Investigational agents for polymyalgia rheumatica treatment: assessing the critical needs for future development.

INTRODUCTION: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder characterized by pain and stiffness in the shoulder and pelvic girdles, constitutional symptoms, and elevated acute-phase reactants. Glucocorticoids (GCs) remain the first-choice treatment for PMR, but relapses are common. Identification of steroid-sparing agents is therefore of utmost importance. AREAS COVERED: The efficacy of conventional immunosuppressive drugs is controversial. The use of interleukin (IL)-6 receptor inhibitors proved to be effective and safe in treating PMR patients. Currently, there are 12 ongoing clinical trials exploring potential treatments such as leflunomide, low-dose IL-2, rituximab, abatacept, secukinumab, Janus kinase inhibitors, and selective inhibitors like SPI-62 and ABBV 154. EXPERT OPINION: The high efficacy of IL-6 R receptor inhibitors as well as the numerous drug trials currently recruiting suggest that several therapeutic options will be available in the near future. Accurate diagnosis and early stratification of PMR patients according to the giant cell arteritis-PMR Spectrum Disease 'GPSD' and potential risk factors for relapsing disease or GC-related adverse events are crucial to identify patients who would benefit most from GC-sparing agents. The development of internationally accepted definitions for remission and relapse is urgently needed. Early referral strategies to specialist settings would improve disease stratification and personalized treatment.

Cutting-Edge Strategies for Renal Tumour-like Lesions in Granulomatosis with Polyangiitis: A Systematic Review.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is characterised by granulomatous inflammation and small-to-medium vessel necrotising vasculitis, mainly affecting respiratory tract and kidneys. Renal involvement presenting as tumour-like lesions poses diagnostic and treatment challenges. METHODS: Following the observation of a GPA patient presenting with multiple renal tumour-like lesions, we conducted a systematic literature review on MEDLINE/PubMed, EMBASE, and Cochrane databases. Data gathered from the literature were analysed to summarise the diagnostic approach, management, and outcome of renal GPA-related tumour-like lesions. RESULTS: a 49-year-old female presented with persistent constitutional symptoms and multiple bilateral renal lesions. Renal biopsy showed chronic interstitial inflammation with necrotising granulomas. Laboratory tests disclosed positive anti-proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA) leading to a final diagnosis of GPA. She was effectively treated with high-dose glucocorticoids and rituximab. Literature search yielded 41 articles, concerning 42 GPA patients with renal masses, presenting bilaterally in 23.8% of the cases. Positive PR3-ANCA was observed in 86.5% of the cases. Half of 42 patients showed kidney abnormalities. Treatment with glucocorticoids (83.3%) and immunosuppressive agents (80.9%) resulted in an overall good remission rate and favourable prognosis. CONCLUSIONS: GPA should be considered in the differential diagnoses of kidney tumour-like lesions. The diagnosis is challenging, and histological examination greatly contributes to the diagnostic work-up.

Subclinical giant cell arteritis in polymyalgia rheumatica: Concurrent conditions or a common spectrum of inflammatory diseases?

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are common conditions in older adults. Their clinical connection has been recognized over time, with many patients experiencing both conditions separately, simultaneously or in temporal sequence to each other. Early GCA detection is essential to prevent vascular damage, but identifying subclinical GCA in PMR patients remains a challenge and routine screening is not standard practice. Subclinical GCA prevalence in newly diagnosed PMR patients ranges from 23 to 29%, depending on the screening method. Vessel wall imaging and temporal artery biopsy can detect subclinical GCA. Epidemiology and trigger factors show similarities between the two conditions, but PMR is more common than GCA. Genetic and pathogenesis studies reveal shared inflammatory mechanisms involving dendritic cells, pro-inflammatory macrophages, and an IL-6 signature. However, the inflammatory infiltrates differ, with extensive T cell infiltrates seen in GCA while PMR shows an incomplete profile of T cell and macrophage-derived cytokines. Glucocorticoid treatment is effective for both conditions, but the steroid requirements vary. PMR overall mortality might be similar to the general population, while GCA patients with aortic inflammatory aneurysms face increased mortality risk. The GCA-PMR association warrants further research. Considering their kinship, recently the term GCA-PMR Spectrum Disease (GPSD) has been proposed.

Might maintenance therapy be discontinued once clinical remission is achieved in ANCA-associated vasculitis?

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) encompasses a group of rare, multisystem autoimmune disorders characterised by the occurrence of inflammation and damage to small blood vessels, leading to a wide range of clinical manifestations. They include granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Outcomes for patients with MPA and GPA have been transformed over recent years. However, the establishment of effective maintenance therapy aiming to balance the risks of disease relapse with those related to prolonged immunosuppression has become a clinical priority. This review aims to explore two differing perspectives on this unsolved problem. Pros and Cons of the following approaches will be discussed: "Biomarker-guided personalised approach on top of generic maintenance strategy guidelines" or "ANCA specificity-related personalised maintenance treatment after intensive B-cell depletion"?

Combination of monoclonal antibodies targeting type 2 inflammation for severe asthma and eosinophilic granulomatosis with polyangiitis.

Monoclonal antibodies targeting type 2 inflammation are promising treatments for eosinophilic-associated diseases. There is growing interest in the potential benefits of combining two biologics to treat patients with poorly controlled conditions. We present a case of a 54-year-old female patient affected with a relapsing-refractory ANCA myeloperoxidase positive eosinophilic granulomatosis with polyangiitis (EGPA), presenting with difficult-to-treat asthma and rhino-sinusitis manifestations. She failed several biologics, including omalizumab 300 mg, mepolizumab 100 mg, and benralizumab 30 mg every 8 weeks. A switch to dupilumab led to significant eosinophilia (7.69 × 109/L) as well as systemic symptoms, and a deterioration of asthma control. Therefore, a combination of dupilumab-benralizumab was started, leading to better nasal and ear outcomes, asthma control and decrease in blood eosinophils. During the 12-month treatment, no adverse effects were observed. We conducted an extensive literature search in MEDLINE for original articles published until August 1st, 2023 reporting the combination of anti-type 2 biologics. A total of 51 cases were retrieved from the literature. Omalizumab was the most frequently combined drugs (34 cases). Combination therapy led to reduction of asthma exacerbations and glucocorticoid intake, though was ineffective only for one EGPA patient. Only one patient on omalizumab-mepolizumab therapy reported a mild adverse reaction. Combination biologic therapies for conditions which share pathogenic pathways appears to be both safe and effective. This approach may benefit patients with uncontrolled conditions and counter side effects of biologics, like dupilumab-related hypereosinophilia.

Reinforcement learning optimisation for graded metamaterial design using a physical-based constraint on the state representation and action space.

The energy harvesting capability of a graded metamaterial is maximised via reinforcement learning (RL) under realistic excitations at the microscale. The metamaterial consists of a waveguide with a set of beam-like resonators of variable length, with piezoelectric patches, attached to it. The piezo-mechanical system is modelled through equivalent lumped parameters determined via a general impedance analysis. Realistic conditions are mimicked by considering either magnetic loading or random excitations, the latter scenario requiring the enhancement of the harvesting capability for a class of forcing terms with similar but different frequency content. The RL-based optimisation is empowered by using the physical understanding of wave propagation in a such local resonance system to constrain the state representation and the action space. The procedure outcomes are compared against grading rules optimised through genetic algorithms. While genetic algorithms are more effective in the deterministic setting featuring the application of magnetic loading, the proposed RL-based proves superior in the inherently stochastic setting of the random excitation scenario.

Validation of the 2022 American College of Rheumatology/EULAR classification criteria for Takayasu arteritis.

OBJECTIVES: The present study validates the 2022 ACR/European Alliance of Associations for Rheumatology (EULAR) classification criteria for Takayasu's arteritis (TAK), compared with the 1990 ACR TAK classification criteria. METHODS: The fulfilment of 2022 ACR/EULAR and 1990 ACR TAK criteria from four referral centres was assessed for TAK compared with extracranial giant cell arteritis (EC-GCA) and other controls. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio of a positive test (LR+) or negative test (LR-), and area under receiver operating characteristics curve (AUC) were calculated. RESULTS: Among 504 patients with TAK (404 females) and 222 controls (151 females, 144 patients with EC-GCA), the 2022 ACR/EULAR criteria had better sensitivity (95.83% vs 82.94%) and NPV, but poorer specificity (63.51% vs 90.54%), PPV, LR+, LR- and AUC at the pre-determined cut-offs than the 1990 ACR criteria. The 2022 ACR/EULAR criteria had greater specificity (76.06% vs 57.62%) and AUC (0.845 vs 0.771), with similar sensitivity (93% vs 96.53%) in males as in females. The 2022 ACR/EULAR criteria performed similarly with only EC-GCA as controls (sensitivity 95.83%, specificity 60.42%, AUC 0.781). Sensitivity remained similar, whereas specificity was higher for 40-60 years vs <40 years. Cut-offs of ≥6 (sensitivity 91.87%, specificity 82.88%) and ≥7 (sensitivity 86.71%, specificity 86.49%), or removing the point for female sex (sensitivity 92.64%, specificity 81.08%) greatly improved the balance between sensitivity and specificity. CONCLUSION: The poor specificity of the 2022 ACR/EULAR TAK criteria in real-life settings was improved by increasing the cut-off to 6 or 7, or removing the point for female sex.

Bib Sign in Proximal Descending Thoracic Aorta Rupture on CT Angiography: Presentation of a Paradigmatic Case.

Thoracic aortic rupture may present with subtle clinical and CT-angiography findings. Recognition of the imaging features of early rupture is key for timely diagnosis and treatment. This report presents a new sign of incipient proximal thoracic aortic rupture on CT-angiography.

How the First Year of the COVID-19 Pandemic Impacted Patients' Hospital Admission and Care in the Vascular Surgery Divisions of the Southern Regions of the Italian Peninsula.

Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study. Each received a 13-point questionnaire investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs. 2019 (9161 patients): post-EVAR surveillance, hospitalization for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased (1484 (16.2%) vs. 1014 (14.3%), p = 0.0009; 1401 (15.29%) vs. 959 (13.52%), p = 0.0006; and 1558 (17.01%) vs. 934 (13.17%), p < 0.0001, respectively), while admissions for revascularization or major amputations for chronic limb-threatening ischemia and urgent revascularization for symptomatic carotid stenosis significantly increased (1204 (16.98%) vs. 1245 (13.59%), p < 0.0001; 355 (5.01%) vs. 358 (3.91%), p = 0.0007; and 153 (2.16%) vs. 140 (1.53%), p = 0.0009, respectively). Conclusions: The suspension of elective procedures during the COVID-19 pandemic caused a significant reduction in post-EVAR surveillance, and in the hospitalization of asymptomatic carotid stenosis revascularization and Rutherford 3 peripheral arterial disease. Consequentially, we observed a significant increase in admissions for urgent revascularization for symptomatic carotid stenosis, as well as for revascularization or major amputations for chronic limb-threatening ischemia.

Biologic therapy in relapsing polychondritis: navigating between options.

INTRODUCTION: Relapsing polychondritis (RP) is a rare systemic inflammatory disease of unknown etiology, primarily affecting cartilaginous tissue and proteoglycan-rich structures. Clinical manifestations vary from mild symptoms to occasional organ or life-threatening complications. Treatment can be challenging and is mostly based on experience or case reports/series. AREAS COVERED: There is growing literature investigating the role of biologics in the management of RP. TNFα antagonists, abatacept, tocilizumab, rituximab, anakinra and tofacitinib have been prescribed in several RP patients, mainly as second-line treatment, after conventional immunosuppressive agents' failure. EXPERT OPINION: Glucocorticoids represent the gold standard treatment of RP. Conventional immunosuppressants should be administered in refractory patients or when a glucocorticoid-sparing effect is needed. Biologic therapy should be used after failure of conventional treatments or in severe manifestations. TNFα inhibitors are the most prescribed biologic agent, with partial or complete response in several cases, but loss of efficacy may occur over time. Infliximab and adalimumab should be preferred among TNFα antagonists. Abatacept and tocilizumab proved to be effective as second-line biologic agents, but infections are reported with the former. Data on anakinra and rituximab are controversial, therefore they are not recommended as first-line biologic drugs. The use of JAK inhibitors is still anecdotal.

Pressure-induced vascular oxidative stress is mediated through activation of integrin-linked kinase 1/betaPIX/Rac-1 pathway.

High blood pressure induces a mechanical stress on vascular walls and evokes oxidative stress and vascular dysfunction. The aim of this study was to characterize the intracellular signaling causing vascular oxidative stress in response to pressure. In carotid arteries subjected to high pressure levels, we observed not only an impaired vasorelaxation, increased superoxide production, and NADPH oxidase activity, but also a concomitant activation of Rac-1, a small G protein. Selective inhibition of Rac-1, with an adenovirus carrying a dominant-negative Rac-1 mutant, significantly reduced NADPH oxidase activity and oxidative stress and, more importantly, rescued vascular function in carotid arteries at high pressure. The analysis of molecular events associated with mechanotransduction demonstrated at high pressure levels an overexpression of integrin-linked kinase 1 and its recruitment to plasma membrane interacting with paxillin. The inhibition of integrin-linked kinase 1 by small interfering RNA impaired Rac-1 activation and rescued oxidative stress-induced vascular dysfunction in response to high pressure. Finally, we showed that betaPIX, a guanine-nucleotide exchange factor, is the intermediate molecule recruited by integrin-linked kinase 1, converging the intracellular signaling toward Rac-1-mediated oxidative vascular dysfunction during pressure overload. Our data demonstrate that biomechanical stress evoked by high blood pressure triggers an integrin-linked kinase 1/betaPIX/Rac-1 signaling, thus generating oxidative vascular dysfunction.

Resistin impairs insulin-evoked vasodilation.

OBJECTIVE: Since vascular dysfunction is a main trait of obese subjects, in the present study we evaluated the vascular impact of resistin, a recently discovered hormone markedly increased in obesity. RESEARCH DESIGN AND METHODS: We performed our analysis on aortic and mesenteric segments from young and old C57BL/6 mice and on cultured endothelial cells. Resistin-induced vascular effect was evaluated in vitro and in vivo. Molecular analyses were performed by immunoprecipitation and Western blotting. RESULTS: Recombinant murine resistin did not induce changes in either basal vascular tone or phenylephrine-induced vascular contraction. In contrast, both in vivo and in vitro administration of resistin significantly impaired dose-dependent insulin-evoked vasodilation by reducing endothelial nitric oxide synthase (eNOS) enzymatic activity. This effect of resistin was selective for insulin vascular action, since vasodilatation induced by increasing doses of acetylcholine or nitroglycerin was not influenced by the hormone. Molecular analysis of endothelial cells further detailed resistin-induced vascular resistance by showing impairment of insulin-evoked AKT and eNOS phosphorylations after exposure to resistin. Even this latter abnormality is selective of insulin signaling since AKT/eNOS phosphorylations are normally activated during acetylcholine stimulation. More important, the resistin-induced endothelial dysfunction depends on resistin's ability to alter insulin receptor substrate (IRS)-1 tyrosine/serine phosphorylation and its consequent interaction with phosphatidylinositol 3-kinase. CONCLUSIONS: Our results demonstrate that resistin is able to induce a selective vascular insulin resistance-impairing endothelial IRS-1 signaling pathway that leads to eNOS activation and vasodilation.

Selective Rac-1 inhibition protects from diabetes-induced vascular injury.

Diabetes mellitus is a main risk factor for vascular diseases. Vascular injury induced by diabetes mellitus is characterized by endothelial dysfunction attributable to an increased oxidative stress. So far, the molecular mechanisms involved in the vasculotoxic effects of diabetes are only partially known. We examined the effect of diabetes mellitus on oxidative stress and Rac-1 activation, a small G-protein involved in the activation of NADPH oxidase. Our results show that oxidative stress in vessels of different murine models of diabetes mellitus and in endothelial cells treated with high glucose is associated with an increased Rac-1/PAK binding and Rac-1 translocation from cytosol to plasma membrane, thus demonstrating an enhanced Rac-1 activity. More important, selective Rac-1 inhibition by an adenoviral vector carrying a dominant negative mutant of Rac-1 protected from oxidative stress and vascular dysfunction induced by diabetes mellitus. Our study demonstrates that Rac-1 plays a crucial role in diabetes-induced vascular injury, and it could be a target of novel therapeutic approaches to reduce vascular risk in diabetes mellitus.