Long-Term Data on Efficacy and Safety of Selexipag for Digital Systemic Sclerosis Vasculopathy.

OBJECTIVE: Raynaud phenomenon (RP) and digital ulcers (DUs) are the main signs of digital vasculopathy in systemic sclerosis (SSc). Selexipag is an oral prostacyclin agonist approved for SSc-related pulmonary arterial hypertension. Following our previous preliminary short-course report, we herein present long-term data on selexipag safety and efficacy in the treatment of SSc digital vasculopathy. METHODS: Selexipag was administered to patients with SSc with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies. Each subject was assessed at baseline and after 3, 6, and 12 months. Clinical outcomes related to RP and DUs were evaluated along with modified Rodnan skin score of the fingers. Digital perfusion was assessed by laser speckle contrast analysis (LASCA). Nailfold videocapillaroscopy (NVC) was also performed. RESULTS: Eight patients with SSc (63% female, mean age 50.1 years) received selexipag. After 12 months of treatment, RP was reported to significantly decrease in the number of daily episodes and mean duration (P < 0.001 and P = 0.01, respectively). All patients achieved a complete healing of their DUs (P = 0.03) within 6 months. A progressive reduction of fingers skin score was observed (P = 0.03). No structural changes of capillaries were noted on NVC. Conversely, LASCA revealed an important increase in total digital perfusion (P = 0.004) despite seasonal variability. The safety profile was consistent with that reported in the literature. CONCLUSION: We observed a sustained efficacy of selexipag on SSc digital vasculopathy during 1 year of administration. Our promising results encourage the design of a new randomized controlled trial to evaluate the effect of selexipag on SSc digital vasculopathy.

Lung ultrasound and high-resolution computed tomography quantitative variations during nintedanib treatment for systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: Lung ultrasound (LUS) and high-resolution computed tomography (HRCT) are commonly used for the evaluation of interstitial lung disease (ILD). Nintedanib (NIN) is an antifibrotic therapy approved for systemic sclerosis-associated ILD (SSc-ILD). We assessed LUS and quantitative HRCT changes in SSc-ILD patients treated with NIN during a one-year follow-up, evaluating relationships between imaging variations and functional or quality-of-life outcomes. METHODS: SSc-ILD patients who started NIN were enrolled and followed for twelve months. Pulmonary function tests and patient-reported outcome measures (PROMs) were assessed half-yearly and quarterly, respectively. LUS was performed quarterly evaluating the presence of B-lines (BL) and pleural line irregularities (PLI). HRCT was repeated after one year and quantitatively analysed with CALIPER software. RESULTS: Ten patients (70% female, mean age 62 years) were enrolled. The mean total number of both BL and PLI was constantly decreased during NIN treatment, being significantly reduced after twelve months (from 175.1 ± 66.7-120.8 ± 70.3 for BL, p= 0.005 and from 50.6 ± 32.5-37.2 ± 22.4 for PLI, p= 0.05). Male gender, smoking habit and baseline forced vital capacity <70% predicted were associated with worse LUS outcomes. A greater reduction of both BL and PLI was observed in those who improved in PROMs, especially modified Medical Research Council dyspnoea scale (p= 0.016 and p= 0.04, respectively) and Saint George's Respiratory Questionnaire (p= 0.006 and p= 0.026, respectively). No significant changes in the CALIPER percentages of normal parenchyma or ILD elements were observed after twelve months of NIN, thus paralleling the stabilization obtained at pulmonary function tests. CONCLUSIONS: We present preliminary results on NIN effects on SSc-ILD as assessed by LUS, a useful method for frequently repeated monitoring, and CALIPER, a valid implementation whenever a HRCT is performed.

Comparison of different forms of Raynaud's phenomenon by LASCA proximal-distal gradient perfusion.

OBJECTIVE: To evaluate finger proximal-distal gradient (PDG) perfusion in subjects with primary Raynaud's phenomenon (PRP), then making comparisons with systemic sclerosis (SSc) patients and healthy controls (HC). METHODS: Consecutive adult PRP subjects were enrolled, along with an equal number of SSc and HC. Peripheral blood perfusion of the hands was assessed by laser speckle contrast analysis (LASCA). PDG was then calculated applying a generalizable formula independent of both intra- and inter-personal factors. Non-specific anti-nuclear autoantibody (ANA) isolated positivity was assessed. RESULTS: Fifty PRP patients (88 % female, mean age 45 ± 17.9 years) were enrolled, along with 50 SSc patients and 50 HC. After adjusting mean PDG results for age and sex, no significant differences emerged between PRP and SSc (1.80 ± 0.43 vs 1.76 ± 0.53; p = 0.294). Conversely, PRP values were significantly reduced when compared to HC (2.72 ± 0.37; p < 0.001). Among PRP subjects, no significant differences were found regarding isolated ANA positivity (1.86 ± 0.44 vs 1.74 ± 0.44; p = 0.42). CONCLUSION: PRP and SSc seems to share the same basal PDG perfusion impairment assessed by LASCA. Isolated ANA positivity, in the absence of clinical and capillaroscopic suspicion for secondary causes, should not be considered an exclusion criterion for PRP classification.

Systemic sclerosis: one year in review 2023.

Systemic sclerosis is a rare and chronic connective tissue disease resulting from an intricate pathogenesis and is expressed in very heterogeneous clinical manifestations. Every year many studies try to unravel and shed new insight into the pathogenesis, organ involvement and treatment of this complex and severe disease. We herein provide an overview of the most relevant studies published in the literature in 2022.

Real life data on nintedanib safety: idiopathic pulmonary fibrosis versus systemic sclerosis-interstitial lung disease and strategies adopted to manage adverse effects.

OBJECTIVE: Nintedanib (NIN) is an antifibrotic drug approved to slow the progression of idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-related interstitial lung disease (SSc-ILD). NIN can frequently cause gastrointestinal adverse effects. We aimed to investigate the NIN safety profile in a real life setting, comparing IPF and SSc-ILD patients and evaluating the strategies adopted to manage NIN adverse effects. METHODS: Patients taking NIN for IPF or SSc-ILD were enrolled. Alongside epidemiological and disease-specific data, the period of NIN use and the need for dosage reduction and/or interruption were investigated. Particular attention was paid to possible adverse effects and strategies adopted to manage them. RESULTS: Twenty-seven SSc-ILD and 82 IPF patients were enrolled. No significant differences emerged between the two cohorts regarding the frequency of any possible adverse effect. Although the rates of NIN dosage reduction or interruption were similar between the two subgroups, SSc-ILD presented a mean period before NIN dosage reduction and NIN interruption significantly shorter than IPF (3 ± 2.6 vs 10.5 ± 8.9 months-p < 0.001 and 2.3 ± 0.5 vs 10.3 ± 9.9 months-p = 0.008, respectively). Several different strategies were tried to manage NIN adverse effects: especially in SSc-ILD, the variable combination of diet adjustment set by a nutritionist, probiotics and diosmectite was ultimately successful in maintaining patients on an adequate dose of NIN. CONCLUSION: We presented data on the NIN safety profile in a real life setting, which was similar between SSc-ILD and IPF. A combination of multiple managing strategies and dose adjustment appears essential to cope optimally with NIN adverse effects.

Is oropharyngoesophageal scintigraphy the method of choice for assessing dysphagia in systemic sclerosis? A single center experience.

OBJECTIVES: To evaluate the performance of oropharyngoesophageal scintigraphy (OPES) in the assessment of dysphagia in patients with systemic sclerosis (SSc), and to compare OPES results with those of barium esophagogram. METHODS: Adult SSc patients who underwent OPES for the assessment of dysphagia were enrolled. OPES was performed with both liquid and semisolid boluses and provided information regarding oropharyngeal transit time, esophageal transit time (ETT), oropharyngeal retention index (OPRI), esophageal retention index (ERI), and site of bolus retention. Barium esophagogram results were also collected. RESULTS: Fifty-seven SSc patients (87.7% female, mean age 57.7 years) with dysphagia were enrolled. OPES identified at least one alteration in each patient and findings were generally worse for the semisolid bolus. Esophageal motility was widely impaired with 89.5% of patients with an increased semisolid ERI, and middle-lower esophagus was the most frequent site of bolus retention. However, oropharyngeal impairment was highlighted by widespread increased OPRI, especially in anti-topoisomerase I positivity. Older patients and with longer disease duration presented slower semisolid ETT (p = 0.029 and p = 0.002, respectively). Eleven patients with dysphagia had a negative barium esophagogram: all of them presented some alterations in OPES parameters. CONCLUSION: OPES revealed a marked SSc esophageal impairment, in terms of both slowed transit time and increased bolus retention, but also shed light on oropharyngeal swallowing alterations. OPES showed high sensitivity, being able to detect swallowing alterations in dysphagic patients with negative barium esophagogram. Therefore, the use of OPES for the assessment of SSc-related dysphagia in clinical practice should be promoted.

Definition and application of proximal-distal gradient finger perfusion in systemic sclerosis by laser speckle contrast analysis.

OBJECTIVE: In patients with systemic sclerosis (SSc) the perfusion of the fingers shows an alteration of the physiological proximal-distal gradient (PDG). The aim of this study is to provide a generalizable definition of PDG, applying it in a cohort of SSc patients and healthy controls (HC) using laser speckle contrast analysis (LASCA). METHODS: Adult consecutive SSc patients and HC were enrolled. Peripheral blood perfusion of the hands was evaluated by LASCA, subsequently obtaining 3 different regions of interest: from the distal interphalangeal joint to the fingertip (DIST), from the metacarpophalangeal joint to the distal interphalangeal joint (PROX), and of the whole finger (TOT). A PDG formula independent of both intra- and inter-personal factors was then built. The PDG formula so obtained was: [(DIST × 2.63) - PROX]/TOT. RESULTS: Ninety-four SSc patients (79.8% female, mean age 58.7 years) were enrolled. Applying the PDG formula, SSc patients revealed mean PDG values significantly lower than HC (1.82 ± 0.44 PU vs 2.70 ± 0.38 PU; p < 0.0001). Patients with a previous history of digital ulcers presented significant lower PDG values (p = 0.002). The ROC curve analysis identified in 2.28 PU the best PDG cut-off value between SSc and HC, with 86% sensibility and 90% specificity. CONCLUSION: This study provided a PDG formula generalizable to all kind of subjects, applying it in SSc with great sensibility and specificity using LASCA, the best non-invasive imaging technique for the dynamical evaluation of peripheral perfusion. LASCA-PDG appears also as a tool able to identify a subclinical microangiopathic impairment.

Systemic sclerosis: one year in review 2022.

Systemic sclerosis (SSc) is an autoimmune disease characterised by microvasculopathy, immune dysregulation, and skin and visceral organ fibrosis. Every year novel insights into the pathogenesis, organ involvement and treatment of this severe disease are published in the scientific community.In this review we report an overview of some of the most relevant contributions published in 2021.

Cardiovascular burden in systemic sclerosis: QRISK3 versus Framingham for risk estimation.

OBJECTIVES: To compare two algorithms for cardiovascular (CV) risk estimation in systemic sclerosis (SSc) patients, investigating correlations with disease characteristics. METHODS: Traditional CV risk factors and SSc-specific characteristics were assessed in a cohort of SSc patients. Framingham and QRISK3 algorithms were used to estimate the risk of developing a CV disease over the next 10 years. RESULTS: Seventy-two SSc patients were enrolled. Among those 56 without previous CV events, Framingham reported a median risk score of 9.6%, classifying 24 (42.9%) subjects at high risk. QRISK3 showed a median risk score of 15.8%, with 36 (64.3%) patients considered at high risk. Both algorithms revealed a significant role of some traditional risk factors and a noteworthy potential protective role of endothelin receptor antagonists (p = .003). QRISK3 was also significantly influenced by some SSc-specific characteristics, such as limited cutaneous subset (p = .01), interstitial lung disease (p = .04), and non-ischemic heart involvement (p = .03), with the first two maintaining statistical significance in the multivariate analysis (p = .02). CONCLUSIONS: QRISK3 classifies more SSc patients at high risk to develop CV diseases than Framingham, reflecting the influence of some SSc-specific characteristics. If its predictive accuracy were prospectively verified, the use of QRISK3 as a tool in the early detection of SSc patients at high CV risk should be recommended.

One year in review 2021: systemic sclerosis.

Systemic sclerosis is a rare and chronic connective tissue disease with a multifaceted pathogenesis characterised by heterogeneous multi-organ clinical manifestations. Every year, many studies contribute to enrich the knowledge on the pathogenesis, organ involvement and treatment of this complex and severe disease. We herein provide an overview on the most relevant contributions published in the literature in 2020.

One year in review 2020: systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterised by diffuse microangiopathy and immune dysregulation which ultimately results in widespread fibrosis of the skin and internal organs. This complex autoimmune disease is characterised by heterogeneous clinical manifestations and variable disease course in which the severity of pathology dictates the disease prognosis and course. Every year novel insights into the pathogenesis, organ involvement and treatment of this severe disease are published. Herewith, we provide an overview of the most significant literature contributions published last year, with the aim of helping the clinician in the understanding and management of SSc patients.

Framingham, ACC/AHA or QRISK3: which is the best in systemic lupus erythematosus cardiovascular risk estimation?

OBJECTIVES: Our objective was to compare three algorithms for cardiovascular (CV) risk estimation, namely Framingham, ACC/AHA and QRISK3, in a cohort of patients with systemic lupus erythematosus (SLE). METHODS: Consecutive patients with SLE according to the ACR criteria were enrolled. Traditional risk factors, ongoing therapies, comorbidities and SLE-specific evaluations were assessed. In those without previous myocardial infarction or stroke, Framingham, ACC/AHA and QRISK3 algorithms were then used to estimate the individual risk of developing a CV disease over the next 10 years. RESULTS: Patients eligible for CV risk estimation were 123 out of 135 enrolled. Framingham index reported a median risk score of 4.7% (IQR 9.5-2.2), considering 29 patients (23.6%) at high CV risk. ACC/AHA index showed a median risk score of 1.4% (IQR 4.5-0.7), with 17 patients (13.8%) at high-risk. QRISK3 revealed a median risk score of 6.2% (IQR 12.5-2.8), making it possible to classify 44 patients (35.8%) at high CV risk. The subgroup analysis of subjects older than 40 years confirmed the same number of high-risk patients for both Framingham and ACC/AHA, whereas QRISK3 classified 38 subjects at high CV risk. CONCLUSIONS: QRISK3 classifies a greater number of SLE patients at high-risk of developing CV diseases over the next 10 years in comparison with classic algorithms as Framingham and ACC/AHA. If its predictive accuracy were confirmed by longitudinal data, QRISK3 could become an important tool in the early detection of a considerable part of CV high-risk SLE patients that would be underestimated when applying classic algorithms.

The impact of skin calcinosis on digital ulcers in patients with SSc: clinical and prognostic stratification using the "wound bed score".

Digital ulcers (DUs) represent one of the major burdens for patients with systemic sclerosis (SSc), especially when associated with skin calcinosis (SC). The aim of this work is to evaluate the impact of SC in DUs of patients with SSc for clinical characteristics and prognosis assessed by the wound bed score (WBS). We prospectively enrolled 55 patients with DUs and SSc followed in our dedicated wound care clinic. For all the patients we collected clinical and anthropometric data and characteristics of the DU, and we calculated the WBS for each DU. Ninety-nine DUs were evaluated (24 with SC). SC was prevalent in limited cutaneous SSc (75%) and in patients with longer disease duration (P = 0.02). SC-DUs were prevalent at the fingertip (P = 0.04). The healing time was significantly higher in patients with SC (10.4 ± 7.9 weeks) compared with non-SC (7.0 ± 5.7 weeks) P = 0.03. The WBS negatively correlated with the time to achieve complete healing (r = -0.237 P = 0.023) and the correlation was maintained in the non-SC (r = -0.46, P = 0.033). DUs in SSc patients with SC are common and difficult to heal. When DUs are treated in dedicated centres, the prognosis is good. The WBS is fast and easy and maybe commonly applied in clinical practice.

One year in review 2019: novelties in the treatment of rheumatoid arthritis.

The current treatment approach in rheumatoid arthritis (RA) follows a stepwise management, starting from early introduction of conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs), moving to biological (b) DMARDs and targeted synthetic (ts) DMARDs. In the last few years, new drugs with different mechanisms of action have demonstrated their efficacy in treating such a disabling condition, and their approval, along with other more "experienced" treatments, has established their effectiveness on disease activity, damage accrual prevention, patients' quality of life improvement, confirming their safety profile. Moreover, new molecular pathways are under investigation as potential targets of new advanced therapies. Clinicians' capability of stratifying treatment strategies and decisions has improved, with several new tools for the optimisation of long-term management of RA; however, a high proportion of patients are refractory to the available drugs. Finally, as RA is a systemic disease, the knowledge in multi-systemic complications of the disease has grown, as well as the possibility in improving extra-articular manifestations of the disease, although certain drugs have potentially relevant non-articular effects, which need to be monitored. This narrative review summarises the most relevant studies published over the last year in the field of treatment of RA, with the major aim to let clinicians and researchers reflect on "what is new", "what is effective" and "what is safe".

One year in review 2019: systemic sclerosis.

Systemic sclerosis (SSc) is a complex disorder characterised by the involvement of small arteries, microvessels and connective tissue, with deposition of fibrotic tissue and microvascular obliteration in the skin and internal organs. Due to the multifaceted nature of the disease, several articles are published in the medical literature every year, aimed at exploring different aspects of the pathogenesis, internal organ involvement and clinical aspects, and possible therapeutic approaches. In this article we have reviewed the literature on SSc of the past year, with the aim of identifying novel approaches that may help the treating physician in the clinical management of patients.

One year in review 2018: systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune condition characterised by a wide spectrum of clinical manifestations, partly related to the disease itself, but also linked to its comorbidities and drugs adverse reactions. Following the previous annual reviews, we focused on new insights in SLE clinical features, pathogenic pathways, biomarkers of specific organ involvement and therapeutic strategies. We finally concentrated on SLE aspects that could significantly influence patients' quality of life and that need to be investigated in detail through the development and validation of disease-specific patient-reported outcomes.

One year in review 2018: systemic sclerosis.

Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year the scientific world contributes to enrich the knowledge on the pathogenesis, clinical manifestations, diagnosis and treatment of this complex and severe disease. Herewith, we provide an overview of the most significant literature contributions published over the last year.

Autonomic dysfunction in systemic sclerosis: A scoping review.

INTRODUCTION: Over the years several lines of evidence have implied a pathological involvement of autonomic nervous system (ANS) in systemic sclerosis (SSc). However, the relationship between autonomic dysfunction and SSc is not yet fully understood. The aims of this scoping review were to map the research done in this field and inform future research to investigate pathogenic hypotheses of ANS involvement. METHODS: We performed a scoping review of publications collected through a literature search of MEDLINE and Web of Science databases, looking for dysautonomia in SSc. We included original data from papers that addressed ANS involvement in SSc regarding pathogenesis, clinical presentation and diagnostic tools. RESULTS: 467 papers were identified, 109 studies were selected to be included in the present review, reporting data from a total of 2742 SSc patients. Cardiovascular system was the most extensively investigated, assessing heart rate variability with 24 h HolterECG or Ewing's autonomic tests. Important signs of dysautonomia were also found in digital vasculopathy, gastrointestinal system and SSc skin, assessed both with non-invasive techniques and histologically. Research hypotheses mainly regarding the relationship between sympathetic system - ischemia and the role of neurotrophins were then developed and discussed. CONCLUSION: We described the currently available evidence on pathogenesis, clinical presentation and diagnostic assessment of dysautonomia in SSc patients. A strong influence of ANS deregulation on SSc clearly emerges from the literature. Future research is warranted to clarify the mechanisms and timing of autonomic dysfunction in SSc.

Preliminary Clinical and Laser Speckle Contrast Analysis Data on Selexipag Efficacy for the Treatment of Digital Vasculopathy in Systemic Sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is burdened by Raynaud phenomenon (RP) and digital ulcers (DUs), and sometimes standard vasoactive therapies are ineffective or contraindicated. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. We aimed to evaluate the clinical and instrumental efficacy of selexipag in SSc digital vasculopathy. METHODS: Patients with SSc with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies were administered selexipag. RP- and DU-related clinical outcomes were evaluated, and digital perfusion was assessed by laser speckle contrast analysis (LASCA), all at baseline and after 3 months. RESULTS: Selexipag was administered to 9 patients with SSc (66.6% female, mean age 52.3 [SD 16.6] yrs). One patient had to stop the drug because of adverse effects. After 3 months of selexipag administration, there was a significant reduction in RP daily episodes (P = 0.01) and RP mean duration (P = 0.04). The number of DUs decreased from 10 to 4 without reaching statistical significance. A significant improvement in mean perfusion of the fingers (P = 0.02) was observed with LASCA. CONCLUSION: Selexipag showed good potential for the treatment of SSc digital vasculopathy. Our results are certainly preliminary, yet quite encouraging. New trials for the evaluation of selexipag efficacy in SSc digital vasculopathy are needed.

Multiparametric Skin Assessment in a Monocentric Cohort of Systemic Sclerosis Patients: Is There a Role for Ultra-High Frequency Ultrasound?

Background: To assess skin involvement in a cohort of patients with systemic sclerosis (SSc) by comparing results obtained from modified Rodnan skin score (mRSS), durometry and ultra-high frequency ultrasound (UHFUS). Methods: SSc patients were enrolled along with healthy controls (HC), assessing disease-specific characteristics. Five regions of interest were investigated in the non-dominant upper limb. Each patient underwent a rheumatological evaluation of the mRSS, dermatological measurement with a durometer, and radiological UHFUS assessment with a 70 MHz probe calculating the mean grayscale value (MGV). Results: Forty-seven SSc patients (87.2% female, mean age 56.4 years) and 15 HC comparable for age and sex were enrolled. Durometry showed a positive correlation with mRSS in most regions of interest (p = 0.025, ρ = 0.34 in mean). When performing UHFUS, SSc patients had a significantly thicker epidermal layer (p < 0.001) and lower epidermal MGV (p = 0.01) than HC in almost all the different regions of interest. Lower values of dermal MGV were found at the distal and intermediate phalanx (p < 0.01). No relationships were found between UHFUS results either with mRSS or durometry. Conclusions: UHFUS is an emergent tool for skin assessment in SSc, showing significant alterations concerning skin thickness and echogenicity when compared with HC. The lack of correlations between UHFUS and both mRSS and durometry suggests that these are not equivalent techniques but may represent complementary methods for a full non-invasive skin evaluation in SSc.