Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

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 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; 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 × 10-13). 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.

miR-146a and miR-146b regulate the expression of ICAM-1 in giant cell arteritis.

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-1ß, 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-1ß and IL-17 increased miR-146a expression while IL-1ß, IL-6+sIL6R and IFNγ increased miR-146b expression. IFNγ and IL-1ß 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-1ß, IFNγ). miR-146a and miR-146b seem responsible for the increase of soluble ICAM-1.

CCL18, CHI3L1, ANG2, IL-6 systemic levels are associated with the extent of lung damage and radiomic features in SARS-CoV-2 infection.

OBJECTIVE AND DESIGN: We aimed to identify cytokines whose concentrations are related to lung damage, radiomic features, and clinical outcomes in COVID-19 patients. MATERIAL OR SUBJECTS: Two hundred twenty-six patients with SARS-CoV-2 infection and chest computed tomography (CT) images were enrolled. METHODS: CCL18, CHI3L1/YKL-40, GAL3, ANG2, IP-10, IL-10, TNFα, IL-6, soluble gp130, soluble IL-6R were quantified in plasma samples using Luminex assays. The Mann-Whitney U test, the Kruskal-Wallis test, correlation and regression analyses were performed. Mediation analyses were used to investigate the possible causal relationships between cytokines, lung damage, and outcomes. AVIEW lung cancer screening software, pyradiomics, and XGBoost classifier were used for radiomic feature analyses. RESULTS: CCL18, CHI3L1, and ANG2 systemic levels mainly reflected the extent of lung injury. Increased levels of every cytokine, but particularly of IL-6, were associated with the three outcomes: hospitalization, mechanical ventilation, and death. Soluble IL-6R showed a slight protective effect on death. The effect of age on COVID-19 outcomes was partially mediated by cytokine levels, while CT scores considerably mediated the effect of cytokine levels on outcomes. Radiomic-feature-based models confirmed the association between lung imaging characteristics and CCL18 and CHI3L1. CONCLUSION: Data suggest a causal link between cytokines (risk factor), lung damage (mediator), and COVID-19 outcomes.

Eosinophilic giant cell arteritis: A different subset of disease?

OBJECTIVES: To describe the clinical findings, response to therapy and course of patients with transmural eosinophilic infiltration at temporal artery biopsy (TAB). METHODS: The study consisted of a retrospective cohort of 254 consecutive GCA patients with evidence of transmural inflammation at TAB seen at the Santa Maria Nuova Hospital over a 28-year period. The findings of the 22 patients with eosinophilic infiltration (≥ 20 eosinophils/hpf) at TAB were compared with those of 232 patients without. Among these 232 patients, we sampled 42 GCA patients matched for age, sex and follow-up duration to the 22 with eosinophilic infiltration, to compare allergic manifestations. RESULTS: GCA patients with eosinophilic infiltration compared to those without presented more frequently cranial symptoms (p = 0.052), headaches (p = 0.005), abnormalities of TAs at physical examination (p = 0.045), jaw claudication (p = 0.024), and systemic manifestations (p = 0.016) and had higher CRP levels at diagnosis (p = 0.001). Regarding histological lesions, a severe transmural inflammation, laminar necrosis and intraluminal acute thrombosis were more frequently observed in patients with eosinophilic infiltration (p = 0.066, p < 0.001, and p = 0.010, respectively). Long-term remission and flares were similar in the two groups. When 21 GCA patients with eosinophilic infiltration were compared to 42 without, blood eosinophilic counts at diagnosis were normal and no patients had evidence or developed allergic manifestations and/or clinical findings of systemic necrotizing vasculitis. CONCLUSION: Patients with transmural eosinophilic infiltration represent a subset of GCA with cranial disease and more severe inflammation.

Effects of upadacitinib on enthesitis in patients with psoriatic arthritis: a post hoc analysis of SELECT-PsA 1 and 2.

OBJECTIVES: To characterize the effect of upadacitinib 15 mg once daily (UPA15) on enthesitis in patients with psoriatic arthritis from the SELECT-PsA Phase 3 trials. METHODS: Patients with an inadequate response/intolerance to ≥ 1 non-biologic DMARD (SELECT-PsA 1) or ≥ 1 biologic DMARD (SELECT-PsA 2) received UPA15, adalimumab 40 mg every other week or placebo (weeks 0-24) switched to UPA15 (week 24 onward). The Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada (SPARCC) index were used to assess improvement in enthesitis, enthesitis resolution, maintenance of enthesitis resolution, and protection from enthesitis development through week 56. RESULTS: Data from 639 patients receiving UPA15 and 635 patients receiving placebo (including 317 patients who switched from placebo to UPA15) were analysed. UPA15 led to higher rates of enthesitis resolution vs placebo at week 24 (LEI: 59.8% vs 38.0%; SPARCC index: 50.6% vs 31.5%, respectively) and greater improvements in the LEI (-1.7 vs -1.0) and SPARCC index (-3.4 vs -1.9); improvements were maintained through week 56. Improvements were observed after 12 weeks of UPA15 treatment. Over 90% of patients without enthesitis (LEI = 0) at baseline receiving UPA15 were enthesitis-free at week 56, and UPA15 prevented recurrence of enthesitis at week 56 in > 80% of patients with enthesitis at baseline who achieved resolution (LEI = 0) at week 24. CONCLUSIONS: UPA15 is associated with a comprehensive improvement in enthesitis, with improvements observed after 12 weeks of treatment. Additionally, treatment with UPA15 was associated with maintaining an enthesitis-free state after resolution and protection against new-onset enthesitis. CLINICALTRIALS.GOV IDENTIFIERS: NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2).

A comprehensive review on the role of mesenchymal stromal/stem cells in the management of rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease with systemic manifestations. Although the success of immune modulatory drug therapy is considerable, about 40% of patients do not respond to treatment. Mesenchymal stromal/stem cells (MSCs) have been demonstrated to have therapeutic potential for inflammatory diseases. AREAS COVERED: This review provides an update on RA disease and on pre-clinical and clinical studies using MSCs from bone marrow, umbilical cord, adipose tissue, and dental pulp, to regulate the immune response. Moreover, the clinical use, safety, limitations, and future perspective of MSCs in RA are discussed. Using the PubMed database and ClincalTrials.gov, peer-reviewed full-text papers, abstracts and clinical trials were identified from 1985 through to April 2023. EXPERT OPINION: MSCs demonstrated a satisfactory safety profile and potential for clinical efficacy. However, it is mandatory to deepen the investigations on how MSCs affect the proinflammatory deregulated RA patients' cells. MSCs are potentially good candidates for severe RA patients not responding to conventional therapies but a long-term follow-up after stem cells treatment and standardized protocols are needed. Future research should focus on well-designed multicenter randomized clinical trials with adequate sample sizes and properly selected patients satisfying RA criteria for a valid efficacy evaluation.

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.

Senescent cells in giant cell arteritis display an inflammatory phenotype participating in tissue injury via IL-6-dependent pathways.

OBJECTIVES: Age is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker algorithm in temporal artery biopsies (TABs) of GCA patients. METHODS: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence. RESULTS: Senescent cells were present in GCA arteries at higher proportion compared with PMR (9.50% vs 2.66%, respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts, and macrophages while MMP-9 by senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 10.02% vs 4.37%, respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6R blockade. CONCLUSIONS: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis.

Efficacy and safety of avacopan in patients with ANCA-associated vasculitis receiving rituximab in a randomised trial.

OBJECTIVES: To evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE trial. METHODS: Key efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included the Glucocorticoid Toxicity Index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, health-related quality of life and safety. RESULTS: Of the 330 patients who received study medication, 214 (64.8%) received rituximab (once weekly for 4 weeks), with a mean age of 59.8 years; 163 (76.2%) had renal vasculitis and 125 (58.4%) were newly diagnosed. Remission at week 26 and sustained remission at week 52 were achieved by 83/107 (77.6%) and 76/107 (71.0%) patients in the avacopan group and 81/107 (75.7%) and 60/107 (56.1%) in the prednisone taper group, respectively. The relapse rate, recovery of renal function, speed of reduction in albuminuria and glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 34.6% and 39.3% of patients in the avacopan and prednisone taper groups, respectively. CONCLUSIONS: These data suggest that in patients with ANCA-associated vasculitis receiving rituximab, efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52, with a favourable safety profile. In addition, avacopan was associated with improved renal outcomes and lower glucocorticoid toxicity. These results demonstrate the efficacy and safety of avacopan in patients receiving background induction therapy with rituximab. TRIAL REGISTRATION NUMBER: NCT02994927.

Upadacitinib for the treatment of adult patients with active psoriatic arthritis.

INTRODUCTION: Psoriatic arthritis (PsA) is a rheumatic disorder that may be responsible for relevant articular impairment. The recently licensed Janus Kinase (JaK) inhibitors represent a new opportunity to improve PsA treatment. This review deals with the clinical usefulness of the selective JaK-1 inhibitor upadacitinib (UPA) in patients with PsA. COVERED AREAS: Two phase-III studies are available: SELECT-PsA 1, performed in patients with an inadequate response to non-biological therapies, and SELECT-PsA 2, conducted in biologic-experienced patients. Long-term extension results and post-hoc analysis data of these two trials are also available. EXPERT OPINION: The results provided by the trials indicate that UPA may be used to treat all of the clinical manifestations of PsA. Venous thromboembolism, cardiovascular events, and malignancy, the most feared adverse events associated with JaK inhibitor use, were not increased in the trial populations, yet long-term observational studies are needed to make sure that UPA is safe in this respect.

Effectiveness and safety of a 26-week taper regimen of glucocorticoid in GCA patients: Results from a prospective cohort study.

OBJECTIVES: To assess the effectiveness and safety of the 26-week tapering regimen of glucocorticoids (GC) used in the GiACTA trial in a prospective cohort of treatment-naive, biopsy-proven GCA patients. METHODS: Patients with a new diagnosis of biopsy-proven GCA enrolled in the GC arm of the START project (molecular stratification of patients with GCA to tailor GC and tocilizumab therapy) were included. All patients were treated with the 26-week taper regimen of GC used in the GiACTA trial. The primary endpoint was the rate of relapse-free remission at week 52. The secondary endpoints were the proportion of patients with incident aortic damage, cumulative GC doses and GC-related adverse events (AE). RESULTS: 22 patients were included between December 2018 and February 2022. At week 52, 10 patients (45 %, 95 % CI 24-68) were in relapse-free remission. After a median (IQR) follow-up of 35 (22-40) months, 7 patients (32 %, 95 % CI 14-55) were in relapse-free remission. 18 patients with baseline large-vessel imaging underwent CT angiography at the end of the follow-up. No patients had evidence of new aortic dilation, significant progression of aortic damage or large vessel stenosis. 15/22 patients (68 %) had at least one relapse during follow-up. No patients developed visual or cerebrovascular manifestations during relapses. 15/22 (68 %) patients had at least one GC-related AE. CONCLUSIONS: A 26 week taper regimen of GC was effective and safe in inducing and maintaining remission in a sizeable proportion of newly diagnosed GCA patients. However, the frequency of GC-related adverse events was high.

The usual Interstitial pneumonia pattern in autoimmune rheumatic diseases.

Usual Interstitial Pneumonia (UIP) is characterized by progression of lung parenchyma that may be observed in various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis and connective tissue diseases. From a diagnostic point of view, a UIP pattern related to ARDs may display imaging and pathological features able to distinguish it from that related to IPF, such as the "straight-edge" sign at HRCT and lymphoplasmacytic infiltrates at histologic specimens. Multidisciplinary approach (MDD), involving at least pulmonologist, rheumatologist and radiologist, is fundamental in the differential diagnosis process, but MDD is also required in the evaluation of severity, progression and response to treatment, that is based on the combination of changes in symptoms, pulmonary function trends, and, in selected patients, serial CT evaluation. Differently from IPF, in patients with ARDs both functional evaluation and patient-reported outcomes may be affected by systemic involvement and comorbidities, including musculoskeletal manifestations of disease. Finally, in regards to pharmacological treatment, immunosuppressants have been considered the cornerstone of therapy, despite the lack of solid evidence in most cases; recently, antifibrotic drugs were also proposed for the treatment of progressive fibrosing ILDs other than IPF. In ARD-ILD, the therapeutic choice should balance the need for the control of systemic and lung involvements with the risk of adverse events from multi-morbidities and -therapies. Purpose of this review is to summarize the definition, the radiological and morphological features of the UIP pattern in ARDs, together with risk factors, diagnostic criteria, prognostic evaluation, monitoring and management approaches of the UIP-ARDs.

Management of psoriatic arthritis: a consensus opinion by expert rheumatologists.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease involving several articular and extra-articular structures. Despite the important progresses recently made in all of the aspects of this disease, its management is still burdened by unresolved issues. The aim of this exercise was to provide a set of statements that may be helpful for the management of PsA. Methods: A group of 38 Italian rheumatologists with recognized expertise in PsA selected and addressed the following four topics: "early PsA," "axial-PsA," "extra-articular manifestations and comorbidities," "therapeutic goals." Relevant articles from the literature (2016-2022) were selected by the experts based on a PubMed search. A number of statements for each topic were elaborated. Results: Ninety-four articles were selected and evaluated, 68 out of the 1,114 yielded by the literature search and 26 added by the Authors. Each of the four topic was subdivided in themes as follows: transition from psoriasis to PsA, imaging vs. CASPAR criteria in early diagnosis, early treatment for "early PsA"; axial-PsA vs. axialspondyloarthritis, diagnosis, clinical evaluation, treatment, standard radiography vs. magnetic resonance imaging for "axial PsA"; influence of inflammatory bowel disease on the therapeutic choice, cardiovascular comorbidity, bone damage, risk of infection for "comorbidities and extra-articular manifestations"; target and tools, treat-to-target strategy, role of imaging for "therapeutic goals." The final document consisted of 49 statements. Discussion: The final product of this exercise is a set of statements concerning the main issues of PsA management offering an expert opinion for some unmet needs of this complex disease.

Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: preliminary data of a real-life multicenter study.

BACKGROUND: Upadacitinib (UPA) is a selective JAK inhibitor recently approved for the treatment of psoriatic arthritis (PsA). In this post-approval study, we aimed to evaluate the effectiveness and safety of UPA over 24 weeks and identify clinical predictors of response, in a multicentric cohort of patients affected by PsA. METHODS: One hundred and twenty-six patients with PsA treated with UPA were enrolled in 10 Italian centres. UPA effectiveness outcomes, such as the proportion of patients with MDA status, DAPSA remission, and low disease activity, ASDAS-CRP inactive and low disease activity, and change from baseline in DAPSA and ASDAS-CRP scores, were evaluated every 12 weeks until week 24. The proportion of DAPSA minor, moderate, and major improvement, and ASDAS clinically important improvement (CII) and major improvement (MI) were considered as well. All treatment-related adverse events were collected during the observation period. Clinical predictors of MDA response at week 24 were evaluated through multivariate analysis. RESULTS: At baseline, 124/126 (98%) and 54/126 (43%) patients showed peripheral and axial involvement, respectively; 110 (87%) patients were intolerant or resistant to biologic DMARDs.  At 24 weeks, MDA status, DAPSA remission, and ASDAS-CRP inactive disease were achieved in 47%, 23%, and 48% of patients, respectively. Minor, moderate, and major DAPSA improvement was observed in 67%, 39%, and 23%, respectively; while 65% and 35% achieved ASDAS-CRP CII and MI, respectively. The mean change from baseline was 15.9 ± 13.5 (p < 0.001) for DAPSA and 1.21 ± 0.97 (p < 0.001) for ASDAS-CRP. Thirteen patients (10%) discontinued UPA due to a lack of efficacy or non-serious adverse events. No serious adverse events were observed. Male gender (OR 2.54, 95% CI 1.03-6.25 p = 0.043), being naïve to biological DMARDs (OR 4.13, 95% CI 1.34-12.71, p = 0.013) and elevated baseline CRP (OR 2.49, 95% CI 1.02-6.12, p = 0.046) were associated with MDA response at week 24. CONCLUSIONS: This is one of the first real-life studies supporting the effectiveness of UPA and its safety profile in PsA patients. Furthermore, the study identifies predictors of MDA response to UPA treatment at 6 months.

Unilateral Relapsing Primary CNS Vasculitis: Description of 3 Cases From a Single-Institutional Cohort of 216 Cases.

OBJECTIVES: To define the frequency and characteristics of patients with unilateral relapsing involvement in a cohort of patients with adult primary CNS vasculitis (PCNSV). METHODS: We retrospectively studied a cohort of 216 patients with PCNSV seen at the Mayo Clinic, Rochester, MN from 1983 to 2022. Twenty-five patients (19.8%) had at least 2 flares. Three of them (1.4%) had unilateral relapsing vasculitis. We described these 3 patients and compared them with the entire cohort of 216 patients. RESULTS: All 3 patients had angiography-negative and biopsy-positive PCNSV with granulomatous-necrotizing and lymphocytic vasculitides and amyloid beta-related angiitis. The main manifestation at diagnosis and during flares was seizures. Unilateral lesions with gadolinium enhancement were the main MRI finding. Spinal fluid examination at diagnosis was normal in 2 patients. All had multiple flares (from 4 to 10) and were treated with long-term high-dose prednisone and numerous traditional immunodepressive drugs, and one received rituximab for steroid resistance. All 3 patients had slight disability with mild cognitive impairment at last follow-up. DISCUSSION: Unilateral relapsing involvement represents a rare subset of PCNSV with peculiar characteristics and can be observed in all neuropathologic patterns.

C-reactive protein gene polymorphisms influence susceptibility and outcomes of biopsy-proven giant cell arteritis in Italian patients.

OBJECTIVES: To investigate potential associations between the two functional C-reactive protein (CRP) gene polymorphisms at position 3872C>T (rs1205) and 4741G>C (rs3093068) and susceptibility, clinical expression, laboratory and pathological findings, and outcomes of giant cell arteritis (GCA) in a Nothern Italian population. METHODS: One hundred and seventy Italian patients with biopsy-proven GCA resident in Reggio Emilia area, Italy, and 200 healthy controls from the same geographic area were genotyped for rs1205 and rs3093068 CRP gene polymorphisms by molecular methods. The patients were subgrouped on the basis of the presence or absence of clinical manifestations, histological and laboratory findings, and outcomes. RESULTS: The distribution of rs1205 genotype was significantly different between GCA patients and controls (p=0.018). Homozygosity for T allele was significantly more frequent in GCA patients compared to controls [p=0.006; odds ratio (OR): 2.28 (95% CI: 1.1, 4.8)]. The distribution of rs3093068 genotype differed significantly between GCA patients and controls (p=0.010). Allele C and the carriers of the C allele (C/C+C/G) of rs3093068 genotype were significantly less frequent in GCA patients compared to controls [p=0.002, OR: 0.39 (95% CI: 0.24-0.73); p=0.002, OR: 0.35 (95% CI: 0.17-0.70), respectively]. No significant associations were found between the two polymorphisms and baseline clinical manifestations. The carriers of the allele C of rs3093068 genotype had significantly higher CRP values at diagnosis (13.2±5.0 vs. 8.3±6.0 mg/dl, p=0.007). Homozygosity for T allele of rs1205 genotype had a significantly more frequent eosinophil infiltration of the temporal artery wall (21.4% vs. 6.0%) (p=0.010, OR 4.28;1.31-13.98) than patients carrying the allele C. Carriers of the allele T of rs1205 genotype had lower glucocorticoid (GC) treatment duration (p=0.041), lower cumulative total GC dose (p=0.017), and higher prevalence of long-term remission (p=0.024). CONCLUSIONS: CRP gene rs1205 and rs3093068 polymorphisms influence GCA susceptibility and its outcomes.

Prevalence and distribution of vascular calcifications at CT scan in patients with and without large vessel vasculitis: a matched cross-sectional study.

OBJECTIVES: The aim of this study was to compare the prevalence, entity and local distribution of arterial wall calcifications evaluated on CT scans in patients with large vessel vasculitis (LVV) and patients with lymphoma as reference for the population without LVV. METHODS: All consecutive patients diagnosed with LVVs with available baseline positron emission tomography-CT (PET-CT) scan performed between 2007 and 2019 were included; non-LVV patients were lymphoma patients matched by age (±5 years), sex and year of baseline PET-CT (≤2013; >2013). CT images derived from baseline PET-CT scans of both patient groups were retrospectively reviewed by a single radiologist who, after setting a threshold of minimum 130 Hounsfield units, semiautomatically computed vascular calcifications in three separate locations (coronaries, thoracic and abdominal arteries), quantified as Agatston and volume scores. RESULTS: A total of 266 patients were included. Abdominal artery calcifications were equally distributed (mean volume 3220 in LVVs and 2712 in lymphomas). Being in the LVVs group was associated with the presence of thoracic calcifications after adjusting by age and year of diagnosis (OR 4.13, 95% CI 1.35 to 12.66; p=0.013). Similarly, LVVs group was significantly associated with the volume score in the thoracic arteries (p=0.048). In patients >50 years old, calcifications in the coronaries were more extended in non-LVV patients (p=0.027 for volume). CONCLUSION: When compared with patients without LVVs, LVVs patients have higher calcifications in the thoracic arteries, but not in coronary and abdominal arteries.

Reduced Graphene Oxide Electrolyte-Gated Transistor Immunosensor with Highly Selective Multiparametric Detection of Anti-Drug Antibodies.

The advent of immunotherapies with biological drugs has revolutionized the treatment of cancers and auto-immune diseases. However, in some patients, the production of anti-drug antibodies (ADAs) hampers the drug efficacy. The concentration of ADAs is typically in the range of 1-10 pm; hence their immunodetection is challenging. ADAs toward Infliximab (IFX), a drug used to treat rheumatoid arthritis and other auto-immune diseases, are focussed. An ambipolar electrolyte-gated transistor (EGT) immunosensor is reported based on a reduced graphene oxide (rGO) channel and IFX bound to the gate electrode as the specific probe. The rGO-EGTs are easy to fabricate and exhibit low voltage operations (≤ 0.3 V), a robust response within 15 min, and ultra-high sensitivity (10 am limit of detection). A multiparametric analysis of the whole rGO-EGT transfer curves based on the type-I generalized extreme value distribution is proposed. It is demonstrated that it allows to selectively quantify ADAs also in the co-presence of its antagonist tumor necrosis factor alpha (TNF-α), the natural circulating target of IFX.

Altered pathways of keratinization, extracellular matrix generation, angiogenesis, and stromal stem cells proliferation in patients with systemic sclerosis.

Objective: Systemic sclerosis is characterized by endothelial dysfunction, autoimmunity abnormalities, and fibrosis of the skin and internal organs. The pathogenetic mechanisms underlying systemic sclerosis vasculopathy are still not clarified. A complex cellular and extracellular network of interactions has been studied, but it is currently unclear what drives the activation of fibroblasts/myofibroblasts and the extracellular matrix deposition. Methods: Using RNA sequencing, the aim of the work was to identify potential functional pathways implied in systemic sclerosis pathogenesis and markers of endothelial dysfunction and fibrosis in systemic sclerosis patients. RNA-sequencing analysis was performed on RNA obtained from biopsies from three systemic sclerosis patients and three healthy controls enrolled in our University Hospital. RNA was used to generate sequencing libraries that were sequenced according to proper transcriptomic analyses. Subsequently, we performed gene set enrichment analysis of differentially expressed genes on the entire list of genes that compose the RNA-sequencing expression matrix. Results: Gene set enrichment analysis revealed that healthy controls were characterized by gene signatures related to stromal stem cells proliferation, cytokine-cytokine receptor interaction, macrophage-enriched metabolic network, whereas systemic sclerosis tissues were enriched in signatures associated with keratinization, cornification, retinoblastoma 1 and tumor suppressor 53 signaling. Conclusion: According to our data, RNA-sequencing and pathway analysis revealed that systemic sclerosis subjects display a discrete pattern of gene expression associated with keratinization, extracellular matrix generation, and negative regulation of angiogenesis and stromal stem cells proliferation. Further analysis on larger numbers of patients is needed; however, our findings provide an interesting framework for the development of biomarkers useful to explore potential future therapeutic approaches.

Therapeutic Effects of Apremilast on Enthesitis and Dactylitis in Real Clinical Setting: An Italian Multicenter Study.

INTRODUCTION: Enthesitis and dactylitis are difficult-to-treat features of psoriatic arthritis (PsA), leading to disability and affecting quality of life. OBJECTIVE: The aim of this study is to evaluate enthesitis (using the Leed enthesitis index (LEI)) and dactylitis at 6 and 12 months in patients treated with apremilast. METHODS: Patients affected by PsA from fifteen Italian rheumatological referral centers were screened. The inclusion criteria were: (a) enthesitis or dactylitisphenotype; (b) treatment with apremilast 30 mg bid. Clinical and treatment history, including PsA disease activity, were recorded. Mann-Whitney and chi-squared tests were used to assess the differences between independent groups, and Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. A p-value of <0.05 was considered statistically significant. RESULTS: The Eph cohort consisted of 118 patients (median LEI 3); the Dph cohort included 96 patients with a median dactylitis of 1 (IQR 1-2). According to an intention to treat analysis, 25% and 34% of patients with enthesitis achieved remission (i.e., LEI = 0) in T1 and T2. The remission of dactylitis was 47% in T1 and 44% in T2. The per protocol analysis (patients observed for at least 12 months) showed that both dactylitis and LEI significantly improved in T1 (median LEI 1 (IQR 1-3)) and T2 (median LEI 0 (IQR 1-2)). CONCLUSION: Eph and Dph PsA patients treated with apremilast experienced a significant improvement in enthesitis and dactylitis activity. After 1 year, enthesitis and dactylitis remission was achieved in more than one-third of patients.