Identification of biomarkers involved in the resolution phase of inflammation: a translational study of Specialized Pro-resolving Mediators role in Rheumatoid Arthritis

OBJECTIVES: Rheumatoid Arthritis (RA) is a chronic autoimmune disease in which uncontrolled inflammation lead by cells from innate and adaptive immune system leads to tissue damage and disability. To date, the wider pharmacological armamentarium significantly increased the chance of disease control and sustained clinical remission achievement in RA. However, little is known about the mechanisms involved in the resolution phase of inflammation in rheumatic diseases as well as the possible role of Specialized Pro-resolving Mediators (SPMs) as putative pathogenetic and/or therapeutic targets. The aim of this translation study was to dissect whether SPMs and their receptors ERV1, ALX/FPR2 and BLT1 might act as soluble or tissue biomarkers in RA useful for patient stratification across disease phases in clinical practice, improving the therapy management. Moreover, the secondary outcome was wider aiming to increase our knowledge about RA pathophysiology of remission status in. METHODS: 68 patients with RA (27 naïve-to-treatment, 23 DMARDs-not-responder and 18 in sustained clinical and ultrasound remission respectively) were enrolled in the study and underwent PB drawing and ultrasound-guided ST biopsy (n=48). 13 patients with undifferentiated peripheral inflammatory arthritis (UPIA) and 9 with osteoarthritis (OA) were enrolled as comparison groups. Demographic, clinical, immunological and ultrasonographic features were collected for each patient. Determination of serum cytokines and chemokines concentrations (IL-1beta, TNF-alpha, IL-6, IFN-gamma, IL-12p70, IL-10, IL-4, IL-2, Chemerin and GAS6) were performed by ELISA. Furthermore, SPMs and Arachidonic Acid (AA) derived pro-inflammatory molecules determinations in snap frozen synovial tissue biopsies from RA patients in different disease phases (active and remission respectively) were performed by LC-MS/MS. Expression of ERV1, ALX/FPR2 and BLT1 in CD45+CD3+ and CD45+CD19+ was assessed by FACS on PB and on synovial tissue-derived cell suspensions. Moreover, ERV1, ALX/FPR2 and BLT1 expression was assessed by FACS on NK cells (CD45+CD3-CD19-CD56+), neutrophils and monocytes (CD45+CD14+) from PB and macrophages (CD45+CD11b+CD64+) from ST only respectively. Synovitis degree was determined using a H&E based semiquantitative score. Some ST samples were used for quantification of ERV1, ALX/FPR2 and BLT1 genes expression by RT-PCR. RESULTS: Synovial tissue inflammation in terms of semiquantitive score and the cytokine milieu in peripheral blood directly mirror the disease Activity status in RA. RT-PCR on ST samples revealed that ST from RA in high disease activity was enriched of SPM receptors when compared to RA in sustained remission and OA (ERV1: 4.4 vs 1.1 (p= 0.012) and 1.2 (p= 0.005); ALX/FPR2: 4.9 vs 1.5 (p= 0.0006) and 0.8 (p= 0.003); BLT1: 5.9 vs 1.6 (p= 0.016) and 1.1 (p= 0.002) respectively). In particular, C-Reactive Protein (CRP) serum levels, directly correlated with BLT1 expression on PB-derived CD45+CD14+ cells (r=0.27; p=0.023) of RA regardless to the disease phase. Conversely, ST of RA in sustained remission was depleted of BLT1 in CD45+CD3+ cells compared to other conditions (OA p=0.017; UPIA p=0.002; naïve-to-treatment RA p=0.01). LC-MS/MS analysis revealed that synovial tissue of RA in sustained remission the ratio between SPM and AA-derived pro-inflammatory molecules is significantly increased when compared to synovial tissue of RA patients with high disease activity (101.3 vs 2153.00 (84.06-3333.00) respectively) CONCLUSIONS: SPM receptors expression in PB and ST compartments are reciprocally related to disease activity across disease phases in RA suggesting a putative active modulatory role in maintaining the remission phase

Faster steroid-free remission with tocilizumab compared to methotrexate in giant cell arteritis: a real-life experience in two reference centres

: Glucocorticoids (GCs) are still the mainstay of treatment of giant cell arteritis (GCA). Although GCs are highly effective in GCA, the high burden of toxicity of GCs as well as the disease relapse during GC tapering is well documented. To compare the efficacy and rapidity of TCZ and MTX as steroid-sparing agents in a real-life cohort of GCA patients. A retrospective analysis was conducted including patients with newly diagnosed GCA from the Rheumatology Units of Udine and Rome. The inclusion criterion was the treatment with TCZ or MTX as first steroid-sparing drug. 112 GCA patients (81 females) with a median age of 70 (IQ 65-75) years were collected. Thirty-one out of 112 (27.7%) patients were treated with TCZ (162 mg/week), while 81/112 (72.3%) patients received MTX (up to 20 mg/week) as a GC-sparing agent. At month 6 after GCA onset, 5/31 (16.1%) patients in TCZ group and none in MTX group were in GC-free sustained remission (p value = 0.001). Similarly, at month 12, 64.5% (20/31) and 11.1% (9/81) of patients were in sustained GC-free remission in TCZ and MTX group, respectively (p value <0.001). At month 24 of follow-up, at least one relapse of the disease occurred in 7/31 (22.6%) in TCZ-treated and 28/81 (34.6%) in MTX-treated patients, respectively (p value = 0.22). TCZ allowed a faster discontinuation of steroid therapy than MTX in GCA patients, without increasing the risk of relapse

Autoimmune inflammation as a key risk factor for heart failure with preserved ejection fraction: the different types of inflammation driving to HFpEF

ImportanceHeart failure with preserved ejection fraction (HFpEF), defined by an ejection fraction &gt;50%, has emerged as the most prevalent form of heart failure at the community level. Multiple comorbidities, including diabetes, hypertension, obesity, atrial fibrillation, renal diseases, and autoimmune conditions, have been linked to its development. These conditions share common pathways involving oxidative stress, metabolic dysregulation, ischemia, and a chronic inflammatory milieu.ObservationsPatients with autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) exhibit an increased risk of developing HFpEF, often through mechanisms involving chronic inflammation and endothelial dysfunction, which precede the clinical manifestation of HFpEF. Clinical studies have demonstrated that the risk of developing HFpEF exists independently of traditional cardiovascular risk factors, underscoring the pivotal role of chronic inflammation and autoimmunity as key contributors to its pathogenesis.Conclusions and relevanceThe translational implication is that the distinct inflammatory pathways driving these autoimmune diseases (e.g., myeloid-T cells and T-B cell-mediated inflammation in RA, and B cell-driven inflammation in SLE and SSc) should become personalized therapeutic targets to prevent HFpEF progression. Early intervention with novel therapies, such as sodium-glucose cotransporter type 2 (SGLT2) inhibitors, could be crucial in managing these patients during the early disease stages. Additionally, the H2FPEF score should be routinely employed to facilitate early diagnosis and risk stratification, providing a robust framework for personalized management strategies

Risankizumab e Upadacitinib nel Trattamento dell'Artrite Psoriasica: Meccanismi Diversi, Obiettivo Comune

Psoriatic arthritis (PsA) is a chronic inflammatory disease with a complex clinical phenotype. Its main clinical manifestations are peripheral arthritis, spondylitis, enthesitis, and dactylitis that over time lead to axial and peripheral joint deformities. In addition, different extra-musculoskeletal manifestations (i.e. psoriasis, inflammatory bowel disease and uveitis) and co-morbidities (e.g. metabolic syndrome and cardiovascular disease) are often present. The etiopathogenesis of PsA is not entirely clear, although it is believed to result from a complex interaction of environmental, genetic, and immunological factors, with the dysregulation of the immune system causing a persistent inflammatory response, tissue damage, and pathological bone remodeling. The identification of the key inflammatory mediators of PsA has led to the development of specific inhibitors of interleukin 23 and Janus kinases, including risankizumab (anti-interleukin 23 antibody) and upadacitinib (Janus Kinase inhibitor). Herein, we report the results of the clinical trials that led to the approval of risankizumab and upadacitinib in PsA and their safety profile. In addition, four clinical cases are discussed emphasizing the importance of finding the correct balance among symptom control, treatment efficacy, and possible side effects in the management of the patient with PsA. The different clinical cases involve PsA patients with very heterogeneous articular and extra-musculoskeletal manifestations treated with risankizumab and upadacitinib. While the therapeutic choice was mainly dictated by the need to control the most debilitating symptomatology for the patient, in all the cases the treatment with of risankizumab or upadacitinib has led to the improvement in the extramusculoskeletal manifestations of the disease as wel

The Role of Tumor Biomarkers in Tailoring the Approach to Advanced Ovarian Cancer

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD&rsquo;s connection with platinum-based therapy and PARP inhibitors&rsquo; response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool

Rheumatoid Arthritis from Easy to Complex Disease: From the "2022 GISEA International Symposium"

: Rheumatoid Arthritis (RA) is a systemic disease with many different clinical phenotypes. RA could be classified according to disease duration, seropositivity for rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA), joint subtype, clinical behaviourbehavior and many other subgroups. In this review, we summarize and discuss the multifaceted aspects of RA, focusing on the relationship between autoimmunity status and clinical outcome, achievement of remission and influence on treatment response, from the 2022 International GISEA/OEG Symposium

Retention rate of biologic and targeted synthetic anti-rheumatic drugs in elderly rheumatoid arthritis patients: data from GISEA registry

Objectives: An increased number of elderly individuals affected by rheumatoid arthritis (RA) has been reported, including both patients with RA onset in advanced age and patients aged with the disease. In this registry-based study, we aimed to analyze the retention rate and cause of discontinuation of biologic (b) and targeted synthetic (ts)-disease-modifying anti-rheumatic drugs (DMARDs) in RA patients over 65 year old. Methods: RA patients enrolled in the Italian GISEA registry and starting a b- or a ts-DMARD over 65 years of age were included. Demographic, clinical, serologic, and therapeutic features were collected. Results: A total of 1,221 elderly RA patients were analyzed (mean age 71.6 +/- 5.2 years). RA was diagnosed before 65 years in 72.5% of cases, a 60.6% of patients experienced a previous b- or ts-DMARD. In patients older than 65 initiating a new b- or ts-DMARDS, tumor necrosis factor alpha inhibitors (TNFi) were prescribed in 29.6% of patients, abatacept in 24.8%, anti-interleukin 6 receptor antagonists (anti-IL6R) in 16.3%, Janus kinases inhibitors (JAKi) in 24.9%, and rituximab in 4.4%. The main causes of discontinuation were primary or secondary inadequate responses (66.1%). The median retention rate for all treatments was 181.3 weeks. A statistically higher retention rate was observed for abatacept when compared to TNFi (p = 0.02), JAKi (p &lt; 0.001), and anti-IL6R (p &lt; 0.001), and for TNFi vs. JAKi (p = 0.013). Conclusion: We described, in a real-life setting, elderly RA patients treated with a biologic or a ts-DMARD in Italy. Loss of efficacy was the main cause of discontinuation, and the DMARD safety profile suggests that age does not contraindicate their use. Our study reinforced that the control of disease activity is mandatory

Development of a Nomogram Predicting the Risk of Persistence/Recurrence of Cervical Dysplasia

Background: Cervical dysplasia persistence/recurrence has a great impact on women's health and quality of life. In this study, we investigated whether a prognostic nomogram may improve risk assessment after primary conization. Methods: This is a retrospective multi-institutional study based on charts of consecutive patients undergoing conization between 1 January 2010 and 31 December 2014. A nomogram assessing the importance of different variables was built. A cohort of patients treated between 1 January 2015 and 30 June 2016 was used to validate the nomogram. Results: A total of 2966 patients undergoing primary conization were analyzed. The median (range) patient age was 40 (18-89) years. At 5-year of follow-up, 6% of patients (175/2966) had developed a persistent/recurrent cervical dysplasia. Median (range) recurrence-free survival was 18 (5-52) months. Diagnosis of CIN3, presence of HR-HPV types, positive endocervical margins, HPV persistence, and the omission of HPV vaccination after conization increased significantly and independently of the risk of developing cervical dysplasia persistence/recurrence. A nomogram weighting the impact of all variables was built with a C-Index of 0.809. A dataset of 549 patients was used to validate the nomogram, with a C-index of 0.809. Conclusions: The present nomogram represents a useful tool for counseling women about their risk of persistence/recurrence after primary conization. HPV vaccination after conization is associated with a reduced risk of CIN2+

COVID-19 and RA share SPP1 myeloid pathway that drives PD-L1pos neutrophils and CD14pos monocytes

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that BALF macrophage clusters FCN1pos and FCN1posSPP1pos predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48highS100A12pos and CD48posSPP1pos that drive Rheumatoid Arthritis (RA) synovitis. BALF macrophage cluster FABP4pos predominant in healthy lung was transcriptionally related to STM cluster TREM2pos that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and remained high in post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared to other causes of severe pneumonia, and immunohistochemistry localized SPP1pos macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives pro-inflammatory activation of CD14pos monocytes and development of PD-L1pos neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 monitoring

Practice patterns and 90-day treatment-related morbidity in early-stage cervical cancer

To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) Trial on patterns of care and surgery-related morbidity in early-stage cervical cancer