Devis Benfaremo

Safety and effectiveness of tocilizumab in systemic sclerosis: a multicentre French-Italian study

Expert Perspectives: Defining and managing progressive pulmonary fibrosis in systemic sclerosis

Expert perspectives define and manage progressive pulmonary fibrosis in systemic sclerosis, highlighting clinical implications.

The role of integrated gastro-rheumatological care in IBD-associated Spondyloarthritis in achieving joint–gut remission: Four-year outcomes from the real-world SPIB cohort

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.

PubChem-143070699 emerged as the most promising VEGF receptor 2 inhibitor candidate from a virtual screen of 450 million compounds, demonstrating a predicted binding affinity of 1.32 nM.

Computational screening and molecular dynamics identified PubChem-143070699 as a highly stable, nanomolar-affinity candidate for VEGFR2 inhibition, providing structural insights for future drug development.

Micro- and Macro-Vascular Disease in Systemic Sclerosis and Very Early SSc (VEDOSS): Results from a Monocentric Observational Study

This observational study identifies macrovascular disease in very early systemic sclerosis, suggesting improved risk assessment methods.

Systemic Sclerosis: A Key Model of Endothelial Dysfunction

This narrative review highlights the role of endothelial dysfunction in vascular injury in systemic sclerosis, suggesting new therapeutic strategies.

Axial psoriatic arthritis in patients not fulfilling the back pain entry features of the ASAS Classification Criteria for Axial Spondyloarthritis: findings from the ATTRACT Study

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.

Hypogammaglobulinemia in patients affected by limited cutaneous systemic sclerosis: Case series and review of the literature

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.

Pos0810 Therapeutic Choices-Efficacy of the Integrative Management and Patient-Reported Outcomes in Patients With Ibd-Associated Spondylarthritis: A 4-Year Observational Study (The Spib Cohort)

Background: Spondyloarthritis associated with Inflammatory Bowel Diseases (SpA-IBD) are immune-mediated diseases classified in the group of Spondyloarthritis (SpAs) and, concordantly, the association of joint and gut inflammation supports a tailored multidisciplinary approach. Objectives: In this study, we describe the distinctive clinical features of a large SpA-IBD patients' cohort and assess the therapeutic strategies used in integrative clinical real-world management, focusing on their effectiveness over a long period of clinical observation. Methods: Consecutive patients affected by IBD (Crohn's Disease or Ulcerative Colitis), were screened [1], referred to our Spondyloarthritis Clinic and, if diagnosed as SpA-IBD, enrolled in the SPIB Cohort (SPondyloarthritis in Inflammatory Bowel disease) [2]. The cohort underwent comprehensive gastroenterological and rheumatological assessments at baseline, 3, 6, and every 12 months [2]for 4 years. Extensive clinical data, and rheumatological and gastroenterological disease activity scores, were collected at each evaluation (Table 1), guiding a gastro-rheumatological approach towards an appropriate treatment strategies. Results: Since October 2016, 159 consecutive patients (mean age 49.1±13.6 years, 59% females) were diagnosed with SpA-IBD, 89 (56.0%) with axial involvement (axSpA-IBD) and 70 (44.0%) with peripheral involvement (pSpA-IBD). The female gender was significantly more represented in pSpA-IBD than in axSpA-IBD (p<0.032), and the duration of musculoskeletal symptoms was higher in axSpA-IBD than in pSpA-IBD (p<0.004) (Table 1). At baseline, patients reported high disease activity across all domains and relevant impairment in physical functioning and quality of life. Thirty-seven (23.3%) patients were assuming steroids (mean prednisone equivalent dose – PED: 7.81±8.31 mg) and 106 (66.7%) csDMARDs; 60 (37.7%) patients were already treated with b/tsDMARDs: 56/60 (93.3%) TNFi, and 4/60 (6.7%) Vedolizumab. Following the integrated gastro-rheumatological assessment, therapy with b/tsDMARDs was started in 46 patients more (+28.9%), accounting for a total number of 106 patients treated with: TNFi in 96/106 (90.6%), anti-IL-12/23 in 2/106 (1.9%), JAKi in 4/106 (3.8%), and Vedolizumab in 4/106 (3.8%). Therapy with oral steroids and/or csDMARDs was maintained in 27 (17.0%; mean PED 1.23±4.01) and 109 (68.8%) patients, respectively (Figure 1B). From 12 to 24-month follow-up, b/tsDMARDs were prescribed in 74/98 (75.5%) patients as follows: 91.9% TNFi, 2.7% anti-IL-12/23, 2.7% JAKi, 2.7% Vedolizumab, whereas therapy with oral steroids and csDMARDs was maintained in 10 (10.2%; mean PED 0.39±1.36) and 75 (76.5%) patients, respectively (Figure 1B). Subsequently, at the 36-month follow-up, therapy b/tsDMARDs was maintained in a similar percentage of patients (45/56, 80.4%), with an increase of anti-IL-12/23 (8.9%), JAKi (2.2%), and Vedolizumab (4.4%), and this therapeutic trend was substantially maintained until the 48-month follow up (Figure 1B). Therapy with oral corticosteroids and/or csDMARDs was continued, but at a lower dose, in a similar percentage of patients from the 36 to 48-month follow-up (Figure 1B). From baseline to month 48, the integrative gastro-rheumatologic management resulted in a significant improvement in all disease activity scores (except the pMayo score), along with a significant improvement in physical functioning and quality of life (Figure 1A). Conclusion: The SPIB Cohort is a representative and large cohort of SpA-IBD patients, characterized by a long-time clinical follow-up through integrated gastro-rheumatologic management. Our study demonstrates that thigh cooperation between rheumatologists and gastroenterologists enables a comprehensive assessment with the development of tailored and effective therapeutic strategies. REFERENCES: [1] Benfaremo D al. J Rheumatol 2021;48:179-187. [2] Luchetti MM et al. Eur J Intern Med 2019;64:76-84. Acknowledgements: NIL. Disclosure of Interests: Giulia Marchionni: None declared, Valentino Paci: None declared, Lucia Perini: None declared, Alen Zabotti: None declared, Alice Agostinelli: None declared, Ilaria Cimaroli: None declared, Raffaella Sordillo: None declared, Federico Fiorini: None declared, Raissa Di Zio: None declared, Emanuele Bendia: None declared, Antonio Benedetti: None declared, Devis Benfaremo: None declared, Michele Maria Luchetti AbbVie, Amgen, Eli Lilly, Janssen, Novartis and Pfizer., AbbVie, Janssen, Novartis and Pfizer, Abbvie, Gianluca Moroncini AbbVie, Janssen, Novartis and Pfizer, AbbVie, Janssen and Pfizer.

Ab1195 Nintedanib Restores Endothelial Function in Patients With Systemic Sclerosis: Preliminary Findings of a Monocentric Study

Background: Nintedanib is approved for the treatment of interstitial lung disease (ILD) associated with systemic sclerosis (SSc). Some experimental evidence supports the hypothesis that nintedanib may act on the vasculature by attenuating vascular remodeling and improving microvascular architecture¹, although these effects remain unclear. Objectives: The aim of this study was to evaluate the effect of nintedanib on systemic microcirculation and endothelial function assessed by flow-mediated dilation of the brachial artery (FMD) in patients with SSc-ILD. Methods: In this prospective observational study, 10 consecutive patients affected by SSc-ILD were enrolled, according to the following inclusion criteria: 1. Age > 18 years; 2. Progressive disease according to INBUILD criteria; 3. Indication for antifibrotic therapy with nintedanib; 4. Signature of the informed consent. There were no exclusion criteria. For each patient, clinical-demographic data were collected including: sex, age, duration and localization of disease, disease subset (limited or diffuse skin subset), antibody specificity, modified Rodnan skin score (mRSS), capillaroscopic pattern (early, active or late), previous and current therapy. All patients were assessed at baseline, 6 months and 12 months with the following tests: FMD, nailfold videocapillaroscopy (NVC), ultra-high frequency skin ultrasound (HFUS), spirometry and DLCO, 6-minute walking test (6MWT) and lung ultrasound. Data were analyzed using the Wilcoxon signed-rank test. Results: Of the 10 enrolled patients (10 F, median age 60.5 years), 5 had diffuse SSc and 5 limited SSc, with a median mRSS of 4.5 and median disease duration of 12 years. All patients received nintedanib 150 mg BID. Two patients reduced the dosage to 100 mg BID (after 6 and 9 months, respectively), while one patient definitively stopped treatment after 6 months due to persistent gastrointestinal adverse effects (diarrhea and nausea). At baseline, 90% of patients had FMD values lower than 10% (threshold above which FMD values are considered normal) with a median value of 4.16% (3.03 - 10.34). At 6 months, FMD values increased in 70% of patients, although in 80% of cases the values remained lower than 10%, with a median value of 8.83% (0 - 23.07). At 12 months, FMD values increased in all patients compared to baseline, with a median value of 12% (9.37-18.18) (p < 0.05) (Figure 1). No statistically significant differences were observed in capillaroscopic parameters (i.e. median number of capillaries and giant capillaries) at baseline and after 6 and 12 months. Also, no statistically significant differences were noted with regard to mRSS and skin and lung ultrasound measures. Nintedanib was able to stabilize (< 10% decline) or improve FVC at 12 months in 60% of cases and TLC in 90% of cases. However, a decline in DLCO > 15% was observed in 40% of cases. Finally, there was a statistically significant improvement (p < 0.05) in the 6MWT at 12 months. Conclusion: Although nintedanib did not demonstrate a significant impact on the nailfold microcirculation, data from this small pilot study suggest a positive effect on endothelial function assessed by FMD. Further studies should explore the hypothesis of a beneficial effect of nintedanib on endothelial function and vascular remodeling. REFERENCES: [1] Tsutsumi T, Nagaoka T, Yoshida T, et al. Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation. PLoS One. 2019 Jul 24;14(7):e0214697. Acknowledgements: NIL. Disclosure of Interests: None declared.

Speckle-tracking global longitudinal strain predicts death and cardiovascular events in patients with systemic sclerosis

Aims Albeit often asymptomatic, heart involvement in systemic sclerosis (SSc) represents a negative prognostic factor, accounting for nearly one-fourth of all deaths. Global longitudinal strain (GLS) is accurate in detecting heart involvement in patients with SSc and no overt cardiac disease and allows early detection and longitudinal monitoring, but its association with clinical endpoints has not been tested so far. The primary outcome was the association between left and right GLS and mortality for all causes. The secondary outcome was the association between left and right GLS and hospitalizations. Methods and results A prospective longitudinal study enrolling all consecutive patients with SSc without structural heart disease or previous cardiovascular event. A total of 164 patients were enrolled, of whom 19 (11.5%) died during follow-up and 48 (29.3%) were hospitalized. Both left (LV) and right ventricle (RV) GLS at enrolment were independently associated with an increased risk of death for all causes and hospitalizations. Patients with biventricular GLS impairment, respectively, had a 4.2-, 4.9-, and 13.9-fold increased risk of death when compared with patients with only LV, only RV, or no impairment (P < 0.001). The incidence of hospitalization in patients with biventricular GLS impairment was nearly four times higher when compared with patients with only LV or only RV impairment, and nine times higher when compared with normal biventricular GLS (P < 0.001). Conclusion Biventricular GLS is associated with an increased risk of death and hospitalization in patients with SSc during a median of 3-year follow-up, acting as a reliable and accurate prognostic tool in everyday practice.

Role of cognitive impairment and malnutrition as determinants of quality of life in patients with systemic sclerosis

Background: Increasing evidence supports the presence of cognitive impairment in patients with systemic sclerosis. Malnutrition is a well-known severe complication of systemic sclerosis and is a consequence of multiple factors, mainly oropharyngeal and gastrointestinal involvement. Recent studies have shown a link between nutrition and cognitive decline in several chronic diseases. Thus, we decided to evaluate a possible association between malnutrition and cognitive impairment in patients with systemic sclerosis. Methods: In total, 100 consecutive systemic sclerosis patients were enrolled in a cross-sectional study to assess clinical and demographic features, nutritional status (body mass index, Global Leadership Initiative on Malnutrition criteria), gastrointestinal involvement (University of California Los Angeles Gastrointestinal Scale 2.0, Eat Assessment Tool 10), cognitive function (Montreal Cognitive Assessment), anxiety and depression (Patient Health Questionnaire 9, Beck Depression Inventory II), and quality of life (Short Form 36, Health Assessment Questionnaire-Disability Index, Scleroderma Health Assessment Questionnaire). Patients were stratified for the presence/absence of malnutrition and cognitive decline and compared for clinical characteristics and quality-of-life measures. Results: Half of the patients had cognitive impairment (Montreal Cognitive Assessment < 26). These patients were older, had more comorbidities, and a significantly worse quality of life. There were no statistically significant associations with body mass index, malnutrition, and gastrointestinal involvement. About one-third of patients had clinically relevant malnutrition. They were older, had higher skin score, lung and esophageal involvement. They also showed significantly worse scores for dysphagia, gastrointestinal symptoms, functional disability, and quality of life. Gastrointestinal symptoms and dysphagia, but not body mass index and Montreal Cognitive Assessment, were significantly associated with depression scores, which in turn were negatively associated to quality-of-life measures. With regression analysis, cognitive impairment was predicted only by age, whereas malnutrition was significantly associated with age, dysphagia, and modified Rodnan skin scores. Conclusion: In this study, we showed that cognitive impairment and malnutrition are not directly linked but are both independently associated with greater functional disability and worse quality of life of patients with systemic sclerosis. Early recognition of these comorbidities is therefore pivotal to better address the chronic needs of patients affected by this disease.

Skin ultrasound in systemic sclerosis: past, present and exciting future

Tânia Santiago, Devis Benfaremo, Gianluca Moroncini; Skin ultrasound in systemic sclerosis: past, present, and exciting future, Rheumatology Advances in Practic

Adeno‐Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis

OBJECTIVE: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFRα is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus-PDGFRα complex. METHODS: The binding of monomeric human PDGFRα to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFRα locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFRα were evaluated by SPR using SSc monoclonal anti-PDGFRα antibodies and immunoaffinity-purified anti-PDGFRα antibodies from sera of patients with SSc. RESULTS: AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P < 0.001). In SSc lungs, AAV5 localized in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFRα was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFRα antibodies identified spatially contiguous epitopes derived from PDGFRα and AAV5 that interacted with SSc agonistic antibodies to PDGFRα. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls. CONCLUSION: These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc.

The ATTRACT study: screening for the early identification of axial psoriatic arthritis in a cohort of Italian psoriatic patients

OBJECTIVE: There is growing interest in the early identification of patients with axial PsA (axPsA). We aimed to evaluate whether a dermatology-based screening strategy could help to identify axPsA patients. METHODS: The dermatologist-centred screening (DCS) questionnaire was administrated by dermatologists to consecutive patients fulfilling the inclusion criteria [(i) age ≥18 years and (ii) clinical diagnosis of psoriasis made by a dermatologist] to identify patients eligible (affirmative answers 1-3c of the DCS) for rheumatological evaluation. Clinical, laboratory, genetic and imaging data were collected from all referred patients. RESULTS: Among the 365 patients screened, 265 fulfilled the inclusion criteria and 124/265 (46.8%) were eligible for rheumatological referral. Diagnosis of axPsA, with or without peripheral PsA (pPsA), was made in 36/124 (29.0%) patients; pPsA without axial involvement was found in 21/124 (16.9%) patients. Back pain at screening was recorded in 174 (66%) patients, with 158 (60%) reporting a back pain duration longer than 3 months and 140 (53%) reporting back pain onset before the age of 45 years. Active inflammatory and/or structural post-inflammatory changes in the sacroiliac joints and/or spine were observed in all axPsA patients. Patients with PsA showed a numerically longer duration of back pain and higher CRP levels in comparison with patients with psoriasis without PsA. CONCLUSION: The DCS tool proved to be a valuable screening strategy for detecting and characterizing patients with axPsA in a real-life cohort of psoriasis patients in a dermatological setting and helped to identify a substantial number of patients affected by undiagnosed pPsA.

Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: preliminary data of a real-life multicenter study

BACKGROUND: Upadacitinib (UPA) is a selective JAK inhibitor recently approved for the treatment of psoriatic arthritis (PsA). In this post-approval study, we aimed to evaluate the effectiveness and safety of UPA over 24 weeks and identify clinical predictors of response, in a multicentric cohort of patients affected by PsA. METHODS: One hundred and twenty-six patients with PsA treated with UPA were enrolled in 10 Italian centres. UPA effectiveness outcomes, such as the proportion of patients with MDA status, DAPSA remission, and low disease activity, ASDAS-CRP inactive and low disease activity, and change from baseline in DAPSA and ASDAS-CRP scores, were evaluated every 12 weeks until week 24. The proportion of DAPSA minor, moderate, and major improvement, and ASDAS clinically important improvement (CII) and major improvement (MI) were considered as well. All treatment-related adverse events were collected during the observation period. Clinical predictors of MDA response at week 24 were evaluated through multivariate analysis. RESULTS: At baseline, 124/126 (98%) and 54/126 (43%) patients showed peripheral and axial involvement, respectively; 110 (87%) patients were intolerant or resistant to biologic DMARDs. At 24 weeks, MDA status, DAPSA remission, and ASDAS-CRP inactive disease were achieved in 47%, 23%, and 48% of patients, respectively. Minor, moderate, and major DAPSA improvement was observed in 67%, 39%, and 23%, respectively; while 65% and 35% achieved ASDAS-CRP CII and MI, respectively. The mean change from baseline was 15.9 ± 13.5 (p < 0.001) for DAPSA and 1.21 ± 0.97 (p < 0.001) for ASDAS-CRP. Thirteen patients (10%) discontinued UPA due to a lack of efficacy or non-serious adverse events. No serious adverse events were observed. Male gender (OR 2.54, 95% CI 1.03-6.25 p = 0.043), being naïve to biological DMARDs (OR 4.13, 95% CI 1.34-12.71, p = 0.013) and elevated baseline CRP (OR 2.49, 95% CI 1.02-6.12, p = 0.046) were associated with MDA response at week 24. CONCLUSIONS: This is one of the first real-life studies supporting the effectiveness of UPA and its safety profile in PsA patients. Furthermore, the study identifies predictors of MDA response to UPA treatment at 6 months.

Skin Gene Expression Profiles in Systemic Sclerosis: From Clinical Stratification to Precision Medicine

Systemic sclerosis, also known as scleroderma or SSc, is a condition characterized by significant heterogeneity in clinical presentation, disease progression, and response to treatment. Consequently, the design of clinical trials to successfully identify effective therapeutic interventions poses a major challenge. Recent advancements in skin molecular profiling technologies and stratification techniques have enabled the identification of patient subgroups that may be relevant for personalized treatment approaches. This narrative review aims at providing an overview of the current status of skin gene expression analysis using computational biology approaches and highlights the benefits of stratifying patients upon their skin gene signatures. Such stratification has the potential to lead toward a precision medicine approach in the management of SSc.

Screening and Analysis of Possible Drugs Binding to PDGFRα: A Molecular Modeling Study

The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor involved in several metabolic pathways, not only physiological but also pathological, as in tumor progression, immune-mediated diseases, and viral diseases. Considering this macromolecule as a druggable target for modulation/inhibition of these conditions, the aim of this work was to find new ligands or new information to design novel effective drugs. We performed an initial interaction screening with the human intracellular PDGFRα of about 7200 drugs and natural compounds contained in 5 independent databases/libraries implemented in the MTiOpenScreen web server. After the selection of 27 compounds, a structural analysis of the obtained complexes was performed. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were also performed to understand the physicochemical properties of identified compounds to increase affinity and selectivity for PDGFRα. Among these 27 compounds, the drugs Bafetinib, Radotinib, Flumatinib, and Imatinib showed higher affinity for this tyrosine kinase receptor, lying in the nanomolar order, while the natural products included in this group, such as curcumin, luteolin, and epigallocatechin gallate (EGCG), showed sub-micromolar affinities. Although experimental studies are mandatory to fully understand the mechanisms behind PDGFRα inhibitors, the structural information obtained through this study could provide useful insight into the future development of more effective and targeted treatments for PDGFRα-related diseases, such as cancer and fibrosis.

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.

PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.