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Rheumatology (Oxford, England) Sep 2023
Topics: Humans; Giant Cell Arteritis; Ultrasonography; Takayasu Arteritis
PubMed: 36951506
DOI: 10.1093/rheumatology/kead134 -
Neuroimaging Clinics of North America Feb 2024Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by the accumulation of amyloid-beta peptide (Aβ) within the leptomeninges and smaller blood... (Review)
Review
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by the accumulation of amyloid-beta peptide (Aβ) within the leptomeninges and smaller blood vessels of the brain. CAA can be both noninflammatory and inflammatory, and the inflammatory version includes Aβ-related angiitis (ABRA). ABRA is a vasculitis of the central nervous system related to an inflammatory response to Aβ in the vascular walls, which necessitates differentiating ABRA from noninflammatory CAA, as ABRA may require immunosuppressive treatment. MR imaging is typically the most effective imaging modality of choice to screen for these conditions, and they should be obtained at varying time points to track disease progression.
Topics: Humans; Amyloid beta-Peptides; Cerebral Amyloid Angiopathy; Vasculitis; Brain; Arteritis
PubMed: 37951701
DOI: 10.1016/j.nic.2023.09.001 -
Clinical Rheumatology Aug 2023
Topics: Humans; Hypertension, Pulmonary; Takayasu Arteritis; Pulmonary Artery; Heart Septal Defects, Atrial
PubMed: 37093404
DOI: 10.1007/s10067-023-06607-7 -
Clinical Immunology (Orlando, Fla.) Oct 2023Markers of extracellular mitochondria are present in giant cell arteritis (GCA) patients. However, their role in promoting inflammation and platelet activation is no...
Markers of extracellular mitochondria are present in giant cell arteritis (GCA) patients. However, their role in promoting inflammation and platelet activation is no known. To investigate this, isolated mitochondria were opsonized with plasma from GCA patients or healthy individuals and incubated with peripheral blood mononuclear cells (PBMCs) or platelets and assessed for inflammatory cytokine production and platelet activation. Plasma from GCA patients promoted increased mitochondrial-mediated cytokine production by PBMCs as compared to healthy controls (p < 0.05). Mitochondria opsonized with plasma factors from patients with GCA induced higher platelet activation as compared to mitochondria opsonized with plasma factors from healthy individuals (p = 0.0015). Platelet levels of P-selectin were associated with disease activity in GCA (r = 0.34, p = 0.01). GCA patients have impaired ability to regulate the clearance of extracellular mitochondria, possibly contributing to excessive inflammation and platelet activation. Targeting key drivers of mitochondrial extrusion and/or their clearance could lead to new therapeutic interventions in GCA.
Topics: Humans; Giant Cell Arteritis; Leukocytes, Mononuclear; Inflammation; Platelet Activation; Cytokines
PubMed: 37625669
DOI: 10.1016/j.clim.2023.109746 -
The Lancet. Rheumatology Dec 2023Medium-dose glucocorticoids can improve symptoms in nearly all patients with polymyalgia rheumatica. According to its good safety profile, abatacept could be used... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Medium-dose glucocorticoids can improve symptoms in nearly all patients with polymyalgia rheumatica. According to its good safety profile, abatacept could be used instead of glucocorticoids in early polymyalgia rheumatica. We aimed to determine whether the efficacy of abatacept is sufficient to justify larger studies in early polymyalgia rheumatica.
METHODS
To evaluate whether abatacept allows low disease activity without glucocorticoids in early polymyalgia rheumatica, we conducted a proof-of-concept, randomised, double-blind, placebo-controlled, parallel-group trial. Participants were recruited from five centres in France (in Brest, Le Mans, Morlaix, Dinan and Saint Malo, and Strasbourg) and were included if they had recent-onset (<6 months) polymyalgia rheumatica with a C-reactive protein (CRP) polymyalgia rheumatica activity score (PMR-AS) of more than 17 without any signs or symptoms of giant cell arteritis (clinical and [F]fluorodeoxyglucose PET-CT evaluation). Participants were randomly assigned (1:1) to receive weekly subcutaneous abatacept (125 mg) or matching placebo, with glucocorticoid rescue therapy allowed in cases of high disease activity, for 12 weeks, and then glucocorticoid treatment based on disease activity, until week 36. Investigators, patients, outcome assessors, and sponsor personnel were masked to group assignments. The primary endpoint was low disease activity (CRP PMR-AS ≤10) at week 12 without glucocorticoids and without rescue treatment. The study was powered to demonstrate a 60% difference in response rates between groups. Open-ended adverse events were collected at each visit by clinicians and were categorised following system organ class classification after study completion. The ALORS trial is registered with ClinicalTrials.gov, NCT03632187.
FINDINGS
34 patients (22 women and 12 men) were randomly assigned between Dec 13, 2018, and Oct 21, 2021. All patients who had been randomly assigned were included in the analysis. The primary endpoint was reached by eight (50%) of 16 patients in the abatacept group and four (22%) of 18 patients in the placebo group (relative risk 2·2 [0·9-5·5]); crude p=0·15; adjusted p=0·070). Eight (50%) patients in the abatacept and 15 (83%) in the placebo group had adverse events. Four patients (one [6%] in the abatacept group and three [17%] in the placebo group) had serious adverse events. There were no deaths or new safety concerns.
INTERPRETATION
This study suggests that the effect of abatacept alone is not strong enough to justify larger studies in early polymyalgia rheumatica. This is only a first step in deciding whether a larger study should be conducted in early polymyalgia rheumatica and does not exclude a potential effect of abatacept in glucocorticoid-dependent polymyalgia rheumatica.
FUNDING
BMS Pharma France.
Topics: Female; Humans; Male; Abatacept; C-Reactive Protein; Giant Cell Arteritis; Glucocorticoids; Polymyalgia Rheumatica; Positron Emission Tomography Computed Tomography; Proof of Concept Study
PubMed: 38251563
DOI: 10.1016/S2665-9913(23)00246-1 -
International Journal of Rheumatic... Nov 2023
Topics: Humans; Polyarteritis Nodosa; Hemorrhage
PubMed: 37540086
DOI: 10.1111/1756-185X.14839 -
Rheumatology (Oxford, England) Sep 2023
Topics: Humans; Takayasu Arteritis; Infant; Child, Preschool
PubMed: 36975614
DOI: 10.1093/rheumatology/kead131 -
CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.JCI Insight Aug 2023Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with...
Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed proinflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase-ANCA (MPO-ANCA) titers with a reduction in NET formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.
Topics: Humans; Mice; Animals; Extracellular Traps; Antibodies, Antineutrophil Cytoplasmic; CD47 Antigen; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Glomerulonephritis; Granulomatosis with Polyangiitis; Mucocutaneous Lymph Node Syndrome; Giant Cell Arteritis
PubMed: 37368493
DOI: 10.1172/jci.insight.167486 -
The Lancet. Rheumatology Jun 2024Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci.
METHODS
We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings.
FINDINGS
We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10).
INTERPRETATION
We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis.
FUNDING
Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.
Topics: Giant Cell Arteritis; Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Genetic Loci; Female; Male; Aged; Polymorphism, Single Nucleotide; Middle Aged; Case-Control Studies
PubMed: 38734017
DOI: 10.1016/S2665-9913(24)00064-X -
Rheumatic Diseases Clinics of North... Nov 2023Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by biallelic mutations in the adenosine deaminase 2 gene. The diagnosis of DADA2 is... (Review)
Review
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by biallelic mutations in the adenosine deaminase 2 gene. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. Symptoms range from cutaneous vasculitis and polyarteritis nodosa-like lesions to stroke. The vasculopathy of DADA2 can affect many organ systems, including the gastrointestinal and renal systems. Hematologic manifestations occur early with hypogammaglobulinemia, lymphopenia, pure red cell aplasia, or pancytopenia. Treatment can be challenging. Tumor necrosis factor inhibitors are helpful to control inflammatory symptoms. Hematopoietic stem cell transplant may be needed to treat refractory cytopenias, vasculopathy, or immunodeficiency.
Topics: Humans; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Polyarteritis Nodosa; Vasculitis; Mutation
PubMed: 37821195
DOI: 10.1016/j.rdc.2023.06.004