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 psoriatic arthritis (axPsA). We aimed to evaluate whether a dermatology-based screening strategy could help to identify axPsA patients. METHODS: The dermatologist-centered screening (DCS) questionnaire was administrated by Dermatologists to consecutive patients fulfilling the inclusion criteria (1. age ≥ 18 years and 2. 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. 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 Pso 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.

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.

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.

Gut epithelial impairment, microbial translocation and immune system activation in inflammatory bowel disease-associated spondyloarthritis.

OBJECTIVES: Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients. METHODS: Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line. RESULTS: Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells. CONCLUSION: SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients.

Dual-energy computed tomography for the detection of sacroiliac joints bone marrow oedema in patients with axial spondyloarthritis.

OBJECTIVES: To investigate the diagnostic performance of dual-energy computed tomography (DECT) in detection bone marrow oedema (BME) in patients with sacroiliitis associated with axial spondyloarthritis (axial SpA). METHODS: Patients with axial SpA according to the ASAS criteria underwent DECT and 1.5-T magnetic resonance imaging (MRI). DECT was post-processed for generating virtual non-calcium (VNCa) images. The presence of abnormal bone marrow attenuation was scored on DECT VNCa images and MRI using a four-point classification system: 0-1 = absent or non-significant oedema, 2 = oedema present in a third of the articular surface, 3 = oedema present in 2/3 of the articular surface, 4 = diffuse oedema throughout the articular surface. Diagnostic accuracy values for BME were calculated for DECT images (quantitative assessment) by using receiver operating characteristic (ROC) curves analysis, applying MRI as gold standard. RESULTS: Eighty sacroiliac joints from 40 axial SpA patients were included for study analysis, and 36 sacroiliac joints (45%) were classified as having BME at MRI and compared to DECT. Sensitivity, specificity, and positive likelihood ratio (LR+) in the identification of BME at DECT were 90.0%, 92.8%, and 12.6 respectively. Negative LR was 0.11, positive predictive value 93.1%, and negative predictive value 89.7%. The area under the curve (AUC) was 0.953 in the differentiation of the presence of BME. A cut-off value of -1.6 HU (Youden's index = 0.828) yielded a sensitivity of 90.0% and specificity of 92.8%, with an LR+ of 12.6, in the detection of BME in the sacroiliac joints. CONCLUSIONS: DECT VNCa images had good diagnostic performance in the evaluation of the extent of BME in patients with sacroiliitis associated with axial SpA.

Safety of intermediate dose of low molecular weight heparin in COVID-19 patients.

Coagulopathy represents one of the most important determinants of morbidity and mortality in coronavirus disease-19 (COVID-19). Whether standard thromboprophylaxis is sufficient or higher doses are needed, especially in severe patients, is unknown. To evaluate the safety of intermediate dose regimens of low-weight molecular heparin (LWMH) in COVID-19 patients with pneumonia, particularly in older patients. We retrospectively evaluated 105 hospitalized patients (61 M, 44 F; mean age 73.7 years) treated with subcutaneous enoxaparin: 80 mg/day in normal weight and mild-to-moderate impair or normal renal function; 40 mg/day in severe chronic renal failure or low bodyweight (< 45 kg); 100 mg/day if bodyweight was higher than 100 kg. All the patients had radiologically confirmed pneumonia and 63.8% had severe COVID-19. None of the patients had fatal haemorrhage; two (1.9%) patients had a major bleeding event (one spontaneous hematoma and one gastrointestinal bleeding). Only 6.7% of patients needed transfusions of red blood cells. One thrombotic event (pulmonary embolism) was observed. When compared to younger patients, patients older than 85 years had a higher mortality (40% vs 13.3%), but not an increased risk of bleeding or need for blood transfusion. The use of an intermediate dose of LWMH appears to be feasible and data suggest safety in COVID-19 patients, although further studies are needed.

Abnormal liver function tests predict transfer to intensive care unit and death in COVID-19.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a relevant threat for humans worldwide. Abnormality in liver function tests (LFTs) has been commonly observed in patients with COVID-19, but there is controversy on its clinical significance. The aim of this study was to assess the prevalence, the characteristics and the clinical impact of abnormal LFTs in hospitalized, non-critically ill patients with COVID-19. METHODS: In this multicentre, retrospective study, we collected data about 565 inpatients with COVID-19. Data on LFTs were collected at admission and every 7 ± 2 days during the hospitalization. The primary outcome was a composite endpoint of death or transfer to intensive care unit (ICU). RESULTS: Upon admission 329 patients (58%) had LFTs abnormality. Patients with abnormal LFTs had more severe inflammation and higher degree of organ dysfunction than those without. During hospitalization, patients with abnormal LFTs had a higher rate of transfer to ICU (20% vs 8%; P < .001), acute kidney injury (22% vs 13%, P = .009), need for mechanical ventilation (14% vs 6%; P = .005) and mortality (21% vs 11%; P = .004) than those without. In multivariate analysis, patients with abnormal LFTs had a higher risk of the composite endpoint of death or transfer to ICU (OR = 3.53; P < .001). During the hospitalization, 86 patients developed de novo LFTs abnormality, which was associated with the use of tocilizumab, lopinavir/ritonavir and acetaminophen and not clearly associated with the composite endpoint. CONCLUSIONS: LFTs abnormality is common at admission in patients with COVID-19, is associated with systemic inflammation, organ dysfunction and is an independent predictor of transfer to ICU or death.

Videofluorography swallow study in patients with systemic sclerosis: correlation with clinical and radiological features.

OBJECTIVES: The aim of our study was to assess the role of videofluorography (VFG) in the evaluation of swallowing and oesophageal peristalsis in patients with systemic sclerosis (SSc). METHODS: From June 2014 to September 2017, 55 consecutive SSc patients, defined according to the 2013 ACR/EULAR classification criteria, underwent VFG study using a remote-controlled digital device. In order to evaluate possible abnormalities, 18 dynamic parameters were chosen, dividing the act of swallowing into three phases: oral, pharyngeal and oesophageal phases. The following dynamic radiological findings were considered: veil motility in phonation, leakage, drooling, salivation and presence of residues in the oral cavity, pharyngeal residues, penetration, aspiration, altered motility of the upper oesophageal sphincter, efficacy of primary peristaltic contractions, oesophageal clearance capacity, reflux, oesophagitis and motility of the lower oesophageal sphincter. RESULTS: The VFG study was well tolerated in all patients. Dysfunctions of oesophageal motility were common and included abnormal motility of UES (12.7%) and LES (76.4%), inadequate primary peristalsis (52.7%), abnormal secondary peristalsis (29.1%) and non-peristaltic contractions (40%). A defective oesophageal clearance was observed in 69.4% of patients. Moreover, most patients presented signs of oesophageal reflux (63.6%), oesophagitis (81.8%) and hiatal hernia (80%). Pharyngeal abnormalities were less common and involved up to 50% of patients. Oesophageal dysfunction and defective clearance were associated with dcSSc and pulmonary involvement. CONCLUSIONS: The VFG study is a useful technique for the morphological and functional evaluation of swallowing in SSc patients.

A validation study of the Simple Psoriatic Arthritis Screening (SiPAS) questionnaire to screen psoriasis patients for psoriatic arthritis.

OBJECTIVES: To validate in a multicentric cohort of patients a self-administered PsA screening tool, called Simple Psoriatic Arthritis Screening (SiPAS) questionnaire, to screen psoriasis patients for signs and symptoms of PsA. METHODS: The SiPAS questionnaire was validated in a multicentric Italian cohort of psoriasis patients referred to two rheumatological centres. RESULTS: A total of 202 psoriasis patients were screened with SiPAS in the validation study. Sixty-two psoriasis patients (30.7%) were diagnosed with PsA. The five screening questions (1. Have you ever had a finger or a toe and/or another joint swollen and painful without any apparent reason?; 2. Occasionally, has an entire finger or toe become swollen, making it look like a 'sausage'?; 3. Do you wake up at night because of low back pain?; 4. Have you had pain in your heels?; 5. Has a doctor ever diagnosed you with psoriatic arthritis?) with a dichotomous response, demonstrated high sensitivity and specificity for predicting PsA. Likelihood ratios for individual parameters varied between 2.06 and 4.75. Using the Bayesian Analysis, the presence of three of five items answered as "yes" showed respectively a sensibility and a specificity of 79% and 87%, with a positive likelihood ratio of 6.14. CONCLUSIONS: The SiPAS questionnaire is able to quickly screen psoriasis patients for PsA. A SiPAS score ≥3 is an indication for referral to a rheumatologist. The SiPAS needs further validation.

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.

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.

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.

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.

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.

Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches.

Systemic sclerosis (SSc) is a systemic, immune-mediated chronic disorder characterized by small vessel alterations and progressive fibrosis of the skin and internal organs. The combination of a predisposing genetic background and triggering factors that causes a persistent activation of immune system at microvascular and tissue level is thought to be the pathogenetic driver of SSc. Endothelial alterations with subsequent myofibroblast activation, excessive extracellular matrix (ECM) deposition, and unrestrained tissue fibrosis are the pathogenetic steps responsible for the clinical manifestations of this disease, which can be highly heterogeneous according to the different entity of each pathogenic step in individual subjects. Although substantial progress has been made in the management of SSc in recent years, disease-modifying therapies are still lacking. Several molecular pathways involved in SSc pathogenesis are currently under evaluation as possible therapeutic targets in clinical trials. These include drugs targeting fibrotic and metabolic pathways (e.g., TGF-ß, autotaxin/LPA, melanocortin, and mTOR), as well as molecules and cells involved in the persistent activation of the immune system (e.g., IL4/IL13, IL23, JAK/STAT, B cells, and plasma cells). In this review, we provide an overview of the most promising therapeutic targets that could improve the future clinical management of SSc.

6 and 12 month outcomes in patients following COVID-19-related hospitalization: a prospective monocentric study.

The long-term consequences of COVID-19 in those who recover from acute infection requiring hospitalization have not been defined yet. In this study, we aim to describe the long-term symptoms and respiratory outcomes over 12 months in patients hospitalized for severe COVID-19. In this prospective cohort study, patients admitted to hospital for severe COVID-19 were prospectively followed up at 6 and 12 months after discharge from the Hospital of Fermo, Italy. Patients were interviewed for persisting symptoms and underwent physical examination, routine blood test, pulmonary function tests, chest high-resolution CT (HRCT), and 6 min walking test. A total of 64 patients were evaluated and participated in this study. The mean age of participants was 68 years, 41 (64%) were males, and the median body mass index (BMI) was 26 kg/m2. After 6 months, 36% of patients reported persistent dyspnea, 37.5% persistent fatigue, 30.6% hair loss, 14% arthralgia and 11% memory and attention deficits. The rate of these symptoms reduced at the 12 month follow-up. At least 50% of the patients reported anxiety and depression symptoms. At 6 months 57.4% of patients showed reduced DLCO and 21.3% reduced FVC% and improvement at 12 months was noted for FVC but not for DLCO and TLC. Persistent radiographic abnormalities, most commonly ground-glass opacities and interstitial changes, were observed at both timepoints in many patients. Long-term symptoms and pulmonary deficits are common in patients admitted for severe COVID-19. Further studies are needed to assess the clinical significance of long-term consequences of severe COVID-19.