The predictive role of the TAPSE/sPAP ratio for cardiovascular events and mortality in systemic sclerosis with pulmonary hypertension.

Introduction: Reduced TAPSE/sPAP ratio has recently emerged as a predictive parameter risk factor for PH, however its role in SSc has been poorly investigated. The aim of the study was to investigate the prognostic value of the TAPSE/sPAP ratio for the prediction of mortality and cardiovascular events in patients with SSc complicated by PH. A comparison between SSc patients with PAH (SSc-PAH) and those with PH and significant ILD (SSc-PH) was also carried out. Materials and methods: A retrospective single-center study in which all patients having SSc-complicated by PH-referring to the Scleroderma-Unit of the AOU Policlinico of Modena, from October 2013 to October 2023 were evaluated. All SSc patients underwent recurrent clinical examination, routine blood chemistry analysis, functional, instrumental evaluation. Results: 61 SSc patients (F/M 52/9) were enrolled. During the follow-up, 60.1% of patients experienced at least one cardiovascular event and 62% died. The main causes of death were PH (39.4%) and other heart-related events (39.4%). The TAPSE/sPAP ratio was significantly lower in deceased patients compared to survivors (mm/mmHg 0.3 ± 0.12SD vs. 0.48 ± 0.17SD, p < 0.001). Compared to the SSc-PAH subgroup, the SSc-PH patients had lower survival rates (55.3 ± 31.2 SD months vs. 25 ± 19 SD, p = 0,05). At the multivariate analysis, TAPSE/sPAP ratio <0.32 mm/mmHg, male gender, and the presence of significant ILD were identified as independent predictors of mortality and cardiovascular events. Conclusion: Our work confirmed the predictive role of the TAPSE/sPAP ratio for mortality and cardiovascular events in patients with SSc complicated by PH.

Assessing hand grasp in patients with systemic sclerosis using the 16-grasp test: Preliminary results from a multidisciplinary study group.

BACKGROUND: Reports on hand dysfunction and rehabilitation in SSc are quite scarce in the literature and mainly focus on functional assessment tools, such as the Duruoz Hand Index and the HAMIS test for evaluating hand mobility by simulating specific grasps with nine different objects. PURPOSE OF THE STUDY: This study aimed to provide an adequate assessment methodology for hand grasp dysfunctions in patients suffering from systemic sclerosis (SSc) through the 16-grasp test. STUDY DESIGN: Case-control study. METHODS: Ninety-seven consecutive SSc patients were recruited at our Scleroderma Unit, where a 16-grasp test was performed by all patients and supervised by an experienced hand therapist. Sixteen different patterns of grasp have been divided into power grasps and precision pinch and two more modalities: static and dynamic prehension evaluation on scale from 0 to 4. We also compared previous evaluations on 19 of patients recruited. RESULTS: The majority of SSc patients (84 females and 13 males; mean age 56.0±12.0 years; mean disease duration 8.0±6.0 years) displayed grasp dysfunctions; in particular 48% and 54% reported slight difficulty in the right and left grasps respectively, 6% medium difficulty in both hands, and only 3% and 1% experienced severe difficulty respectively, while 31.5% had no issues in either hand. Our results showed that the limited cutaneous subset (lcSSc) scored a lower deficit for either grasp compared to diffuse form (dcSSc). No statistically significant differences in total grasp deficit had been noticed when comparing patients having a disease duration < 5 years or longer. In the retrospective study on 19 of these patients, 8 out of 10 lcSSc patients showed no significant changes, while in 2 out of 10, slight improvements were observed in both hands. However, in the dcSSc group, 4 out of 9 worsened bilaterally while the grasp scores for 5 of them remained unchanged. CONCLUSION: Our study reported hand involvement in both lcSSc and dcSSc forms, more significantly in dcSSc patients. This test is intended to be a more objective means of assessing grasp alterations linked to scleroderma hand deformities. Furthermore, thanks to its intuitiveness, the test may be useful for engineers designing personalized ergonomic assistive devices.

Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case-control study from the Italian national multicenter "SPRING" (Systemic Sclerosis Progression InvestiGation) Registry.

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, "late" scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets.

Impact of COVID-19 and vaccination campaign on 1,755 systemic sclerosis patients during first three years of pandemic. Possible risks for individuals with impaired immunoreactivity to vaccine, ongoing immunomodulating treatments, and disease-related lung involvement during the next pandemic phase.

Introduction: The impact of COVID-19 pandemic represents a serious challenge for 'frail' patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic. Patients and method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines. Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients (death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001). Conclusions: An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A careful monitoring of response to COVID-19 vaccines together with adequate preventive/therapeutical strategies are highly recommendable in the near course of pandemic in this frail patients' population.

Real life use of prostacyclin analog (iloprost), a multi-centric survey data from the Scleroderma study group Emilia Romagna (Sclero-RER) and review of the literature.

BACKGROUND AND AIM: Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out. RESULTS: All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses). CONCLUSIONS: These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available.

Significant nailfold capillary loss and late capillaroscopic pattern are associated with pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: To evaluate differences in nailfold videocapillaroscopy (NVC) findings between systemic sclerosis-SSc patients with and without a diagnosis of pulmonary arterial hypertension (PAH). METHODS: 110 SSc patients were enrolled in this cross-sectional, case-control, multi-centre study. Patients were divided into cases (SSc-PAH confirmed by right hearth catheterization-RHC) and controls (SSc-nonPAH with low probability of PAH). NVC patterns (early, active, and late) and morphological parameters (microvascular density, non-specific abnormalities, giant capillaries, micro-haemorrhages, avascular areas) were considered using a semiquantitative scoring system. RESULTS: SSc-PAH patients showed higher frequencies of late pattern (p < 0.01), non-specific abnormalities (p < 0.01), lower capillary density (p < 0.01), higher avascular areas (p < 0.01), and a higher mean NVC score (p < 0.01). Contrarily, the early/active pattern (p < 0.01) and a higher rate of micro-haemorrhages (p = 0.04) were more frequent in non-PAH patients. By the multivariate analysis, SSc-PAH patients, compared to non-PAH, had more non-specific abnormalities (27/55, 49.1% vs 10/55, 18.2%, adjusted OR: 16.89, 95%CI: 3.06-93.16), a lower capillary density (grade 3, 20/55, 36.4% vs 5/55, 9.1%, adjusted OR: 38.33, 95%CI: 2.34-367.80), and avascular areas (18/55, 32.7% vs 10/55, 18.2%, adjusted OR: 16.90, 95%CI: 2.64-44.35). A correlation was found between the mean pulmonary arterial pressure-mPAP and avascular areas (p < 0.01), capillary density (p < 0.01), and non-specific abnormalities (p < 0.01). A clinical model including the NVC variables may be able to predict the diagnosis of PAH. CONCLUSIONS: Our results indicate that the distinctive peripheral microcirculatory injury of SSc, i.e capillary loss and morphological abnormalities, appear more severe and pronounced in patients with SSc-PAH.

Altered pathways of keratinization, extracellular matrix generation, angiogenesis, and stromal stem cells proliferation in patients with systemic sclerosis.

Objective: Systemic sclerosis is characterized by endothelial dysfunction, autoimmunity abnormalities, and fibrosis of the skin and internal organs. The pathogenetic mechanisms underlying systemic sclerosis vasculopathy are still not clarified. A complex cellular and extracellular network of interactions has been studied, but it is currently unclear what drives the activation of fibroblasts/myofibroblasts and the extracellular matrix deposition. Methods: Using RNA sequencing, the aim of the work was to identify potential functional pathways implied in systemic sclerosis pathogenesis and markers of endothelial dysfunction and fibrosis in systemic sclerosis patients. RNA-sequencing analysis was performed on RNA obtained from biopsies from three systemic sclerosis patients and three healthy controls enrolled in our University Hospital. RNA was used to generate sequencing libraries that were sequenced according to proper transcriptomic analyses. Subsequently, we performed gene set enrichment analysis of differentially expressed genes on the entire list of genes that compose the RNA-sequencing expression matrix. Results: Gene set enrichment analysis revealed that healthy controls were characterized by gene signatures related to stromal stem cells proliferation, cytokine-cytokine receptor interaction, macrophage-enriched metabolic network, whereas systemic sclerosis tissues were enriched in signatures associated with keratinization, cornification, retinoblastoma 1 and tumor suppressor 53 signaling. Conclusion: According to our data, RNA-sequencing and pathway analysis revealed that systemic sclerosis subjects display a discrete pattern of gene expression associated with keratinization, extracellular matrix generation, and negative regulation of angiogenesis and stromal stem cells proliferation. Further analysis on larger numbers of patients is needed; however, our findings provide an interesting framework for the development of biomarkers useful to explore potential future therapeutic approaches.

One-year clinical experience on the use of Nintedanib in systemic sclerosis.

We reviewed 11 patients with systemic sclerosis-related ILD who were referred to our Scleroderma Unit from January 2020 to January 2021 and started Nintedanib. Non-specific interstitial pneumonia (NSIP) was prevalent (45%), usual interstitial pneumonia (UIP) and UIP/NSIP pattern were both 27%. Only one patient had a history of smoking. Eight patients were on mycophenolate mofetil (MMF), eight were treated with corticosteroids (mean dose 5 mg/day of Prednisone or equivalent), and three were on Rituximab. The mean modified British Council Medical Questionnaire (mmRC) decreased from 3 to 2.5. Two patients had to reduce their daily dose to 200 mg/day for severe diarrhoea. Nintedanib was generally well tolerated.

Systemic sclerosis sine scleroderma: clinical and serological features and relationship with other cutaneous subsets in a large series of patients from the national registry 'SPRING' of the Italian Society for Rheumatology.

OBJECTIVE: To describe demographic, clinical and laboratory features of systemic sclerosis sine scleroderma (ssSSc) in a large multicentre systemic sclerosis (SSc) cohort. METHODS: Data involving 1808 SSc patients from Italian Systemic sclerosis PRogression INvestiGation registry were collected. The ssSSc was defined by the absence of any cutaneous sclerosis and/or puffy fingers. Clinical and serological features of ssSSc were compared with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. RESULTS: Among patients with SSc, only 61 (3.4%) were classified as having ssSSc (F/M=19/1). Time from Raynaud's phenomenon (RP) onset to diagnosis was longer in ssSSc (3 years, IQR 1-16.5) than lcSSc (2 years, IQR 0-7), and dcSSc (1 year, IQR 0-3) (p<0.001). Clinical ssSSc phenotype was comparable to lcSSc, except for digital pitting scars (DPS) (19.7% vs 42%, p=0.01), but significantly milder than dcSSc, particularly for digital ulcers (DU) (6.6% vs 35.7%, p<0.001), oesophagus (46.2% vs 63.5%, p=0.009), lung (mean diffusion capacity for carbon monoxide 72.2±19.6 vs 62.4±22.8, p=0.009; mean forced vital capacity 105.6±21.7 vs 89.2±20.9, p<0.001) and major videocapillaroscopic alterations (late pattern 8.6% vs 47.6%, p<0.001). Moreover, in ssSSc the percentages of anticentromere and antitopoisomerase were comparable to lcSSc (40% and 18.3% vs 36.7% and 26.6%), but divergent respect to dcSSc (8.6% and 67.4%, p<0.001). CONCLUSION: The ssSSc is a quite rare disease variant characterised by clinico-serological features comparable to lcSSc, but significantly different from dcSSc. Overall, longer RP duration, low percentages of DPS and peripheral microvascular abnormalities, and increased anti-centromere seropositivity distinguish ssSSc. Further investigations based on national registries might provide useful insights on the actual relevance of the ssSSc within the scleroderma spectrum.

Real-life efficacy and safety of nintedanib in systemic sclerosis-interstitial lung disease: data from an Italian multicentre study.

INTRODUCTION: Nintedanib (NTD) has been shown to be effective in systemic sclerosis (SSc)-interstitial lung disease (ILD). Here we describe the efficacy and safety of NTD in a real-life setting. METHODS: Patients with SSc-ILD treated with NTD were retrospectively evaluated at 12 months prior to NTD introduction; at baseline and at 12 months after NTD introduction. The following parameters were recorded: SSc clinical features, NTD tolerability, pulmonary function tests and modified Rodnan skin score (mRSS). RESULTS: 90 patients with SSc-ILD (65% female, mean age 57.6±13.4 years, mean disease duration 8.8±7.6 years) were identified. The majority were positive for anti-topoisomerase I (75%) and 77 (85%) patients were on immunosuppressants. A significant decline in %predicted forced vital capacity (%pFVC) in the 12 months prior to NTD introduction was observed in 60%. At 12 months after NTD introduction, follow-up data were available for 40 (44%) patients and they showed a stabilisation in %pFVC (64±14 to 62±19, p=0.416). The percentage of patients with significant lung progression at 12 months was significantly lower compared with the previous 12 months (60% vs 17.5%, p=0.007). No significant mRSS change was observed. Gastrointestinal (GI) side effects were recorded in 35 (39%) patients. After a mean time of 3.6±3.1 months, NTD was maintained after dose adjustment in 23 (25%) patients. In nine (10%) patients, NTD was stopped after a median time of 4.5 (1-6) months. During the follow-up, four patients died. CONCLUSIONS: In a real-life clinical scenario, NTD, in combination with immunosuppressants, may stabilise lung function. GI side effects are frequent and NTD dose adjustment may be necessary to retain the drug in patients with SSc-ILD.

Topical Cannabidiol in the Treatment of Digital Ulcers in Patients with Scleroderma: Comparative Analysis and Literature Review.

OBJECTIVE: To explore the effect of topical cannabidiol (CBD) in treating digital ulcers in patients with systemic sclerosis (SSc). METHODS: In total, 45 patients with SSc who had digital ulcers were consecutively enrolled between January 2019 and December 2019. Of the participants, 25 were treated with CBD during surgical debridement and 20 were treated with standard local therapy. A numeric rating scale for pain and Health Assessment Questionnaire Disability Index were administered at the baseline and at the end of treatment. RESULTS: Local treatment with CBD was significantly associated with lower pain scores, higher health assessment scores, and an increase in participants' total hours of sleep. Patients in the control group more frequently required additional analgesic therapy. CONCLUSIONS: Topical CBD may be a valuable tool to treat pain related to digital ulcers in patients with SSc.

Lung vascular changes as biomarkers of severity in systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: It has recently become possible to assess lung vascular and parenchymal changes quantitatively in thoracic CT images using automated software tools. We investigated the vessel parameters of patients with SSc, quantified by CT imaging, and correlated them with interstitial lung disease (ILD) features. METHODS: SSc patients undergoing standard of care pulmonary function testing and CT evaluation were retrospectively evaluated. CT images were analysed for ILD patterns and total pulmonary vascular volume (PVV) extents with Imbio lung texture analysis. Vascular analysis (volumes, numbers and densities of vessels, separating arteries and veins) was performed with an in-house developed software. A threshold of 5% ILD extent was chosen to define the presence of ILD, and commonly used cut-offs of lung function were adopted. RESULTS: A total of 79 patients [52 women, 40 ILD, mean age 56.2 (s.d. 14.2) years, total ILD extent 9.5 (10.7)%, PVV/lung volume % 2.8%] were enrolled. Vascular parameters for total and separated PVV significantly correlated with functional parameters and ILD pattern extents. SSc-associated ILD (SSc-ILD) patients presented with an increased number and volume of arterial vessels, in particular those between 2 and 4 mm of diameter, and with a higher density of arteries and veins of <6 mm in diameter. Considering radiological and functional criteria concomitantly, as well as the descriptive trends from the longitudinal evaluations, the normalized PVVs, vessel numbers and densities increased progressively with the increase/worsening of ILD extent and functional impairment. CONCLUSION: In SSc patients CT vessel parameters increase in parallel with ILD extent and functional impairment, and may represent a biomarker of SSc-ILD severity.

Molecular Pathways of Breast Cancer in Systemic Sclerosis: Exploratory Immunohistochemical Analysis from the Sclero-Breast Study.

Several authors reported an increased risk of cancer in SSc patients, including breast cancer (BC). Nevertheless, the mechanisms underlying this association have not yet been clarified. SSc and BC share several molecular pathways, which seem to play a common etiopathogenetic role. The previously published Sclero-Breast study demonstrated the development of BC with a good prognosis among these patients, which could be explained by an autoimmune background as a possible mechanism for limiting tumor extension. Here, we report the results of an IHC analysis of molecular pathways known to be common drivers for both diseases, with the aim to better define the mechanisms underlying a good prognosis of BC in patients affected by SSc. The analysis demonstrated higher TILs rates in all BC subgroups, with a high rate of PD-L1 expression especially in TNBC and HER2-positive BC, suggesting a less aggressive behavior in these patients compared to the general population. These results support a possible de-escalation strategy of cancer therapies in these fragile patients. These data could represent a starting point for future prospective studies based on the clinical application of these biomarkers with a larger sample size to promote a personalized and targeted oncological treatment for this specific subset of patients.

Analysis of cryoproteins with a focus on cryofibrinogen: a study on 103 patients.

OBJECTIVES: Cryofibrinogen (CF) is an abnormal protein in plasma that precipitates at 4 °C and dissolves at 37 °C. Whilst serum cryoglobulins (CGs) analysis is common practice, CF investigation is rarely performed. This study aims to describe the testing methodology developed at our laboratory, potential pitfalls for all analytical phases, the distribution among hospital wards and clinical conditions underlying test requests and clinical conditions in which to order CF analysis is useful. METHODS: Retrospective analysis of laboratory samples received between January 2019 and June 2021 with CF testing requests. RESULTS: A complete protocol for CF pre-analytical, analytical and post-analytical phases are supplied. Most test requests were received from the rheumatology department for systemic sclerosis or liver transplant screening. Among the 103 in-patients included, CF+ was confirmed in 68 patients (66%). Of observed CF+ patients (n=68) most cases were CGs- (n=44, 67%). Isolated CF was found in 43% of the cases. Among CF- patients (n=35; 34%) only 2 patients had positive CGs (CGs+). Among rheumatology patients (n=66), isolated CF+ was observed in 45% (n=30/66), whilst among patients with systemic sclerosis with CF+ (n=19), isolated CF+ was detected in 79% (n=15/19). CONCLUSIONS: Described analytical procedures may be used for the creation of harmonized recommendations and indications for CF analysis. Isolated CF positivity among hospitalized patients, predominantly rheumatology and systemic sclerosis patients, appears higher than rates previously reported in literature. We propose CF test recommendations should be included in investigation protocols for diseases where cryofibrinogenemia may occur.

Peripheral Microangiopathy Changes in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Data From a Multicenter Observational Study.

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10-15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the "late" pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

Geographical heterogeneity of clinical and serological phenotypes of systemic sclerosis observed at tertiary referral centres. The experience of the Italian SIR-SPRING registry and review of the world literature.

INTRODUCTION: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. MATERIALS AND METHODS: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. RESULTS: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. CONCLUSION: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities.

Absent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseases.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable.

Prevalence and Death Rate of COVID-19 in Autoimmune Systemic Diseases in the First Three Pandemic Waves. Relationship with Disease Subgroups and Ongoing Therapies.

OBJECTIVE: Autoimmune systemic diseases (ASD) represent a predisposing condition to COVID-19. Our prospective, observational multicenter telephone survey study aimed to investigate the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients. METHODS: The study included 3,918 ASD pts (815 M, 3103 F; mean age 59±12SD years) consecutively recruited between March 2020 and May 2021 at the 36 referral centers of COVID-19 and ASD Italian Study Group. The possible development of COVID-19 was recorded by means of a telephone survey using a standardized symptom assessment questionnaire. RESULTS: ASD patients showed a significantly higher prevalence of COVID-19 (8.37% vs. 6.49%; p<0.0001) but a death rate statistically comparable to the Italian general population (3.65% vs. 2.95%). Among the 328 ASD patients developing COVID-19, 17% needed hospitalization, while mild-moderate manifestations were observed in 83% of cases. Moreover, 12/57 hospitalized patients died due to severe interstitial pneumonia and/or cardiovascular events; systemic sclerosis (SSc) patients showed a significantly higher COVID-19-related death rate compared to the general population (6.29% vs. 2.95%; p=0.018). Major adverse prognostic factors to develop COVID-19 were: older age, male gender, SSc, pre-existing ASD-related interstitial lung involvement, and long-term steroid treatment. Of note, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs. 46.99%; p=0.000), as well as the SSc patients treated with low dose aspirin (with 5.57% vs. without 27.84%; p=0.000). CONCLUSION: During the first three pandemic waves, ASD patients showed a death rate comparable to the general population despite the significantly higher prevalence of COVID-19. A significantly increased COVID-19- related mortality was recorded in only SSc patients' subgroup, possibly favored by preexisting lung fibrosis. Moreover, ongoing long-term treatment with csDMARDs in ASD might usefully contribute to the generally positive outcomes of this frail patients' population.

Photobiomodulation Therapy: A New Light in the Treatment of Systemic Sclerosis Skin Ulcers.

INTRODUCTION: Skin ulcers (SU) represent one of the most frequent manifestations of systemic sclerosis (SSc), occurring in almost 50% of scleroderma patients. SSc-SU are often particularly difficult to treat with conventional systemic and local therapies. In this study, a preliminary evaluation of the role and effectiveness of blue light photobiomodulation (PBM) therapy with EmoLED® in the treatment of scleroderma skin ulcers (SSc-SU) was performed. METHODS: We retrospectively analyzed 12 consecutive SSc patients with a total of 15 SU on finger hands. All patients were treated with adequate systemic therapy and local treatment for SU; after a standard skin ulcer bed preparation with debridement of all lesions, EmoLED® was performed. All patients were locally treated every week during 2 months of follow-up; SU data were collected after 4 weeks (T4) and 8 weeks (T8). Eight SSc patients with comparable SU were also evaluated as controls. RESULTS: The application of EmoLED® in addition to debridement apparently produced faster healing of SU. Complete healing of SU was recorded in 41.6% cases during EmoLED® treatment. Significant improvements in SU area, length, and width, wound bed, and related pain were observed in EmoLED® patients from T0 to T8. Control subjects treated with standard systemic/local therapies merely showed an amelioration of SU area and width at the end of the follow-up. No procedural or post-procedural adverse events were reported. CONCLUSIONS: The positive clinical results and the absence of side effects suggest that EmoLED® could be a promising tool in the management of SSc-SU, with an interesting role to play in the healing process in addition to conventional systemic and local treatments.

Sex-related Differences in Systemic Sclerosis: A Multicenter Cross-sectional Study From the National Registry of the Italian Society for Rheumatology.

OBJECTIVE: There is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics. METHODS: A multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared. RESULTS: The overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs. CONCLUSION: Our study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.