The Critical Window of Very Early Systemic Sclerosis: A Model for a specialized early systemic sclerosis Clinic

The Critical Window of Very Early Systemic Sclerosis: A Model for a specialized early systemic sclerosis Clinic | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Critical Window of Very Early Systemic Sclerosis: A Model for a specialized early systemic sclerosis Clinic Yasser El Miedany, Maha Elgaafary, Mary Wadie, Safaa Mahran, Rahma A Elziaty, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7004778/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background This study, led by the Egyptian Society for Microcirculation in Rheumatic Diseases, aimed to address the oversight of very early systemic sclerosis (SSc) as a pre-systemic sclerosis stage, hypothesizing that current clinical practices primarily focus on diagnosing SSc only when it meets established classification criteria. Identification of this patients’ cohort at such early phase is window of opportunity to treat those at high risk of skin fibrosis or organ involvement before such events occur. Objective The aim of this work was to establish a standardized, multidisciplinary clinic dedicated to the early assessment, diagnosis, and management of patients with very early systemic sclerosis (veSSc). Methods The methodology adhered to the PRISMA guidelines for reporting systematic reviews. To develop the clinical care standards framework, key clinical questions were systematically formulated using the PICO framework (Population, Intervention, Comparison, Outcome), a comprehensive literature review was conducted from 2010 to 2025 across multiple databases and a geographically diverse task force of national experts was assembled to participate in a two-round Delphi process to assess consensus levels. Results 12 key clinical questions were systematically developed using the PICO (Population, Intervention, Comparison, Outcome) framework. Following a review of the literature, and with eh endorsement of the Egyptian society for microcirculation in rheumatic diseases, a Delphi process was carried out. Consensus was reached (i.e. ≥75%of respondents strongly agreed or agreed) on the wording, the grade of recommendation and level of evidence of all the clinical standards identified by the scientific committee. Conclusion Setting up a very early systemic sclerosis (SSc) clinic involves establishing a system for early detection and management of SSc, focusing on patients with Raynaud's phenomenon and other early symptoms. The goal is to identify individuals at risk of progressing to SSc and offer prompt, targeted interventions. very early systemic sclerosis clinic veSSc PROMs Raynaud’s VEDOSS systemic sclerosis SSc Early Risk Assessment & Stratification (SSc-ERAS) Egyptian Society for microcirculation in rheumatic diseases Figures Figure 1 Figure 2 Figure 3 Background Systemic sclerosis (SSc) is a chronic and complex autoimmune condition. It affects connective tissues resulting in fibrosis of both the skin and internal organs as well as extensive vasculopathy. It also triggers the formation of autoantibodies. The disease presents a major challenge for health care professional in standard practice because of its complex and multifaceted nature [ 1 ]. Due to its intricate and varied nature, this disease poses a significant challenge for clinicians in standard practice. The disease follows an unpredictable course, accompanied by clinical variability and the potential for serious health impacts, including significant morbidity and mortality. This emphasizes how important it is to have a timely and precise diagnosis, implement patient specific therapy techniques as well as management strategies tailored to the individual subject [ 2 – 4 ]. A definite diagnosis for SSc, however, is typically a drawn-out process that frequently happens after irreversible organ damage has already occurred. This delay in diagnosis draws attention to a crucial phase of the disease, which is often overlooked or under-recognised: very early systemic sclerosis (veSSc) [ 6 ]. The concept of veSSc highlights the existence of a pre-classification phase where individuals show some clinical manifestations suggestive of the disease and warrant further assessment. These symptoms are usually linked with SSc-specific autoantibodies or abnormal nailfold capillaroscopy (NFC), or may include isolated puffy fingers with similar immunological or microvascular abnormalities [ 6 – 9 ]. Although these early clues might not fully meet the 2013 ACR/EULAR classification criteria for SSc [ 2 ], they offer a crucial window of opportunity for intervention. By identifying and intervening early in the disease's path, there's a chance to change its course, reduce the severity of organ involvement, and ultimately improve patient outcomes. Diagnosing and managing very early systemic sclerosis (veSSc) is crucial for several important reasons. Firstly, the underlying pathogenic processes, including endothelial dysfunction and fibroblast activation, tend to begin to develop and progress even before the disease meets formal classification criteria. [ 10 ]. Identifying these processes early offers the chance to halt or slow their progression, helping to prevent significant and irreversible damage, especially in high-risk individuals. Moreover, the diverse nature of systemic sclerosis is apparent right from its initial stages. By identifying specific serological and microvascular profiles, doctors can better assess risk, predict how the disease might progress, and tailor monitoring and interventions accordingly. [ 11 ] For instance, the presence of anti-RNA polymerase III antibodies at the veSSc stage might suggest a heightened risk of rapid skin progression and potential kidney issues. [ 12 ] Managing veSSc requires a distinctly different approach than that used for established SSc. While outright immunosuppressive therapy might not be needed for every veSSc patient, it's crucial to monitor closely, address RP aggressively, and intervene early when new symptoms emerge. Thus, it is essential to stratify patients at every stage of the disease, to properly assess, monitor, and manage them [ 13 ]. A clinic specialized in veSSc can offer the right setting and expertise for this tailored approach. Such a clinic would set up standardized assessment protocols, including comprehensive clinical evaluations, detailed autoantibody testing, thorough nailfold capillaroscopy (NFC), and initial organ screening. This organized strategy not only improves early diagnostic accuracy, but also supports collecting valuable long-term data to deepen the global understanding of veSSc's progression. The aim of this work to establish a standardized, multidisciplinary clinic dedicated to the early assessment, diagnosis, and management of patients with very early systemic sclerosis (veSSc). This initiative, set up by the Egyptian Society for Microcirculation in Rheumatic Diseases will enable timely intervention, enhance patient outcomes, and drive forward research during this crucial stage of the disease. Methodology Study design: This work was led by the Egyptian Society for microcirculation in rheumatic diseases. The study was based on the hypothesis that current clinical practices disproportionately focus on diagnosing SSc meeting the published classification criteria, often overlooking very early systemic sclerosis as a pre-systemic sclerosis stage, The study design was formulated based on the CEG guideline development process protocol which involves a qualitative synthesis of scientific evidence and consensus, based on the existing scientific evidence and clinical experience. The manuscript conformed to the preferred reporting items for systematic reviews and meta-analyses guidelines for reporting systematic reviews [14]. Ethics approval and consent to participate This study was performed in accordance with the Helsinki Declaration. The Clinical, Evidence-based, Guidelines” (CEG) initiative protocol was approved the local ethical committee: ethical approval code: 34842/8/21. Written ethics approval from the experts sharing in this work was deemed unnecessary according to national regulations. As per the Egyptian national Ethical Committee regulations, verbal informed consent was required from all the participants included in the study. All the participants were kept anonymous, in compliance with data protection regulations. Developing the clinical care standards framework: To ensure a structured and focused approach, the key clinical questions underpinning this project were systematically developed using the PICO (Population, Intervention, Comparison, Outcome) framework. This allowed for clear definition of the patient group, the intervention of interest, any relevant comparators, and the outcomes to be evaluated. Review of the literature was carried out over the period 2010-2025 to address these key clinical questions using PubMed, Embase, the Cochrane library, Google scholar and scientific society websites. MeSH Terms (Pubmed): (("very early systemic sclerosis" OR "very early systemic sclerosis"[All Fields]) OR ("pre-scleroderma"[All Fields] OR "pre scleroderma"[All Fields]) OR ("VEDOSS"[All Fields] OR "Very Early Diagnosis of Systemic Sclerosis"[All Fields])) Embase: ('very early systemic sclerosis'/exp OR 'pre-scleroderma'/exp OR 'vedoss'/exp OR 'early systemic sclerosis'/exp OR (very early AND 'systemic sclerosis') OR ('pre scleroderma') OR VEDOSS) AND ('systematic review'/exp OR 'systematic review (topic)'/de OR 'meta analysis'/exp OR 'scoping review'/exp OR (systematic* AND review*) OR meta-analys* OR scoping*) AND [2010-2025]/py Task force : A task force was invited to share in the Delphi process. The geographical distribution of the Task Force was ensured to reflect the national representation of the experts involved. Delphi process: The Delphi process was conducted in two rounds to assess the degree of consensus. Participants rated each variable on a 1-9 Likert scale, based on the RAND/UCLA methodology, where 1-3 indicated disagreement, 4-6 were considered undefined, and whereas 7-9 represent agreement. The responses from the first round were analysed, statements revised and presented for the second round. The task force members were encouraged to re-evaluate their responses anonymously based on this additional information. The levels of agreement on each statement of recommendation were defined as ‘high’ if after the second round of votes, all votes on a statement fell into the agreement bracket (7-9) [15-17]. Key clinical questions: Who would be the targeted population of this service set up? What would be the optimal clinic workflow from patient referral to follow-up? Which blood investigations should be routinely performed for diagnosis and monitoring? How should patients’ symptoms be reported and quantified? How should patients be stratified for risk assessment and future complications? What kind of management plan would be most effective for these patients? What strategies should be implemented for disease monitoring? What would a comprehensive follow-up assessment entail, and how often should it occur? How should the clinic manage the transition of care for specific patient groups (adolescents)? What kind of patient education program should be implemented? What strategies should be used for data collection, and how can the clinic contribute to research? How would the clinic ensure continuous quality improvement in its services? What ongoing education and training would be provided for the healthcare professionals? Results Literature research and evidence selection: Figure (1) is a flow chart for the study selection process Developed Clinical Standards: Targeted population: i. Patients: Definition of Very Early Systemic Sclerosis (veSSc): Patients who meet at least one of the following criteria, in the absence of sufficient criteria to be classified as definite SSc according to the 2013 ACR/EULAR classification criteria [2] These criteria are based on the preliminary criteria for the very early diagnosis of systemic sclerosis [6] and the review of the literature: 1. Raynaud's Phenomenon (RP) with Antinuclear Antibodies (ANA) positive (any pattern and titre deemed clinically significant). 2. Raynaud's Phenomenon (RP) with SSc-specific antibodies positive (e.g., ACA, anti-Scl-70, anti-RNA polymerase III). 3. Raynaud's Phenomenon (RP) with abnormal nailfold capillaroscopy (NFC) findings (SSc pattern: normal or low density, capillary apical width 30-50 um, giant capillaries, capillary haemorrhages). 4. Isolated puffy fingers with ANA positive or SSc-specific antibodies positive or abnormal NFC findings . 5. New onset of otherwise unexplained digital ulcers in the presence of RP. The veSSc clinic is set up to provide service as a specialized multi-disciplinary unit. ii. Healthcare Professionals: The clinic team: This team comprises several essential members: · Lead Rheumatologist : Leading the team is a rheumatologist, with acknowledged experience in systemic sclerosis (SSc) and early connective tissue diseases. The lead rheumatologist will oversee the patient care, ensure accurate diagnoses, and coordinate treatment plans. · Specialist Nurse: a dedicated specialist nurse, who brings a wealth of experience in handling connective tissue diseases. This nurse will focus on educating patients, monitoring symptoms, supporting medication management, and scheduling appointments. · Nailfold Capillaroscopy specialist who is skilled in performing and interpreting NFC studies. · Pulmonary Function Technician , who is trained in conducting spirometry and DLCO tests. In addition, access to specialists should be readily available depending on each patient's specific needs and clinical symptoms. These include: · Gastroenterologist: with expertise in dealing with oesophageal dysmotility, GERD, and other gastrointestinal manifestations associated with SSc. · Cardiologist: with expertise in the diagnosis and management of pulmonary hypertension, myocardial involvement, and arrhythmias in patients with SSc. · Dermatologist: Expertise in dealing with SSc associated skin changes and the treatment of digital ulcers. · Renal Physician: Expertise in addressing scleroderma renal crisis and the management of renal affection. · Physiotherapist/Occupational Therapist : These practitioners have expertise in setting up the appropriate exercise program, provide help and technical support to maintain function and manage musculoskeletal symptoms. · Psychologist/Counsellor : Their role is to address the psychological impact of chronic disease. 2. Patient’s assessment and clinic workflow? I. Referral Pathway: · Patients can be referred from primary care doctors, general neurologists, dermatologists, and other specialists who recognize patients meeting the veSSc criteria. · A standardized referral form should be used, as shown in Figure (2). This form should include essential clinical history, details of Raynaud's phenomenon such as its onset, frequency, and severity, any other indicative symptoms like swollen fingers, tight skin, fatigue, or joint pain, previous tests including ANA/ENA results and other autoantibodies, and NFC reports, if available. II. Initial Assessment (First Clinic Visit): o Comprehensive Clinical History: Detailed questioning about the characteristics of RP, onset, course and progression of any other symptoms (such as skin changes, musculoskeletal pain, fatigue, gastrointestinal symptoms, shortness of breath, etc.), past medical history, family history of autoimmune diseases, medication history, and relevant social background. o Physical Examination: General examination (Blood pressure, pulse, temperature, body weight, height and BMI), clinical assessment of the skin (looking for subtle changes like puffy fingers, early sclerodactyly, digital ulcers), musculoskeletal system (joint tenderness, tendons’ inflammation or localized swelling), and other organ systems. o Nailfold Capillaroscopy (NFC): Carried out by a trained HCP/technician to assess for SSc-specific microangiopathy patterns. Images will be recorded and interpreted by the lead rheumatologist or a designated expert. III. Blood Investigations a. Baseline Inflammatory Markers: ESR, CRP. b. Full Autoantibody Panel: ANA (with pattern and titre), SSc-specific antibodies (ACA, anti-Scl-70, anti-RNA polymerase III, anti-U1-RNP, anti-PM-Scl, anti-fibrillarin, etc.), and other relevant autoantibodies (e.g., RF, anti-CCP, anti-dsDNA) to rule out overlap syndromes. c. Baseline Organ Function Tests: Assessment of kidney functions (electrolytes, creatinine, eGFR), liver function tests (ALT, Albumin, ALP, bilirubin), thyroid function tests (TSH, FT4), and creatine kinase (CK). d. N-terminal pro-B-type natriuretic peptide (NT-proBNP): this serves as a baseline marker for potential cardiac involvement or pulmonary hypertension risk. e. Urine Analysis: checking for proteinuria, haematuria. IV. Patient-Reported Outcome Measures (PROMs): i. Raynaud's PROMs: To quantify RP severity and frequency [18]. ii. Health Assessment Questionnaire Disability Index (HAQ-DI): To assess functional disability. iii. Scleroderma PROMs questionnaire [19] V. Patient education: Educating Patients: Providing detailed insights on veSSc, how it might develop over time, why regular monitoring is crucial, and what resources are available to support patients. VI. Stratification and Risk Assessment: · After an initial assessment, patients will be classified into different risk levels. These categories will help determine the likelihood of patients progressing to full-blown SSc , as well as the risk of developing specific organ issues. · To stratify patients, several factors are considered, including: - The presence and type of SSc-specific antibodies; for example, anti-RNA polymerase III antibodies are often linked to fast progression and skin involvement. - The severity of NFC abnormalities, identified as very early, early, active, or late patterns. - Whether the patient has puffy fingers. - Elevated levels of NT-proBNP. - Specific ANA patterns, such as the nucleolar pattern, which might indicate a higher risk or systemic/organ affection. - The patient reported symptoms, including fatigue and joint pain. VII. Management Plan Management should be tailored to the individual patient’s condition. a. Raynaud's Phenomenon Management: - Lifestyle advice (avoiding cold exposure, stop smoking or at least smoking cessation). - First-line therapy: Calcium channel blockers (e.g., nifedipine, amlodipine). - Second line: Consideration of other vasodilators (e.g., topical nitrates, phosphodiesterase-5 inhibitors, prostaglandins) based on severity and response [20]. b. Symptom Management: - Pain relief: (NSAIDs with caution due to potential renal risk, paracetamol). - Hyperacidity: Proton pump inhibitors (PPIs) for gastroesophageal reflux symptoms. - Skin symptoms: Emollients for dry skin. c. Patients’ monitoring? Risk-Based Monitoring: - Low-Risk Patients: Regular follow-up (e.g., every 6-12 months) including clinical assessment, RP scoring, PROMs, and annual NFC assessment. Consider annual check for autoantibodies and NT-proBNP. - Intermediate-Risk Patients: More frequent follow-up (e.g., every 3-6 months) including clinical assessment, RP scoring, PROMs, reassess NFC every 6 months, and regular close monitoring of organ functions, NT-proBNP and whenever appropriate auto-antibodies. Consider baseline pulmonary function tests (spirometry, DLCO) and echocardiogram. - High-Risk Patients: Close monitoring (e.g., every 1-3 months) including comprehensive clinical and laboratory assessments, frequent NFC, PFTs, echocardiogram, and consideration of early referral to relevant specialists. Figure (3) shows SSc Early Risk Assessment & Stratification (SSc-ERAS) algorithm. d. Early Intervention (Consideration in High-Risk Cases): i. Low-dose methotrexate: May be considered for persistent arthralgia or early inflammatory features, with regular monitoring. ii. Mycophenolate mofetil: Can be considered in patients with high-risk antibody profiles (e.g., anti-RNA polymerase III) or early signs of skin involvement, with regular monitoring. iii. Clinical Trial Enrollment: may actively consider and offer enrollment in relevant clinical trials investigating early interventions in veSSc. e. Referral to Specialists: Prompt referral to gastroenterology, cardiology, pulmonology, dermatology, or nephrology based on clinical findings and risk assessment. f. Physical therapy/ Rehabilitation: In the very early stages of SSc, physiotherapy plays an important role in improving and maintaining unction, preventing contractures, and managing symptoms like Raynaud's. Table (1) shows an example of the different physiotherapy modalities that can implemented. Individualized program, focussing on specific patient’s requirements and limitations is essential. The importance of early intervention important? - Delaying Contractures: Early physiotherapy can help delay or prevent the development of contractures, which can severely impact quality of life. - Maintaining Function: It can help maintain and improve the patient’s ability to perform daily activities. - Managing Symptoms: Physiotherapy can help manage pain, stiffness, and other symptoms of SSc. - Early Detection: Physiotherapy may help identify early signs of organ involvement, allowing for timely intervention. VIII. Follow-Up Assessments: a. Regular follow-up appointments as determined by the risk stratification and individual patient needs. b. At each visit: i. Review of clinical and relevant organ symptoms and RP characteristics. ii. Physical examination. iii. Assessment of PROMs. iv. Review of any new investigations or specialist consultations. v. Adjustment of management plan as needed. c. Periodic repeat investigations (blood tests, NFC, PFTs, echocardiogram) based on risk stratification and clinical evolution. d. Regular monitoring for progression to definite SSc according to the 2013 ACR/EULAR classification criteria [2]. IX. Transition to Standard SSc Clinic: a. When a patient meets the 2013 ACR/EULAR classification criteria for definite SSc [2], they will be transitioned to the standard SSc clinic for ongoing management according to established protocols. However, the data collected during their time in the veSSc clinic are vital for understanding the disease evolution. X. Data Collection and Research: · A dedicated database should be collected including the outcomes of comprehensive clinical assessment, laboratory results, imaging findings, and PROMs scores. The data on all patients should be enrolled in the veSSc clinic. · This database will be invaluable for: o Characterizing the veSSc cohort. o Identifying predictors of progression to definite SSc. o Evaluating the effectiveness of early interventions. o Supporting participation in multicenter research studies. · Ethical approval will be obtained for data collection and research activities. XI. Quality Improvement: Audits/ re-auding should be carried out regularly to assess the clinic processes and patient outcomes to ensure protocol adherence and identify areas for improvement. Patient reported experience [21] / feedback, along with insights from the multidisciplinary team, should be actively sought out and used to refine how our clinic operates. XII. Education and Training: - To equip every member of the veSSc clinic team with the necessary skills, ongoing education and training should be offered to guarantee expertise in diagnosing and managing early SSc. - Opportunities to collaborate and share knowledge with other veSSc centers should pursued. Discussion Very early systemic sclerosis is a challenge in the standard clinical practice. This has been attributed to its heterogenous clinical manifestations and the importance of detecting the illness at early stage, where medical intervention might help prevent the progression of the disease and in particular organ damage [22]. Another challenge is that most of the patients presenting with very early systemic sclerosis manifestations, do not meet the 2013 ACR/EULAR classification criteria [23] inspite of its higher sensitivity in comparison to the former 1980 classification criteria. This protocol addresses such limitation and outlines a framework for establishing a specialized veSSc clinic, aiming to identifying this patients cohort at such early stage of the disease and identifying who have the potential to progress into definite SSc. Therefore, it should be regularly updated to include the latest advances in diagnosing and managing systemic sclerosis. Very mild systemic sclerosis patients require need a very different follow-up scheme. By putting this protocol into practice, it would facilitate early diagnosis, enhance risk stratification, and explore the potential for interventions during the initial phases of this complex illness. Ultimately, this should lead to improved patient outcomes and a deeper understanding of systemic sclerosis in its early stages. Figure 2 provides a visual guide in the form of an algorithm to assist with assessment and management. This can be consider as a road map, navigating the complex paths of patient care and clinical decisions. pathway within the clinic. Analysis of this very early group of SSc patients is of particular interest and high importance for disease management because very early intervention has been reported to profoundly improve disease course and outcome in a variety of different inflammatory rheumatic diseases [24,25]. In conclusion, the phase before a formal SSc diagnosis is critical, yet it often goes unnoticed. Setting up specialized veSSc clinics is vital for appropriate and timely identification of the patients at this pre‑scleroderma phase. By concentrating on this subtle phase of SSc and recognizing the disease trajectories, this represents a window of opportunity and opens a new approach for preventive medicine. The expert care and systematic method at a veSSc clinic are essential for turning our increasing understanding of veSSc into real-life benefits for patients. Abbreviations ANA Anti-nuclear Anti-body DLCO carbon monoxide diffusion ILD Interstitial Lung disease NFC Nailfold capillaroscopy NT-proBNP N-terminal pro B-type natriuretic peptide PFT Pulmonary function testing PROMs patient reported outcome measures RP Raynaud’s Phenomenon SSc systemic sclerosis SSc-ERAS Systemic Sclerosis Early Risk Assessment & Stratification VEDOS Very Early Diagnosis of Systemic Sclerosis veSSc very early systemic sclerosis Declarations Competing Interests The authors declare that Mohammed Hassan Abu-Zaid is associate editor in the Egyptian Rheumatology and Rehabilitation, Waleed Hassan, Safaa Mahran and Yasser El Miedany are from editorial board of the journal. Author Contribution Y El Miedany and M Elgaafary carried out the literature review. Y El Miedany, M. Elgaafary, M Wadie, S. Mahran, W. Hassan, M. Abu Zaid, Y. Abdel Fattah and W. Elwakil contributed in the Delphi Process. YEM, RE and WE shared in reviewing the results of the Delphi. Y El Miedany, M. Elgaafary, M Wadie, S. Mahran, W. Hassan, M. Abu Zaid, Y. Abdel Fattah and W. Elwakil shared in the manuscript writing. Data Availability Data are available on reasonable request References Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117:557–567 van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. 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Lancet 389:2338–2348 Tables Table (1): Suggested physiotherapy Model for patients with very early / established systemic sclerosis Massage Exercise Splinting Moisturise skin (can use a brush to apply the moisturiser) Orofacial stretching exercise Hand exercise Aerobic exercises Resistance Exercise Hydrotherapy Support Joints Facial massage Exercise for small mouth opening stretching Cardiovascular exercise Build muscle strength Improve mobility Prevent deformity Skin massage Help maintain facial mobility Range of motion Respiratory Exercise Improve fitness Resistive exercise Static splints Can use specific gadgets to massage prevent or manage stiffness. Ex. Yoga, Pilates, tai chi. Should be carried out daily Examples: Walking, cycling, dancing Use elastic resistance bands at home for exercise. Light weight lifting Improve mobility and reduce pain dynamic splints can indeed exacerbate Raynaud's phenomenon Additional Declarations Competing interest reported. The authors declare that Mohammed Hassan Abu-Zaid is associate editor in the Egyptian Rheumatology and Rehabilitation, Waleed Hassan, Safaa Mahran and Yasser El Miedany are from editorial board of the journal. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Aug, 2025 Reviews received at journal 01 Aug, 2025 Reviews received at journal 27 Jul, 2025 Reviewers agreed at journal 26 Jul, 2025 Reviewers agreed at journal 25 Jul, 2025 Reviewers invited by journal 25 Jul, 2025 Editor assigned by journal 17 Jul, 2025 Submission checks completed at journal 16 Jul, 2025 First submitted to journal 16 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Miedany","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYBADGQZmBgYJIEMOxDvwgAgtPDAtxmAtCURpYYBoSWwAsfBpMTh+/PGHj3tseHTbmQ/e+LnjcPr8sMMPgbbYyek24NByJsdMcsazNB6zw2zJlr1nDuduvJ1mANSSbGx2AIeWAzlszDwHDgO18JhJ8LYBtcxOAGk5kLgNl5bzzx9//nPgP1AL/zfJv22H0w1np3/Ar+VGgoE0w4EDIFvYpIG2JMhL5+C3RfLGGzPJngPJIL8YW8u2pRtukM4pOJBggNsvfOfTH3/4ccBOzuz84Yc337ZZy8vPTt/84UMFUASHFgU08WZggIAdjF05CMg3oPLrMERGwSgYBaNgFAAAObpnnBuPxkgAAAAASUVORK5CYII=","orcid":"","institution":"Canterbury Christ Church University","correspondingAuthor":true,"prefix":"","firstName":"Yasser","middleName":"El","lastName":"Miedany","suffix":""},{"id":491554147,"identity":"5c5dcf82-30c7-4ecd-8f92-d11ab97fbc20","order_by":1,"name":"Maha Elgaafary","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Maha","middleName":"","lastName":"Elgaafary","suffix":""},{"id":491554148,"identity":"539ba39a-fdd9-49b0-b09f-a2b005419eab","order_by":2,"name":"Mary Wadie","email":"","orcid":"","institution":"Kasr Alainy Cairo University","correspondingAuthor":false,"prefix":"","firstName":"Mary","middleName":"","lastName":"Wadie","suffix":""},{"id":491554149,"identity":"504bafda-a448-403b-a3b1-b6e58442b102","order_by":3,"name":"Safaa Mahran","email":"","orcid":"","institution":"Assiut University","correspondingAuthor":false,"prefix":"","firstName":"Safaa","middleName":"","lastName":"Mahran","suffix":""},{"id":491554151,"identity":"fe7c122a-a930-4df6-b7c5-62613ac27ff9","order_by":4,"name":"Rahma A Elziaty","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Rahma","middleName":"A","lastName":"Elziaty","suffix":""},{"id":491554153,"identity":"741e1d58-7c4e-4106-90b0-2450b9d9d134","order_by":5,"name":"Waleed Hassan","email":"","orcid":"","institution":"Benha University","correspondingAuthor":false,"prefix":"","firstName":"Waleed","middleName":"","lastName":"Hassan","suffix":""},{"id":491554155,"identity":"204d4e14-42de-48bb-ab83-36ffe8254bb1","order_by":6,"name":"Mohamed Hassan Abu-Zaid","email":"","orcid":"","institution":"Tanta University","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"Hassan","lastName":"Abu-Zaid","suffix":""},{"id":491554160,"identity":"7a2dc763-b945-406a-9cfd-f09ab7aa9bc2","order_by":7,"name":"Yousra Hisham Abdel-Fattah","email":"","orcid":"","institution":"Alexandria University","correspondingAuthor":false,"prefix":"","firstName":"Yousra","middleName":"Hisham","lastName":"Abdel-Fattah","suffix":""},{"id":491554161,"identity":"8c73b00b-5efc-4052-b479-1d0adce4570f","order_by":8,"name":"Elwakil Walaa","email":"","orcid":"","institution":"Alexandria University","correspondingAuthor":false,"prefix":"","firstName":"Elwakil","middleName":"","lastName":"Walaa","suffix":""}],"badges":[],"createdAt":"2025-06-29 20:53:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7004778/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7004778/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87882101,"identity":"89e29ae3-903d-4bdd-92d3-99dc139f0129","added_by":"auto","created_at":"2025-07-30 04:27:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":19607,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart for the study selection process\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7004778/v1/4fba3a156562b33ea59cc22a.png"},{"id":87882701,"identity":"a00a5291-15fc-4353-bf84-53bdcde62f50","added_by":"auto","created_at":"2025-07-30 04:43:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":103682,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7004778/v1/75c704d8f1a9d69db056485a.png"},{"id":87882321,"identity":"9b6f13f0-ee62-486b-8af9-b8a19948b825","added_by":"auto","created_at":"2025-07-30 04:35:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":74097,"visible":true,"origin":"","legend":"\u003cp\u003eSystemic Sclerosis (SSc) Early Risk Assessment \u0026amp; Stratification (SSc-ERAS) Algorithm\u003c/p\u003e\n\u003cp\u003eRP: Raynaud’s Phenomenon, ANA: Anti-nuclear Anti-body, DLCO: carbon monoxide diffusion, NFC: Nailfold capillaroscopy, SSc: PROMs: Patient Reported Outcome measures, PFT: Pulmonary function testing, NT-proBNP: N-terminal pro B-type natriuretic peptide, Systemic Sclerosis, ILD: Interstitial Lung disease,\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7004778/v1/7329d3731a40d9f2f1d5c9f8.png"},{"id":87883040,"identity":"5db6ae19-46d7-4a8e-ae03-f71fe15e7057","added_by":"auto","created_at":"2025-07-30 04:51:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1568879,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7004778/v1/43c83830-91ca-435c-8062-6444836dcc14.pdf"}],"financialInterests":"Competing interest reported. The authors declare that Mohammed Hassan Abu-Zaid is associate editor in the Egyptian Rheumatology and Rehabilitation, Waleed Hassan, Safaa Mahran and Yasser El Miedany are from editorial board of the journal.","formattedTitle":"The Critical Window of Very Early Systemic Sclerosis: A Model for a specialized early systemic sclerosis Clinic","fulltext":[{"header":"Background","content":"\u003cp\u003eSystemic sclerosis (SSc) is a chronic and complex autoimmune condition. It affects connective tissues resulting in fibrosis of both the skin and internal organs as well as extensive vasculopathy. It also triggers the formation of autoantibodies. The disease presents a major challenge for health care professional in standard practice because of its complex and multifaceted nature [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Due to its intricate and varied nature, this disease poses a significant challenge for clinicians in standard practice. The disease follows an unpredictable course, accompanied by clinical variability and the potential for serious health impacts, including significant morbidity and mortality. This emphasizes how important it is to have a timely and precise diagnosis, implement patient specific therapy techniques as well as management strategies tailored to the individual subject [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A definite diagnosis for SSc, however, is typically a drawn-out process that frequently happens after irreversible organ damage has already occurred. This delay in diagnosis draws attention to a crucial phase of the disease, which is often overlooked or under-recognised: very early systemic sclerosis (veSSc) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe concept of veSSc highlights the existence of a pre-classification phase where individuals show some clinical manifestations suggestive of the disease and warrant further assessment. These symptoms are usually linked with SSc-specific autoantibodies or abnormal nailfold capillaroscopy (NFC), or may include isolated puffy fingers with similar immunological or microvascular abnormalities [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although these early clues might not fully meet the 2013 ACR/EULAR classification criteria for SSc [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], they offer a crucial window of opportunity for intervention. By identifying and intervening early in the disease's path, there's a chance to change its course, reduce the severity of organ involvement, and ultimately improve patient outcomes.\u003c/p\u003e\u003cp\u003eDiagnosing and managing very early systemic sclerosis (veSSc) is crucial for several important reasons. Firstly, the underlying pathogenic processes, including endothelial dysfunction and fibroblast activation, tend to begin to develop and progress even before the disease meets formal classification criteria. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Identifying these processes early offers the chance to halt or slow their progression, helping to prevent significant and irreversible damage, especially in high-risk individuals. Moreover, the diverse nature of systemic sclerosis is apparent right from its initial stages. By identifying specific serological and microvascular profiles, doctors can better assess risk, predict how the disease might progress, and tailor monitoring and interventions accordingly. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] For instance, the presence of anti-RNA polymerase III antibodies at the veSSc stage might suggest a heightened risk of rapid skin progression and potential kidney issues. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eManaging veSSc requires a distinctly different approach than that used for established SSc. While outright immunosuppressive therapy might not be needed for every veSSc patient, it's crucial to monitor closely, address RP aggressively, and intervene early when new symptoms emerge. Thus, it is essential to stratify patients at every stage of the disease, to properly assess, monitor, and manage them [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. A clinic specialized in veSSc can offer the right setting and expertise for this tailored approach. Such a clinic would set up standardized assessment protocols, including comprehensive clinical evaluations, detailed autoantibody testing, thorough nailfold capillaroscopy (NFC), and initial organ screening. This organized strategy not only improves early diagnostic accuracy, but also supports collecting valuable long-term data to deepen the global understanding of veSSc's progression.\u003c/p\u003e\u003cp\u003eThe aim of this work to establish a standardized, multidisciplinary clinic dedicated to the early assessment, diagnosis, and management of patients with very early systemic sclerosis (veSSc). This initiative, set up by the Egyptian Society for Microcirculation in Rheumatic Diseases will enable timely intervention, enhance patient outcomes, and drive forward research during this crucial stage of the disease.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003e\u003cstrong\u003eStudy design:\u0026nbsp;\u003c/strong\u003eThis work was led by the Egyptian Society for microcirculation in rheumatic diseases. The study was based on the hypothesis that current clinical practices disproportionately focus on diagnosing SSc meeting the published classification criteria, often overlooking very early systemic sclerosis as a pre-systemic sclerosis stage, The study design was formulated based on the CEG guideline development process protocol which involves a qualitative synthesis of scientific evidence and consensus, based on the existing scientific evidence and clinical experience. The manuscript conformed to the preferred reporting items for systematic reviews and meta-analyses guidelines for reporting systematic reviews [14].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in accordance with the Helsinki Declaration. The Clinical, Evidence-based, Guidelines\u0026rdquo; (CEG) initiative protocol was approved the local ethical committee: ethical approval code: 34842/8/21. Written ethics approval from the experts sharing in this work was deemed unnecessary according to national regulations. As per the Egyptian national Ethical Committee regulations, verbal informed consent was required from all the participants included in the study. All the participants were kept anonymous, in compliance with data protection regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeveloping the clinical care standards framework:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure a structured and focused approach, the key clinical questions underpinning this project were systematically developed using the PICO (Population, Intervention, Comparison, Outcome) framework. This allowed for clear definition of the patient group, the intervention of interest, any relevant comparators, and the outcomes to be evaluated. Review of the literature was carried out over the period 2010-2025 to address these key clinical questions using PubMed, Embase, the Cochrane library, Google scholar and scientific society websites.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMeSH Terms (Pubmed): ((\u0026quot;very early systemic sclerosis\u0026quot; OR \u0026quot;very early systemic sclerosis\u0026quot;[All Fields]) OR (\u0026quot;pre-scleroderma\u0026quot;[All Fields] OR \u0026quot;pre scleroderma\u0026quot;[All Fields]) OR (\u0026quot;VEDOSS\u0026quot;[All Fields] OR \u0026quot;Very Early Diagnosis of Systemic Sclerosis\u0026quot;[All Fields]))\u003c/p\u003e\n\u003cp\u003eEmbase: (\u0026apos;very early systemic sclerosis\u0026apos;/exp OR \u0026apos;pre-scleroderma\u0026apos;/exp OR \u0026apos;vedoss\u0026apos;/exp OR \u0026apos;early systemic sclerosis\u0026apos;/exp OR (very early AND \u0026apos;systemic sclerosis\u0026apos;) OR (\u0026apos;pre scleroderma\u0026apos;) OR VEDOSS) AND (\u0026apos;systematic review\u0026apos;/exp OR \u0026apos;systematic review (topic)\u0026apos;/de OR \u0026apos;meta analysis\u0026apos;/exp OR \u0026apos;scoping review\u0026apos;/exp OR (systematic* AND review*) OR meta-analys* OR scoping*) AND [2010-2025]/py\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTask force\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eA task force was invited to share in the Delphi process. The geographical distribution of the Task Force was ensured to reflect the national representation of the experts involved.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDelphi process:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Delphi process was conducted in two rounds to assess the degree of consensus. Participants rated each variable on a 1-9 Likert scale, based on the RAND/UCLA methodology, where 1-3 indicated disagreement, 4-6 were considered undefined, and whereas 7-9 represent agreement. The responses from the first round were analysed, statements revised and presented for the second round. The task force members were encouraged to re-evaluate their responses anonymously based on this additional information. The levels of agreement on each statement of recommendation were defined as \u0026lsquo;high\u0026rsquo; if after the second round of votes, all votes on a statement fell into the agreement bracket (7-9) [15-17].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKey clinical questions:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eWho would be the targeted population of this service set up?\u003c/li\u003e\n \u003cli\u003eWhat would be the optimal clinic workflow from patient referral to follow-up?\u003c/li\u003e\n \u003cli\u003eWhich blood investigations should be routinely performed for diagnosis and monitoring?\u003c/li\u003e\n \u003cli\u003eHow should patients\u0026rsquo; symptoms be reported and quantified?\u003c/li\u003e\n \u003cli\u003eHow should patients be stratified for risk assessment and future complications?\u003c/li\u003e\n \u003cli\u003eWhat kind of management plan would be most effective for these patients?\u003c/li\u003e\n \u003cli\u003eWhat strategies should be implemented for disease monitoring?\u003c/li\u003e\n \u003cli\u003eWhat would a comprehensive follow-up assessment entail, and how often should it occur?\u003c/li\u003e\n \u003cli\u003eHow should the clinic manage the transition of care for specific patient groups (adolescents)?\u003c/li\u003e\n \u003cli\u003eWhat kind of patient education program should be implemented?\u003c/li\u003e\n \u003cli\u003eWhat strategies should be used for data collection, and how can the clinic contribute to research?\u003c/li\u003e\n \u003cli\u003eHow would the clinic ensure continuous quality improvement in its services?\u003c/li\u003e\n \u003cli\u003eWhat ongoing education and training would be provided for the healthcare professionals?\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eLiterature research and evidence selection:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure (1)\u0026nbsp;is a flow chart for the study selection process\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeveloped Clinical Standards:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTargeted population:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ei.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Patients: Definition of Very Early Systemic Sclerosis (veSSc):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who meet \u003cstrong\u003eat least one\u003c/strong\u003e of the following criteria, in the absence of sufficient criteria to be classified as definite SSc according to the 2013 ACR/EULAR classification criteria [2] These criteria are based on the\u0026nbsp;preliminary criteria for the very early diagnosis of systemic sclerosis [6] and the review of the literature:\u003c/p\u003e\n\u003cp\u003e1. \u003cstrong\u003eRaynaud\u0026apos;s Phenomenon (RP)\u003c/strong\u003e with \u003cstrong\u003eAntinuclear Antibodies (ANA)\u003c/strong\u003e positive (any pattern and titre deemed clinically significant).\u003c/p\u003e\n\u003cp\u003e2. \u003cstrong\u003eRaynaud\u0026apos;s Phenomenon (RP)\u003c/strong\u003e with \u003cstrong\u003eSSc-specific antibodies\u003c/strong\u003e positive (e.g., ACA, anti-Scl-70, anti-RNA polymerase III).\u003c/p\u003e\n\u003cp\u003e3. \u003cstrong\u003eRaynaud\u0026apos;s Phenomenon (RP)\u003c/strong\u003e with \u003cstrong\u003eabnormal nailfold capillaroscopy (NFC) findings\u003c/strong\u003e (SSc pattern: normal or low density, capillary apical width 30-50 um, giant capillaries, capillary haemorrhages).\u003c/p\u003e\n\u003cp\u003e4. \u003cstrong\u003eIsolated puffy fingers\u003c/strong\u003e with \u003cstrong\u003eANA positive\u003c/strong\u003e or \u003cstrong\u003eSSc-specific antibodies positive\u003c/strong\u003e or \u003cstrong\u003eabnormal NFC findings\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e5. \u003cstrong\u003eNew onset of otherwise unexplained digital ulcers\u003c/strong\u003e in the presence of RP.\u003c/p\u003e\n\u003cp\u003eThe veSSc clinic is set up to provide service as a specialized multi-disciplinary unit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eii.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Healthcare Professionals:\u003c/strong\u003e \u003cstrong\u003eThe clinic team:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis team comprises several essential members:\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eLead Rheumatologist\u003c/strong\u003e: Leading the team is a rheumatologist, with acknowledged experience in systemic sclerosis (SSc) and early connective tissue diseases. The lead rheumatologist will oversee the patient care, ensure accurate diagnoses, and coordinate treatment plans.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eSpecialist Nurse:\u003c/strong\u003e a dedicated specialist nurse, who brings a wealth of experience in handling connective tissue diseases. This nurse will focus on educating patients, monitoring symptoms, supporting medication management, and scheduling appointments.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eNailfold Capillaroscopy specialist\u003c/strong\u003e who is skilled in performing and interpreting NFC studies.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003ePulmonary Function Technician\u003c/strong\u003e, who is trained in conducting spirometry and DLCO tests.\u003c/p\u003e\n\u003cp\u003eIn addition, access to specialists should be readily available depending on each patient\u0026apos;s specific needs and clinical symptoms. These include:\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eGastroenterologist:\u003c/strong\u003e with expertise in dealing with oesophageal dysmotility, GERD, and other gastrointestinal manifestations associated with SSc.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eCardiologist:\u003c/strong\u003e with expertise in the diagnosis and management of pulmonary hypertension, myocardial involvement, and arrhythmias in patients with SSc.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eDermatologist:\u003c/strong\u003e Expertise in dealing with SSc associated skin changes and the treatment of digital ulcers.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eRenal Physician:\u003c/strong\u003e Expertise in addressing scleroderma renal crisis and the management of renal affection.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003ePhysiotherapist/Occupational Therapist\u003c/strong\u003e: These practitioners have expertise in setting up the appropriate exercise program, provide help and technical support to maintain function and manage musculoskeletal symptoms.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003ePsychologist/Counsellor\u003c/strong\u003e: Their role is to address the psychological impact of chronic disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Patient\u0026rsquo;s assessment and clinic workflow?\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eI.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Referral Pathway:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients can be referred from primary care doctors, general neurologists, dermatologists, and other specialists who recognize patients meeting the veSSc criteria.\u003c/p\u003e\n\u003cp\u003e\u0026middot; A standardized referral form should be used, as shown in Figure (2). This form should include essential clinical history, details of Raynaud\u0026apos;s phenomenon such as its onset, frequency, and severity, any other indicative symptoms like swollen fingers, tight skin, fatigue, or joint pain, previous tests including ANA/ENA results and other autoantibodies, and NFC reports, if available.\u003c/p\u003e\n\u003cp\u003eII. \u003cstrong\u003eInitial Assessment (First Clinic Visit):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eo \u003cstrong\u003eComprehensive Clinical History:\u003c/strong\u003e Detailed questioning about the characteristics of RP, onset, course and progression of any other symptoms (such as skin changes, musculoskeletal pain, fatigue, gastrointestinal symptoms, shortness of breath, etc.), past medical history, family history of autoimmune diseases, medication history, and relevant social background.\u003c/p\u003e\n\u003cp\u003eo \u003cstrong\u003ePhysical Examination:\u003c/strong\u003e General examination (Blood pressure, pulse, temperature, body weight, height and BMI), clinical assessment of the skin (looking for subtle changes like puffy fingers, early sclerodactyly, digital ulcers), musculoskeletal system (joint tenderness, tendons\u0026rsquo; inflammation or localized swelling), and other organ systems.\u003c/p\u003e\n\u003cp\u003eo \u003cstrong\u003eNailfold Capillaroscopy (NFC):\u003c/strong\u003e Carried out by a trained HCP/technician to assess for SSc-specific microangiopathy patterns. Images will be recorded and interpreted by the lead rheumatologist or a designated expert.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIII.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Blood Investigations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea. \u003cstrong\u003eBaseline Inflammatory Markers:\u003c/strong\u003e ESR, CRP.\u003c/p\u003e\n\u003cp\u003eb. \u003cstrong\u003eFull Autoantibody Panel:\u003c/strong\u003e ANA (with pattern and titre), SSc-specific antibodies (ACA, anti-Scl-70, anti-RNA polymerase III, anti-U1-RNP, anti-PM-Scl, anti-fibrillarin, etc.), and other relevant autoantibodies (e.g., RF, anti-CCP, anti-dsDNA) to rule out overlap syndromes.\u003c/p\u003e\n\u003cp\u003ec. \u003cstrong\u003eBaseline Organ Function Tests:\u003c/strong\u003e Assessment of kidney functions (electrolytes, creatinine, eGFR), liver function tests (ALT, Albumin, ALP, bilirubin), thyroid function tests (TSH, FT4), and creatine kinase (CK).\u003c/p\u003e\n\u003cp\u003ed. \u003cstrong\u003eN-terminal pro-B-type natriuretic peptide (NT-proBNP):\u003c/strong\u003e this serves as a baseline marker for potential cardiac involvement or pulmonary hypertension risk.\u003c/p\u003e\n\u003cp\u003ee. \u003cstrong\u003eUrine Analysis:\u003c/strong\u003e checking for proteinuria, haematuria.\u003c/p\u003e\n\u003cp\u003eIV. \u003cstrong\u003ePatient-Reported Outcome Measures (PROMs):\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ei. \u003cstrong\u003eRaynaud\u0026apos;s PROMs:\u003c/strong\u003e To quantify RP severity and frequency [18].\u003c/p\u003e\n\u003cp\u003eii. \u003cstrong\u003eHealth Assessment Questionnaire Disability Index (HAQ-DI):\u003c/strong\u003e To assess functional disability.\u003c/p\u003e\n\u003cp\u003eiii. \u003cstrong\u003eScleroderma PROMs questionnaire [19]\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eV.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Patient education:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEducating Patients: Providing detailed insights on veSSc, how it might develop over time, why regular monitoring is crucial, and what resources are available to support patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVI.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Stratification and Risk Assessment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; After an initial assessment, patients will be classified into different risk levels. These categories will help determine the likelihood of patients progressing to full-blown SSc , as well as the risk of developing specific organ issues.\u003c/p\u003e\n\u003cp\u003e\u0026middot; To stratify patients, several factors are considered, including:\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;The presence and type of SSc-specific antibodies; for example, anti-RNA polymerase III antibodies are often linked to fast progression and skin involvement.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;The severity of NFC abnormalities, identified as very early, early, active, or late patterns.\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Whether the patient has puffy fingers.\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Elevated levels of NT-proBNP.\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Specific ANA patterns, such as the nucleolar pattern, which might indicate a higher risk or systemic/organ affection.\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;The patient reported symptoms, including fatigue and joint pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVII.\u0026nbsp; \u0026nbsp; \u0026nbsp;Management Plan\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eManagement should be tailored to the individual patient\u0026rsquo;s condition.\u003c/p\u003e\n\u003cp\u003ea. \u003cstrong\u003eRaynaud\u0026apos;s Phenomenon Management:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Lifestyle advice (avoiding cold exposure, stop smoking or at least smoking cessation).\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;First-line therapy: Calcium channel blockers (e.g., nifedipine, amlodipine).\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Second line: Consideration of other vasodilators (e.g., topical nitrates, phosphodiesterase-5 inhibitors, prostaglandins) based on severity and response [20].\u003c/p\u003e\n\u003cp\u003eb. \u003cstrong\u003eSymptom Management:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Pain relief: (NSAIDs with caution due to potential renal risk, paracetamol).\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Hyperacidity: Proton pump inhibitors (PPIs) for gastroesophageal reflux symptoms.\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Skin symptoms: Emollients for dry skin.\u003c/p\u003e\n\u003cp\u003ec. \u003cstrong\u003ePatients\u0026rsquo; monitoring?\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk-Based Monitoring:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- \u003cstrong\u003eLow-Risk Patients:\u003c/strong\u003e Regular follow-up (e.g., every 6-12 months) including clinical assessment, RP scoring, PROMs, and annual NFC assessment. Consider annual check for autoantibodies and NT-proBNP.\u003c/p\u003e\n\u003cp\u003e- \u003cstrong\u003eIntermediate-Risk Patients:\u003c/strong\u003e More frequent follow-up (e.g., every 3-6 months) including clinical assessment, RP scoring, PROMs, reassess NFC every 6 months, and regular close monitoring of organ functions, NT-proBNP and whenever appropriate auto-antibodies. Consider baseline pulmonary function tests (spirometry, DLCO) and echocardiogram.\u003c/p\u003e\n\u003cp\u003e- \u003cstrong\u003eHigh-Risk Patients:\u003c/strong\u003e Close monitoring (e.g., every 1-3 months) including comprehensive clinical and laboratory assessments, frequent NFC, PFTs, echocardiogram, and consideration of early referral to relevant specialists. Figure (3) shows SSc Early Risk Assessment \u0026amp; Stratification (SSc-ERAS) algorithm.\u003c/p\u003e\n\u003cp\u003ed. \u003cstrong\u003eEarly Intervention (Consideration in High-Risk Cases):\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ei. \u003cstrong\u003eLow-dose methotrexate:\u003c/strong\u003e May be considered for persistent arthralgia or early inflammatory features, with regular monitoring.\u003c/p\u003e\n\u003cp\u003eii. \u003cstrong\u003eMycophenolate mofetil:\u003c/strong\u003e Can be considered in patients with high-risk antibody profiles (e.g., anti-RNA polymerase III) or early signs of skin involvement, with regular monitoring.\u003c/p\u003e\n\u003cp\u003eiii. \u003cstrong\u003eClinical Trial Enrollment:\u003c/strong\u003e may actively consider and offer enrollment in relevant clinical trials investigating early interventions in veSSc.\u003c/p\u003e\n\u003cp\u003ee. \u003cstrong\u003eReferral to Specialists:\u003c/strong\u003e Prompt referral to gastroenterology, cardiology, pulmonology, dermatology, or nephrology based on clinical findings and risk assessment.\u003c/p\u003e\n\u003cp\u003ef. \u003cstrong\u003ePhysical therapy/ Rehabilitation:\u003c/strong\u003e In the very early stages of SSc, physiotherapy plays an important role in improving and maintaining unction, preventing contractures, and managing symptoms like Raynaud\u0026apos;s. Table (1) shows an example of the different physiotherapy modalities that can implemented. Individualized program, focussing on specific patient\u0026rsquo;s requirements and limitations is essential.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe importance of early intervention important?\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Delaying Contractures: Early physiotherapy can help delay or prevent the development of contractures, which can severely impact quality of life.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Maintaining Function: It can help maintain and improve the patient\u0026rsquo;s ability to perform daily activities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Managing Symptoms: Physiotherapy can help manage pain, stiffness, and other symptoms of SSc.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp; \u0026nbsp; \u0026nbsp;Early Detection: Physiotherapy may help identify early signs of organ involvement, allowing for timely intervention.\u003c/p\u003e\n\u003cp\u003eVIII. \u003cstrong\u003eFollow-Up Assessments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea.\u0026nbsp; \u0026nbsp;Regular follow-up appointments as determined by the risk stratification and individual patient needs.\u003c/p\u003e\n\u003cp\u003eb.\u0026nbsp; \u0026nbsp;At each visit:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ei.\u0026nbsp;Review of clinical and relevant organ symptoms and RP characteristics.\u003c/p\u003e\n\u003cp\u003eii.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Physical examination.\u003c/p\u003e\n\u003cp\u003eiii.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Assessment of PROMs.\u003c/p\u003e\n\u003cp\u003eiv.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Review of any new investigations or specialist consultations.\u003c/p\u003e\n\u003cp\u003ev.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Adjustment of management plan as needed.\u003c/p\u003e\n\u003cp\u003ec.\u0026nbsp; \u0026nbsp;Periodic repeat investigations (blood tests, NFC, PFTs, echocardiogram) based on risk stratification and clinical evolution.\u003c/p\u003e\n\u003cp\u003ed.\u0026nbsp; \u0026nbsp;Regular monitoring for progression to definite SSc according to the 2013 ACR/EULAR classification criteria [2].\u003c/p\u003e\n\u003cp\u003eIX. \u003cstrong\u003eTransition to Standard SSc Clinic:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea.\u0026nbsp; \u0026nbsp;When a patient meets the 2013 ACR/EULAR classification criteria for definite SSc [2], they will be transitioned to the standard SSc clinic for ongoing management according to established protocols. However, the data collected during their time in the veSSc clinic are vital for understanding the disease evolution.\u003c/p\u003e\n\u003cp\u003eX. \u003cstrong\u003eData Collection and Research:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; A dedicated database should be collected including the outcomes of comprehensive clinical assessment, laboratory results, imaging findings, and PROMs scores. The data on all patients should be \u0026nbsp;enrolled in the veSSc clinic.\u003c/p\u003e\n\u003cp\u003e\u0026middot; This database will be invaluable for:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eo Characterizing the veSSc cohort.\u003c/p\u003e\n\u003cp\u003eo Identifying predictors of progression to definite SSc.\u003c/p\u003e\n\u003cp\u003eo Evaluating the effectiveness of early interventions.\u003c/p\u003e\n\u003cp\u003eo Supporting participation in multicenter research studies.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Ethical approval will be obtained for data collection and research activities.\u003c/p\u003e\n\u003cp\u003eXI. \u003cstrong\u003eQuality Improvement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAudits/ re-auding should be carried out regularly to assess the clinic processes and patient outcomes to ensure protocol adherence and identify areas for improvement.\u003c/p\u003e\n\u003cp\u003ePatient reported experience [21]\u0026nbsp;/ feedback, along with insights from the multidisciplinary team, should be actively sought out and used to refine how our clinic operates.\u003c/p\u003e\n\u003cp\u003eXII. \u003cstrong\u003eEducation and Training:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e- To equip every member of the veSSc clinic team with the necessary skills, ongoing education and training should be offered to guarantee expertise in diagnosing and managing early SSc.\u003c/p\u003e\n\u003cp\u003e- Opportunities to collaborate and share knowledge with other veSSc centers should pursued.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVery early systemic sclerosis is a challenge in the standard clinical practice. This has been attributed to its heterogenous clinical manifestations and the importance of detecting the illness at early stage, where medical intervention might help prevent the progression of the disease and in particular organ damage [22]. Another challenge is that most of the patients presenting with very early systemic sclerosis manifestations, do not meet the 2013 ACR/EULAR classification criteria [23]\u0026nbsp;inspite of its higher sensitivity in comparison to the former 1980 classification criteria. This protocol addresses such limitation and outlines a framework for establishing a specialized veSSc clinic, aiming to identifying this patients cohort at such early stage of the disease and identifying who have the potential to \u0026nbsp;progress into definite SSc. Therefore, it should be regularly updated to include the latest advances in diagnosing and managing systemic sclerosis.\u003c/p\u003e\n\u003cp\u003eVery mild systemic sclerosis patients require need a very different follow-up scheme. By putting this protocol into practice, it would facilitate early diagnosis, enhance risk stratification, and explore the potential for interventions during the initial phases of this complex illness. Ultimately, this should lead to improved patient outcomes and a deeper understanding of systemic sclerosis in its early stages. Figure 2 provides a visual guide in the form of an algorithm to assist with assessment and management. This can be consider as a road map, navigating the complex paths of patient care and clinical decisions. pathway within the clinic. Analysis of this very early group of SSc patients is of particular interest and high importance for disease management because very early intervention has been reported to profoundly improve disease course and outcome in a variety of different inflammatory rheumatic diseases [24,25].\u003c/p\u003e\n\u003cp\u003eIn conclusion, the phase before a formal SSc diagnosis is critical, yet it often goes unnoticed. Setting up specialized veSSc clinics is vital for appropriate and timely identification of the patients at this pre‑scleroderma phase. By concentrating on this subtle phase of SSc and recognizing the disease trajectories, this represents a window of opportunity and opens a new approach for preventive medicine. The expert care and systematic method at a veSSc clinic are essential for turning our increasing understanding of veSSc into real-life benefits for patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eANA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnti-nuclear Anti-body\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDLCO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecarbon monoxide diffusion\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eILD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInterstitial Lung disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNFC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNailfold capillaroscopy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNT-proBNP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eN-terminal pro B-type natriuretic peptide\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePFT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePulmonary function testing\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePROMs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epatient reported outcome measures\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRaynaud\u0026rsquo;s Phenomenon\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSSc\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esystemic sclerosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSSc-ERAS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSystemic Sclerosis Early Risk Assessment \u0026amp; Stratification\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eVEDOS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eVery Early Diagnosis of Systemic Sclerosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eveSSc\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003every early systemic sclerosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eThe authors declare that Mohammed Hassan Abu-Zaid is associate editor in the Egyptian Rheumatology and Rehabilitation, Waleed Hassan, Safaa Mahran and Yasser El Miedany are from editorial board of the journal.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eY El Miedany and M Elgaafary carried out the literature review. Y El Miedany, M. Elgaafary, M Wadie, S. Mahran, W. Hassan, M. Abu Zaid, Y. Abdel Fattah and W. Elwakil contributed in the Delphi Process. YEM, RE and WE shared in reviewing the results of the Delphi. Y El Miedany, M. Elgaafary, M Wadie, S. Mahran, W. Hassan, M. Abu Zaid, Y. Abdel Fattah and W. Elwakil shared in the manuscript writing.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData are available on reasonable request\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVarga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117:557\u0026ndash;567\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, M\u0026uuml;ller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. 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Isr Med Assoc J 18:141\u0026ndash;143\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbraham DJ, Krieg T, Distler J, Distler O (2009) Overview of pathogenesis of systemic sclerosis. Rheumatology 48(suppl):iii3\u0026ndash;iii7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003edoi.org/10.1093/rheumatology/ken481\u003c/span\u003e\u003cspan address=\"10.1093/rheumatology/ken481\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBlaja E, Jordan S, Mihai CM, Dobrota R, Becker MO, Maurer B, Matucci-Cerinic M, Distler O (2021) The Challenge of Very Early Systemic Sclerosis: A Combination of Mild and Early Disease? 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Ther Med 23(3):430\u0026ndash;438\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl Miedany Y, Elgaafary M, Toth M, Palmer D, Elziaty RA Towards tailored patient\u0026rsquo;s management approach: Constuct validity and reliability of a patient reported outcome measures questionnaire for assessing Raynaud\u0026rsquo;s phenomenon patients. Ann Rheum Dis 84: 672\u0026ndash;673\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl Miedany Y, El Gaafary M, El Aroussy N (2018) et alFRI0472 Towards a multidimensional patient reported outcome measures assessment: development and validation of a questionnaire for patients with systemic sclerosis/scleroderma. Ann Rheum Dis 77:764\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl Miedany Y, Hadidi E, El Menyawi K (2024) Egyptian evidence-based consensus on clinical practice recommendations for the management of systemic sclerosis. 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Ann Rheum Dis 69:1809\u0026ndash;1815\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDistler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD et al (2019) Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 380:2518\u0026ndash;2528\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP (2010) Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM 103:109\u0026ndash;115\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBurmester GR, Pope JE (2017) Novel treatment strategies in rheumatoid arthritis. Lancet 389:2338\u0026ndash;2348\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable (1): Suggested physiotherapy Model for patients with very early / established systemic sclerosis\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"907\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMassage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 666px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExercise\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSplinting\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eMoisturise skin (can use a brush to apply the moisturiser)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eOrofacial stretching exercise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eHand exercise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003eAerobic exercises\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eResistance\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eExercise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHydrotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSupport\u003c/p\u003e\n \u003cp\u003eJoints\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eFacial massage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eExercise for small mouth opening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003estretching\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003eCardiovascular\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eexercise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBuild muscle strength\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eImprove mobility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003ePrevent\u0026nbsp;\u003c/p\u003e\n \u003cp\u003edeformity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eSkin massage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eHelp maintain facial mobility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eRange of motion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003eRespiratory\u003c/p\u003e\n \u003cp\u003eExercise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eImprove fitness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eResistive exercise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eStatic splints\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eCan use specific gadgets to massage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003eprevent or manage stiffness.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eEx. Yoga, Pilates, tai chi. Should be carried out daily\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003eExamples:\u003c/p\u003e\n \u003cp\u003eWalking, cycling, dancing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eUse elastic resistance bands at home for exercise. Light weight lifting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eImprove mobility and reduce pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003edynamic splints can indeed exacerbate Raynaud\u0026apos;s phenomenon\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"egyptian-rheumatology-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"43166","submissionUrl":"https://submission.springernature.com/new-submission/43166/3","title":"Egyptian Rheumatology and Rehabilitation","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"very early systemic sclerosis, clinic, veSSc, PROMs, Raynaud’s, VEDOSS, systemic sclerosis, SSc Early Risk Assessment \u0026 Stratification (SSc-ERAS), Egyptian Society for microcirculation in rheumatic diseases","lastPublishedDoi":"10.21203/rs.3.rs-7004778/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7004778/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThis study, led by the Egyptian Society for Microcirculation in Rheumatic Diseases, aimed to address the oversight of very early systemic sclerosis (SSc) as a pre-systemic sclerosis stage, hypothesizing that current clinical practices primarily focus on diagnosing SSc only when it meets established classification criteria. Identification of this patients\u0026rsquo; cohort at such early phase is window of opportunity to treat those at high risk of skin fibrosis or organ involvement before such events occur.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThe aim of this work was to establish a standardized, multidisciplinary clinic dedicated to the early assessment, diagnosis, and management of patients with very early systemic sclerosis (veSSc).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e The methodology adhered to the PRISMA guidelines for reporting systematic reviews. To develop the clinical care standards framework, key clinical questions were systematically formulated using the PICO framework (Population, Intervention, Comparison, Outcome), a comprehensive literature review was conducted from 2010 to 2025 across multiple databases and a geographically diverse task force of national experts was assembled to participate in a two-round Delphi process to assess consensus levels.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e12 key clinical questions were systematically developed using the PICO (Population, Intervention, Comparison, Outcome) framework. Following a review of the literature, and with eh endorsement of the Egyptian society for microcirculation in rheumatic diseases, a Delphi process was carried out. Consensus was reached (i.e. \u0026ge;75%of respondents strongly agreed or agreed) on the wording, the grade of recommendation and level of evidence of all the clinical standards identified by the scientific committee.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eSetting up a very early systemic sclerosis (SSc) clinic involves establishing a system for early detection and management of SSc, focusing on patients with Raynaud's phenomenon and other early symptoms. The goal is to identify individuals at risk of progressing to SSc and offer prompt, targeted interventions.\u003c/p\u003e","manuscriptTitle":"The Critical Window of Very Early Systemic Sclerosis: A Model for a specialized early systemic sclerosis Clinic","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-30 04:27:42","doi":"10.21203/rs.3.rs-7004778/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-04T07:37:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-01T22:56:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-27T18:34:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80136856992531566831366277846719934094","date":"2025-07-26T15:21:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"168740220085816614616445167613393456728","date":"2025-07-25T23:11:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-25T08:45:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-17T14:45:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-17T00:27:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Egyptian Rheumatology and Rehabilitation","date":"2025-07-16T22:14:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"egyptian-rheumatology-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"43166","submissionUrl":"https://submission.springernature.com/new-submission/43166/3","title":"Egyptian Rheumatology and Rehabilitation","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cd8f7a12-606e-4e76-b541-783708f11fc0","owner":[],"postedDate":"July 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-27T10:23:36+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-30 04:27:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7004778","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7004778","identity":"rs-7004778","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}