Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is one of the leading causes of morbidity and mortality in SSc, affecting up to three-quarters of patients. The disease course is highly heterogeneous, ranging from indolent, nonprogressive forms to rapidly progressive pulmonary fibrosis (PPF). Identifying patients at risk for progression remains a key clinical challenge. Routine screening with high-resolution computed tomography at diagnosis and regular pulmonary function test monitoring are essential for early detection and timely management. Recent efforts have sought to harmonize the definition of PPF across fibrosing ILDs, recognizing shared clinical and pathophysiological mechanisms beyond idiopathic pulmonary fibrosis. Approximately 20% to 30% of patients with SSc-ILD develop PPF, yet reliable predictors of progression remain elusive. Advances in imaging, functional assessment, and molecular biomarkers hold promise for improving risk stratification. Therapeutic approaches have evolved from conventional immunosuppression toward combination and antifibrotic strategies. Mycophenolate mofetil remains the preferred first-line therapy, whereas nintedanib is the only antifibrotic agent approved for both SSc-ILD and PPF, having demonstrated efficacy in slowing lung function decline. Combination therapy, particularly mycophenolate mofetil with nintedanib or biologics such as rituximab and tocilizumab, is gaining traction in clinical practice despite limited comparative data. Emerging antifibrotic and anti-inflammatory agents offer new therapeutic prospects. This review summarizes current understanding of PPF in SSc-ILD, focusing on its evolving definition, prognostic determinants, and treatment landscape, and highlights unmet needs for personalized, evidence-based management.

Background: Systemic sclerosis (SSc) is characterized by endothelial dysfunction leading to progressive vascular injury and fibrosis. While microvascular involvement is well established as an early disease feature, macrovascular disease has been historically underrecognized and poorly investigated in very early disease stages. Integrated assessments across the SSc spectrum, including very early diagnosis of systemic sclerosis (VEDOSS), remain limited. Methods: In this cross-sectional observational study, patients with established SSc, VEDOSS, and primary Raynaud's phenomenon (PRP) were prospectively enrolled between October 2023 and April 2025. Participants underwent comprehensive microvascular and macrovascular evaluation, including nailfold videocapillaroscopy, multisegmental arterial Doppler ultrasound (carotid, aortic, and lower limb districts), flow-mediated dilation, and measurement of endothelial biomarkers (vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and circulating endothelial cells (CECs)). Traditional cardiovascular risk was estimated using Systematic Coronary Risk Estimation 2 (SCORE2). Results: Sixty-two female subjects were included (34 SSc, 14 VEDOSS, and 14 PRP). Microvascular abnormalities followed the expected disease continuum, with capillaroscopic changes present in 57% of VEDOSS and 91% of SSc patients. Although SCORE2 estimates and carotid intima-media thickness were comparable across groups, macrovascular abnormalities were more frequent in SSc (52.9%) and VEDOSS (50%) compared with PRP (21.4%). VCAM-1, ICAM-1, and CEC levels were significantly increased in SSc compared with PRP, whereas no significant differences were observed between VEDOSS and PRP. Conclusions: These findings support a unified micro- and macro-vascular disease model in SSc and demonstrate that macrovascular involvement is detectable already in the VEDOSS phase. Conventional cardiovascular risk scores underestimate the true vascular burden, highlighting the need for disease-specific risk stratification tools integrating vascular imaging and endothelial biomarkers.

The vascular endothelial growth factor (VEGF) receptor 2, a membrane tyrosine kinase receptor activated by VEGF-A, triggers endothelial cell proliferation, migration, survival, and angiogenesis. With the aim of identifying additional new ligands or acquiring novel information to craft potent drugs, the focus of this study was to point to this macromolecule as to a possible target for selective modulators or inhibitors. Using the Pharmit server, pharmacophore-based screening of about 450 million compounds was performed, yielding candidate ligands evaluated through molecular modeling tools such as molecular docking, molecular dynamics, and 3D quantitative structure–activity relationship analysis. The best complex, PubChem-143070699/VEGFR2, matched the proposed pharmacophore model and predicted nanomolar affinity. While experimental evidence remains mandatory to decipher the mechanisms underlying VEGFR2 inhibitors, the predicted structural insights gleaned from this research hold promise for advancing the development of increasingly potent and precisely targeted therapies for VEGFR-associated conditions, such as cancer and fibrosis-related diseases.

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:Spondyloarthritis associated with inflammatory bowel disease (Spa-IBD) often requires a customised multidisciplinary approach. The aim of this study was to evaluate long-term outcomes of a cohort of SpA-IBD patients with a multidisciplinary management. METHODS:Consecutive patients with SpA-IBD were assessed at our multidisciplinary Gastro-Rheumatological Clinic and enrolled in the SPIB (SpA in Inflammatory Bowel Disease) cohort. The primary endpoint was the proportion of patients achieving remission in both intestinal and articular domains at four years. Secondary outcomes included the cohort's baseline clinical features, progressive improvement in disease activity scores, treatment patterns, and predictors of remission. RESULTS:The cohort includes 159 patients (58% Crohn's disease, 42% ulcerative colitis). At baseline, 56% of patients were diagnosed with axial SpA-IBD, and 44% with peripheral SpA-IBD. At baseline, 0.6% of patients were in combined intestinal and articular remission, and this proportion gradually increased to 5.7% at six months and 26.3% at four years. Clinical outcomes at 4 years included improvements in TJC (Δ-3.8), SJC (Δ-1.0), LEI score (Δ-0.3), DAPSA remission status (+36.0%), ASDAS inactive disease status (+38.0%), and remission status for CDAI (+19.3%) and pMayo (+26.2%) scores. At 2 years, bDMARD therapy increased by 36%, while corticosteroid use decreased by 35%. In multivariable analysis, male gender predicted remission during follow-up (OR 2.80, 95% CI 1.21-6.76), whereas axial disease (OR 0.41, 0.17-0.96) and enthesitis (OR 0.26, 0.11-0.59) were negative predictors. CONCLUSIONS:The long-term results of the SPIB cohort highlight the value of close collaboration between rheumatologists and gastroenterologists in the application of joint-gut remission strategies.

Background:Hypogammaglobulinemia is a condition that can be related to both primary and secondary immunodeficiencies. While the role of primary immunodeficiency in immune-mediated diseases is well known, its occurrence in systemic sclerosis is not reported. Objectives:This study aims to describe the clinical features associated with hypogammaglobulinemia in a cohort of limited cutaneous systemic sclerosis patients. Methods:We retrospectively reviewed medical records of systemic sclerosis patients from two Italian referral centres (2010-2024). Included patients had limited cutaneous systemic sclerosis and presented reduced serum concentrations of one or more Ig isotypes (IgG < 700 mg/dL, IgA < 70 mg/dL or IgM < 50 mg/dL) in at least two separate measurements. Patients with secondary causes of hypogammaglobulinemia were excluded. Data collected included demographics, clinical features, Ig levels, infection history and comorbidities. Results:We identified 30 systemic sclerosis patients (93% female, mean age 62 years) with limited cutaneous involvement and hypogammaglobulinemia. Most patients were positive for anti-centromere antibodies and received periodic intravenous infusions of prostaglandin analogues. No patient received immunosuppressive therapy. Median (interquartile range) serum IgG levels 519.5 (175) mg/dL, median IgA 65.5 (48) mg/dL and median IgM 71.5 (49) mg/dL. Four patients who met the European Society for Immunodeficiencies (ESID) criteria for common variable immunodeficiency experienced recurrent infections and had associated immune-mediated diseases. Five patients had selective IgA deficiency, with frequent immune-mediated comorbidities (thyroiditis, Sjögren's syndrome, arthritis, psoriasis). The other patients exhibited mild IgG deficiency without a significant infectious history. Conclusions:This is the first study describing a cohort of patients with limited cutaneous systemic sclerosis and hypogammaglobulinemia. Our population presented a high prevalence of immune-mediated comorbidities but low infection rates. Further research is needed to explore the underlying mechanisms and clinical significance of hypogammaglobulinemia in these patients.

Objective Application of the ASAS classification criteria for axSpA in classifying axPsA is a topic of debate. In this study, we aimed to determine the prevalence of axPsA in patients with psoriasis and back pain who do not meet the entry pain features of the ASAS classification criteria.Methods Patients reporting late-onset back pain (LoBP, after the age of 45) or non-chronic back pain (NcBP, lasting less than months) in the DCS screening tool were included in a group termed 'non-ASAS back pain' (non-ASAS/BP). They underwent clinical/instrumental assessment aimed at axPsA diagnosis and were compared with those patients fulfilling both of two ASAS entry pain features at the screening (ASAS/BP).Results After rheumatological evaluation, 50/265 (18.8%) patients, 34/50 (68%) LoBP and 16/50 (32%) NcBP, were categorized as the non-ASAS/BP group. In comparison with ASAS/BP patients, the mean age was higher, and the prevalence of IBP was lower. Clinical disease activity was similar between the two groups. AxPsA was confirmed in 6/50 (12%) non-ASAS/BP patients, which is a lower incidence than in the ASAS/BP group (29.0%). Finally, non-ASAS/BP axPsA patients showed a similar proportion of inflammatory and post-inflammatory radiographic and/or MRI changes as shown in ASAS/BP axPsA patients.Conclusion This study demonstrates that among psoriatic patients who experience late-onset or non-chronic back pain, thereby not fulfilling ASAS entry pain features, a considerable proportion may be affected by active axPsA.

Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets.