Tânia Santiago
email: tlousasantiago@hotmail.com

Eduardo Santos

Barbara Ruaro

Gemma Lepri

Lorraine Green

Marie Wildt

Shinji Watanabe

Alain Lescoat

Roger Hesselstrand

Francesco Del Galdo

John D Pauling

Annamaria Iagnocco

Jap Da Silva

Silva

Ultrasound and elastography in the assessment of skin involvement in systemic sclerosis: A systematic literature review focusing on validation and standardization -WSF Skin Ultrasound Group

Keywords: Skin Ultrasound, Skin elastography, Systemic sclerosis

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Systemic sclerosis (SSc) is an autoimmune rheumatic disease characterized by vascular damage and fibrosis of the skin and/or internal organs, with high clinical burden and unsatisfactory treatment. [START_REF] Allanore | Systemic sclerosis[END_REF] Skin fibrosis is a clinical hallmark of the disease, 2 and an important marker of disease activity, 3 severity 4,5 and prognosis. [START_REF] Domsic | Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma[END_REF][START_REF] Steen | The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time[END_REF] The extent of skin involvement and its rate of progression are associated with internal organ involvement, functional disability, and survival. [START_REF] Clements | Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial[END_REF] This makes skin assessment a crucial issue for both clinical practice and research.

The modified Rodnan skin score (mRSS) is the current gold standard to evaluate skin involvement. It is a semi-quantitative score based on the palpation of the skin at 17 anatomical sites. 2 It is often used as primary or secondary outcome in clinical trials. The mRSS is also a major component of the composite response index in diffuse cutaneous SSc [START_REF] Khanna | The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis[END_REF] and it is included in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) disease activity score. [START_REF] Valentini | The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis: derivation and validation of a preliminarily revised EUSTAR activity index[END_REF] This underlines the importance of skin assessment, however the mRSS has several important limitations, including its subjectivity and intra-and inter-observer variability (around 12% and 25%, respectively). [START_REF] Czirjak | Skin involvement in systemic sclerosis[END_REF][START_REF] Amjadi | Course of the modified Rodnan skin thickness score in systemic sclerosis clinical trials: analysis of three large multicenter, double-blind, randomized controlled trials[END_REF] It is poorly sensitive to change in patients with limited cutaneous SSc and it has shown a modest performance in discriminating drug versus placebo in most clinical trials. [START_REF] Khanna | Tocilizumab in systemic sclerosis: a randomised, doubleblind, placebo-controlled, phase 3 trial[END_REF][START_REF] Khanna | Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial[END_REF][START_REF] Elhai | Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study[END_REF] Novel therapies are dearly needed, but current measures of effect are too blunt to support progress. This emphasizes the need for more accurate and sensitive tools to assess skin in SSc.

The potential use of skin ultrasound and elastography to this purpose has been addressed in several studies over the last three decades. [START_REF] Ch'ng | A systematic review of ultrasonography as an outcome measure of skin involvement in systemic sclerosis[END_REF][START_REF] Santiago | Ultrasonography for the Assessment of Skin in Systemic Sclerosis: A Systematic Review[END_REF][START_REF] Hughes | The role of ultrasound in systemic sclerosis: On the cutting edge to foster clinical and research advancement[END_REF] Although these tools are considered promising, their actual value as a correlate or surrogate of skin involvement in SSc remains unclear, with limited existing integration in current clinical practice and research. The "Skin Ultrasound Working Group", that has been recently created under the auspices of the World Scleroderma Foundation (WSF), aims to develop recommendations for the standardization of the procedures and reports on the assessment of the skin by ultrasound and elastography in SSc.

We herein present the results of a systematic literature review (SLR) performed to support the development of these recommendations by highlighting the achievements and limitations of accumulated evidence. In addition, we evaluated whether available information supports the use of skin ultrasound and elastography as an surrogate outcome measure in SSc, according to the outcome measures in rheumatologic clinical trials (OMERACT) filter 2.1 instrument selection algorithm (OFISA). [START_REF] Beaton | Instrument Selection Using the OMERACT Filter 2.1: The OMERACT Methodology[END_REF] Specifically, this SLR focuses on the pillars of truth, discrimination and feasibility.

Methods

Literature search

This SLR was conducted according to the Cochrane Handbook [START_REF] Higgins | Cochrane Handbook for Systematic Reviews of Interventions version 6[END_REF] and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [START_REF] Page | The PRISMA 2020 statement: an updated guideline for reporting systematic reviews[END_REF] . The SLR protocol, which was not registered but is available upon request, was established a priori and strictly adhered to.

In the first meeting of the Skin Ultrasound Working Group of the WSF the key research questions were framed, following the population, intervention, comparator and outcome -PICO -format. This referred to the procedures/methods used for image acquisition in skin ultrasound and elastography, as well their analysis and interpretation in patients with SSc.

The population of interest consisted of adult patients (>18years) with SSc fulfilling the 1980 ACR criteria [START_REF]Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee[END_REF] , 2013 ACR/EULAR [START_REF] Van Den Hoogen | classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative[END_REF] or classified by their cutaneous subtype as defined by LeRoy et al. [START_REF] Leroy | Scleroderma (systemic sclerosis): classification, subsets and pathogenesis[END_REF] Eligible studies were full research articles, of all types, conveying results of original research, including at least one defined group of patients with SSc, and reporting a structured evaluation and clear definition of the ultrasound scanning protocol. Details of the inclusion criteria are presented in supplementary material table S1.

Search strategy and study selection

The SLR was conducted by two reviewers (TS and ES). The search strategy was developed by one of the reviewers (ES), with accredited experience in this field.

Medline, Cochrane Library and Embase databases were searched without language restrictions, for papers published from 1 January 1979 until 31 May 2021. This start date was chosen because the first B-mode ultrasound image of human skin was reported in 1979. 22 Details on complete search strategies are provided in the supplementary material table S1.

All identified citations were uploaded into an EndNote VX7 (Clarivate Analytics, PA, USA) library and the duplicates removed. The reviewers (TS and ES) screened independently all title and abstracts to identify potentially eligible studies, which were, then, reviewed in full text.

Extraction of study characteristics and results

Papers fulfilling the inclusion criteria were submitted to data extraction.

Both reviewers independently retrieved data using a predefined data extraction sheet, validated by the task force and informed by the EULAR checklist recommendations for the reporting of ultrasound studies in rheumatic diseases [START_REF] Costantino | EULAR recommendations for the reporting of ultrasound studies in rheumatic and musculoskeletal diseases (RMDs)[END_REF] : studies main characteristics (year of publication, country, design, participants, disease characteristics), ultrasound outcome domains, equipment, blinding, scanning/acquisition procedures, ultrasound scoring system, contextual factors and feasibility. Authors of papers were contacted to request missing or additional data, where required.

Evaluation was made strictly following OFISA and Handbook [START_REF]Chapter 5: Instrument selection for core outcome measurement sets -Workbook[END_REF] . The successive phases of evaluations are described below:

Evaluation of the methodological quality per measurement property, per study

The methodological quality (risk of bias) of each study was assessed by two independently reviewers (TS, ES), using the COSMIN-OMERACT Good Metrics Checklist (table S2). [START_REF]Chapter 5: Instrument selection for core outcome measurement sets -Workbook[END_REF] Quality assessment was rated using a colour code: 'Green' if good methods were used, 'Amber' if there were some methodological concerns but the data were acceptable for inclusion, and 'Red' if there was a high risk of bias, as indicated by OMERACT.

Discrepancies between reviewers regarding study selection, data extraction and risk of bias assessment were resolved by consensus or with a third reviewer (JAPS).

Evaluating the performance of measurement properties per study

Each study was assessed using the OMERACT provisional standards for adequate performance and assigned ratings of + (positive support for the measurement property), ± (ambivalent support, inconclusive), or -(instrument did not reach performance standards for that measurement property) (table S3). [START_REF]Chapter 5: Instrument selection for core outcome measurement sets -Workbook[END_REF]

Summary ratings of individual measurement properties per domain

All studies rated amber or green were synthesized to generate an overall rating for the individual measurement properties for each domain based on the OMERACT Handbook -"Criteria for Final Rating". [START_REF]Chapter 5: Instrument selection for core outcome measurement sets -Workbook[END_REF] This rating summarises the quality and quantity of studies, the consistency of the results, and the performance of individual instruments.

A colour grading was used as recommended: GREEN indicates 'Good to go', RED indicates 'Stop, do not continue', WHITE indicates 'No evidence' and AMBER indicates 'There is a concern, or caution, or weakness, but it is good enough to go forward, perhaps with a research agenda to move it to GREEN or RED'.

Results

Study selection

The literature review yielded 3248 references (Figure 1

THICKNESS

Study characteristics

Thirty-seven studies evaluated the ultrasound-thickness of skin tissues.

They were published between 1985 and 2021, most being observational and cross-sectional (table 1). Six studies were longitudinal: 4 evaluated spontaneous change over time [START_REF] Akesson | Ultrasound examination of skin thickness in patients with progressive systemic sclerosis (scleroderma)[END_REF][START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Akesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Santiago | How much of skin improvement over time in systemic sclerosis is due to normal ageing? A prospective study with shear-wave elastography[END_REF] and 2 changes due to interventions. 30 31 All studies were based in a single centre.

In total, 1439 SSc patients (~80% female and ~60% with a limited form) were evaluated. Thirty-two studies had a control group. Cases were defined according to the 1980 ARA criteria in 20 studies (55.5%), to the 2013 ACR/EULAR classification criteria in 12 (30%) and both criteria in 2 studies (9%). [START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF] The Le Roy criteria were used in 2 studies (5.5%) (table S2). [START_REF] Sulli | Correlations between nailfold microangiopathy severity, finger dermal thickness and fingertip blood perfusion in systemic sclerosis patients[END_REF][START_REF] Kaloudi | High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis[END_REF]

Description of image acquisition and analysis

Most studies reported using linear probes with variable frequencies ranging from 10 to 50MHz (table S3). The ultrasound equipment brand and system were mentioned in 32 (86.5%) studies. Twenty-eight (75.6%) studies mentioned that the probe was placed perpendicularly to the skin. Probe position was not described in the remaining studies (25%). Half of the studies reported using a layer of gel to minimize the compression induced by the transducer on the skin. Only one study reported the use of a standoff silicone interface. [START_REF] Akesson | Ultrasound examination of skin thickness in patients with progressive systemic sclerosis (scleroderma)[END_REF] One third of the studies reported that sonographers were blinded to local mRSS (table S4). Only a few studies mentioned the sonographers experience with skin ultrasound. [START_REF] Geso | Reliability of ultrasound measurements of dermal thickness at digits in systemic sclerosis: role of elastosonography[END_REF][START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter? Article[END_REF][START_REF] Sousa-Neves | Ultrasound assessment of skin thickness performed on fingers: a tool for estimating overall severity of skin disease in Systemic Sclerosis patients?[END_REF][START_REF] Li | High-frequency ultrasound of the skin in systemic sclerosis: An exploratory study to examine correlation with disease activity and to define the minimally detectable difference[END_REF][START_REF] Yang | Quantification of skin stiffness in patients with systemic sclerosis using real-time shear wave elastography: a preliminary study[END_REF][START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF][START_REF] Naredo | Performance of ultra-high-frequency ultrasound in the evaluation of skin involvement in systemic sclerosis: a preliminary report[END_REF] Eight studies (22.2%) reported the timing of the measurements within the day; and only 2 (5.5%) mentioned that ultrasound was performed at room temperature, without further specification. [START_REF] Sedky | Systemic sclerosis: an ultrasonographic study of skin and subcutaneous tissue in relation to clinical findings[END_REF][START_REF] Daoudi | Photoacoustic and high-frequency ultrasound imaging of systemic sclerosis patients[END_REF] In half of the studies, the quality criterion for acceptance of an ultrasound image was described as the adequate depiction of epidermis, dermis, and subcutis, with distinct and parallel interfaces between them (table S3). The remaining studies did not describe their quality criteria or did so insufficiently.

Overall, the skin sites examined corresponded to all or some of the Rodnan skin sites, or at least in the same body area. However, the exact definition of landmarks for each site scanned varied considerably. Two studies only assessed the palmar aspects of the fingers. [START_REF] Daoudi | Photoacoustic and high-frequency ultrasound imaging of systemic sclerosis patients[END_REF][START_REF] Grembiale | Correlation between elastosonography and nailfold microvascular alterations in systemic sclerosis patients[END_REF] Thirteen studies (35.1%) measured solely the dermis, 13 (35.1%) assessed the epidermis and dermis, 3 studies evaluated epidermis, dermis and subcutaneous layer [START_REF] Sousa-Neves | Ultrasound assessment of skin thickness performed on fingers: a tool for estimating overall severity of skin disease in Systemic Sclerosis patients?[END_REF][START_REF] Scheja | Comparison of high frequency (20 MHz) ultrasound and palpation for the assessment of skin involvement in systemic sclerosis (scleroderma)[END_REF][START_REF] Serup | Ring size measurement of the digits in females suffering from generalized scleroderma (acrosclerosis). A simple method to quantify skin and soft tissue affection[END_REF] and yet 1 study evaluated dermis and hypodermis [START_REF] Naredo | Performance of ultra-high-frequency ultrasound in the evaluation of skin involvement in systemic sclerosis: a preliminary report[END_REF] (table S3). Seven studies (19.4%) did not describe which skin layers were evaluated.

All studies reported thickness in millimetres, but the scoring system varied:

the number of ultrasound images taken from each skin site was variable across studies, as well as the number of thickness measurements per skin site. The average result of these measurements was used for statistical analysis. Except for one study, [START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] it's unclear whether the image analysis was performed during the ultrasound evaluation or later.

Feasibility

For the ultrasound assessment of the 17 Rodnan skin sites, Moore et al [START_REF] Moore | Seventeen-point dermal ultrasound scoring system--a reliable measure of skin thickness in patients with systemic sclerosis[END_REF] reported that image acquisition took ~20minutes; and, Sulli et al [START_REF] Sulli | Subclinical dermal involvement is detectable by high frequency ultrasound even in patients with limited cutaneous systemic sclerosis[END_REF] took 20-25 minutes, including skin image acquisition and analysis. No additional feasibility parameters were reported. Following synthesis of the results and risk of bias, this measurement property was rated AMBER.

Convergent validity against mRSS, skin biopsy, and other constructs

The validity of ultrasound-measured thickness vs mRSS was studied in 22 and confirmed in 20 studies, by demonstration of a mild to moderate correlation between ultrasound-measured thickness and local site-specific mRSS (table S4).

Four studies assessed histological findings, [START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF][START_REF] Ihn | Ultrasound measurement of skin thickness in systemic sclerosis[END_REF] but only 2 evaluated convergent validity of ultrasound vs histological parameters. These 2 studies used forearm skin biopsies from 13 [START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF] and 20 [START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] participants, respectively, and found moderate to good correlations between skin thickness measured by ultrasound and histological findings. These preliminary analyses of convergent validity with tissue histology is encouraging but further work is desirable.

Correlations between ultrasound skin thickness and a variety of other measures were explored in several studies, including nailfold videocapillaroscopy (NVC), [START_REF] Sulli | Subclinical dermal involvement is detectable by high frequency ultrasound even in patients with limited cutaneous systemic sclerosis[END_REF][START_REF] Sulli | Dermal thickness, peripheral blood perfusion and nailfold microangiopathy in systemic sclerosis patients[END_REF][START_REF] Ruaro | Correlations between nailfold microvascular damage and skin involvement in systemic sclerosis patients[END_REF] Laser Speckle Contrast Analysis, [START_REF] Kaloudi | High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis[END_REF][START_REF] Sulli | Dermal thickness, peripheral blood perfusion and nailfold microangiopathy in systemic sclerosis patients[END_REF][START_REF] Ruaro | Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients[END_REF] cartilage oligomeric matrix protein (COMP), [START_REF] Hesselstrand | COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker[END_REF] EUSTAR disease activity index, [START_REF] Li | High-frequency ultrasound of the skin in systemic sclerosis: An exploratory study to examine correlation with disease activity and to define the minimally detectable difference[END_REF] hand mobility in scleroderma, [START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Sousa-Neves | Ultrasound assessment of skin thickness performed on fingers: a tool for estimating overall severity of skin disease in Systemic Sclerosis patients?[END_REF] health assessment questionnaire [START_REF] Kaloudi | High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis[END_REF] and spectral angle mapper. [START_REF] Chen | Hyperspectral imaging for skin assessment in systemic sclerosis: A pilot study[END_REF] The committee decided that these comparisons make a smaller contribution to convergent validity, given the heterogeneous factors contributing to the parameters under evaluation.

Inter-, Intra-rater and test-retest reliability

Eighteen studies performed reliability assessments (table S4). The median ICC varied from 0.84 (0.65 -0.94) for inter-reader, and 0.92 (0.55 -0.97) for intra-reader reliability. [START_REF] Moore | Seventeen-point dermal ultrasound scoring system -A reliable measure of skin thickness in patients with systemic sclerosis[END_REF][START_REF] Vanhaecke | FREQUENCY ULTRASONOGRAPHY: RELIABLE TOOL TO MEASURE SKIN FIBROSIS IN SSC? A systematic literature review and additional pilot study[END_REF] One small study [START_REF] Ruaro | The impact of transducer frequency in ultrasound evaluation of subclinical skin involvement in limited cutaneous systemic sclerosis patients[END_REF] compared the intrareader reliability with probes of 18 and 22MHz, and found them to be similar.

Inter-and intra-rater reliability was rated GREEN. No studies evaluated testretest reliability.

Discriminatory capacity across different participants groups

Thirty-four studies compared ultrasound-measured thickness in SSc patients vs controls (table 2). Thickness was higher in SSc patients than in controls, at group level, in almost all Rodnan sites (mRRS≥1) and in all studies. Six studies reported on the ultrasound-measured thickness of clinically unaffected skin (mRSS=0) and all found it to be thicker in patients than in controls, at least in some Rodnan sites. [START_REF] Kaloudi | High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF][START_REF] Sulli | Subclinical dermal involvement is detectable by high frequency ultrasound even in patients with limited cutaneous systemic sclerosis[END_REF][START_REF] Ihn | Ultrasound measurement of skin thickness in systemic sclerosis[END_REF][START_REF] Ruaro | Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients[END_REF][START_REF] Hesselstrand | High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease[END_REF][START_REF] Li | Skin ultrasound in SSc: An exploratory study to examine correlation with disease activity and to define the minimally detectable difference[END_REF] Two studies identified that dermal thickness decreased as the clinical phase progressed from oedematous to the atrophic phase. [START_REF] Kaloudi | High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis[END_REF][START_REF] Hesselstrand | High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease[END_REF] Therefore this property was rated GREEN for thickness.

Sensitivity to change

Four studies reported change over time. [START_REF] Akesson | Ultrasound examination of skin thickness in patients with progressive systemic sclerosis (scleroderma)[END_REF][START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Akesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF] In these studies ultrasound dermal thickness decreased and patients became more similar to the control population between the first and the fourth year of follow up. [START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF] None of the studies made comparisons with mRSS nor did they use appropriate statistical methods to evaluate sensitivity to change (e.g., effect size of standardized response mean). Following synthesis of the results and risk of bias, this domain was rated AMBER for sensitivity to change.

Clinical trial discrimination and threshold of meaning

Two small studies investigated the impact of two interventions:

photochemotherapy [START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF] and bosentan. [START_REF] Kuhn | Effect of bosentan on skin fibrosis in patients with systemic sclerosis: A prospective, open-label, non-comparative trial[END_REF] Photochemotherapy was associated with a significant decrease in ultrasound-measured dermal thickness.

Bosentan treatment determined only a slight but not significant trend towards improvement of this parameter, from week 0 to 24, despite a statistically significant improvement in mRSS. Both studies had a small sample size and used very limited and questionable statistical analyses. This measurement property was rated AMBER.

A single study [START_REF] Li | Skin ultrasound in SSc: An exploratory study to examine correlation with disease activity and to define the minimally detectable difference[END_REF] reported threshold of meaning. An ultrasoundmeasured thickness cut-off value of 7.4mm (sensitivity 77.4% and specificity 87.1%), was found as the minimum difference distinguishing normal from scleroderma skin, when using a composite measure of the sum of total skin thickness of five skin sites. This measurement property was rated AMBER.

Results regarding SOMP table for thickness are summarized in table 2.

ECHOGENICITY

Study characteristics

Eleven studies, published between 1996 and 2020, evaluated echogenicity (table 1). Seven were observational and cross-sectional, and 4 investigated sensitivity to change over time [START_REF] Akesson | Ultrasound examination of skin thickness in patients with progressive systemic sclerosis (scleroderma)[END_REF][START_REF] Akesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Hesselstrand | High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease[END_REF][START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF] or due to an intervention. [START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF] In total, 476 SSc patients (~87% female and ~50% with a limited form) were evaluated. Seven studies had a control group. Cases were defined according to the 1980 ARA criteria in 8 studies, and 2013 EULAR/ACR in 2 and both in one study (table S2).

Description of image acquisition and analysis

All studies evaluated echogenicity together with thickness, with or without stiffness (table S3). The use of a linear probe, with frequencies from 18 to 20Mhz was reported in all studies apart from 3 which did not provide probe details. [START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF][START_REF] Seidenari | A quantitative description of echographic images of sclerotic skin in patients with systemic sclerosis, as assessed by computerized image analysis on 20 MHz Bscan recordings[END_REF][START_REF] Hassan | High frequency skin ultrasonography in systemic sclerosis[END_REF] The ultrasound brand and system were mentioned in all studies, but one. [START_REF] Hassan | High frequency skin ultrasonography in systemic sclerosis[END_REF] Five studies (45.5%) reported that the sonographer was blinded for the mRSS (table S4). Only 1 study mentioned the sonographers' experience with ultrasound. [START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF] Four studies (36.4%) gave data regarding time of the day of the ultrasound assessment and none reported on temperature. [START_REF] Akesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF][START_REF] Hesselstrand | COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker[END_REF][START_REF] Hesselstrand | High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease[END_REF] The quality criteria for image acceptance demanded a clear echo definition of the interfaces between the epidermis, dermis, and subcutis by A-mode ultrasound and of the echogenicity of the layers of interest, by B-mode (table S3). All studies assessed skin sites corresponding to Rodnan skin sites, or at least in same body area, although the exact definition of landmarks for each site varied.

Six (54.5%) studies evaluated epidermis and dermis, 2 (18.2%) studies focused on the dermis [START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF][START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF] and 1 (9%) study evaluated all three layers. [START_REF] Scheja | Comparison of high frequency (20 MHz) ultrasound and palpation for the assessment of skin involvement in systemic sclerosis (scleroderma)[END_REF] Two studies did not define which skin layers were evaluated (table S3).

Echogenicity was reported in a quantitative scale, except for one study [START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF] , which used a semiquantitative scale. Most of the included studies (72.3%) measured this domain in a scale graded from 0 (black) to 255 (white) pixels, in a selected region of interest. [START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Hesselstrand | High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease[END_REF][START_REF] Åkesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Seidenari | A quantitative description of echographic images of sclerotic skin in patients with systemic sclerosis, as assessed by computerized image analysis on 20 MHz Bscan recordings[END_REF] Different software applications were used to this purpose. A low value is taken as indicative of high water content, suggesting oedema, and increased echogenicity as suggestive of fibrosis.

Two other studies have applied a 0-100 scoring system. [START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF][START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF] In general, it is not clear whether image analysis was performed during ultrasound evaluation or later. Four studies reported on whether readers were blinded to the clinical information during image analysis and scoring. [START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] Feasibility None of the studies included reported the time needed for image acquisition or analysis.

Inter-, Intra-rater and test-retest reliability

Four studies reported reliability assessments for ultrasoundechogenicity of the skin (table S4). Two studies (one [START_REF] Scheja | Comparison of high frequency (20 MHz) ultrasound and palpation for the assessment of skin involvement in systemic sclerosis (scleroderma)[END_REF] of them high risk of bias) reported ICCs of 0.92 to 0.98, for inter-reader reliability. [START_REF] Akesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Scheja | Comparison of high frequency (20 MHz) ultrasound and palpation for the assessment of skin involvement in systemic sclerosis (scleroderma)[END_REF] In 1 study, inter-reader reliability was not satisfactory (ICC <0.75). [START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF] Two studies with low-risk of bias evaluated intra-reader reliability demonstrating ICC values ranging from 0.648 to 0.88, depending on skin sites. [START_REF] Akesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] Therefore, following synthesis of the results and risk of bias, interand intra-rater reliability was rated AMBER. None of the studies performed test-retest reliability.

Convergent validity against mRSS, skin biopsy, and other constructs

The validity of ultrasound-echogenicity against mRSS was evaluated in six studies and confirmed in four, by demonstration of a low to moderate correlation with local site-specific mRSS. 32,59 28,54 A study investigated ultrasound-echogenicity against features of skin biopsy (collagen content), with negative results. [START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] In another study, the authors reported significant correlation between changes in extracellular matrix production in vitro and concomitant changes in ultrasound echogenicity over time. [START_REF] Akesson | Ultrasound examination of skin thickness in patients with progressive systemic sclerosis (scleroderma)[END_REF] Construct validity against skin mRSS and biopsy was rated GREEN and AMBER, respectively.

Discriminatory capacity across different participants groups

The comparison of skin ultrasound echogenicity in patients vs controls was the object of 7 studies (table 3). In all of them the groups differed significantly in almost all skin sites assessed. [START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Seidenari | A quantitative description of echographic images of sclerotic skin in patients with systemic sclerosis, as assessed by computerized image analysis on 20 MHz Bscan recordings[END_REF][START_REF] Hou | A preliminary study of acoustic radiation force impulse quantification for the assessment of skin in diffuse cutaneous systemic sclerosis[END_REF] One recent study found dermal echogenicity to be increased in clinically unaffected skin sites (mRSS=0) of SSc patients compared to controls. [START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] One study including patients in early disease stages found an inverse correlation between skin echogenicity and thickness, at the 5 sites evaluated. [START_REF] Hesselstrand | High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease[END_REF] This measurement property was rated as GREEN.

Sensitivity to change

Four studies evaluated sensitivity to change over time and all identified significant increases of echogenicity in five skin areas over one year of followup. [START_REF] Hesselstrand | The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis[END_REF][START_REF] Akesson | Longitudinal development of skin involvement and reliability of high frequency ultrasound in systemic sclerosis[END_REF][START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF] None of the four studies made direct comparisons with mRSS and statistical analysis of sensitivity to change was limited and questionable. This measurement property was rated AMBER.

Discrimination and threshold of meaning

In a single small study, including 13 SSc patients, photochemotherapy was associated with a significant increase of ultrasound echogenicity after treatment. [START_REF] Hashikabe | Quantitative echographic analysis of photochemotherapy on systemic sclerosis skin[END_REF] This measurement property was rated AMBER.

No threshold of meaning has been reported.

Results regarding SOMP table for echogenicity are summarized in table 3.

STIFFNESS

Study characteristics

Sixteen studies, published between 2010 and 2020, evaluated stiffness, and all, but one 29 , were observational and cross-sectional (table 1).

In total, 478 SSc patients (~92% female and ~50% with a limited form) were evaluated. Twelve studies had a control group. Cases were defined according to the 1980 ARA criteria in 8 studies, the 2013 ACR/EULAR classification criteria in 7, and both criteria in one study (4.4%).

Description of image acquisition and analysis

Seven studies assessed both stiffness and thickness. [START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF][START_REF] Geso | Reliability of ultrasound measurements of dermal thickness at digits in systemic sclerosis: role of elastosonography[END_REF][START_REF] Yang | Quantification of skin stiffness in patients with systemic sclerosis using real-time shear wave elastography: a preliminary study[END_REF][START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF][START_REF] Chen | Hyperspectral imaging for skin assessment in systemic sclerosis: A pilot study[END_REF][START_REF] Hou | A preliminary study of acoustic radiation force impulse quantification for the assessment of skin in diffuse cutaneous systemic sclerosis[END_REF] Ten studies employed shear-wave elastography and six used compression elastography (table S3). Most studies used linear probes, with frequency ranging from 6.4 to 18MHz. In three studies, a standoff gel pad was used to provide an acoustic interface to prevent local artefacts. [START_REF] Sobolewski | Applicability of shear wave elastography for the evaluation of skin strain in systemic sclerosis[END_REF][START_REF] Zhang | An Ultrasound Surface Wave Technique for Assessing Skin and Lung Diseases[END_REF][START_REF] Cannaò | Technical feasibility of real-time elastography to assess the peri-oral region in patients affected by systemic sclerosis[END_REF] The remaining mentioned the use of a generous layer of gel to maintain a minimal compression of the probe to the skin.

Nine (56.3%) of the studies reported that sonographers were blinded to local-mRSS when performing image acquisition, and 7 (43.4%) stated that sonographers had previous experience with musculoskeletal ultrasound (table S4). Two studies gave data regarding the setting conditions, in particular room temperature and/or time of the day. [START_REF] Yang | Quantification of skin stiffness in patients with systemic sclerosis using real-time shear wave elastography: a preliminary study[END_REF][START_REF] Sobolewski | Applicability of shear wave elastography for the evaluation of skin strain in systemic sclerosis[END_REF] All, but one study, [START_REF] Cannaò | Technical feasibility of real-time elastography to assess the peri-oral region in patients affected by systemic sclerosis[END_REF] performed elastography in skin Rodnan sites, but the number of sites evaluated varied from 2 (forearms and fingers) [START_REF] Iagnocco | Ultrasound elastography assessment of skin involvement in systemic sclerosis: lights and shadows[END_REF] to all 17

Rodnan sites. [START_REF] Liu | A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter?[END_REF][START_REF] Hou | A preliminary study of acoustic radiation force impulse quantification for the assessment of skin in diffuse cutaneous systemic sclerosis[END_REF] The landmarks for each skin assessment site varied. Only one study evaluated the peri-oral region. [START_REF] Cannaò | Technical feasibility of real-time elastography to assess the peri-oral region in patients affected by systemic sclerosis[END_REF] Six (37.5%) studies evaluated epidermis and dermis and 2 [START_REF] Geso | Reliability of ultrasound measurements of dermal thickness at digits in systemic sclerosis: role of elastosonography[END_REF][START_REF] Chen | Hyperspectral imaging for skin assessment in systemic sclerosis: A pilot study[END_REF] evaluated only the dermis. Eight studies (50%) did not specify the skin layers examined. Studies used different dedicated softwares and machine models, although most of them provided a color-graded elastogram superimposed on the B-mode image.

Elastography was described in a quantitative or in a semi-quantitative color scale [START_REF] Geso | Reliability of ultrasound measurements of dermal thickness at digits in systemic sclerosis: role of elastosonography[END_REF][START_REF] Sobolewski | Applicability of shear wave elastography for the evaluation of skin strain in systemic sclerosis[END_REF][START_REF] Iagnocco | Ultrasound elastography assessment of skin involvement in systemic sclerosis: lights and shadows[END_REF][START_REF] Çildağ | The relationship between the degree of skin fibrosis by sonoelastography and the degree of pulmonary involvement in scleroderma[END_REF][START_REF] Aryan | Sonoelastography for skin evaluation in sclerodermic patients[END_REF] (table S3). Quantitative values were reported in different units across studies, i.e., meters per second, m/s; elastic modulus in Kilopascal, kPa; or global percentage of hardness.

There was considerable underreporting regarding the methodology used in the scoring system. Few studies detailed the size and shape (round or square) of the region of interest (ROI). The number of images scanned per site, the number of measurements per image and the exact position of the ROIs inside the elastogram was heterogeneous or unreported in many studies.

Feasibility

Only one study reported the time needed for image acquisition and analysis as being about 2 minutes per skin site. [START_REF] Santiago | A preliminary study using virtual touch imaging and quantification for the assessment of skin stiffness in systemic sclerosis[END_REF] Therefore, this property was rated AMBER.

Inter-, Intra-rater reliability and test-retest reliability

Nine studies reported reliability assessments (table S4). The ICCs varied from 0.72 to 0.97 for intra-reader, and 0.7 to 0.987 for inter-reader reliability. [START_REF] Santiago | How much of skin improvement over time in systemic sclerosis is due to normal ageing? A prospective study with shear-wave elastography[END_REF][START_REF] Geso | Reliability of ultrasound measurements of dermal thickness at digits in systemic sclerosis: role of elastosonography[END_REF][START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF][START_REF] Hou | A preliminary study of acoustic radiation force impulse quantification for the assessment of skin in diffuse cutaneous systemic sclerosis[END_REF][START_REF] Sobolewski | Applicability of shear wave elastography for the evaluation of skin strain in systemic sclerosis[END_REF][START_REF] Cannaò | Technical feasibility of real-time elastography to assess the peri-oral region in patients affected by systemic sclerosis[END_REF][START_REF] Iagnocco | Ultrasound elastography assessment of skin involvement in systemic sclerosis: lights and shadows[END_REF][START_REF] Santiago | A preliminary study using virtual touch imaging and quantification for the assessment of skin stiffness in systemic sclerosis[END_REF] Therefore, stiffness was rated GREEN for this measurement property. No studies reported test-retest reliability.

Convergent validity against mRSS, biopsy and other constructs

Ultrasound-stiffness validity against mRSS was assessed in 9 studies and confirmed in 6 (table 4). Stiffness showed a moderate to strong positive correlation with local site-specific mRSS. Construct validity against skin histological findings, showed conflicting results in 2 studies. [START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] In 1 of the studies no clear correlation could be established between histological skin thickness and ultrasound skin stiffness. [START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF] One study found that both ultrasound stiffness and local mRSS correlated strongly with histological dermal collagen content. [START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] Construct validity against mRSS and biopsy was rated GREEN and AMBER, respectively.

One study evaluated the correlations between ultrasound stiffness and nailfold videocapillaroscopy patterns in 20 SSc patients. [START_REF] Hesselstrand | COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker[END_REF] The late pattern (n=12) was independently associated with increased stiffness.

Discriminatory capacity across different participants groups

The comparison of stiffness between patients and controls was the object of 13 studies. Ultrasound stiffness was found to be higher in SSc patients than in controls in almost all Rodnan sites, in 12 studies. In 1 study there was no differences in elastography strain ratio at the forearms and fingers, between 31 SSc patients and 19 controls. [START_REF] Chen | Hyperspectral imaging for skin assessment in systemic sclerosis: A pilot study[END_REF] Patients with SSc had stiffer skin compared to controls even in areas of clinically unaffected skin i.e., local Rodnan score of zero. [START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF][START_REF] Sobolewski | Applicability of shear wave elastography for the evaluation of skin strain in systemic sclerosis[END_REF][START_REF] Santiago | A preliminary study using virtual touch imaging and quantification for the assessment of skin stiffness in systemic sclerosis[END_REF] This measurement property was rated GREEN.

Sensitivity to change

A single longitudinal study showed that skin stiffness decreased significantly and differently in almost all Rodnan skin sites, in 21 SSc patients as well as in 15 controls, over 5 years of follow-up. [START_REF] Santiago | How much of skin improvement over time in systemic sclerosis is due to normal ageing? A prospective study with shear-wave elastography[END_REF] This demonstrated a higher sensitivity to change over time than mRSS. [START_REF] Santiago | How much of skin improvement over time in systemic sclerosis is due to normal ageing? A prospective study with shear-wave elastography[END_REF] The authors did not perform statistical subgroup analysis nor did they report standardized response mean. On this basis, this property was rated AMBER.

Discrimination and threshold of meaning

No studies have reported clinical trial discrimination or threshold of meaning. This was rated WHITE.

Results regarding SOMP table for echogenicity are summarized in table 4.

Discussion

This SLR summarizes the measurement properties of three skin when direct compared with histologic skin thickness (in 2 studies [START_REF] Chen | Ultrasound assessment of skin thickness and stiffness: The correlation with histology and clinical score in systemic sclerosis[END_REF][START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] ) and good to excellent inter-and intra-reliability. Stiffness demonstrated convergent validity against mRSS, good reliability (with ICCs often >0.75, for inter-an intra-rater reliability) as well as cross-sectional construct validity and some evidence (a single study [START_REF] Flower | High frequency ultrasound assessment of systemic sclerosis skin involvement: intra-observer repeatability and relationship with clinician assessment and dermal collagen content[END_REF] ) for sensitivity to change against histological findings. Convergent validity of echogenicity against skin biopsy showed inconclusive data; and inter-and intra-rater reliability needs further studies to draw definite evidence. The main knowledge gaps shared by the three candidates that need to be addressed moving forward are related to feasibility and discrimination, i.e., test-retest reliability, sensitivity to change, discrimination and thresholds of meaning.

Feasibility is an area of weakness shared by all 3 ultrasound and elastography domains. Ultrasound is well accepted by patients and ultrasound machines are widely available to rheumatologists in European countries. [START_REF] Mandl | Implementation and role of modern musculoskeletal imaging in rheumatological practice in member countries of EULAR[END_REF][START_REF] Neto | Musculoskeletal ultrasound among rheumatologists in Portugal: state of practice and training[END_REF] In addition, skin ultrasound may require minimal training to experienced sonographers. However, the time needed for image acquisition and analysis, the dedicated ultrasound software that are needed as well as their costs and technical demands were underreported in the published studies. The potential advantages and limitations of ultrasound examination in a reduced number of body areas has not been assessed.

Evidence for convergent validity against mRSS for the 3 ultrasound domains was derived, mainly, from low-risk bias studies with consistent findings. However, some authors argue that ultrasound outcome domains may actually reflect properties of the skin different from those assessed by the currently validated mRSS, rendering their direct comparisons questionable. [START_REF] Santiago | A preliminary study using virtual touch imaging and quantification for the assessment of skin stiffness in systemic sclerosis[END_REF] It is important to note that almost all studies included patients with established disease, with mean disease duration of ≥ 4 years. The evidence based on convergent validity and responsiveness involving subgroups of patients with different cutaneous forms (limited vs diffuse), different clinical (oedematous vs fibrotic vs atrophic) and time phases (pre vs early vs established) is scarce precludes separate analysis at this point. [START_REF] Hesselstrand | High frequency ultrasound of skin involvement in systemic sclerosis -a follow-up study[END_REF][START_REF] Kaloudi | High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis[END_REF][START_REF] Hesselstrand | High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease[END_REF] It is important that future research addresses the performance of ultrasound measurements in the different disease subsets.

Almost three quarters of the studies used a case-control design and underreported data on enrolment, which may result in overoptimistic estimates of diagnostic accuracy. Furthermore, it is important to note that if ultrasound is to be used to aid early diagnosis, normality reference data for the relevant anatomical sites is required.

Two candidate ultrasound outcome domains (thickness and stiffness)

have been reported to be reliable, with often ICC >0.75 for inter-reader and >0.85 for intra-reader. However, about one third of the published studies used mixed populations (combining SSc patients and controls) to provide reliability results (table S6).

Another area of weakness of all candidate outcomes is discrimination, in particular the absence of evidence for test-retest reliability and sensitivity to change. The threshold of meaning is also of crucial importance, if these ultrasound domains are to serve as outcome measures in future clinical trials: in order to have an acceptable measurement error any given measurement must provide smallest detectable change that is smaller than the minimally important difference. [START_REF]Chapter 5: Instrument selection for core outcome measurement sets -Workbook[END_REF] Contextual factors have been relatively overlooked in the published studies and their importance has been recently highlighted by EULAR recommendations. [START_REF] Costantino | EULAR recommendations for the reporting of ultrasound studies in rheumatic and musculoskeletal diseases (RMDs)[END_REF] The potential effects of either ambient conditions (room temperature, time of the day) or patient conditions (age, gender, smoking, skin temperature, menopausal status..) on skin ultrasound outcome domains, need to be clarified before they can be ignored.

In summary, the measurement properties of the 3 candidate outcome domains to assess skin involvement in SSc show promising quality, despite a relevant number of knowledge gaps. However, underlying this evidence synthesis, and questioning its accuracy, is the remarkable heterogeneity and lack of information in a variety of technical aspects that may have decisive impact on the conclusions. These include i), probes' frequency, ii) number and precise definition of skin sites assessed, iii) skin layers evaluated, iv) scoring system (i.e., number of images scanned per site, number of measurements per image and position of ROIs within the image), and v) blinding during image acquisition and analysis. All these aspects hinder direct comparisons of studies and undermine their external validity, thus requiring further and harmonized investigation. In particular, we emphasize that the evaluation of the methodological quality (risk of bias) of the studies did not include the skin layers evaluated. However, we recognize that this is a crucial aspect that needs standardization. The use of higher frequency probes (at least 18MHz)

will allow the separate evaluation of the skin layers and this should be reported, to address differences in the involvement of dermis and hypodermis layers. [START_REF] Naredo | Performance of ultra-high-frequency ultrasound in the evaluation of skin involvement in systemic sclerosis: a preliminary report[END_REF] Finally, the recent development of a SSc-specific patient-reported outcome instrument for assessing skin involvement will enable future investigators to examine the convergent validity between ultrasound assessment of skin in SSc and how patients 'feel' and 'function'. [START_REF] Man | Development and validation of a patient-reported outcome instrument for skin involvement in patients with systemic sclerosis[END_REF] Also, a crucial future step to define sensitivity to change and clinical validity of skin ultrasound would be its inclusion as a secondary or exploratory endpoint in the context of randomised controlled trials.

Standardization of procedures and reporting seems, therefore, a crucial step to further develop and consolidate the contribution of ultrasound skin evaluation in SSc, together with research focused on the knowledge gaps identified herein. This SLR therefore provides a substrate for future recommendations and evidence-based research.

  ultrasound and elastography candidate outcome domains -thickness, echogenicity, and stiffness -and informs the direction of future work necessary to endorse them as outcome domains for the assessment of skin pathology in SSc. None of these domains fully satisfies the OMERACT OFISA criteria, although the unmet needs vary between them.The synthesis of available evidence underlying the ratings, comprising quality and quantity of studies, consistency of results, and performance of the ultrasound outcome domain across measurement properties, favours thickness as the outcome with more robust support. Studies demonstrated promising data concerning its construct validity against mRSS, positive results

This research received a specific grant from World Scleroderma Foundation, Project title "Skin Ultrasound Working Group", 2021. TS, ES and JAPS; Data collection and interpretation: TS and ES; TS prepared the first version of the manuscript. reports grants and/or personal fees from AstraZeneca, Abbvie, Boehringer Ingelheim, Capella, Chemomab, Jannsen, JDP: reports grants and/or personal fees from Boehringer Ingelheim, Janssen, Permeatus and Sojournix Pharma outside of the submitted work.

World Scleroderma Foundation for funding this project.

Ethical approval information

Data sharing not applicable as no datasets generated and/or analysed for this study. All data relevant to the study are included in the article or uploaded as supplementary information.

Author Disclosure Statement

The authors of the manuscript "Ultrasound in skin involvement in systemic sclerosis: a systematic literature review focusing on validation and standardization" have the below list of conflict of interest: No data stated for the time interval between testing, appropriateness for this and were if there were a proportion of people expected to change in one or both groups? (Improvement or deterioration) and were hypotheses formulated regarding the anticipated mean differences in change scores between subgroups a priori and were the statistical methods adequate for the hypotheses tested (relative efficiencies, pooled treatment effect sizes, standardized mean differences).

5

No data on whether measurements were conducted independently or if the design of the study held all other factors constant except for the source of variability being examined or were the test conditions similar for the measurements? (e.g., type of administration, environment, instructions) were the correct statistic used?

6

No data regarding blinding of image acquisition and analysis; correlation between RSS and ultrasound-thickness rh0=0.36, p<0.001.

7

No data regarding comparison with change of mRSS and no statistical methods appropriate for the testing situation.

8

No date regarding time interval between testing stated and appropriate; no statistical methods adequate for the hypotheses tested.

9

No data regarding blinding of image acquisition and analysis.

No data whether measurements were conducted independently or if the design of the study held all other factors constant except for the source of variability being examined or were the test conditions similar for the measurements and inter-reader correlation rho=0.59.

11

No data regarding patient selection, e.g., consecutive, or random sample patients enrolled, case-control avoided or avoid inappropriate exclusions.

12 No data whether the anchor clearly related to the target domain of interest (i.e. good correlation between anchor and instrument) and analysis wasn´t done separately for improvement and deterioration.

• Case-control studies.

¥ Studies reporting ultrasound-thickness of clinically affected skin in patients thicker than in controls.

OMERACT Summary of evidence for measurement properties of thickness. Color designates quality of evidence: green=good methods used, use this evidence;

amber=some cautions but we will use this evidence. In the rating row, color designates overall evidence-based instrument rating for the core instrument set: green= at least 2 pieces of evidence with good methods and consistent findings of adequate or better performance; amber=in between green and red; red= inadequate performance in at least 1 study that used good methods, white=no evidence.

Arithmetic signs designate the performance of the instrument according to that study (for each measurement property studied): "+" adequate or better performance, "+/-" equivocal performance, "-" less than adequate/poor performance. 2 No data whether design of the study held all other factors constant except for the source of variability being examined and the statistic method used.

3 No data whether the design and statistical methods adequate for the hypotheses to be tested. [START_REF] Domsic | Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma[END_REF] No data whether the criterion for change is considered an adequate gold standard OR is the construct for change clear or were the statistical methods appropriate for the testing situations. [START_REF] Steen | The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time[END_REF] No data stating time interval between testing stated and appropriateness; no statistical methods adequate for the hypotheses tested. [START_REF] Clements | Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial[END_REF] ICC of two readers skin echogenicity classification was 0.608, p<0.001. [START_REF] Khanna | The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis[END_REF] Dermal echogenicity increased in clinically unaffected skin site in SSc compared with controls, at the finger, hand, forearm and abdomen. [START_REF] Czirjak | Skin involvement in systemic sclerosis[END_REF] ICC for echogenicity 0.648-0.865.

OMERACT Summary of evidence for measurement properties of echogenicity. Color designates quality of evidence: green=good methods used, use this evidence;

amber=some cautions but we will use this evidence. In the rating row, color designates overall evidence-based instrument rating for the core instrument set: green= at least 2 pieces of evidence with good methods and consistent findings of adequate or better performance; amber=in between green and red; red= inadequate performance in at least 1 study that used good methods, white=no evidence.

Arithmetic signs designate the performance of the instrument according to that study (for each measurement property studied): "+" adequate or better performance, "+/-" equivocal performance, "-" less than adequate/poor performance.

Rating (RAGW) (put on master checklist)

Overall

Rating (RAGW) (put on master checklist) Overall rating for instrument across properties

Provisional endorsement: needs additional feasibility, construct validity against biopsy, test retest reliability, Sensitivity to change, clinical trial discrimination and threshold of meaning [START_REF] Allanore | Systemic sclerosis[END_REF] No data whether design of the study held all other factors constant except for the source of variability being examined and the statistic method used.

2 No data regarding cost of the ultrasound equipment or software, required training, time for image acquisition or analysis. [START_REF] Valentini | The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis: derivation and validation of a preliminarily revised EUSTAR activity index[END_REF] No data regarding patient selection, e.g., consecutive or random sample patients enrolled, case-control avoided or avoidance of inappropriate exclusions. [START_REF] Domsic | Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma[END_REF] No data whether the design and statistical methods adequate for the hypotheses to be tested.

¥ Studies reporting ultrasound-stiffness of clinically affected skin in patients stiffer than in controls.

OMERACT Summary of evidence for measurement properties of stiffness. Color designates quality of evidence: GREEN=good methods used, use this evidence;

amber=some cautions but we will use this evidence. In the rating row, color designates overall evidence-based instrument rating for the core instrument set: GREEN = at least 2 pieces of evidence with good methods and consistent findings of adequate or better performance; amber=in between GREEN and red; red= inadequate performance in at least 1 study that used good methods, white=no evidence.

Arithmetic signs designate the performance of the instrument according to that study (for each measurement property studied): "+" adequate or better performance, "+/-" equivocal performance, "-" less than adequate/poor performance.


Lisheng Kuang

Maud Marchal

Paolo Robuffo Giordano

Claudio Pacchierotti

Rolling Handle for Hand Motion Guidance and Teleoperation

This paper presents a grounded haptic device able to provide force feedback. The device is composed of a biaxial rocker module and a grounded base which houses two servomotors actuating a mobile platform through three constrained coupling structures. The mobile platform can apply kinesthetic haptic feedback to the user hand, while the biaxial rocker module has two analog channels which can be used to provide inputs to external systems.

Introduction

Grounded haptic feedback systems have been used in a plethora of applications, including robotic teleoperation and guidance. Representative examples of such interfaces include the Virtuose (Haption, FR), Omega.x (Force Dimension, CH), Falcon (Novint Tech., USA) and Phantom (Geomagic, 3D Systems, USA) series. Most common haptic devices are designed as robots of the impedance type, having small amounts of inertia and friction, enabling to freely and naturally move in space when no force feedback is provided. In such systems, the user controls the position of the device that, in turn, provide a force feedback.

In this paper, we present the preliminary design of a force feedback haptic handle for virtual rendering and robotic teleoperation. It improves upon the handle presented in [START_REF] Kuang | Design of a 2-dof haptic device for motion guidance[END_REF], that did not enable the user to provide any input. With respect to [START_REF] Kuang | Design of a 2-dof haptic device for motion guidance[END_REF], the proposed device includes a biaxial rocker module and it is able to provide significantly larger forces.

Rolling Handle with Force Feedback

The parallel mechanism

The design of the bilateral handle is inspired from [START_REF] Kuang | Design of a 2-dof haptic device for motion guidance[END_REF], for which the mechanism was in turn originally inspired by [START_REF] Okada | Development of a cybernetic shoulder-a 3-dof mechanism that imitates biological shoulder motion[END_REF]. Three identical supporting legs, as shown in Fig. 1, are evenly placed around the the z axis of the two platforms, forming an interlaced structure with no interference between them. Two revolute joints on the two sides of the leg generate reciprocal force and constrain the mobility between each linkage. Gruebler-Kutzbach criterion (G-K criterion) or modified G-K can be used to analyze the mobility of the proposed handle, achieving a motion along 2 degrees of freedom (DoF). The motion of the upper platform is confined on the surface of a sphere centered in the center of the lower platform.

Two servomotors are installed on the lower platform, with the motor shaft connected to the distal revolute joint on the leg, providing 2-DoF actuation. The two legs equipped with the servomotors have an active rotation on the lower joint and a passive rotation on the other three joints. By varying the actuation of the servomotors, the upper platform can reach any position within its workspace (the surface of a sphere, as mentioned above and shown in Fig. 1).

User input for bilateral control

On the top of the upper platform, we installed a biaxial rocker module as to enable the user to provide directional 2-D input. This module has one button digital output and (X, Y ) 2-axis analog output through rocker potentiometer. The two analog channels can also be used to represent the rotation angle about two mutually perpendicular axes, for instance, two of the Euler angles (Roll -P itch -Y aw) in 3D space. This input can also be used to control the free-space motion of the handle, similarly to a standard impedance-type haptic interface.

Use cases

We develop a goal-following game to test the effectiveness of the haptic force feedback generated by the handle as well as the intuitiveness of using the biaxial rocker module. A 2D GUI interface was developed with Matlab. The servomotors of the handle were controlled through an Arduino board. Preliminary tests indicated that the device is easy to use and intuitive to follow. An extensive human subjects will be subject of future work.

Conclusion and Future Work

The proposed device is inspired from our previous work presented in [START_REF] Kuang | Design of a 2-dof haptic device for motion guidance[END_REF]. We improved upon its design by including more powerful motors, able to provide force feedback to the user, a biaxial rocker module, to enable the user to provide 2D navigational input to the system, and making the design more ergonomic and comfortable to use.

In future work, we will integrate the proposed device in a power wheelchair, so as to provide the driver with information about the presence of surrounding obstacles [START_REF] Devigne | Power wheelchair navigation assistance using wearable vibrotactile haptics[END_REF]. This scenario is inspired by the collaborative Inria project DOR-NELL, where we aim at developing a multisensory haptic handle for helping disabled people using mobility aids such as power wheelchairs, white canes, and walkers.

Fig. 1 .

 1 Fig. 1. (a) The device in its resting position, with the lower platform secured to an external support and the user hand posed on the upper one. (b) CAD of the device. The grey dotted lines show the surface of the sphere on which the upper platform moves. The user can provide directional input information through the biaxial rocker module.

Fig. 2 .

 2 Fig.2. The handle moves towards the goal point (in green, invisible to the user) to guide the user towards it. The closer the position of the user in the virtual environment (yellow point) to the goal spot, the smaller tilt of the handle with respect to its vertical resting position.

Fig. shows

  Fig. shows the considered 2D environment. The current position of the user in the virtual environment is shown in yellow, controlled by the user through the biaxial rocker module. A random goal point, not visible by the user, is generated. The handle tilts toward the (invisible) goal point, guiding the user towards the objective position. The closer the position of the user in the virtual environment to the goal spot, the smaller tilt of the handle with respect to its vertical resting position. The task ends when the user reaches the goal point.Preliminary tests indicated that the device is easy to use and intuitive to follow. An extensive human subjects will be subject of future work.

This work has received funding from the Inria Défi project "DORNELL" and the China Scholarship Council No. 201908440309.


Damien Chablat

Riccardo Mattacchione

Erika Ottaviano

Design of a robot for the automatic charging of an electric car

In this paper, a robot with parallel architecture is proposed for charging an electric vehicle having the charging socket on its front side. Kinematic models are developed to design the robot for a given workspace that corresponds to the car's plug placements. A demonstrator composed by commercial components is shown.

Introduction

Nowadays, the automotive industry develops electric vehicles with associated tools for a broad range of customers and users. To charge the batteries, most users still have to manually connect the car to a charging station or home outlet. In addition, to enhance the range of electric cars, the batteries are equipped with a larger capacity and require a high charging intensity, which must be performed by large cables. Approximately one meter of cable consisting of four wires with a section of 25mm 2 each has a mass of approximately 0.9 Kg. Therefore, some pioneering studies have been developed to explore the possibility of using a robot that could relieve the user from the task of log in and out the plug. However, among the other possible industrial applications in the automotive industry, only a few robots are designed exclusively for recharging electric cars. In August 2015, the car manufacturer Tesla presented a snake robot for charging Tesla Model S cars. This robot has the morphology of a snake and can detect the vehicle's charging port and connect to it autonomously. The charging cover opens automatically when the parked vehicle is ready to be charged. Once the connection between the robot and the vehicle is established, the charging process can be started. The idea behind this concept is that the driver does not need to get out of the car to charge the vehicle [START_REF] Walzel | Automated robot-based charging system for electric vehicles[END_REF]).

In July 2017, Wolkswagen company unveiled discreetly the prototype of the future Gen.E. A robotic articulated arm equipped with a combo plug is installed on the side of the vehicle. The robot is designed for underground and multi-store garages for autonomous charging of the vehicle. Except the snake robot, whose architecture is unique, the mechanical architecture of the robot for charging the Gen.E is the KUKA serial architecture. The end-effector is adapted for the insertion of the power outlet into the electric vehicle. The DC quick charging process starts with communication between the vehicle and the electric filling station. The vehicle transmits its data to the charging station, which gives back the target position for the automated parking [START_REF] Walzel | Automated robot-based charging system for electric vehicles[END_REF]). The charging socket of the vehicle has to be in a target area of 200 by 200 mm. Afterwards, a camera on the robot detects the exact position of the charging socket, with an accuracy of mm. After, the gripper picks up the DC-Connector and connects with the charging socket of the vehicle. After having linked the DC-Connector, the charging process starts. Once the battery is fully charged, the robot automatically unplugs the DC-Connector.

Another automatic recharge system is the NRG-X, it can be adapted to any EV or PHEV and is capable of fast charging. Furthermore, it has a tolerance for inaccurate parking positions. The NRG-X system is based on a combination of conductive and inductive charging beneath the vehicle, thus an adapter for the vehicle is necessary [START_REF] Miseikis | 3d vision guided robotic charging station for electric and plug-in hybrid vehicles[END_REF]). It has to be noted that although industrial robots can very well adapt to several tasks, their design and production remain very expensive for the application.

For public places, such as car parks, shared solutions have been proposed [START_REF] Walzel | Automated robot-based charging system for electric vehicles[END_REF]). However, this solution is expensive in terms of infrastructure and cannot be used for individual houses. The price of an industrial robot is about 20-40% of the price of a car. Research projects in this context aim to develop specific robots by reducing the number of actuators [START_REF] Yuan | Concept design and load capacity analysis of a novel serial-parallel robot for the automatic charging of electric vehicles[END_REF]) or overcoming the effects of gravity on actuators [START_REF] Gao | Robotically operated vehicle charging station[END_REF]) and [START_REF] Ketfi | Dispositif automatise de charge d'un véhicule électrique[END_REF]), these are the main objectives on which this article is based. This is the main reason why the French company Renault decided in 2018-2019 to develop a less expensive charging robot for its upcoming electric cars (Kamga (2017)). The specifications for the robot indicate that it has to be mounted on the garage wall and will recharge the battery by facing the car. The robot must be small, precise, and stiff. It must allow the plug to be inserted in safely and properly way. The main requirements are: (a) Insertion and withdrawal forces: 70 N, ±10 N, (b) Depth of insertion: 40 mm, ±20 mm, (c) Distance between plug and socket: 20 mm, +10 mm, (d) Workspace: 200 ×200 ×20 mm 3 , (e) Degree of freedom: 3, (f) Location accuracy: 0.5 mm, ±0.1 mm, (g) Length of electric cables: 1500 mm, +500 mm, (h) Weigh of electric cables: 1.4 kg,+0.45 kg, (i) Plug diameter: 65 mm, ±5 mm, (j) Total weigh of the robot: 10 kg, +5 kg, and (k) Occupied space 1500 ×200 mm 2 .

2 Design requirements of a robot for the automatic charging of an electric car Our work focuses on the Renault Zoe, for this car, the plug is placed on the front and is slightly inclined. The mobility required for the robot could be at least three translations if the car is on a horizontal floor, plus a translation along the insertion axis for the electric plug. By using the flexibility of the insertion tool, it is possible to avoid using a wrist or spatial mechanisms, [START_REF] Figliolini | The synthesis of the axodes of spatial four-bar linkages[END_REF]), [START_REF] Figliolini | The synthesis of the axodes of rccc linkages[END_REF]).

To reduce the cost of the robot, it is possible to mix the vertical movement with the insertion direction. Figure 1 depicts the car and the dexterous workspace of the robot. Several robot architectures were analyzed before settling on a parallel P-Pi-R-P type robot for planar motion [START_REF] Rea | The design of a novel tilt seat for inversion therapy[END_REF]) put in series with a linear actuator for insertion movement where P stands for prismatic actuated joints, Pi for a four-bar mechanism similar to an RR mechanism but with opposite bars parallel two by two, and R for revolute joint.

The main advantages of this architecture are, simplified design [START_REF] Wenger | A comparative study of parallel kinematic architectures for machining applications[END_REF]; Ottaviano and Rea ( 2013)), and the forces applied to the actuators decrease as the end-effector moves away from the base. This will be the case when inserting the plug.

Mechanism understudy

The kinematics of the robot can be written in three stages, (i) the alpha mechanism which allows translations of the end-effector in one plane, (ii) the beta mechanism which does the insertion of the plug, and (iii) the gamma mechanism which is the assembly of the first two.

The α mechanism: P-Pi-R-P planar parallel robot

The first mechanism aims to achieve a planar displacement. To choose this architecture, the constraint of storage on a wall and the reduction of on-board weight lead to the choice of prismatic joints.

The design parameters of the α mechanism are the following:

• L: the length of the two arms;

• L 2 : the length of the robot's base;

• L 3 : the distance between B and C

• ρ 1 and ρ 2 : the length of the left and right linear actuator;

• [x, y]: the coordinate of point V located in the middle of (B, C);

• [0, e py ]: the offset from V to F ;

• [e 1x + ρ 1 , e 1y ]: the coordinate of A; According to the kinematic scheme in Figure 2, the constraint equations that can be obtained are the following

• [L 2 -ρ 2 -e 2x ,
(x -e 1x -ρ 1 -L 3 /2) 2 + (y -e 1y ) 2 = L 2 (1) (L 2 -x -L 3 /2 -e 2x -ρ 2 ) 2 + (y -e 2y ) 2 = L 2 (2)
with Eqs. 1-2, the inverse kinematic equations can be obtained as

ρ 1 = x -e 1x -L 3 /2 -2L 2 -(y -e 1y ) 2 (3)
ρ 2 = L 2 -x -L 3 /2 -e 2x -2L 2 -(y -e 1y ) 2 (4)
Solving Eqs. 1-2 for the Cartesian coordinates x and y allows the evaluation of two assembly modes. However, only one will be accessible, thanks to the joint limits [START_REF] Wenger | A comparative study of parallel kinematic architectures for machining applications[END_REF]).

To avoid the singularity of the Pi joint in the folded position, the offset e py is defined. The inclined placement of the parallelogram allows sufficient stiffness to be maintained when the robot is close to its base in the folded position. Indeed, the stiffness of a parallelogram is proportional to the area formed by the four bars [START_REF] Majou | Design of a 3 axis parallel machine tool for high speed machining: The orthoglide[END_REF]). The placement of the bar (DF ) does no influence on the kinematics, but it does influence the stiffness of the robot.

In Figure 3, two singular postures are depicted to define the boundaries of the workspace and to separate into two aspects by the parallel singularity. The IIM-type singularity of the four-bar mechanism defined in [START_REF] Zlatanov | Singularity analysis of mechanisms and robots via a velocity-equation model of the instantaneous kinematics[END_REF]) is avoided thanks to the offset e py . For this mechanism, the constraint equations define P with respect to the Cartesian frame z ′ -y ′ . According to Figure 4, it is possible to note that:

r 2 r 1 E B C V A D F B C V F E D A
• ρ 3 : is the length of the linear actuator that defines the coordinate of H with respect to G; • [e 3y , e 3z ]: is the coordinate of H with respect to P ;

• [e 4y , e 4z : is the coordinate of V in the reference frame z ′ -y ′ .

• [x ′ , y ′ : is the coordinate of P in the reference frame z ′ -y ′ . According to the kinematic scheme in Figure 4, the constraint equations that can be obtained are the following z ′ = e 3z + ρ 3 cos(θ)

(5) y ′ = e 3y + ρ 3 sin(θ) (6)

and, its inverse kinematic as

ρ 3 = (z ′ -e 3z ) 2 + (y ′ -e 3y ) 2 (7)
The offset actuator reduces the volume of the robot when it is folded1 .

The γ mechanism

The merging of the mechanisms described in earlier subsections gives a 3 d.o.f. robot, the γ mechanism. For verifying the operation of the robot prototype, an Arduino micro-controller can be used. Figure 5 shows a CAD model in CATIA V5 with components from Makeblock (2022).

Workspace analysis

The workspace of a robot can be defined as the set of points that can be reached by its end-effector [START_REF] Khalil | Modeling, identification and control of robots[END_REF]). This is the space where the robot can operate and carry out tasks. In this work, the workspace is evaluated according to the reference point V of the α mechanism. It is important to know the positions V can reach to avoid issues such as singularity configurations, interference, collisions. Workspace is assessed as an intersection of two sets of points2 . Following distances have to be defined:

• e 5x : is the distance between the y-axis and the a joint, when the left actuator is at the end of its stroke; • e 6x : is the distance between the y-axis and the e joint, when the right actuator is at the end of its stroke; • e 7x : is the distance between the y-axis and the e joint when the right actuator is at the end of his stroke. The complete workspace is displayed in Figure 7. The workspace boundaries can be described analytically using five equations that can be used to verify whether the end-effector can reach a specified position or not.

(x - L 3 2 -e 1x ) 2 + (y -e 1y ) 2 ≥ L, (x + L 3 2 -e 7x ) 2 + (y -e 2y ) 2 ≥ L (x - L 3 2 -e 5x ) 2 + (y -e 1y ) 2 ≤ L, (x + L 3 2 -e 6x ) 2 + (y -e 2y ) 2 ≤ L
To analyse the position of the end-effector, a regular workspace shape is considered. In our case, we evaluate the largest square that gives an inner tangent to the boundaries of the workspace [START_REF] Chablat | An interval analysis based study for the design and the comparison of threedegrees-of-freedom parallel kinematic machines[END_REF]). The side length of the square is given by l b and, for algebraic computation, a Lame curve is used,

(x -x c ) n + (y -y c ) n = l n b (8)
with n a positive even integer and (x c , y c ) are the center of the workspace.

To limit the computation cost, n is set at 6 as a first approximation and then to 12 to better approximate the square shape. To find the position of the regular workspace, the methodology defined by Chablat et al. ( 2012) is used. The optimisation problem is written as the intersection of the robot workspace boundary with the boundary of the desired regular workspace whose placement depends on (x c , y c ) . If the set of solutions obtained is non-zero, then we have found a candidate solution for the robot realization. This calculation was carried out using the Siropa library, whose functions are presented in [START_REF] Jha | Workspace, joint space and singularities of a family of delta-like robot[END_REF]). To simplify the design, only commercial components from (Makeblock (2022)) have been used, without the need for machining. Several bar sizes were tested. This demonstrates that this robot can easily be built. The main sizes are L = 532mm, L 2 = 1300mm, and L 3 = 160mm. For this set of design parameters, a set of possible placements for the regular workspace was found by using Cylindrical Algebraic Decomposition [START_REF] Moroz | Cusp points in the parameter space of rpr-2prr parallel manipulators[END_REF]. Figure 8 presents several regions where there is no intersection between the regular workspace and the workspace of the robot. However, only one region is included in the workspace of the robot.

If the robot can reach the desired workspace, we must be checked that the stiffness and workspace properties are under the specifications. The stiffness of the mechanism is therefore analysed in nine different configurations,

Stiffness analysis

To evaluate the stiffness of the robot to meet the specifications, simulations in CATIA were performed. The robot's stiffness is analysed in its working space. Two types of simulations have been taken into account: (i) when ρ 1 and ρ 2 move, i.e. the α mechanism, and (ii) when ρ 3 moves, i.e. the β mechanism. The materials used are mainly aluminium, except for the shafts, the bearings, and slide guides, which are made of steel. In all simulations, the self-weight of the structure is taken into account. As ball bearings are used, there is little backlash in the robot. The bending of the end-effector is due to the bending of the arms. The finite element analysis gives us the following results for case (i), Table 1 and case (ii), Table 2. However, as we are using an external sensor-based controller, an embedded camera, the most important issue is to have a constant deformation. The control is realized using a Rasberry Pi 4 board, which allows the use of a touch screen, a camera to detect the position of the socket, and a serial link to an Arduino board (Microcontroller Me Auriga MakeBlock). Two stepper motors are used (42BYG Geared Stepper Motor) with two belts and four pulleys for the α mechanism, and a DC motor and a ball screw for the β mechanism (Makeblock DC25 with sensor, 86 rpm). MakeBlock modules are used for the input-output connection with the Arduino board. A Python program manages a user interface, the camera with OpenCV functions, and the communication with the Arduino board. To locate the plug on the car, we use a QR code stuck next to the plug. When the robot moves, the QR code seen by the camera is used to adjust the trajectory before starting the insertion of the plug3 .

Conclusions

In this article, we presented a robot that allows the insertion of a plug into an electric car for charging. This robot is designed for the Zoe car but could be adapted to other vehicles having a front charging system, like the Nissan Leaf. To reduce manufacturing costs, off-the-shelf components were used in combination with hybrid kinematics with a simple kinematic model. A prototype was realized as a proof of concept associated with the patent application. A GitHub repository will soon be created to make the CAD and source code of the control available.

Figure 1 .

 1 Figure 1. Workspace of robot and the Zoe car

Figure 2 .

 2 Figure 2. Kinematic scheme of the α mechanism

Figure 3 .

 3 Figure 3. Parallel and serial singular configuration of the α mechanism

Figure 4 .

 4 Figure 4. Kinematic scheme of the β mechanism.

Figure 5 .

 5 Figure 5. CAD mode of robot

Figure 7 .

 7 Figure 7. Workspace of the α mechanism.

Figure 8 .Figure 9 .

 89 Figure 8. Possible placements of the regular workspace

Figure 10 .

 10 Figure 10. Boundaries conditions and gravity load in the CAD modelling

Table 2 .

 2 Maximum displacements for the β mechanism

	Position Max displacement [mm]
	1	0.995
	2	0.993
	3	0.991	ρ 3	Max displacement
	4	0.990	[mm]	[mm]
	5	0.996	50	1.080
	6	0.989	75	0.996
	7	1.030	100	0.936
	8	1.010	125	0.907
	9	1.030	150	0.958
	Table 1. Maximum displacements
	throughout the workspace

See movie: https://youtu.be/lCRXJ5tpTMM

See the movie: https://youtu.be/Y0uyeXuP5Eg

See the movie: https://youtu.be/P5wCgRqSyDQ

Acknowledgements

This work was supported by the project Chair between Renault and Centrale Nantes about performances of electric vehicles propulsion.