Case report on activated PI3K-delta syndrome.

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) [OMIM 615513] is an inborn error of immunity with autosomal dominant inheritance caused by a pathogenic variant in the PIK3CD gene. The prevalence ratio of APDS is < 1: 1,000,000 newborns. The main clinical features of APDS are sinopulmonary infections, benign lymphoproliferation, autoinflammatory disease, and a major risk of lymphoid neoplasms. CLINICAL CASE: A 17-year-old female with a history of pneumonia at 9 months of age subsequently developed recurrent respiratory tract infections, bronchiectasis, perforated otitis media, unilateral tonsillar lymphoid hyperplasia, pansinusitis, recurrent oral candidiasis, and chronic rhinitis. Laboratory studies reported persistent leukopenia and lymphopenia, low CD4 lymphocyte subpopulation, and persistently elevated immunoglobulin M immunoglobulin studies with values up to 692 mg/dL. An inborn error of immunity next-generation sequencing and multiplex ligation-dependent probe amplification analysis detected a heterozygous pathogenic variant in the PIK3CD gene, compatible with APDS. Treatment with monthly injectable gamma globulin and prophylactic antibiotics was started, allowing better control of the infectious processes. CONCLUSION: This is the second case of APDS reported in Mexico in the literature. It is important to be aware of this condition to make a timely diagnosis, which requires a high clinical suspicion and immunological and genetic studies to provide adequate treatment and prevent complications.

INTRODUCCIÓN: El síndrome de la Fosfoinositida 3-cinasa delta activado (Activated Phosphoinositide 3-kinase δ síndrome, APDS) [OMIM 615513] es un error innato de la inmunidad con patrón de herencia autosómica dominante causada por una variante patogénica heterocigota del gen PIK3CD. Su prevalencia es < 1: 1,000,000 nacidos vivos. Las principales manifestaciones clínicas son infecciones sinopulmonares, linfoproliferación benigna, autoinmunidad y aumento del riesgo de malignización linfoide. CASO CLÍNICO: Femenino de 17 años de vida con antecedentes de neumonía a los 9 meses de edad, posteriormente infecciones de vías respiratorias recurrentes, bronquiectasias, otitis media perforada, hiperplasia linfoide de amigdala unilateral, pansinusitis, candidiasis oral recurrente y rinitis crónica. Los estudios de laboratorio reportaron leuco linfopenia persistente, subpoblación linfocitaria con CD4 baja y estudios de inmunoglobulinas con IgM persistentemente elevada con valor de hasta 692 mg/dl. Se realizó estudio molecular de secuenciación de siguiente generación (NGS por sus siglas en inglés Next-Generation Sequencing) y amplificación de sondas dependientes de ligandos múltiples (MLPA por sus siglas en inglés Multiplex Ligation-dependent Probe Amplification) dirigido a errores innatos de la inmunidad que detectó una variante patogénica en estado heterocigoto en el gen PIK3CD, compatible con APDS. Se inició tratamiento con gammaglobulina intravenosa mensual y antibiótico profiláctico, permitiendo mejor control de los procesos infecciosos. CONCLUSIONES: Este es el segundo caso reportado en la literatura de APDS en México, por lo que es importante su conocimiento para poder realizar un diagnóstico oportuno, para el cual se requiere una alta sospecha clínica, además de estudios inmunológicos y genéticos, con la finalidad de otorgar el tratamiento adecuado y prevenir complicaciones.

Beyond rheumatoid nodules in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease predominantly affecting synovial joints. Extra-articular manifestations, including skin involvement, can also occur. The most frequent cutaneous manifestation in RA patients is rheumatoid nodules, occurring in 20-30% of seropositive individuals. These nodules are typically firm, painless, and located on pressure points such as the hands and elbows. However, in a minority of cases, other skin conditions can complicate RA, notably palisaded neutrophilic granulomatous dermatitis (PNGD). PNGD presents as erythematous papules or plaques, often pruritic and distributed symmetrically over extensor surfaces, making it challenging to differentiate from rheumatoid nodules. Histopathological examination is crucial to establish the diagnosis. High clinical suspicion and appropriate referral to Dermatology are essential for accurate diagnosis and management. Treatment of PNGD is focused on underlying disease control. Other options include topical, intralesional or systemic corticosteroids, dapsone or hydroxychloroquine. Herein, we present the case of a 71-year-old woman with RA who developed PNGD, highlighting the importance of a multidisciplinary approach for achieving a favorable clinical outcome.

Portuguese Recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). METHODS: A task force comprising 21 rheumatologists, two surgeons (vascular and plastic), two nurses, and one patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. RESULTS: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. CONCLUSIONS: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

Modification of eating habits and lifestyle during COVID-19 in university students from Mexico and Peru.

Objective: It was to evaluate changes in lifestyle habits and health behavior among university students in Peru and Mexico during periods of confinement associated with the COVID-19 pandemic and to identify possible relationships between these changes and sociodemographic variables, health status, and technology consumption. Methods: It was a quantitative, observational, and cross-sectional study conducted among a population of 739 Mexican students and 305 Peruvian students, most of whom were women (n =778, 74.5%) and non-graduates (n =921, 88.2%). The questionnaire scale for changes in lifestyles during the quarantine period has been previously validated. Results: The association between sociodemographic factors and dimensions of change in healthy lifestyles was evaluated, and it was shown that gender and country of residence were significant for all dimensions of healthy lifestyle (p < 0.05), except for the level of education, which did not show significance about the change in the dimensions of media consumption (p = 0.875) and physical activity (p = 0.239). Within the dimensions mentioned, it can be stated that women are more likely than men to change their eating habits (adjusted prevalences (aPR) = 1.08, p < 0.001), media consumption (aPR = 1.04, p < 0.001), and physical activity (aPR = 1.02, p < 0.001). Meanwhile, participants from Peru are more likely than participants from Mexico to change physical activity (aPR = 1.14, p < 0.001) and media consumption (aPR = 1.22, p < 0.001). Finally, graduate students were more likely than undergraduate students to change eating habits (aPR = 1.09, p = 0.005) and unhealthy habits (aPR = 1.06, p = 0.030). Conclusion: It was concluded that there were lifestyle changes in Mexican and Peruvian university students in their eating habits, physical activity, internet consumption, and food delivery.

West Nile Virus Seroprevalence in Wild Birds and Equines in Madrid Province, Spain.

West Nile virus (WNV) is a re-emerging flavivirus, primarily circulating among avian hosts and mosquito vectors, causing periodic outbreaks in humans and horses, often leading to neuroinvasive disease and mortality. Spain has reported several outbreaks, most notably in 2020 with seventy-seven human cases and eight fatalities. WNV has been serologically detected in horses in the Community of Madrid, but to our knowledge, it has never been reported from wild birds in this region. To estimate the seroprevalence of WNV in wild birds and horses in the Community of Madrid, 159 wild birds at a wildlife rescue center and 25 privately owned equines were sampled. Serum from thirteen birds (8.2%) and one equine (4.0%) tested positive with a WNV competitive enzyme-linked immunosorbent assay (cELISA) designed for WNV antibody detection but sensitive to cross-reacting antibodies to other flaviviruses. Virus-neutralization test (VNT) confirmed WNV antibodies in four bird samples (2.5%), and antibodies to undetermined flavivirus in four additional samples. One equine sample (4.0%) tested positive for WNV by VNT, although this horse previously resided in a WN-endemic area. ELISA-positive birds included both migratory and resident species, juveniles and adults. Two seropositive juvenile birds suggest local flavivirus transmission within the Community of Madrid, while WNV seropositive adult birds may have been infected outside Madrid. The potential circulation of flaviviruses, including WNV, in birds in the Madrid Community raises concerns, although further surveillance of mosquitoes, wild birds, and horses in Madrid is necessary to establish the extent of transmission and the principal species involved.

Systematic literature review to inform the Portuguese recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. METHODS: A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. RESULTS: Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. CONCLUSION: The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

Lessons learnt from the recent recommendations for the non-pharmacological management of systemic sclerosis.

In inflammatory rheumatic diseases, including, systemic sclerosis (SSc) there is growing evidence that treatment strategies should not only target disease control in terms of clinical features and laboratory tests but consider distinct interventions to mitigate all domains of perceived disease impact. The results of a multicentric work based on data from the Rheumatic Diseases Portuguese Registry (Reuma.pt)/Scleroderma indicated that the optimization of outcomes for patients with SSc would in all probability require assessment of the needs of individual patients and consider adjunctive interventions in clinical practice to mitigate all significantly affected domains of disease impact. Recently, in June 2023, a task force under the auspices of EULAR, comprising rheumatologists, health professionals and patient advocates published four overarching principles and twelve recommendations for the non-pharmacological management of people living with SSc and systemic lupus erythematosus (SLE).

10-year experience of early arthritis clinic at a tertiary rheumatology center: achievements and challenges.

OBJECTIVES: To characterize patients evaluated in our Early Arthritis Clinic (EAC) in the first ten years; to assess diagnostic delay and its underlying causes; and to evaluate the level of agreement between the referring physician and the rheumatologist regarding the presence of referral criteria. METHODS: Cross-sectional study including patients attending EAC between 2012 and 2021. Demographic data, provenience, final diagnosis, referral criteria and time related to diagnosis delay were retrieved from clinical files and the Portuguese Registry of Rheumatic Patients (reuma.pt). Characteristics of the patients and the time variables were analysed with descriptive statistical analysis. The agreement between the referring physician and rheumatologist regarding the referral criteria was evaluated using Cohen's Kappa. RESULTS: A total of 440 patients (68.9% females, mean age of 54±16.7 years) were referred, mostly from primary care (71.6%). Inflammatory Rheumatic Disease was diagnosed in 65.7% of the patients, with 58.9% classified as early arthritis. The median time from onset of symptoms to referral for EAC was 76 days (IQR 33.5-144.0); the median time from referral to the first EAC was 34 (IQR 19.0-46.0) days, and the median time from onset of symptoms to first EAC was 114.5 (IQR 66.8-190.3) days (16.3 weeks). Only about 10% were observed by a Rheumatologist before six weeks after symptom onset. The level of agreement between the referring physician and the rheumatologist was slight to fair to clinical criteria and moderate to substantial to laboratory criteria. CONCLUSIONS: A significant delay still is observed in patients with early arthritis suspicion, being the time from onset of symptoms to referral is the most relevant. A low agreement between referral and Rheumatologists suggests that non-rheumatologists education/training is needed. Identifying the barriers that prevent the adequate referral of patients is necessary to define strategies to improve it.

Validation of the Portuguese Version of the Scleroderma Health Assessment Questionnaire.

The Health Assessment Questionnaire Disability Index (HAQ-DI) was completed with five visual analog scales to assess systemic sclerosis (SSc) called Scleroderma HAQ (SHAQ). We performed a validation of the European Portuguese version of SHAQ for patients with SSc. Patients with different forms of SSc from five Hospital Centers were invited. The reliability of the Portuguese SHAQ was evaluated by internal consistency and by test-retest reliability. Content validity was checked by two rheumatologists and by a panel of patients. Construct validity was assessed by structural validity and by known-groups hypothesis tests. Criterion validity was addressed with selected dimensions from the UCLA GIT 2.0, the SF-36v2, and the EuroQoL EQ-5D-5L. A total of 102 SSc patients agreed to participate, 31 of which answered to the retest. HAQ-DI demonstrated high internal consistency reliability (α = 0.866) and SHAQ also showed high test-retest reliability (ICC 0.61-0.95). We evidenced the unidimensionality of all VASs. HAQ-DI scores were worse in males, patients older than 65 years, and individuals with a diffuse form of SSc. Criterion validity was mainly evidenced through the correlation between the HAQ-DI and SF-36v2 physical summary measure (r = -0.688) and EQ-5D-5L index score (r = -0.723). Likewise, the SHAQ overall disease severity VAS was also correlated with SF-36v2 physical summary measure (r = -0.628). Mental score correlations were smaller. With the exception of the Raynaud's VAS, all the other VASs correlated well with similar clinical variables. This paper provides evidence to demonstrate how reliable and valid the European Portuguese version of SHAQ is, to be used in SSc patients to assess the clinical severity under the perspective of patients.

A Spanish Survey on the Perioperative Use of Antimicrobials in Small Animals.

Appropriate use of perioperative antimicrobials can significantly reduce the risk of post-operative infections. However, inappropriate antimicrobial use can result in the creation of multidrug-resistant bacteria, increased costs, host flora disruption, side effects and increased risk of hospital-acquired infections. This survey evaluated the current perioperative use of antimicrobials in small animals by Spanish veterinarians using a web-based questionnaire. Responses were represented using descriptive statistics and a statistical analysis of the association between demographic data and perioperative antimicrobial use was performed. Pre-operative antimicrobials were administered in clean surgery by up to 68.3% of participants, 81.0% in clean-contaminated surgery and 71.3% in dirty surgery, while in the post-operative period, antimicrobials were administered by up to 86.3% of participants in clean surgery, 93.2% in clean-contaminated surgery and 87.5% in dirty surgery. Factors considered "very important" for antimicrobial selection were the degree of wound contamination, patient immunosuppression and use of prosthesis. The most frequently used antimicrobial was beta-lactamase-resistant (or potentiated) penicillin. Post-operative antimicrobial use was associated with participants without specific surgical postgraduate training. This study highlights an overuse of antimicrobials in perioperative procedures in small animal surgery in Spain. Therefore, evidence-based guidelines and further education regarding the correct use of antimicrobial prophylaxis are recommended.

Umbilical-Cord-Derived Mesenchymal Stromal Cells Modulate 26 Out of 41 T Cell Subsets from Systemic Sclerosis Patients.

Systemic sclerosis (SSc) is an immune-mediated disease wherein T cells are particularly implicated, presenting a poor prognosis and limited therapeutic options. Thus, mesenchymal-stem/stromal-cell (MSC)-based therapies can be of great benefit to SSc patients given their immunomodulatory, anti-fibrotic, and pro-angiogenic potential, which is associated with low toxicity. In this study, peripheral blood mononuclear cells from healthy individuals (HC, n = 6) and SSc patients (n = 9) were co-cultured with MSCs in order to assess how MSCs affected the activation and polarization of 58 different T cell subsets, including Th1, Th17, and Treg. It was found that MSCs downregulated the activation of 26 out of the 41 T cell subsets identified within CD4+, CD8+, CD4+CD8+, CD4-CD8-, and γδ T cells in SSc patients (HC: 29/42) and affected the polarization of 13 out of 58 T cell subsets in SSc patients (HC: 22/64). Interestingly, SSc patients displayed some T cell subsets with an increased activation status and MSCs were able to downregulate all of them. This study provides a wide-ranging perspective of how MSCs affect T cells, including minor subsets. The ability to inhibit the activation and modulate the polarization of several T cell subsets, including those implicated in SSc's pathogenesis, further supports the potential of MSC-based therapies to regulate T cells in a disease whose onset/development may be due to immune system's malfunction.

Influence of contextual factors and reliability of ultrasound skin measures in persons with systemic sclerosis and healthy controls.

OBJECTIVES: To examine the influence of contextual factors upon the evaluation of skin thickness and stiffness by ultrasound and to assess the reliability of these parameters. METHODS: Ultrasound dermal thickness (by B-mode, 18MHz) and skin stiffness (by shear-wave elastography, 9MHz) were assessed in persons with systemic sclerosis (SSc) and in healthy controls. The influence of contextual factors upon repeated measures was evaluated: (i) room temperature (16-17ºC vs. 22-24ºC); (ii) time of day (morning vs. afternoon), and (iii) menstrual cycle phase (menstrual vs. ovulatory). Differences were analysed using the related-samples Wilcoxon signed-rank test. Inter- and intra-rater reliability of ultrasound skin thickness and stiffness were evaluated in the 17 skin Rodnan sites of 20 persons with SSc and 20 healthy controls, under stable contextual conditions. RESULTS: A significant increase in ultrasound dermal thickness was observed at the leg in the afternoon vs morning, in both patients and controls. Similar observations were made for skin stiffness at the leg (in SSc) and at the foot (in SSc and controls) in the afternoon. No significant changes were observed in association with room temperature and menstrual cycle. Intra- and inter-rater-reliability was good to excellent for ultrasound dermal thickness and stiffness, both in SSc and healthy controls. CONCLUSIONS: The timing of the ultrasound procedure within each day seems to influence the ultrasound measures at the legs and feet. Our study corroborates that ultrasound dermal thickness and skin stiffness are reliable domains to quantify skin involvement in SSc.

Creation and Validation of a Portuguese Version of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument.

(1) Background: The UCLA GIT 2.0 questionnaire has been recognized as a feasible and reliable instrument to assess gastrointestinal (GI) symptoms in systemic sclerosis (SSc) patients and their impact on quality of life. The aim of this study was to create and validate UCLA GIT 2.0 for Portuguese patients with SSc. (2) Methods: A multi-center study was conducted enrolling SSc patients. UCLA GIT 2.0 was validated in Portuguese using reliability (internal consistency, item -total correlation, and reproducibility) and validity (content, construct, and criterion) tests. Criterion tests included EQ-5D and SF-36v2. Social-demographic and clinical data were collected. (3) Results: 102 SSc patients were included, 82.4% of them female, and with a mean sample age of 57.0 ± 12.5 years old. The limited form of SSc was present in 62% of the patients and 56.9% had fewer than five years of disease duration. Almost 60% presented with SSc-GI involvement with a negative impact on quality of life. The means for SF-36v2 were 39.3 ± 10.3 in the physical component summary and 47.5 ± 12.1 in the mental component summary. Total GI score, reported as mild in 57.8% of the patients, was highly reliable (ICC = 0.912) and the Cronbach's alpha was 0.954. There was a high correlation between the total GI score and EQ-5D-5L and SF-36v2 scores. (4) Conclusion: The Portuguese version of UCLA GIT 2.0 showed good psychometric properties and can be used in research and clinical practice.

Glucocorticoids prescribing practices in systemic sclerosis: an analysis of the EUSTAR database.

OBJECTIVES: To estimate the prevalence of long-term exposure to glucocorticoids (GCs) and to identify factors associated with, and variations in prescribing practices over time and across recruiting countries. METHODS: We included patients with SSc having a visit recorded in the EUSTAR database from January 2013 onward. We analysed the prevalence and the main features of GCs users, their exposure to GCs over time, and their GCs dosages. Multivariable linear regression was used to analyse the factors identified as associated with GCs intake duration. Time trends, and variations in GCs utilization across recruiting countries were explored. Missing data were imputed using multiple imputation with chained equations. RESULTS: The 9819 patients included were mostly females (85%), the majority had lcSSc (73%), and the median age was 58 years. At baseline, 34% of patients (n = 2769/8109) (48% dcSSc vs 29% lcSSc) were on GCs, and the median dose was 7.5 mg/day. GCs users were more frequently males and anti-Scl70 positive, and more commonly had dcSSc and more severe disease. On average, GCs users spent 25% of their follow-up time (median 33.2 months) on GCs, with no significant between-subsets difference. Notably, 33% (n = 971/2959) and 22% (n = 647/2959) of patients followed up for >1 year had received GCs for >6 and >12 months, respectively. Multivariable analysis showed that patient and disease characteristics poorly explained the variability in GCs exposure (adjusted-R2 = 0.06, P < 0.001). GCs utilization varied within and across countries, and gradually decreased over time (36% in 2013 vs 23% in 2018). CONCLUSIONS: GCs are widely and long-term prescribed in SSc, with significant between-countries and within-country differences. A gradual decrease in their utilization has been observed.

Prevalence, incidence and risk factors for acquisition and colonization of extended-spectrum beta-lactamase- and carbapenemase-producing Enterobacteriaceae from dogs attended at a veterinary hospital in Spain.

The last 10 years have seen a progressive increase in antibiotic resistance rates in bacteria isolated from companion animals. Exposure of individuals to resistant bacteria from companion animals, such as extended-spectrum beta-lactamase- (ESBL) and carbapenemase- (CPE) producing Enterobacteriaceae, can be propitiated. Few studies evaluate the incidence and risk factors associated with colonization by multidrug-resistant bacteria in dogs. This work aims to estimate the prevalence, incidence and risk factors associated with colonization of ESBL-E and CPE-E in 44 canine patients hospitalized in a veterinary hospital. The antimicrobial susceptibility of Enterobacteriaceae strains was analyzed and the molecular detection of resistant genes was performed. A prevalence of 25.0% and an incidence of ESBL-E of 45.5% were observed in dogs colonized by Enterobacteriaceae at hospital admission and release, respectively. Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri and Morganella morganii were identified as ESBL-producing bacterial species. Resistance genes were detected for ESBL-producing strains. No CPE isolates were obtained on the CPE-selective medium. The administration of corticosteroids prior to hospitalization and the presence of concomitant diseases were associated with colonization by these bacteria in dogs. Considering that one-quarter of the patients evaluated were colonized by ESBL-E, companion animals should be considered as potential transmission vehicles and ESBL-E reservoirs for humans. Special care should be taken in animals attended at veterinary hospitals, as the length of stay in the hospital could increase the risks.

The role of skin ultrasound in systemic sclerosis: looking below the surface to understand disease evolution.

Skin ultrasound has shown promising results in the evaluation of skin involvement in patients with systemic sclerosis, as substantiated by a recent systematic literature review from the World Scleroderma Foundation Skin Ultrasound Working Group. In this Viewpoint, we will discuss the role of ultrasound in evaluating skin involvement in patients with systemic sclerosis, particularly the possibility of using this technique to detect an early subclinical skin involvement from the very early phase, suggesting its possible use in both diagnosis and disease follow-up. To detect subclinical skin involvement, it is essential to understand the difference between the skin of patients with systemic sclerosis and that of healthy controls, including defining exactly which structures are affected by the disease and which are spared. The potential of this non-invasive technique might suggest its future role in both clinical practice and clinical trials, possibly replacing invasive and painful procedures such as skin biopsies and promoting patient retention in clinical trials.