Rheumatoid arthritis (RA) patients face increased cardiovascular (CV) risk, yet existing 10-year estimation tools often underperform. This study evaluated whether unsupervised machine learning (uML) clustering can identify distinct RA patient phenotypes with varying major cardiovascular events (MACE) potentially improving risk stratification. A cross-sectional, multi-center cohort of RA patients meeting the 2010 ACR/EULAR classification criteria and without prior CV events was enrolled in January 2019 and followed-up for MACE incidence over 5 years. Clinical and demographic data, including traditional CV risk factors and SCORE2 estimates, were collected. Factor Analysis of Mixed Data (FAMD), a generalization of principal component analysis for mixed data types, was applied in Python (ver.3.9) using Prince (ver.0.7.1). Missing data observations were excluded. Bootstrapped eigenvalue distribution determined the number of FAMD components for clustering, followed by Hierarchical Clustering on Principal Components using Ward’s criterion and Euclidean distance. An XGBoost model assessed feature importance, while ANOVA and Chi-square tests evaluated cluster differences. Among 951 RA patients (mean age 61.8 ± 10.5 years; 81.1

OBJECTIVE:Idiopathic pulmonary fibrosis (IPF) and systemic autoimmune rheumatic disease (SARD)-associated interstitial lung disease (ILD) are lung disorders with distinct clinical trajectories. This study aimed to compare survival and pulmonary function trends between IPF and SARD-ILD. METHODS:We retrospectively analyzed 410 patients with ILD (154 IPF, 256 SARD-ILD) from 6 Italian centers. SARD-ILD subtypes included antisynthetase syndrome (ASyS; n = 58), dermatomyositis (DM; n = 55), systemic sclerosis (SSc; n = 106), and Sjögren disease (SjD, n = 37). Outcomes included 5-year survival and pulmonary function test (PFT) changes. RESULTS:Five-year survival was lower in patients with IPF (mean 33.6 months) than in those with SARD-ILD (mean 56.0 months; P < 0.001). SARD subtypes showed comparable survival: 58.2 months in patients with ASyS, 52.9 months in DM, 55.2 months in SSc, and 58.6 months in SjD. Patients with ASyS and DM demonstrated significant functional improvement, with forced vital capacity (FVC) increasing from 71% to 81% in ASyS (+14.1% relative) and from 69% to 78% in DM (+13%). IPF FVC declined from 78% to 72% (-7.7%). Usual interstitial pneumonia pattern was universal in IPF but seen in < 20% of patients with SARD-ILD. ILD pattern did not significantly influence functional trajectory in patients with SARD-ILD; instead, diagnosis was the primary determinant (multivariable ANOVA P < 0.001). Multivariable analysis confirmed SARD-ILD as a favorable prognostic factor (adjusted hazard ratio [aHR] 0.21), with age (aHR 1.06) and male sex (aHR 1.98) linked to poorer outcomes. CONCLUSION:SARD-ILD is associated with higher survival than IPF. Functional trajectories improved in patients with ASyS and DM, in contrast to the decline observed in those with IPF. Prognosis is more strongly influenced by the underlying diagnosis, supporting a diagnosis-centered approach to disease management.

Although guidelines recommend a multidisciplinary team (MDT) approach for the diagnosis and management of systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD), they lack guidance on MDT composition and function. This Delphi consensus project aimed to define a shared MDT model for managing patients with SARD-ILD. A questionnaire was circulated to an expert panel of 77 Italian pulmonologists, rheumatologists, immunologists, and internal medicine specialists, with statements rated over two voting rounds using a 5-point Likert scale. Response rates were 73

OBJECTIVES:The aim of this prospective multicentre observational study was to evaluate the clinical course and the incidence of interstitial lung disease (ILD) on a population affected with rheumatoid arthritis (RA). METHODS:Three hundred and twenty-five consecutive RA patients with an ongoing treatment with abatacept were enrolled in the study and followed for 24 months. At the enrolment, ILD was recorded in 20.6% of cases. Patients with ILD were followed according to the current clinical practice, while in patients without ILD, a careful assessment for respiratory symptoms and velcro crackles, also by mean of digital tools, was performed every six months. In this regard, each patient was evaluated by mean of VECTOR, a software able to identify velcro crackles with a diagnostic accuracy of 83.9% and a sensitivity of 93.2% in RA patients. RESULTS:During the study, no patients discontinued abatacept for a worsening of lung function, and no difference was recorded in two-year retention rate of abatacept between patients with and without ILD. After 24 months, ILD improved or remained stable in more than 85% of cases, while a worsening of radiologic picture was recorded in 14.9% of cases, mainly with usual interstitial pneumonia. Finally, the incidence rate of new-onset ILD was 0.39/100 patients/year. CONCLUSIONS:In conclusion, the presence of ILD did not affect the retention rate of the drug, suggesting a role for abatacept in the treatment of RA-ILD.

Die gewöhnliche interstitielle Pneumonie (UIP) ist durch die fortschreitende Lungenparenchymveränderung gekennzeichnet, die bei verschiedenen rheumatischen Autoimmunerkrankungen (ARD), einschließlich rheumatoider Arthritis und Bindegewebserkrankungen, beobachtet werden kann. Aus diagnostischer Sicht kann ein UIP-Muster im Zusammenhang mit ARD bildgebende und pathologische Merkmale aufweisen, mit denen es von dem Muster im Zusammenhang mit der idiopathischen Lungenfibrose (IPF) unterschieden werden kann, etwa das «Straight-Edge»-Zeichen in der HRCT und lymphoplasmazytäre Infiltrate bei histologischen Proben. Ein multidisziplinärer Ansatz (MDD), an dem zumindest Pneumologen, Rheumatologen und Radiologen beteiligt sind, ist für den Differenzialdiagnoseprozess von grundlegender Bedeutung. Der MDD ist jedoch auch für die Bewertung des Schweregrads, des Fortschreitens und des Ansprechens auf die Behandlung erforderlich, die auf der Kombination von Veränderungen der Symptome, Entwicklungen der Lungenfunktion und bei ausgewählten Patienten auf einer seriellen CT-Evaluierung basiert. Im Gegensatz zur IPF können bei Patienten mit ARD sowohl die funktionelle Bewertung als auch die von den Patienten berichteten Ergebnisse durch systemische Beteiligung und Komorbiditäten, einschließlich muskuloskelettaler Manifestationen der Erkrankung, beeinflusst werden. Im Hinblick auf die pharmakologische Behandlung wurden Immunsuppressiva trotz des Mangels an solider Evidenz in den meisten Fällen als Eckpfeiler der Therapie angesehen; in letzter Zeit wurden auch antifibrotische Medikamente für die Behandlung von progressiven fibrosierenden interstitiellen Lungenerkrankungen (ILD) außer IPF vorgeschlagen. Bei der ARD-ILD soll die therapeutische Wahl die Notwendigkeit der Kontrolle von systemischen und Lungenbeteiligungen mit dem Risiko unerwünschter Ereignisse durch Multimorbiditäten und -therapien in Einklang bringen. Ziel dieser Übersichtsarbeit ist es, die Definition, die radiologischen und die morphologischen Merkmale des UIP-Musters bei ARD zusammen mit den Risikofaktoren, diagnostischen Kriterien, einer prognostischen Bewertung und Überwachungs- und Behandlungsansätzen der UIP-ARD zusammenzufassen.

In the last decades, consisting evidence supported a close relationship between both innate and adaptive immune systems and the accelerated cardiovascular (CV) disease characterizing autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Indeed, several cell lines involved in the pathogenesis of these autoimmune diseases, such as macrophages and dendritic cells, as well as different T and B lymphocyte subsets, and inflammatory cytokines, have been demonstrated to be directly involved in the mechanisms underlying early atherosclerotic arterial wall damage. Traditional CV risk factors play a concomitant role but do not sufficiently account for the increased prevalence of CV disease in these patients. Indeed, the pathophysiological link between RA and SLE and atherosclerosis is based on complex inflammatory pathways that interconnect these conditions and may explain the significant morbidity and mortality rates demonstrated in these patients, with consequent significant negative effects on quality of life and long-term survival. Consequently, it is intriguing to hypothesize that immunosuppressive drugs commonly used in the treatment of these pathologies may also exert an immunomodulatory and anti-inflammatory effect in mitigating the atherosclerotic damage that has been demonstrated to occur early in the initial stages of the disease. Recognizing risk factors, predicting occurrences and early intervention to prevent CV disease development have emerged as critical objectives in RA and SLE treatment. In this review, we aimed to provide an updated overview of the atherogenic effects exerted by the immune and inflammatory pathways involved in the pathogenesis of RA and SLE. Moreover, we examined the available evidence which may support the potential effects of immunosuppressive therapies in reducing CV damage and, consequently, CV disease risk in these patients.

OBJECTIVE:Some concerns remain about the safety of nintedanib in patients with rheumatoid arthritis-related interstitial lung disease (RA-ILD), such as in the presence of comorbidities or in combination with biologic, targeted synthetic, and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). In this multicenter study, we retrospectively evaluated the safety of nintedanib in a real-world population of patients with RA-ILD from the Italian Group for the Study of Early Arthritis (GISEA) registry and the possible role of comorbidities and DMARDs on drug safety and withdrawal. Our secondary aim was to investigate the causes of nintedanib discontinuation. METHODS:Sixty-five patients treated with nintedanib in accordance with the current therapeutic indications were enrolled in the study. Nintedanib was prescribed in combination with DMARDs and/or steroids in 62 patients (95.4%). RESULTS:The 12-month retention rate of nintedanib was 76.7% and the drug was effective in about 80% of patients with ≥ 6 months of follow-up. Adverse events (AEs) were recorded in 36 subjects (55.3%), and these were mainly gastroenteric. Thirty-one subjects required a reduction of the nintedanib dose; among them, a transient or permanent reduction of the daily dose of nintedanib allowed the continuation of the treatment in 22, whereas 15 (23.1%) withdrew from the drug. All reductions and discontinuations were owing to treatment-related AEs. Comorbidities were significantly associated with side effects in multivariate analysis, whereas AEs due to nintedanib were the main cause of discontinuation. CONCLUSION:Combination therapy with DMARDs did not reduce the safety and effectiveness of nintedanib, and AEs were the main cause of drug withdrawal or dose reduction, mainly owing to comorbidities.

BACKGROUND:Interstitial lung disease (ILD) is a severe pulmonary complication of Sjögren disease (SjD), but its prevalence, natural history and survival are not completely understood. Our study aimed to investigate prevalence, incidence, and mortality of SjD-ILD in a cohort of unselected consecutive SjD patients. METHODS:all consecutive SjD patients referred to our centre were enrolled in the study. A careful assessment for respiratory symptoms was periodically performed for each patient, and high-resolution computed tomography (HRCT) was requested in case of new-onset dyspnoea, persistent dry cough, or detection of velcro crackles by mean of electronic auscultation (VECTOR). FINDINGS:At enrolment, ILD was detected in 61/257 patients with a prevalence of 23.7 %. During a mean follow-up of 42.6 ± 14.6 months, 3 new cases of ILD were recorded, with an incidence of 0.41 new cases per 100 patients/year. Multivariate analysis showed a direct association between ILD and male sex, age at SjD diagnosis, and erythro‑sedimentation rate >40 mm, and an inverse correlation with sicca syndrome. Nonspecific interstitial pneumonia was the most observed HRCT pattern, followed by usual interstitial pneumonia. During the follow-up, 21 patients (8.2 %) died, with a statistically significant difference between the overall survival of patients with (66.5 %±11.7) and without ILD (88.4 %±5.5) (p<0.001). A fibrotic pattern was associated to a worse survival rate, while no difference was observed according to the radiologic pattern. Anti-SSA antibody was a protective factor for death, while the age at diagnosis of SjD, and the extent of ILD at HRCT were directly associated to an increased mortality. INTERPRETATION:ILD can be identified in a high number of SjD patients, inducing a significant impairment in survival. The ILD extent, but not HRCT pattern of ILD, represents the main predictor of mortality. Therefore, careful monitoring, by a multidisciplinary team, should be ensured to all SjD-ILD patients.

We present the case of a 78-year-old man with a complex overlap of inclusion body myositis (IBM) and Sjögren’s disease (SjD), complicated by interstitial lung disease (ILD) and esophageal dysfunction. The patient’s neuromuscular decline was managed with periodic intravenous immunoglobulins (IVIG), while his progressive ILD required a combined immunosuppressive and antifibrotic regimen, including prednisone. This case underscores the diagnostic and therapeutic challenges in managing autoimmune overlap syndromes, particularly the rare coexistence of IBM and SjD-related ILD. We highlight the rationale behind the treatment strategy and the importance of a tailored, multidisciplinary approach in addressing both muscular and pulmonary manifestations.

BACKGROUND AND AIM:Recently, the MIRRA trial demonstrated the efficacy and safety of mepolizumab in refractory or relapsing eosinophilic granulomatosis with polyangiitis (EGPA) and the usefulness of this drug as a steroid-sparing agent. However, until now, only a few evidence is available about its effectiveness and safety in clinical practice. In this paper, we report our experience in the treatment of EGPA patients with mepolizumab in a real-world setting and review the current literature on this topic. METHODS:We retrospectively enrolled 14 patients that underwent mepolizumab therapy for EGPA at any dose and with a follow-up of at least 3 months. For each patient, demographic and clinical manifestations of the disease, laboratory parameters, BVAS, asthma exacerbations, and therapeutic management were recorded at the beginning and at the end of mepolizumab therapy. RESULTS:After a median follow-up of 16 months (3-60), all EGPA patients were in remission for both vasculitis and asthma manifestations. Mepolizumab was associated with a reduction in corticosteroids daily dose, with a significant number of patients able to discontinue corticosteroids (8/14 patients). No patients withdrew mepolizumab and no severe adverse events were recorded.  Conclusion: Our data support the long-term effectiveness of mepolizumab and, in particular, they are suggestive for a good safety profile of this drug among patients with EGPA. In the nearest future, the possibility to obtain a sustained remission in EGPA without the use of steroids should be investigated in larger controlled studies.

Objective. In the absence of national and European guidelines on the treatment of rheumatoid arthritis (RA) with interstitial lung disease (ILD), the Italian Society of Rheumatology decided to develop national clinical practice guidelines on the management of patients with RA-ILD in accordance with the requirements of the National Guideline System of the National Institute of Health. Methods. The development process included a systematic review of the available evidence and its adaptability to the Italian context, followed by a consultation with experts in rheumatology, respiratory diseases, radiology, and representatives of the health professions and patients. Results. The panel decided to develop recommendations in three main scenarios. The first section of recommendations is focused on drugs indicated for RA to assess their safety and efficacy in RA-ILD. The second set of recommendations covered the drugs indicated for the treatment of ILD in patients with RA-ILD (to assess their efficacy and safety in patients with RA). The third part of these guidelines dealt with drugs indicated for the treatment of RA-ILD upon first-line failure. Moreover, the lack or absence of scientific evidence in literature on certain topics, such as the value of a multidisciplinary treatment approach and lung transplantation, led to the decision to proceed through expert consensus to develop good clinical practice guidelines. Conclusions. These guidelines represent a fundamental step towards improving the health management of patients with rheumatological diseases in Italy by providing specific and evidence-based guidelines for the management of RA-ILD. Their use is intended to promote health and reduce the burden of morbidity and mortality in this vulnerable population.

Background: To manage cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) EULAR recommends estimating individual risk at least once every 5 years or when major changes in antirheumatic therapy occur, according to national guidelines or using the SCORE CVD risk prediction model if no national guidelines are available [1]. For the general population, several validated 10-year CV risk estimation tools are widely used in Europe and the United States (US), and some algorithms include RA as an independent CV risk item. However, it has not been ascertained which is the most appropriate CV risk prediction model to be used in daily clinical practice [2], above all in RA patients. Objectives: To test whether differences exist using five different algorithms for estimating 10-year CVD risk in a large cohort of RA patients. Methods: A cross-sectional cohort of RA patients, fulfilling the 2010 ACR/EULAR classification criteria, free from previous CV events, and included in a multicentre Italian data set, was evaluated. All available variables for the 10-year CV risk estimation by the 2021 updated SCORE-2, the Progetto Cuore (PGC) validated in the Italian population, the atherosclerotic CV disease (ASCVD) risk estimator and the Reynolds Risk Score (RRS) derived from the US population, and the Expanded Risk Score for RA (ERS-RA) resulting from the Consortium of Rheumatology Researchers of North America Registry Study data [3], were collected. Individual CV risk was estimated in all patients aged between 35 and 69 years, as the PGC is the model with the narrowest validation in that age group only. Multiple comparisons and correlations among the different algorithms were performed, also stratifying patients into low, intermediate, or high-risk conditions, as specified. All data were analyzed using the GraphPad Prism package (v.9.5.1) with appropriate statistical tests. Results: Data from 810 RA patients [78.3% female; mean age 57±8.2 years; median disease duration of 120 (95%CI 108-120) months] were analyzed. Statistically significant differences in the 10-year CV risk estimation using the different algorithms in the same RA population were detected: the ASCVD risk estimated the highest median CV risk (8.8 %; 95%CI 7.8-9.8) and the PGC the lowest (3.2%; 95%CI 2.9-3.5) (p<0.0001); the SCORE-2 and RRS algorithms did not differ in their estimation of CV risk (5.5%; 95%CI 5.0-5.5 vs 4.8%; 95%CI 4.0-5.5, respectively; p=0,26); while the median 10-year CV risk estimated by the ERS-RA algorithm was 7.3% (95%CI 6.8-7.8) [Figure 1]. The highest Spearman correlation was observed between SCORE-2 and ASCVD risk score (r=0.94 - 95%CI 0.93-0.95; p<0.0001), then with the PGC (r=0.89 - 95%CI 0.88-0.91; p<0.0001), followed by the ERS-RA (r=0.52 - 95%CI 0.46-0.57; p<0.0001), and the lowest correlation was with the RRS (r=0.45 - 95%CI 0.39-0.51; p<0.0001). Categorizing the RA cohort by CV risk class, the PGC significantly classified more patients at low CV risk, while the SCORE-2 classified the highest proportion of patients at intermediate CV risk, and the ERS-RA identified the lowest percentage of patients at intermediate CV risk and the highest percentage of patients at high CV-risk [Figure 2]. Conclusion: Our study demonstrated that five different prediction models used in an Italian cohort of RA patients estimate different probabilities of having a CV event within 10 years, with significant differences in the risk stratification of the same population. Most of the discrepancies may be due to the different variables included in each algorithm and their relative weights in the various models with different population-derived characteristics. However, a good correlation among these five algorithms emerged from this study. Rheumatologists should consider these differences and be confident in using validated and practical models to stratify the CV risk in RA patients. REFERENCES: [1] Agca R, et al. Ann Rheum Dis. 2017; 76: 17-28. [2] Tunstall-Pedoe H. Heart 2011; 97:442-444. [3] Solomon DH, et al. Arthritis Rheumatol. 2015; 67:1995-2003. Acknowledgements: NIL. Disclosure of Interests: None declared.

Background: The European Medicine Agency (EMA) identified measures to minimize the risk of serious side effects with Janus kinase inhibitors (JAKi) for chronic inflammatory disorders. Their prescription must be considered only if no suitable therapeutic alternatives are available in patients aged 65 years or older, in those at increased risk of major cardiovascular (CV) events (MACE), in current or former smokers, and in those at increased risk of cancer [1]. Estimating 10-year CV risk by validated algorithms may be a valid option to evaluate JAKi therapy eligibility in these patients. However, the actual suitability of the 10-year CV risk estimate concerning adherence to EMA guidelines has not been established. Objectives: To assess how the eligibility for JAKi therapy according to EMA guidelines varies depending on whether the physician considers the presence of at least one CV risk factor or estimates the individual CV risk according to the European Society of Cardiology (ESC) algorithm in a cohort of rheumatoid arthritis (RA) patients aged both over and under 65 years. Methods: A cross-sectional cohort of RA patients, fulfilling the ACR/EULAR classification criteria and registered in a multicentre Italian database, was evaluated. All included patients were free from previous CV events and had available variables for 10-year CV risk estimation by SCORE-2 or SCORE-2 OP algorithms [2], multiplied according to EULAR recommendations by 1.5 [3]. All traditional CV risk factors were recorded at inclusion. According to the SCORE charts, patients with an individual estimated 10-year CV risk >7.5%, >10%, or >15% if aged up to 50 years, between 50 and 69 years, or ≥70 years, respectively, were considered at high CV risk. Results: Data on 1140 RA patients [78.7% female; mean age 60±11 years; 411 (36%) patients were ≥ 65 years; median disease duration of 120 (95%CI 114-120) months] were available for analysis. Among traditional CV risk factors, 837 (73.4%) patients had dyslipidemia, 579 (50.8%) hypertension, 476 (41.7%) were overweight, 219 (19.2%) obese, 301 (26.4%) were smokers and 145 (12.7%) had diabetes mellitus. Of note, 379 (92.2%) RA patients aged ≥ 65 years old had at least one traditional CV risk factor and would not be candidates for JAKi therapy according to EMA indications. Stratifying patients according to the 10-year CV risk, 6/180 (3.3%) of patients < 50 years, 108/745 (14.5%) aged 50-69 years and 117/215 (54.4%) > 70 years were at high CV risk. Compared to the consideration of a single traditional CV risk factor if older than 65 years, a significantly lower percentage of RA patients (20.3%, p<0.0001), even considering those younger than 65 years, would not be eligible for JAKi therapy, given their high CV risk according to the SCORE-2. Conclusion: Our study shows that, if a single traditional CV risk factor is considered, more than 90% of RA patients aged ≥ 65 years would not be eligible for JAKi therapy. Whereas individual CV risk stratification according to ESC guidelines reduces the percentage of patients at high CV risk to about 20%, even considering younger patients. Post-hoc analyses of the ORAL Surveillance study showed that patients with previous CV events or a 10-year CV risk >20% had the highest risk of MACE [4]. The CV risk stratification may be considered an appropriate tool to identify patients at higher CV risk in clinical practice and therefore to be candidates for JAKi therapy only if no suitable therapeutic alternatives are available, as the EMA recommends. REFERENCES: [1] European Medicines Agency. Janus kinase inhibitors (JAKi); 2023. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/janus-kinase-inhibitors-jaki[2] SCORE2 working group and ESC Cardiovascular risk collaboration. Eur Heart J 2021; 42:2439-54.[3] Agca R, et al. Ann Rheum Dis. 2017; 76: 17-28.[4] Szekanecz Z, et al Ann Rheum Dis 81:278. Acknowledgements: NIL. Disclosure of Interests: Fabio Cacciapaglia speaker at congresses for Abbvie, Eli Lilly, Galapagos, consultant for Galapagos, Fabiola Atzeni: None declared, Elena Bartoloni: None declared, Elisa Gremese speaker at congresses for Abbvie and Eli Lilly, Andreina Manfredi speaker at congress for Eli Lilly, Matteo Piga: None declared, Garifallia Sakellariou: None declared, Francesca Romana Spinelli speaker at congresses for Abbvie, Eli Lilly and Galapagos, consultant for Abbvie and Galapagos, Ombretta Viapiana: None declared, Gian Luca Erre: None declared.

Objective: The effect of sex and gender-related variables on the evaluation of cardiovascular (CV) risk in rheumatoid arthritis patients has been poorly explored. We investigated the differences in CV risk features and scores according to sex in a wide rheumatoid arthritis (RA) cohort. Methods: This is a cross-sectional analysis of a consecutive RA cohort. Disease-specific clinical and serologic variables, traditional CV risk factors and the 10-year CV risk calculated by the SCORE-2, Progetto CUORE and Expanded Risk Score-RA algorithms were compared in males and females. Results: A total of 820 patients (193 men, 627 women) were included. Disease activity was similar between the two sexes. A significantly higher prevalence of traditional CV risk factors and higher mean CV risk scores were detected in male compared to female patients. In the multiple linear regression analysis, a higher HAQ, csDMARD use and ACPA positivity were significantly associated with an increased CV risk in females, while b/tsDMARDs was associated with a lower CV risk in males according to different algorithms. Conclusions: The distribution of traditional CV risk factors and the 10-year risk of CV disease significantly differed in female and male patients despite similar disease activity. Disease-specific variables may contribute differently to CV risk according to sex. The CV screening in RA should also take into account the different distribution of CV risk factors between sexes.