvement in large-vessel vasculitis is usually managed with high-dose glucocorticoids (giant-cell arteritis) or glucocorticoids and immunosuppressive agents (Takayasu’s disease). However, in large vessel vasculitis, where CNS symptoms are usually due to involvement of extracranial arteries (Takayasu’s disease) or proximal portions of intracranial arteries (giant-cell arteritis), revascularization procedures may also have an important role

Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids

Objectives Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis. Methods We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls. Results We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2. Conclusion Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment

Methylation and Transcriptome Signatures of Monocytes Reveal Novel Pathways Involved in Giant Cell Arteritis Pathogenesis.

Congresos y Conferencias: Comunicación de Congreso - Oral

Transcriptomic and methylomic profiling of CD4+ T-cells in giant cell arteritis with different disease activity.

Comunicación, Congreso, Póster

Relapses in patients with giant-cell arteritis: prevalence, characteristics and associated clinical findings in a longitudinally followed cohort of 106 patients.

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

Blocking GM-CSF receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers and neoangiogenesis in ex vivo cultured arteries from patients with giant cell arteritis

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.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.Quantitative real time PCR, in situ RNA hybridisation, immunohistochemistry, immunofluorescence and confocal microscopy, immunoassay, western blot and ex vivo temporal artery culture.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.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.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ

Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids.

Objectives: Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis. Methods: We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls. Results: We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2. Conclusion: Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment.We thank all the patients and control donors who participated in this study and Sofia Vargas and Gema Robledo for her excellent technical assistance. This research is part of the doctoral degree awarded by E.E.M, within the Biomedicine programme from the University de Granada entitled 'Estudio de las causas moleculares de la arteritis de células gigantes mediante una aproximación sistémica'

LOS PERFILES DE METILACIÓN Y EXPRESIÓN GÉNICA DE MONOCITOS REVELAN NUEVAS VÍAS IMPLICADAS EN LA PATOGÉNESIS DE LA ARTERITIS DE CÉLULAS.

Congresos y Conferencias: Comunicación de Congreso - Póster

Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis

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 (ET1) 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 TAderived 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 (ETB 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 ETB 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