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Aging Jun 2024Estrogen is thought to have a role in slowing down aging and protecting cardiovascular and cognitive function. However, high doses of estrogen are still positively...
High estrogen induces trans-differentiation of vascular smooth muscle cells to a macrophage-like phenotype resulting in aortic inflammation via inhibiting VHL/HIF1a/KLF4 axis.
Estrogen is thought to have a role in slowing down aging and protecting cardiovascular and cognitive function. However, high doses of estrogen are still positively associated with autoimmune diseases and tumors with systemic inflammation. First, we administered exogenous estrogen to female mice for three consecutive months and found that the aorta of mice on estrogen develops inflammatory manifestations similar to Takayasu arteritis (TAK). Then, estrogen intervention was performed on mouse aortic vascular smooth muscle cells (MOVAS cells). Stimulated by high concentrations of estradiol, MOVAS cells showed decreased expression of contractile phenotypic markers and increased expression of macrophage-like phenotypic markers. This shift was blocked by tamoxifen and Krüppel-like factor 4 (KLF4) inhibitors and enhanced by Von Hippel-Lindau (VHL)/hypoxia-inducible factor-1α (HIF-1α) interaction inhibitors. It suggests that estrogen-targeted regulation of the VHL/HIF-1α/KLF4 axis induces phenotypic transformation of vascular smooth muscle cells (VSMC). In addition, estrogen-regulated phenotypic conversion of VSMC to macrophages is a key mechanism of estrogen-induced vascular inflammation, which justifies the risk of clinical use of estrogen replacement therapy.
Topics: Kruppel-Like Factor 4; Animals; Kruppel-Like Transcription Factors; Macrophages; Mice; Hypoxia-Inducible Factor 1, alpha Subunit; Muscle, Smooth, Vascular; Female; Estrogens; Von Hippel-Lindau Tumor Suppressor Protein; Myocytes, Smooth Muscle; Cell Transdifferentiation; Phenotype; Aorta; Inflammation
PubMed: 38843385
DOI: 10.18632/aging.205904 -
Frontiers in Medicine 2024Giant cell arteritis (GCA) is characterized by inflammation of large and medium vessels. First-line therapy for the treatment of GCA are glucocorticoids, which are...
BACKGROUND
Giant cell arteritis (GCA) is characterized by inflammation of large and medium vessels. First-line therapy for the treatment of GCA are glucocorticoids, which are effective while potential adverse effects should be considered, especially during long-term use. The aim was to investigate the incidence of glucocorticoids' adverse effects and potential predictors for them.
MATERIALS AND METHODS
138 GCA patients were retrospectively evaluated for newly developed glucocorticoid adverse effects in 2020. Potential predictors, defined as initial glucocorticoid pulse therapy, relapse of GCA and concomitant polymyalgia rheumatica as well as parameters of inflammation and endothelial dysfunction, including pulse-wave velocity and intima-media-thickness, were measured in 2012.
RESULTS
Potential new glucocorticoid adverse effects per patient was 1 (25th-75th 0-3) of which chronic kidney disease progression (29%), bone fractures (23.2%), cataracts (18.1%), dementia, and arterial hypertension (each at 12.3%) were most commonly recorded. Significant associations were found between occurrence of any relapse and new diabetes mellitus and between initial glucocorticoid pulse therapy and new dementia (all with < 0.05). In multivariate regression analysis, any relapse was a predictor for developing diabetes mellitus (OR 9.23 [95% CI 1.33-64.05], = 0.025). However, no correlations were observed between endothelial dysfunction or inflammatory parameters and development of new glucocorticoid adverse effects.
CONCLUSION
GCA relapses may be associated for development of diabetes mellitus potentially by increasing glucocorticoid doses. Parameters of inflammation and endothelial dysfunction are not suited predictors for glucocorticoid adverse effects.
PubMed: 38841591
DOI: 10.3389/fmed.2024.1382946 -
Arthritis Research & Therapy Jun 2024A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus... (Review)
Review
BACKGROUND
A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature.
METHODS
Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted.
RESULTS
Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them.
CONCLUSIONS
This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).
Topics: Humans; Giant Cell Arteritis; Female; Janus Kinase Inhibitors; Aged; Male; Retrospective Studies; Recurrence; Treatment Outcome; Pyrimidines; Piperidines; Azetidines; Pyrazoles; Sulfonamides; Purines; Aged, 80 and over; Middle Aged; Heterocyclic Compounds, 3-Ring
PubMed: 38840219
DOI: 10.1186/s13075-024-03314-9 -
BMC Medical Imaging Jun 2024While early diagnosis of giant cell arteritis (GCA) based on clinical criteria and contrast-enhanced MRI findings can lead to early treatment and prevention of blindness...
BACKGROUND
While early diagnosis of giant cell arteritis (GCA) based on clinical criteria and contrast-enhanced MRI findings can lead to early treatment and prevention of blindness and cerebrovascular accidents, previously reported diagnostic methods which utilize contrast-enhanced whole head images are cumbersome. Diagnostic delay is common as patients may not be aware of initial symptoms and their significance. To improve current diagnostic capabilities, new MRI-based diagnostic criteria need to be established. This study aimed to evaluate the "multifocal arcuate sign" on short tau inversion recovery (STIR) and contrast-enhanced T1-weighted (CE-T1W) images as a novel extracranial finding for the diagnosis of GCA.
METHODS
A total of 17 consecutive patients (including five with GCA) who underwent CE-T1W and whole-brain axial STIR imaging simultaneously between June 2010 and April 2020 were enrolled. We retrospectively reviewed their MR images. The "multifocal arcuate sign" was defined as "multiple distant arcuate areas with high signal intensity in extracranial soft tissues such as subcutaneous fat, muscles, and tendons." Extracranial abnormal high-signal-intensity areas were classified as "None," when no lesions were detected; "Monofocal," when lesions were detected only in one place; and "Multifocal," when lesions were detected in multiple places. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of "Multifocal" areas were calculated using cross tabulation. Fisher's exact test was used to compare "Multifocal" areas in five patients with GCA and those with other diseases. In addition, mean Cohen's kappa and Fleiss' kappa statistics were used to compare inter-reader agreement.
RESULTS
The sensitivity, specificity, PPV, and NPV of the "multifocal arcuate sign" in patients with GCA were 60%, 92-100%, 75-100%, and 85-86%, respectively. Significantly more patients with GCA had "Multifocal" areas compared to those with other diseases (Fisher's exact test, p = 0.008-0.027). Mean Cohen's kappa and Fleiss' kappa for inter-reader agreement with respect to the five GCA patients were 0.52 and 0.49, respectively, for both STIR and CE-T1W sequences.
CONCLUSIONS
The new radiologic finding of "multifocal arcuate sign" on STIR and CE-T1W images may be used as a radiologic criterion for the diagnosis of GCA, which can make plain MRI a promising diagnostic modality.
Topics: Humans; Giant Cell Arteritis; Aged; Female; Male; Retrospective Studies; Magnetic Resonance Imaging; Contrast Media; Middle Aged; Sensitivity and Specificity; Aged, 80 and over
PubMed: 38840058
DOI: 10.1186/s12880-024-01314-4 -
Nature Jun 2024Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health. This is compounded by the limited efficacy of available treatments...
Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health. This is compounded by the limited efficacy of available treatments and high failure rates during drug development, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.
Topics: Female; Humans; Male; Anti-Inflammatory Agents; Cells, Cultured; Chromosomes, Human, Pair 21; Databases, Factual; Gene Expression Regulation; Genome-Wide Association Study; Genomics; Haplotypes; Inflammation; Inflammatory Bowel Diseases; Macrophages; Proto-Oncogene Protein c-ets-2; Reproducibility of Results; Tumor Necrosis Factors; Interleukin-23
PubMed: 38839969
DOI: 10.1038/s41586-024-07501-1 -
Cureus May 2024Giant-cell arteritis (GCA) is a type of vasculitis characterised by the presence of granulomas. It is the predominant form of systemic vasculitis in adults and primarily...
Giant-cell arteritis (GCA) is a type of vasculitis characterised by the presence of granulomas. It is the predominant form of systemic vasculitis in adults and primarily affects the larger arteries in individuals aged ≥ 50 years. GCA affects the major arteries, such as the aorta and its branches, particularly the outer branches of the external carotid artery. Signs and symptoms can be categorised into cranial, extracranial, and systemic manifestations. Patients with headaches, jaw claudication, and vision disturbances usually have extracranial branches of the external carotid artery. Aside from being the prevailing manifestation of GCA, our primary concern regarding this variant is the potential for irreversible vision loss if not properly identified and addressed. Conversely, the GCA can also affect other major blood vessels such as the aorta. Here, we present the case of a 70-year-old Caucasian female patient with cranial GCA who had experienced a temporal headache three years prior. The patient was successfully treated with prednisolone, which was gradually reduced to a very low level with the assistance of methotrexate. Recently, the patient presented with a dry cough that lasted for two months and elevated inflammatory markers. After thorough research, it was determined that there was no evidence of infection, including atypical infections, and that no abnormalities were found in the lungs. Ultimately, via an 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan, the patient was diagnosed with large vessel giant cell arteritis (LV-GCA). This impacted the aorta, carotid arteries, and subclavian arteries. The patient experienced notable improvement in her cough and a reduction in inflammatory markers after receiving a high dosage of oral prednisolone. This case exemplifies the unusual manifestation of LV-GCA and verifies that recurring symptoms may differ from the original presentation. While dry cough is not commonly listed as a symptom of LV-GCA, it can be present as a manifestation or the sole presentation in certain patients, particularly when inflammatory markers are consistently high and there is no pulmonary disease.
PubMed: 38836133
DOI: 10.7759/cureus.59686 -
Clinical Case Reports Jun 2024Timely recognition of atypical Takayasu arteritis is crucial. Unusual presentations, such as pericardial effusion, can complicate diagnosis. CT angiogram aids in precise...
KEY CLINICAL MESSAGE
Timely recognition of atypical Takayasu arteritis is crucial. Unusual presentations, such as pericardial effusion, can complicate diagnosis. CT angiogram aids in precise diagnosis, guiding targeted immunosuppressive therapy. Multidisciplinary collaboration is vital for comprehensive management, improving patient outcomes in this challenging condition.
ABSTRACT
This case study highlights the diagnostic challenges posed by atypical presentations of Takayasu arteritis (TA), focusing on a 42-year-old male presenting with pericardial effusion. Despite inconclusive initial investigations, a CT angiogram revealed large vessel vasculitis, confirming TA. Management with immunosuppressive therapy led to clinical improvement. This case emphasize the importance of recognizing unusual manifestations of TA for timely diagnosis and appropriate treatment, emphasizing the role of multidisciplinary collaboration in optimizing patient outcomes.
PubMed: 38836110
DOI: 10.1002/ccr3.9051 -
JTCVS Techniques Apr 2024Mid-aortic syndrome is a rare condition characterized by severe aortic narrowing, leading to high upper body blood pressure and organ hypoperfusion, necessitating...
OBJECTIVES
Mid-aortic syndrome is a rare condition characterized by severe aortic narrowing, leading to high upper body blood pressure and organ hypoperfusion, necessitating surgical intervention. Although central bypassing is considered ideal, it involves extensive incisions. To overcome these limitations, less-invasive approaches have been developed. This study aims to introduce a mini-access approach using video-endoscopy and to evaluate the feasibility and outcomes of mini-access ascending aorto-bifemoral bypass surgery.
METHODS
From November 2020 to May 2022, we performed ascending aorta to bifemoral artery bypass operations on 7 patients to treat steno-occlusive diseases in the downstream aorta. A Y-graft was created, and procedures were conducted under general anesthesia using video-endoscopy with limited skin incisions.
RESULTS
Intraoperatively, there were no major complications, and none of the patients required cardiopulmonary bypass support. Furthermore, there were no postoperative mortalities or major complications. Postoperatively, the mean ankle-brachial index significantly improved from 0.59/0.59 to 0.96/0.92 ( = .004), and the mean glomerular filtration rate increased from 61.1 to 85.3 mL/min/1.73 mm ( = .012). Additionally, symptoms of claudication resolved in all patients.
CONCLUSIONS
Videoscope-assisted mini-access aortic bypass surgery not only provides favorable early postoperative outcomes but also represents a technically feasible alternative to traditional surgical approaches for the treatment of steno-occlusive aortic diseases.
PubMed: 38835566
DOI: 10.1016/j.xjtc.2024.01.006 -
Zeitschrift Fur Rheumatologie Jun 2024A German expert committee recommends defining fast-track clinics (FTC) for the acute diagnosis of giant cell arteritis (GCA) as follows: easy and prompt reachability at...
A German expert committee recommends defining fast-track clinics (FTC) for the acute diagnosis of giant cell arteritis (GCA) as follows: easy and prompt reachability at least on weekdays, scheduling appointments ideally within 24 h, examination by a specialist with GCA expertise, ≥ 2 experts per FTC, ≥ 50 patients with suspected GCA per year, sonologists with ≥ 300 (≥ 50) temporal and axillary artery examinations, adherence to standard operating procedures, availability of an ≥ 18 (≥ 15) MHz and a lower frequency linear ultrasound probe, and collaboration with partners for neurology and ophthalmology consultations, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT, possibly CT), and for temporal artery biopsy.
PubMed: 38832967
DOI: 10.1007/s00393-024-01532-9 -
Radiology Case Reports Aug 2024This case describes a rare and complex presentation of Takayasu arteritis, a large vessel vasculitis primarily affecting young females. Unlike typical Takayasu arteritis...
This case describes a rare and complex presentation of Takayasu arteritis, a large vessel vasculitis primarily affecting young females. Unlike typical Takayasu arteritis cases characterized by arterial stenosis, this 34-year-old male presented with an unusually high number of aneurysms affecting the aorta, subclavian arteries, and other segments. This unique abundance of aneurysms complicates diagnosis and management. This disease typically manifests as arterial stenosis, with aneurysms occurring in a minority of cases. The most common site for aneurysms is the ascending aorta, making multifocal aneurysms, as seen in this case, exceptionally rare. Managing multiple aneurysms in Takayasu arteritis is complex, necessitating careful consideration of factors like aneurysm size, morphology, and risk of complications. This case underscores the unique challenges posed by multifocal aneurysms in this condition, highlighting the need for a comprehensive approach to treatment.
PubMed: 38832341
DOI: 10.1016/j.radcr.2024.04.056