VALUTAZIONE DELL'ATEROSCLEROSI SUBCLINICA MEDIANTE MISURAZIONE DELLA RIGIDITA DELLA PARETE AORTICA IN SOGGETTI AFFETTI DA SCLEROSI SISTEMICA: RISULTATI DI UN'ANALISI MONOCENTRICA

La Sclerosi Sistemica (SSc) è una malattia autoimmune sistemica ad eziologia sconosciuta, caratterizzata principalmente da tre elementi: (I) vasculopatia con un patognomonico coinvolgimento del microcircolo, (II) fibrosi di cute e organi interni, (III) flogosi sistemica testimoniata dalla presenza in circolo di autoanticorpi e citochine pro-infiammatorie. E’ una tra le patologie autoimmuni a prognosi più sfavorevole, come evidenziato dai dati di cinque recenti metanalisi che hanno dimostrato un tasso standardizzato di mortalità compreso tra 2,72 e 3,53. L’interessamento polmonare, inteso sia come ipertensione arteriosa polmonare che come fibrosi polmonare, rappresenta al momento la principale causa di mortalità, mentre circa il 20-30% delle morti sono riconducibili a problematiche di natura cardiovascolare (CV) e, sebbene un alto tasso di mortalità CV sia comune anche nella popolazione generale, i pazienti con SSc muoiono per patologie CV più di un decennio prima. E’ ben noto come patologie autoimmuni, quali il lupus eritematoso sistemico, l’artrite reumatoide e la sindrome di Sjögren, presentino un elevato rischio di mortalità precoce principalmente per problematiche CV e che l’aterosclerosi (ATS) subclinica accelerata, unitamente all’azione di fattori di rischio CV tradizionali ed ai mediatori dell’infiammazione cronica e dell’autoimmunità, rappresentino i principali meccanismi patogenetici alla base di tale aumentato rischio CV. Rispetto a quanto dimostrato nei pazienti affetti dalle altre patologie autoimmuni, la prevalenza dell’ATS accelerata in pazienti affetti da SSc appare minore, forse perché, in questa patologia, la componente infiammatoria sembra avere un ruolo secondario nella patogenesi della malattia stessa e, di conseguenza, il danno aterosclerotico subclinico della parete vasale potrebbe avere un decorso meno aggressivo. Un altro aspetto da considerare è che, a differenza delle altre patologie sistemiche autoimmuni, nella SSc si ha un prevalente coinvolgimento del microcircolo mentre non è ancora stato definitivamente accertato se ci possa essere anche una concomitante patologia del macrocircolo e, di conseguenza, un danno aterosclerotico precoce vasale. A dimostrazione di ciò, i dati inerenti la prevalenza dell’ATS subclinica in corso di SSc sono piuttosto contrastanti. I dati derivanti dagli studi condotti negli anni ’60 e ’70, quando la principale causa di morte era la crisi renale sclerodermica, suggerivano che una ATS clinicamente manifesta era rara nella SSc e che il coinvolgimento CV era più facilmente il risultato di un vasospasmo coronarico. Successivamente, le cause di morte si sono modificate e recenti review sistematiche hanno concluso come la prevalenza di ATS sia incrementata in corso di SSc e si correli ad una peggior prognosi. Alla luce di ciò, lo scopo del presente lavoro è stato quello di valutare l’ATS subclinica, tramite la misurazione della pulse wave velocity e dell’augmentation index, in una coorte di pazienti affetti da SSc afferenti alla Struttura Semplice Dipartimentale di Reumatologia dell’Università degli Studi di Perugia, in confronto con un gruppo di soggetti sani, e di indagare le eventuali associazioni con parametri specificamente correlati con la malattia di base

Validation study of predictive value of capillaroscopic skin ulcer risk index (CSURI) in scleroderma patients treated with bosentan

In this validation study, the predictive value of capillaroscopic skin ulcer risk index (CSURI) in scleroderma patients treated with bosentan has been investigated. Seventy-six consecutive SSc patients treated with bosentan 125 mg bid were enrolled in a multicentre study. The area under the curve was 0.69 (95%CI 0.57-0.79, p=0.0019) and, at the validated cut-off value of 2.96, sensitivity was 86.1%, specificity 60.0%, positive and negative likehood ratio 2.15 and 0.23, while negative and positive predictive values were 82.1% and 64.6%, respectively. CSURI showed a lower negative predictive value in the bosentan group when compared with the control group, while the positive predictive value was similar

T Regulatory and T Helper 17 Cells in Primary Sjögren’s Syndrome: Facts and Perspectives

Historically, primary Sjögren’s syndrome (pSS) was thought to be a T helper (h) 1 driven disease due to the predominance of CD4+T lymphocytes and their products in target organs and peripheral blood of patients. In the last decades, the identification of a number of T cell subsets, including Th17, T regulatory (Treg), and follicular helper T cells, challenged this long-standing paradigm and prompted to identify their role in pSS pathogenesis. In addition the impact of abnormal proinflammatory cytokine production, such as IL-6, IL-17, IL-22, and IL-23, has also attracted considerable attention. However, although several studies have been carried out in experimental models and patients with pSS, many aspects concerning the role of Treg cells and IL-17/Th17 cell system in pSS pathogenesis are not fully elucidated. In particular, the role played by different IL-17-producing T cell subsets as well as the effects of pharmacological therapies on Treg/Th17 cell balance represents an intriguing issue. The aim of this review article is to provide an overview of current knowledge on Treg cells and IL-17-producing T cells in pSS pathogenesis. We believe that these insights into pSS pathogenesis may provide the basis for successful therapeutic intervention in this disease

Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients

BACKGROUND: This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors. METHODS: Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments. RESULTS: Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67+-activated CD8+ T cells accompanied by a decrease of B cells and the reduction of CD14Dim CD16bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients. CONCLUSION: Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses. TRIALREGISTRATION NUMBER: NCT02760797

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade

Background This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). Methods Emactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. Results Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. Conclusion Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation