Italian recommendations for the assessment of cardiovascular risk in rheumatoid arthritis: a position paper of the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group of the Italian Society of Rheumatology

Objectives: Rheumatoid arthritis (RA) patients are at high risk of cardiovascular (CV) events. The aim of this position paper is to provide Italian rheumatologists with an easy, feasible and time-saving CV risk assessment in their daily clinical practice. Methods: A narrative review of the literature and an assessment of the methodological strength underlying the current evidence on CV risk assessment in patients with RA were performed. The evidence-based results were shared among the members of the steering committee of the CORDIS study group of the Italian Society of Rheumatology. Subsequently, a unanimously agreed-upon algorithm was discussed and finally approved by the experts. Results: RA patients should have their CV profile monitored using the Italian 'Progetto Cuore' chart, according to the current EULAR recommendations for CV risk management, at least every 5 years. In the presence of high disease activity, or a multi-drug failure condition, when prolonged treatment with glucocorticoids and/or NSAIDs is required, or if hypertension, dyslipidaemia, or diabetes mellitus are concomitant, a more stringent CV risk assessment should be considered. When moderate CV risk is documented, patients should undergo intima-media thickening measurement. The condition of high CV risk requires a cardiological evaluation. Conclusions: This position paper provides five Italian recommendations for CV risk assessment in RA patients. A general and uniform approach to CV risk profiling may be useful to identify those patients who should undertake intensive preventive strategies to improve their CV outcomes

Clinical Features of Diabetes Mellitus on Rheumatoid Arthritis: Data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group

Rheumatoid arthritis (RA) and diabetes mellitus (DM) are linked by underlying inflammation influencing their development and progression. Nevertheless, the profile of diabetic RA patients and the impact of DM on RA need to be elucidated. This cross-sectional study includes 1523 patients with RA and no episodes of cardiovascular events, followed up in 10 Italian University Rheumatologic Centers between 1 January and 31 December 2019 belonging to the "Cardiovascular Obesity and Rheumatic DISease (CORDIS)" Study Group of the Italian Society of Rheumatology. The demographic and clinical features of DM RA patients were compared to non-diabetic ones evaluating factors associated with increased risk of DM. Overall, 9.3% of the RA patients had DM, and DM type 2 was more common (90.2%). DM patients were significantly older (p < 0.001), more frequently male (p = 0.017), with a significantly higher BMI and mean weight (p < 0.001) compared to non-diabetic patients. DM patients were less likely to be on glucocorticoids (p < 0.001), with a trend towards a more frequent use of b/ts DMARDs (p = 0.08), and demonstrated higher HAQ (p = 0.001). In around 42% of patients (n = 114), DM diagnosis preceded that of RA. Treatment lines were identical in diabetic and non-diabetic RA patients. DM is a comorbidity that may influence RA management and outcome. The association between DM and RA supports the theory of systemic inflammation as a condition underlying the development of both diseases. DM may not have a substantial impact on bDMARDs resistance, although further investigation is required to clarify the implications of biological therapy resistance in RA patients

Effects of cytotoxic T-lymphocyte-associated protein 4 compared to TNF inhibitors on lipid profile:Results from an observational multicentre rheumatoid arthritis cohort

AIM: To evaluate the impact of selective cytotoxic T-lymphocyte-associated protein 4 (CTLA-4Ig) compared to tumor necrosis factor inhibitors (TNFi) on cardiovascular (CV) clinical and laboratory outcomes in patients with rheumatoid arthritis (RA).METHODS: We performed a prospective observational multicenter study of RA patients included in the "Cardiovascular Obesity and Rheumatic DISease (CORDIS)" Study Group database, collecting demographic, clinical, and laboratory data of those starting a CTLA-4Ig or TNFi at baseline, 6-month, and 12-month follow-up.RESULTS: Of the 206 RA patients without previous CV events enrolled in the study, 64 received a CTLA-4Ig and 142 a TNFi. The two groups did not differ in age, gender, or smoking habits, and the prevalence of hypertension, diabetes, and metabolic syndrome was similar. Over a follow-up period of 12 months, although no significant differences were found in the disease activity course, we observed that LDL cholesterol levels slightly decreased only in the CTLA-4Ig-treated patients.CONCLUSIONS: Patients treated with both CTLA-4Ig and TNFi did not differ in disease activity response and changes in traditional CV risk factors after 12 months of treatment. However, CTL-A-4Ig treatment is associated with a favorable change in lipid profile at 12-month follow-up.</p

CD123 Is Consistently Expressed on NPM1-Mutated AML Cells

NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1mut and wild-type samples, examining the whole blastic population, as well as CD34+CD38&minus; leukemic cells. We demonstrate that CD123 is highly expressed on NPM1mut cells, with particularly high expression levels showed by CD34+CD38&minus; leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1-mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies

CD123 Is Consistently Expressed on <i>NPM1</i>-Mutated AML Cells

NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1mut and wild-type samples, examining the whole blastic population, as well as CD34+CD38− leukemic cells. We demonstrate that CD123 is highly expressed on NPM1mut cells, with particularly high expression levels showed by CD34+CD38− leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1-mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies

C-reactive protein and 10-year cardiovascular risk in rheumatoid arthritis

Objectives: To evaluate the association between C-reactive protein (CRP) and 10-year risk of cardiovascular (CV) events using the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), based on conventional and RA-specific risk factors but not CRP, in RA patients without previous cardiovascular events. Methods: ERS-RA was calculated in 1,251 "Cardiovascular Obesity and Rheumatic Disease Study (CORDIS)" database patients [(age 60.4(9.3) years; 78% female; disease duration, 11.6(8) years; CDAI, 9(9); CRP, 6.8(12) mg/L].Results: The mean (SD) 10-year risk of CV events was 12.9% (10). After adjusting for the use of DMARDs and biologics, CRP concentrations were significantly associated with 10-year risk of CV events (coefficient=0.005 for each 10 mg/L CRP increment; 95%CI 0.000-0.111; p = 0.047). In mediation analysis, the association between CRP and ERS-RA was not explained by disease activity.Conclusion: In a large cohort of RA patients without previous cardiovascular events, a 20 mg/L increase in CRP concentrations was associated with a 1% increase in 10-year risk of CV events. This suggests that actively tar-geting residual inflammatory risk beyond conventional and RA-specific risk factors might further reduce CV event rates in RA patients

High rates of sustained virological response despite premature discontinuation of directly acting antivirals in HCV-infected patients treated in a real-life setting

In routine clinical practice, HCV-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the pre-defined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years and 53 (14.5%) patients were HIV-coinfected. Liver cirrhosis was observed in 251 (68.8%) subjects and the most represented genotypes were 1b (n=168, 46%) and 3 (n=59, 16.2%). DAA were discontinued a median of 1 (IQR 1-4) weeks before the pre-defined EOT, with 164 (44.9%) patients stopping DAAs at least two weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n=2/4) vs 99.1% (n=109/110) for ≥4 weeks, p=0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3%(n=25/30) vs 94.6%(n=209/221) for ≥8 weeks, p=0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials

NOVEL NPM1 EXON 5 MUTATIONS AND GENE FUSIONS LEADING TO ABERRANT CYTOPLASMIC NUCLEOPHOSMIN IN AML

none32siNucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but sporadically also exon 9 and 11, all causing changes at protein C-terminal end (loss of tryptophans and creation of a nuclear export signal-NES motif) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 AML patients, we found non-exon 12 NPM1 mutations in 5/387 (1.3%) NPM1c+ cases. Besides mutations in exon 9 (n=1) and exon 11 (n=1), novel mutations in exon 5 were discovered (n=3). One more exon 5 mutation was identified in additional 141 AML patients selected for wild-type NPM1 exon 12. Furthermore, 3 NPM1 rearrangements (i.e. NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13,979 AML samples screened by cytogenetic/FISH and RNA sequencing. Functional studies demonstrated that in AML cases the new NPM1 proteins harboured an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting any AML-associated NPM1 genetic lesions. Also, this study highlights the need for developing new specific assays for molecular diagnosis and monitoring of NPM1-mutated AML.noneMartelli, Maria Paola; Rossi, Roberta; Venanzi, Alessandra; Meggendorfer, Manja; Perriello, Vincenzo Maria; Martino, Giovanni; Spinelli, Orietta; Ciurnelli, Raffaella; Varasano, Emanuela; Brunetti, Lorenzo; Ascani, Stefano; Quadalti, Corinne; Cardinali, Valeria; Mezzasoma, Federica; Gionfriddo, Ilaria; Milano, Francesca; Pacini, Roberta; Tabarrini, Alessia; Bigerna, Barbara; Albano, Francesco; Specchia, Giorgina; Vetro, Calogero; Di Raimondo, Francesco; Annibali, Ombretta; Avvisati, Giuseppe; Rambaldi, Alessandro; Falzetti, Franca; Tiacci, Enrico; Sportoletti, Paolo; Haferlach, Torsten; Haferlach, Claudia; Falini, BrunangeloMartelli, Maria Paola; Rossi, Roberta; Venanzi, Alessandra; Meggendorfer, Manja; Perriello, Vincenzo Maria; Martino, Giovanni; Spinelli, Orietta; Ciurnelli, Raffaella; Varasano, Emanuela; Brunetti, Lorenzo; Ascani, Stefano; Quadalti, Corinne; Cardinali, Valeria; Mezzasoma, Federica; Gionfriddo, Ilaria; Milano, Francesca; Pacini, Roberta; Tabarrini, Alessia; Bigerna, Barbara; Albano, Francesco; Specchia, Giorgina; Vetro, Calogero; Di Raimondo, Francesco; Annibali, Ombretta; Avvisati, Giuseppe; Rambaldi, Alessandro; Falzetti, Franca; Tiacci, Enrico; Sportoletti, Paolo; Haferlach, Torsten; Haferlach, Claudia; Falini, Brunangel