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

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

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

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Background Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. Methods STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). Findings Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). Interpretation In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response

Reumatologia. Per studenti e medici di medicina generale

Gli ultimi venti anni hanno assistito ad un netto cambiamento delle caratteristiche e degli obiettivi della pedagogia medica. Partendo da una condizione \u201cprofessorocentrica\u201d nel cui ambito ciascun docente impartiva lezioni dal contenuto e dalle sfumature proprie dell\u2019attivit\ue0 scientifica e clinica di se stesso, si \ue8 lentamente giunti ad una visione \u201cstudentecentrica\u201d tesa, nel Corso di Laurea in Medicina e Chirurgia, alla trasmissione del bagaglio culturale e delle abilit\ue0 pratiche necessari per la formazione del Medico di Medicina Generale. La situazione di partenza presentava il pregio di concedere a ciascun docente la possibilit\ue0 di dare il meglio, permetteva di fare emergere un ridotto numero di studenti eccellenti, che frequentavano queste o quelle aule per scelta e non per obbligo, ma lasciava al proprio destino la grandissima parte degli aspiranti medici, i quali, privi di direttive certe e definite, non riuscivano a focalizzare le conoscenze necessarie alla propria formazione. La condizione attuale supera questi problemi ma presenta ancora un limite. Studenti di Universit\ue0 italiane diverse possono, in questo o in quel campo, acquisire conoscenze di vario livello, essendo alcuni stimolati, sia pure nei limiti del core curriculum, a dirigere la propria attenzione in un settore altri in un altro. Queste considerazioni hanno indotto UNIREUMA (l\u2019associazione che riunisce tutti coloro che a vario titolo svolgono funzioni di docente di Reumatologia nelle Universit\ue0) a dare vita al tentativo di uniformare il bagaglio culturale reumatologico degli studenti di qualsivoglia Universit\ue0. Il razionale di partenza \ue8 stato quello di assegnare a ciascun docente argomenti in cui avesse una comprovata qualificazione scientifica e clinica. La tappa successiva \ue8 stata quella di precisare, in ogni capitolo, quanto lo studente non possa non sapere, corredando ogni capitolo con un questionario a risposte multiple teso a testare l\u2019acquisizione dell\u2019argomento trattato. Consci di non essere stati i primi a ritenere che in un\u2019epoca di crollo dei confini e di mobilit\ue0 sanitaria (dei medici al di l\ue0 di quelle dei pazienti) fosse indispensabile delineare in modo uniforme sul territorio nazionale le caratteristiche e i limiti della preparazione del Medico di Medicina Generale, i Reumatologi hanno dato vita a questo volume che vuole rappresentare il primo di una serie tesa ad uniformare la preparazione dello Specialista in Reumatologia cos\uec come quella di studenti iscritti ad altri Corsi di Laurea che comprendono la disciplina. Questa esigenza, comune ad altri settori, \ue8 resa pi\uf9 cogente per alcune specificit\ue0 della Reumatologia: nata come Patologia Medica delle malattie articolari, ha visto estendere i propri confini per comprendere malattie e sindromi che interessano altre strutture dell\u2019apparato locomotore (tessuti molli, ossa) accomunate dal sintomo dolore muscoloscheletrico o condizioni che interessano soprattutto organi ed apparati diversi (polmone, cuore, rene, etc) ma comportano pi\uf9 o meno frequentemente un interessamento articolare e possono esordire con un\u2019artropatia. Le diversit\ue0 pur esistenti nelle vocazioni scientifiche e cliniche delle varie Scuole non possono tradursi in bagagli culturali differenziati fra studenti di sedi diverse

Reumatologia. Per studenti e medici di medicina generale

UNIREUMA \ue8 un\u2019associazione che riunisce tutti i docenti di Reumatologia delle Universit\ue0 Italiane e che da circa 10 anni promuove iniziative, nell\u2019ambito della pedagogia medica, dedicate precipuamente all\u2019insegnamento ed alla formazione in Reumatologia. Questo libro, che \ue8 ormai alla terza edizione e a cui hanno contribuito tutte le Scuole di Reumatologia delle Universit\ue0 Italiane, \ue8 il portato dalle scelte metodologiche, delle proposte classificative e delle raccomandazioni/linee guida della Comunit\ue0 Scientifica Internazionale di cui i reumatologi italiani sono parte. In particolare per la classificazione delle malattie reumatiche UNIREUMA, congiuntamente con la Societ\ue0 Italiana di Reumatologia (SIR), sta completando una revisione che verr\ue0 riportata nella ristampa di questo libro, ma di cui gi\ue0 tiene conto questa edizione. Sono stati infatti inseriti capitoli completamente nuovi, come quelli dedicati alle malattie autoinfiammatorie ed alla malattia IgG4 correlata; \ue8 stato inserito un nuovo capitolo che tratta dei principi generali di terapia delle malattie reumatologiche; \ue8 stato infine aggiunto un ampio capitolo su malattie reumatiche e gravidanza. Quest\u2019ultimo capitolo \ue8 di particolare importanza ed utilit\ue0 perch\ue9 tratta argomenti in larga misura innovativi e che comunque non trovavano spazio nei libri di Reumatologia n\ue9 sono comunemente oggetto di trattazione nel corso di lezioni. Molti aspetti delle malattie reumatiche hanno registrato profonde revisioni negli ultimi 15 anni ed a questo hanno contribuito nuove acquisizioni delle conoscenze immunologiche riguardo al ruolo di particolari sottopopolazioni di linfociti quali i Treg ed i Th17. Cos\uec come si sono ulteriormente sviluppate le conoscenze dei mediatori solubili (citochine) e dei loro recettori, del ruolo patogeno dell\u2019immunit\ue0 innata, nonch\ue9 dei meccanismi di trasmissione dei segnali coinvolti nella risposta immune. Per ognuno di questi aspetti \ue8 stato possibile sviluppare nuove terapie \u201cmirate\u201d che hanno grandemente modificato la prognosi e la possibilit\ue0 di cura delle principali malattie reumatologiche. Si sono inoltre molto sviluppate nuove conoscenze sull\u2019infiammazione e sui fattori che la inducono e la regolano. Basti pensare a questo proposito alle scoperte che riguardano il ruolo degli adipociti nell\u2019infiammazione, o quello di agenti microbici quali porphyromonas gingivalis nell\u2019Artrite Reumatoide, o infine il ruolo del fumo di sigaretta nelle artriti infiammatorie. Un\u2019ultima considerazione merita il fatto che la trattazione delle malattie reumatologiche non in tutti i corsi di laurea trova lo spazio, in termini di ore di lezione, per una trattazione completa e sistematica di tutte le oltre 150 malattie. Gli studenti troveranno in questo libro la trattazione di tutti gli argomenti di interesse, vuoi per il peso epidemiologico, vuoi per il loro valore scientifico, vuoi infine per gli aspetti terapeutici innovativi

Role of nerve growth factor and tropomyosin receptor kinase A in the pathogenesis of osteoarthritis. Might nerve growth factor be the link interwinding obesity and osteoarthritis?

Letter to the Edito

Multiple sclerosis in childhood. Longitudinal study in 14 cases

The Authors review the literature on the occurrence of multiple sclerosis in children and add 14 personal cases below the age of 15.5 years, the youngest being 6.4 years old. Modality of onset, clinical course, clinical classification according to the criteria proposed by McDonald and Halliday, paraclinical evidence of lesions and disability grade at the last control are widely discussed. Eleven cases were scheduled as clinically definite multiple sclerosis. In the youngest children the recovery may be often complete or the disability grade may be lo