Fabio Cacciapaglia

Objective: Cancer represents a major cause of death 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 the European Scleroderma Trials and Research group: “cases” were defined as patients with SSc who developed cancer at any time point; controls were patients with SSc who were cancer free, matched for age and disease duration. Malignancies were classified as “synchronous” to SSc onset (±3 years), “subsequent” (more than three years after), or “previous” (more than three years before). Clinical, serologic, and treatment associations, as well as survival rates, were analyzed. Results: A total of 454 patients with SSc with cancer (29% synchronous, 51% subsequent, 20% previous) and 454 controls were identified. Mean age was 55 ± 13 years, disease duration was 5 ± 2 years; 88% were female, and 27.5% had diffuse SSc; 30.5% had interstitial lung disease (ILD), 32% had anti‐topoisomerase, and 10% had anti‐POLR3. Synchronous cancers were associated with anti‐POLR3 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.13–3.69), U1RNP (OR 3.56, 95% CI 1.03–12.3), and smoking (OR 1.57, 95% CI 1.01–2.44), but they were negatively associated with digital ulcers (OR 0.55, 95% CI 0.31–0.93). Calcinosis was inversely associated with subsequent cancers (OR 0.42, 95% CI 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, 95% CI 1.12–3.54), anti‐topoisomerase (OR 2.61, 95% CI 1.38–5.04), and smoking. Cancers occurred more frequently in patients treated with cyclophosphamide. Malignancy worsened overall survival, particularly when subsequent. Radiation therapy did not impact mortality rate or new‐onset ILD. Conclusion: Cancer timing and site identify distinct clinical‐serologic associations in SSc, with different prognostic implications. As cancers diagnosed during follow‐up are major determinants of death, our findings inform the implementation of stratified cancer surveillance in SSc. image

Objectives: Pulmonary arterial hypertension (PAH) is a life-threatening complication of SSc. Although selexipag is approved for SSc-PAH, available data are limited. We evaluated the long-term safety and clinical predictors associated with selexipag therapy in a multicentre Italian cohort of SSc-PAH patients. Methods: We retrospectively analysed consecutive SSc patients with PAH diagnosed by right heart catheterization and treated with selexipag. Survival, treatment persistence, 1-year mortality risk (COMPERA 2.0) and predictors of clinical outcomes were assessed using appropriate statistical methods. Results: Fifty-one SSc-PAH patients (94% female, median age 71 years) received selexipag for a median (interquartile range-IQR) duration of 22 (11–44) months. The estimated survival at 3 and 5 years from PAH diagnosis was 88% and 70%, respectively; a lower COMPERA 2.0 was the only significant protective factor. Right ventricular enlargement was associated with higher mortality risk (aOR 0.01, 95% CI 0.01–0.27), higher tricuspid annular plane systolic excursion with lower risk (aOR 1.35, 95% CI 1.04–1.75). After 12 months of treatment, the COMPERA 2.0 was improved in all patients, but a low risk of death was significantly more frequent in patients starting selexipag within 1 year from PAH onset (38% vs 8%, P < 0.01). Treatment persistence reached 84% at 12 months and baseline combination PAH therapy was associated with lower rates of selexipag discontinuation. Conclusions: Selexipag demonstrated a favourable long-term safety profile in SSc-PAH patients. A preserved right ventricular function represents a key determinant for survival, while early therapeutic combination strategies including selexipag are associated with more favourable COMPERA 2.0 mortality risk.

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.

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: Antitopoisomerase I (ATA), anticentromere (ACA) and anti-RNA polymerase III (RNAP3) antibodies are included in the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis (SSc). A subset of patients with SSc satisfy criteria but may lack these specific autoantibodies, being classified as ‘triple-negative’. Methods: We conducted a retrospective evaluation of triple-negative patients with SSc prevalence and clinical features among the multicentric Systemic sclerosis Progression INvestiGation registry. Results: Out of 1480 patients with SSc, 295 (19.9%) were triple-negative, while 1185 (81.1%) had SSc-specific antibodies: ACA (54.3%), ATA (43.6%) and RNAP3 (2.1%). The triple-negative group showed a higher prevalence of myopathy (16.7% vs 10.1%, p=0.003), suggested by higher creatine phosphokinase (CPK) levels (126.2 vs 92.5 U/mL, p=0.002), more frequent CPK increase over 2–3 times (2.4% vs 0.2%, p=0.028). Triple-negative patients also exhibited fewer vascular complications, including digital ulcers (17.3% vs 22.8%, p=0.04) and calcinosis (8.2% vs 12.8%, p=0.027), and a higher prevalence of interstitial lung disease (p<0.001). Consistently, lower diffusing capacity for carbon monoxide (66.4% vs 70.98%, p=0.004) and forced vital capacity (97.01% vs 102.92%, p<0.001) were found in the triple-negative group. Triple-negative patients more frequently received corticosteroids (79.3% vs 67.9%, p=0.003), cyclophosphamide (43.4% vs 26%, p<0.001) and azathioprine (38.5% vs 22.3%, p=0.002), while less frequently received prostanoids (71.6% vs 85.9%, p<0.001), calcium channel blockers (80.1% vs 87.7%, p=0.005) and phosphodiesterase-5 inhibitors (4% vs 20%, p<0.001). Conclusions: A higher prevalence of myopathy and interstitial lung disease and a reduced vascular burden were found in the triple-negative patients, suggesting that the non-specific and non-routinely tested autoantibodies may identify an SSc endotype resembling sclero-myositis.

Background: Systemic sclerosis (SSc) is a heterogeneous autoimmune disease, where autoantibody profiling plays a central role in defining disease subsets and guiding personalized management. Objectives: To investigate the clinical phenotype and long-term outcomes of anti-Th/To positive SSc patients in an international cohort, focusing on interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), malignancy association, organ damage accrual, and mortality within a precision medicine framework. Design: Multicenter case-control study. Methods: Data prospectively collected from 28 European Scleroderma Trial and Research centers were analyzed (CP144). For each anti-Th/To+ case, two anti-Th/To− controls were matched by sex, age at onset, and disease duration to enable detailed phenotypic comparisons. Results: A total of 102 anti-Th/To+ patients were compared to 204 anti-Th/To− matched controls. Anti-Th/To+ patients had a higher prevalence of concomitant anti-Ro52+, lower frequency of diffuse cutaneous involvement, digital ulcers, pitting scars, and telangiectasias. ILD on high-resolution computed tomography and ILD functional progression events were less frequent in anti-Th/To+ patients, and anti-Th/To positivity was not independently associated with ILD in multivariable analysis. Instead, ILD presence was significantly associated with anti-Topoisomerase-1 (anti-Topo1) and anti-Ro52 positivity, and lack of anticentromere antibodies. Similarly, myocarditis was less frequently observed in anti-Th/To+ cases, although myositis had a higher rate than in anti-centromere+ or other lcSSc patients. Other SSc manifestations, including PAH, and malignancies synchronous to SSc onset had similar frequencies between cases and controls. Anti-Th/To+ patients accrued mild organ damage during the disease course, with lower damage index scores than anti-Topo1+ matched controls. No SSc-related deaths occurred in anti-Th/To+ patients, who had survival curves slightly better, although not significantly different, than matched controls. Conclusion: Anti-Th/To+ SSc patients are characterized by low prevalence of major organ involvement, including ILD, when compared to matched controls, mild organ damage, and good survival. These results reinforce the ongoing use of autoantibody profiling—including rarer antibodies—in precision medicine for 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.