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

OBJECTIVES:To describe the prevalence of gastrointestinal (GI) symptoms in SSc and Very Early Diagnosis of SSc (VEDOSS), identify clinical and serological features associated with GI involvement and explore a cranio-caudal pattern of symptom distribution, using data from the Italian SPRING-SIR registry. METHODS:This cross-sectional analysis included patients fulfilling 2013 ACR/EULAR SSc or VEDOSS criteria. GI involvement was defined as symptoms in at least one GI tract segment and categorized as upper and lower. Associations between GI involvement and clinical variables were assessed using logistic and ordinal regression models, adjusting for demographics, disease characteristics and autoantibodies. RESULTS:Among 1917 SSc patients, 56% had GI symptoms, associated with longer disease duration, dcSSc, interstitial lung disease (ILD), digital ulcers (DU), telangiectasias and tobacco exposure. Extensive GI involvement correlated with more severe disease. Ordinal regression identified female sex, dcSSc, ILD, DU, telangiectasias, tobacco exposure and anti-centromere antibodies as variables significantly associated with more extensive GI involvement. Disease duration did not show a significant association with GI symptom extent. Among 211 VEDOSS patients, 41.2% reported GI symptoms (mostly oesophageal), significantly associated with puffy fingers and dyspnoea. Among VEDOSS, puffy fingers and anti-centromere antibodies were independent predictors of presence of oesophageal symptoms. CONCLUSION:GI involvement in SSc is linked to more severe disease and longer disease duration. Disease duration resulted linked to the presence of GI symptoms rather than extent of GI involvement. Puffy fingers and anti-centromere antibodies may associate with presence of early oesophageal symptoms in VEDOSS.

OBJECTIVES:To assess the relationship between disease duration and the prevalence/distribution of nailfold videocapillaroscopy (NVC) patterns, named according to the current classification as 'early', 'active' and 'late', in a large cohort of systemic sclerosis (SSc) patients. METHODS:A cross-sectional analysis was conducted on 1689 patients undergoing standardized NVC. Clinical-serological data and treatments were collected. Statistical comparisons and multivariable logistic regression models were applied, including analyses based on disease duration. RESULTS:The prevalence of NVC patterns was as follows: 'early' 21.6%, 'active' 47.4%, 'late' 25.7% and normal/non-specific 5.3%. The distribution by disease duration showed that the three main patterns were always present. While the 'early' and 'active' progressively decreased (from 30.3% and 51.9% in patients with ≤5 yrs, to 14.6% and 43.5% in those >10 yrs, P < 0.01), the 'late' pattern increased from 13.2% (≤5 yrs) to 36.0% (>10 yrs) (P < 0.001) and was associated with internal organ involvement, anti-topoisomerase antibodies and more therapies (P < 0.01). Conversely, the 'early' and 'active' patterns were associated with the limited-cutaneous subset (P < 0.01) and anti-centromere antibodies (P < 0.001). Multivariable analysis confirmed a strong association between the 'late' pattern and skin/peripheral vascular involvement. Notably, the presence of the 'late' pattern in patients with ≤2 yrs (10.9%) was significantly associated with scleroderma renal crisis (P = 0.012). CONCLUSION:SSc-NVC patterns are not strictly time-dependent and can be observed at any stage of the disease, suggesting that microvascular damage progression is heterogeneous across different disease periods. Therefore, a revised classification of NVC changes considering both disease duration and NVC severity could improve its prognostic accuracy.

Objective To evaluate 6-month clinical outcomes in obese patients with psoriatic arthritis (PsA) who initiated tirzepatide concurrently with biologic therapy compared with those starting biologics alone. Methods Propensity score-matched comparative study at tertiary care rheumatology centres. Patients with PsA with body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity initiating tirzepatide (2.5 mg/week, uptitrated to 5 mg/week after 1 month) with biologic therapy were prospectively enrolled from January 2025. Controls initiating biologics alone (2021–2025) were matched 1:2 on BMI, disease duration, Disease Activity Index for Psoriatic Arthritis (DAPSA) and Psoriasis Area and Severity Index (PASI). Outcomes at 6 months included minimal disease activity, DAPSA low disease activity (≤14), PsA Impact of Disease-12 (PsAID-12) Patient Acceptable Symptom State (PASS ≤4), Health Assessment Questionnaire (HAQ ≤0.5), PASI ≤1, Visual Analogue Scale pain and C reactive protein (CRP). Continuous outcomes were additionally analysed with ANCOVA adjusted for baseline and a mixed (time × group) model. Results Thirty-one patients completed 6 months and were matched to 62 controls. Baseline characteristics were well balanced. The tirzepatide group showed greater BMI reduction (−2.9±2.0 vs +0.4±1.2 kg/m², p<0.001) and lower CRP (4.2±3.8 vs 7.7±3.0 mg/L, p<0.001). PsAID-12 PASS was achieved by 48% vs 21% (OR 3.44, 95% CI 1.38 to 8.63, p=0.009), HAQ≤0.5 by 42% vs 18% (OR 3.27, 95% CI 1.26 to 8.44, p=0.022) and PASI≤1 by 74% vs 52% (OR 2.59, 95% CI 1.03 to 6.56, p=0.045). Baseline-adjusted ANCOVA confirmed significant 6-month differences in favour of tirzepatide for BMI, CRP, PsAID-12 and DAPSA, with a significant time × group interaction for BMI, CRP and PsAID-12. Conclusion Concurrent tirzepatide and biologic initiation in obese PsA was associated with significantly better patient-reported outcomes, skin disease control, baseline-adjusted joint disease activity and CRP reduction at 6 months.

Varicella-zoster virus (VZV) is a neurotropic herpesvirus responsible for varicella and herpes zoster. Beyond its classical clinical manifestations, recent evidence shows that VZV reactivation may contribute to acute cardiovascular events. Vaccination reduces the incidence of herpes zoster and may confer cardiovascular benefits, although causality remains unproven. To summarise current evidence linking VZV infection to cardiovascular risk, evaluate the impact of VZV vaccination in the general and immune-mediated inflammatory disease (IMID) populations, and discuss the hypothesis that increased VZV reactivation under Janus kinase inhibitor (JAKi) therapy may partially explain the major adverse cardiovascular event (MACE) signal observed in the ORAL Surveillance trial. Epidemiologic studies show a consistent association between herpes zoster and a transient increase in MACEs. Mechanistic insights support VZV's ability to infect vascular tissues, induce inflammation, destabilise atherosclerotic plaques, and enhance thrombogenicity. Vaccination with the recombinant zoster vaccine (RZV) effectively prevents herpes zoster and is associated with reduced MACEs in large observational cohorts, although randomised trials powered for cardiovascular endpoints are lacking. In IMID populations, vaccination reduces herpes zoster incidence but has not consistently demonstrated cardiovascular benefit. JAKis, which increase VZV reactivation risk by impairing antiviral immunity, may create episodic vascular insults that contribute to the elevated MACE rates observed with tofacitinib in the ORAL Surveillance trial. VZV reactivation is a plausible and potentially preventable contributor to cardiovascular risk, particularly in older and immunosuppressed individuals. While vaccination shows promise in reducing zoster-associated cardiovascular risk, definitive causal evidence remains lacking. The hypothesised JAKi-VZV-vascular pathway warrants prospective evaluation.

OBJECTIVE:Mycophenolate mofetil (MMF) use in limited cutaneous systemic sclerosis (lcSSc) is relatively uncommon because of the lower fibrotic burden and the predominance of vascular complications. In vitro observations and clinical data from transplanted patients suggest a protective effect of MMF on endothelial function. Our aim was to evaluate the reasons for prescribing MMF treatment in patients with lcSSc and its impact on the need for escalation of vascular complication-related treatments during follow-up. METHODS:Patients with lcSSc enrolled in the Italian Systemic Sclerosis Progression Investigation registry were retrospectively evaluated. All patients treated with MMF were matched to patients not treated with MMF, which was based on a roll-entry time-dependent propensity score built on demographics, clinical features, and baseline treatment. The escalation of vasoactive or vasodilator treatment up to 60 months was defined as the introduction of iloprost, endothelin receptor antagonists, or phosphodiesterase-5 inhibitors on top of the ongoing treatment, because of uncontrolled or newly diagnosed vascular complications. A hazards Cox model was also adopted to quantify the association of MMF treatment with treatment escalation. RESULTS:A total of 1,435 patients with lcSSc were evaluated, of whom 152 were prescribed MMF (17.1% male; mean age at lcSSc onset 48.7 ± 13.9 years, 54.6% anti-Scl70 positive). The prescription of MMF was more common in men and in anti-Scl70 positive, anticentromere negative patients with interstitial lung disease, myositis, and without a history of digital ulcers. After matching 107 patients with MMF-untreated controls, the overall incidence of vasoactive/vasodilator treatment escalation events related to digital ulcers over a median follow-up of 40.5 months (interquartile range 23.3-60.0) was 0.3 per 100 patient-years in the MMF-treated group and 5.4 per 100 patient-years in the matched control group, with a significant difference in treatment escalation-free survival between the two groups (hazard ratio 0.05, 95% confidence interval 0.01-0.38; P value = 0.004). CONCLUSION:In patients with lcSSc, the introduction of MMF has reduced the need for escalation of vasoactive or vasodilator treatment, suggesting that it may also help to prevent vascular complications, which frequently affect patients with lcSSc.

Background Tocilizumab (TCZ) has shown beneficial effects on interstitial lung disease (ILD) in systemic sclerosis (SSc). We aimed to assess the real-life safety and effectiveness of TCZ on several SSc-related domains using data from a French-Italian multicentre cohort.Methods We conducted a retrospective analysis of patients with SSc treated with TCZ across 15 referral centres. The following clinical data were collected at 12 months before TCZ initiation, at baseline and at 12 and 24 months of treatment: modified Rodnan skin score (mRSS), pulmonary function tests, Disease Activity Score in 28 joints using C reactive protein, digital ulcers and cardiac biomarkers. ILD progression was defined as a decline ≥5 in %predicted forced vital capacity (%pFVC) over 12±3 months.Results 197 patients were included (88% female; median age 57 years; median disease duration 9 years); 67% were antitopoisomerase I positive. TCZ monotherapy was used in 29% of cases, methotrexate was the most frequent combined treatment (35%). In SSc-associated ILD, %pFVC declined significantly from −12 months to baseline (81% to 77%; p=0.003). On TCZ introduction, %pFVC stabilised and the proportion of progressors declined from 43% to 24% (p=0.015). Among diffuse cutaneous patients, mRSS decreased significantly at 12 and 24 months. Digital ulcers, arthritis activity and cardiac biomarkers also improved. Infections were the most frequent adverse events (22.8%). TCZ was discontinued in 32% of patients, mainly for inefficacy. Pulmonary arterial hypertension and older age predicted TCZ failure, whereas elevated CRP predicted better response.Conclusions In this large real-life cohort, TCZ was safe and associated with consistent benefits across different domains, supporting its role as a potential disease-modifying treatment in selected patients with SSc.

Background:The sequence and temporal relationship between Raynaud's phenomenon (RP) and the first non-Raynaud's sign/symptom (NRP) in systemic sclerosis (SSc) have been partially investigated. Objectives:To evaluate whether the mode and ages of clinical onset are associated with disease endotype and survival in SSc. Design:We included SSc patients from the Systemic sclerosis Progression INvestiGation registry of the Italian Society of Rheumatology (SPRING-SIR) registry in a cohort study, with post hoc cross-sectional and longitudinal analysis. Methods:Patients were grouped based on age-RP and age-NRP quartiles. Additionally, categories were defined based on mode of onset: RP group-RP onset at least 1 year before NRP; Simultaneous group-RP onset within the same year of NRP; NRP group-RP onset after at least 1 year after NRP. Comparisons were made using Chi-square and ANOVA tests. Logistic, linear, and multinomial regression models were applied to assess associations, while Kaplan-Meier curves and Cox regression were used to assess mortality. Results:A total of 1748 patients were eligible: 682 (39.0%) in the RP group, 1026 (58.8%) in the simultaneous group, and 39 (2.2%) in the NRP group. A higher prevalence of anti-centromere antibodies was found In the RP group, while the simultaneous group had more diffuse cutaneous SSc (dcSSc), anti-topoisomerase-I antibodies, and higher Rodnan's skin score (mRSS). The NRP group presented higher prevalence of pulmonary arterial hypertension. On logistic regression, the simultaneous group was associated with a higher prevalence of dcSSc compared to the RP group (odds ratio, 1.491, 95% confidence interval (CI): 1.032-2.154). Younger age at RP onset was associated with lower systolic pulmonary artery pressure and mRSS. In 943 patients with available follow-up (median 24 months), the simultaneous group had higher mortality compared to the RP group (hazard ratio, 1.975, 95% CI: 1.002-3.893). Conclusion:The timing of RP and NRP onset may help define SSc endotype and survival. Patients with simultaneous RP-NRP onset have more severe disease features and higher mortality risk, emphasizing the relevance of onset timing in disease stratification.

Background:Pulmonary hypertension associated with systemic sclerosis (SSc-PH) carries a significant risk of mortality. Although interstitial lung disease (ILD) often coexists with SSc-PH, its impact on prognosis varies considerably depending on disease extension. The prognostic implications of different degrees of functional impairment secondary to ILD in patients with SSc-PH remain poorly understood. Objectives:This study aimed to stratify patients with SSc-PH according to their functional parameters and to identify potential prognostic factors in different patterns of ILD extension. Design:A retrospective study was conducted on consecutive patients with SSc-PH diagnosed according to the European Society of Cardiology/European Respiratory Society guidelines for PH since 2015, from two Italian Scleroderma Centers. Methods:Patients were classified according to high-resolution computed tomography (HRCT) findings and forced vital capacity (FVC) values as pulmonary arterial hypertension (PAH) without ILD, PH-ILD with FVC ⩾70%, or FVC <70%. Survival analysis, clinical outcomes, and prognostic factors were assessed by Kaplan-Meier curves, multivariate logistic regression, and receiver operating characteristic (ROC) analysis. Results:Fifty-three patients with SSc-PH were enrolled, and their 5-year overall survival rate was 66.7%. The 29 patients with PH-ILD demonstrated significantly lower survival than the 24 patients with PAH (48% vs 87%, p = 0.005). FVC <70% was associated with markedly reduced survival (29% vs 80% for FVC ⩾70%, p = 0.003). ROC analysis confirmed FVC as a significant prognostic marker (area under the curve = 0.713, p = 0.005). Multivariate analysis identified the FVC <70% at PH diagnosis as the only significant predictor of mortality. Moreover, PH-ILD patients with FVC <70% showed the most significant functional deterioration during follow-up, with a 19% decline in FVC and a greater deterioration in World Health Organization functional class. Conclusion:An FVC <70% at baseline represents an important negative prognostic factor in patients with SSc-PH, independently of the extension of ILD on HRCT scan. Functional assessment may complement radiological evaluation and emphasize the importance of routine monitoring of lung function for risk stratification in patients with SSc-PH.

BACKGROUND:Cancer represents a major cause of mortality in systemic sclerosis (SSc). Established risk factors are limited to specific subsets, particularly early diffuse anti-RNA polymerase III (POLR3)-positive disease, needing further exploration. METHODS:We performed a nested case-control study within EUSTAR: cases were SSc patients developing cancer at any timepoint; controls were cancer-free SSc matched for age and disease duration. Malignancies were classified as synchronous to SSc onset (±3 years), subsequent (>3 years after), or previous (>3 years before). Clinical, serological, treatments associations, and survival were analyzed. RESULTS:454 SSc patients with cancer (29% synchronous, 51% subsequent, 20% previous), and 454 controls were identified. Mean age was 55±13 years, disease duration 5±2 years; 88% were female, 27.5% diffuse SSc; 30.5% had interstitial lung disease (ILD), 32% anti-topoisomerase, 10% anti-POLR3. Synchronous cancers were associated with anti-POLR3 (OR 2.06, 95%CI 1.13-3.69), U1RNP (OR 3.56, 1.03-12.3), smoking (OR 1.57, 1.01-2.44), but negatively with digital ulcers (OR 0.55, 0.31-0.93). Calcinosis was inversely associated with subsequent cancers (OR 0.42, 0.17-0.93). Breast cancer showed time-dependent associations with anti-POLR3 and anti-PM/Scl; lung cancer was mainly subsequent and associated with ILD (OR 2.00, 1.12-3.54), anti-topoisomerase (OR 2.61, 1.38-5.04), and smoking. Cancers occurred more frequently in cyclophosphamide-treated patients. Malignancy worsened overall survival, particularly when subsequent. Radiation therapy did not impact mortality or new-onset ILD. CONCLUSIONS:Cancer timing and site identify distinct clinical-serological associations in SSc, with different prognostic implications. As cancers diagnosed during follow-up are major determinants of mortality, our findings inform the implementation of stratified cancer surveillance in SSc.

Sjögren's disease (SjD) is an autoimmune exocrinopathy characterized by heterogeneous extraglandular manifestations (EGM). The systemic immune-inflammation biomarkers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have been proposed as indicators of the inflammatory burden, but data in SjD remain limited. This retrospective multicenter Italian study aimed to evaluate the NLR, PLR, and SII in exocrine SjD patients and across specific EGM. Consecutive patients fulfilling the 2016 ACR/EULAR classification criteria for SjD and with available full blood count data were included. Patients were classified as having exocrine or extraglandular SjD according to the presence of specific EGM. The NLR, PLR, and SII were calculated and compared across disease phenotypes and activity levels. Among 239 SjD patients (96

OBJECTIVES:In clinical practice, standardised reporting of nailfold videocapillaroscopy (NVC) findings is lacking, making the interpretation and comparison of results difficult. We aimed to achieve a national consensus on how to describe NVC findings in routine clinical practice. METHODS:A web-based Delphi consensus study was conducted among members of the Study Group on Capillaroscopy and Microcirculation in Rheumatic Diseases of the Italian Society of Rheumatology (CAPSIR). The study was based on items derived from a previous systematic review and international consensus by the EULAR Study Group on Microcirculation in Rheumatic Diseases (SG_MC/RD). RESULTS:A total of 40 items were proposed during the Delphi process, which was completed by 52 participants from different Italian regions. An agreement was reached on 23 items covering different aspects of the NVC examination: general aspects (2 items), description of the fingers examined (3 items), possible confounding factors (2 items), device description (2 items), image quality (1 item) and details of the NVC examination (13 items). Sixteen of these were considered mandatory for inclusion in the NVC practice report, and 7 were considered optional. CONCLUSIONS:The proposed NVC checklist covers 23 relevant issues in clinical practice, including 16 mandatory items grouped into five categories. This national consensus will improve the reproducibility and generalisability of NVC reporting in daily clinical practice. Furthermore, the outcomes of this NVC consensus process will inform the next European web-based Delphi consensus study, to be conducted among the member countries of the EULAR SG_MC/RD.