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• Baseline HRCT and PFT are paramount in clinically overt (LcSSc and DcSSc) patients. • The majority of clinically overt SSc patients with ILD progresses within 5 years. • Baseline HRCT and PFT are paramount in patients with "early" SSc. • Only a very small proportion of the "early" SSc develop ILD during follow-up. Objectives: The epidemiology of interstitial lung disease (ILD) in systemic sclerosis (SSc) in Belgium is unknown. In literature, its prevalence varies between 19% and 52% in limited/diffuse cutaneous SSc (LcSSc/DcSSc). However, its prevalence in "early" SSc (pre-clinically overt SSc without [yet] skin involvement), nor its incidence rate in SSc (LcSSc/DcSSc/"early" SSc) has ever been described. Against this background, we aimed to determine the prevalence/incidence (rate) and progression of ILD in SSc. Methods: 12-year follow-up data of consecutive SSc patients, included in two Flemish cohorts (University Hospitals Ghent and Leuven), were retrospectively analysed. ILD was classified according to the simplified Goh algorithm. Progression of ILD was defined as a relative decline of FVC ≥10%, a combined relative decline of FVC 5-10% and DLCO ≥15%, or as an increase in HRCT extent. Results: 722 patients (60% LcSSc/ 20% DcSSc/ 20% "early" SSc, median (IQR) follow-up 39 [12-80] months) had baseline HRCT. 243 were rated to have ILD at baseline and 39 during follow-up (prevalence of 34%/ incidence rate of 20.3/1000PY, 95%CI:14.5-27.8). Amongst those with baseline ILD, 60% had lung functional progression at five years of follow-up. In the "early" SSc subgroup, eight patients were rated to have ILD at baseline and three during follow-up (prevalence of 6%/ incidence rate of 5.8/1000 PY, 95%CI:1.2-17.0). Conclusion: Both LcSSc and DcSSc patients should be monitored for ILD evolution. The low prevalence and incidence of ILD in the "early" SSc subgroup may instruct future decisions on the construction of uniform patient follow-up pathways in "early" SSc. [ABSTRACT FROM AUTHOR]

It is unknown whether treatment in very early/early systemic sclerosis (SSc) can affect long-term outcomes. A case-based review was conducted (i) to assess the effect of rituximab (RTX) in very early SSc and (ii) to explore how many clinical trials in SSc targeted early disease and whether treatment of these patients led to better clinical outcomes. We identified cases of very early SSc from our department and performed a search in MEDLINE and Scopus databases for clinical trials in SSc during 2005–2018. Two cases are reported where RTX was administered within 24 months from the appearance of Raynaud's. In the first case, there was an improvement in interstitial lung disease as indicated by the improvement in pulmonary function tests and the regression of changes in high-resolution chest computed tomography. In the second case, a good clinical response in skin fibrosis was observed. The review revealed the following: (i) only one-third of the studies were specifically designed to target early disease, (ii) there is confusion related to disease duration definition across SSc clinical trials but an obvious trend towards improvement was evident during the past years, (iii) the question of whether early implementation of therapy may lead to better clinical outcomes cannot be definitely answered based on existing data and (iv) there is still a very low level of incorporation of the new classification criteria in SSc trials. This review suggests that there may be a window of opportunity in SSc and highlights the need for clinical trials targeting very early/early disease. [ABSTRACT FROM AUTHOR]

Les critères de classification de la sclérodermie systémique ont évolué au cours de trois dernières décennies, permettant une classification de plus en plus précoce. À la fin des années 2000, le groupe européen de recherche sur les sclérodermies (groupe EUSTAR) a validé les notions de sclérodermies très précoces et précoces. Le phénomène de Raynaud, la présence d'anticorps antinucléaires ou de doigts boudinés sont des « drapeaux rouges » qui doivent faire orienter le patient vers un spécialiste, faire réaliser une capillaroscopie et la recherche d'autoanticorps spécifiques de la sclérodermie systémique. Au stade de sclérodermie très précoce, une atteinte cardiaque, pulmonaire ou digestive peut déjà être présente et doit donc être systématiquement recherchée. Nous détaillerons ici les critères de sclérodermie systémique très précoce et précoce, ainsi que les facteurs prédictifs d'évolution vers une sclérodermie systémique. Classification criteria for systemic sclerosis evolved over the last three decades, allowing an earlier classification. In the late 2000s, the EULAR Scleroderma Trials and Research Group validated very early and early systemic sclerosis criteria. Raynaud phenomenon, anti-nuclear antibody positivity and the puffy fingers are "Red flags" that must lead to refer the patient to a specialist and benefit from a capillaroscopy and the specific autoantibodies. At the stage of very early systemic sclerosis, pulmonary, cardiac and digestive involvements may be present and must be screened. Herein, we detail very early and early systemic sclerosis criteria, as well as the predictive factors of evolution towards a systemic sclerosis. [ABSTRACT FROM AUTHOR]

Objectives According to the existence of subclinical organ involvement pre-scleroderma should be divided into two subsets: very early and early disease. Pre-scleroderma patients included in the Spanish Scleroderma Registry (RESCLE) Cohort were reclassified into subsets. Differences were evaluated and the risk of progression to definite systemic sclerosis was estimated. Methods The characteristics of very early and early SSc patients were compared. A logistic regression model was used to determine the risk factors of progression. Results 1632 patients were included, 36 (2.2%) in the very early subset and 111 (6.8%) in the early subset. There were no differences in sex, age at disease onset, duration of Raynaud's phenomenon, antinuclear antibodies or capillaroscopic findings. Three (8.3%) very early SSc patients evolved to definite SSc, 2 (5.6%) of them meeting the ACR/EULAR 2013 criteria, unlike 31 (28%) early SSc patients, 20 (24%) of them meeting the criteria ( p = 0.034). Digestive involvement was an independent risk factor of progression (OR 17; 95% CI, 6.1–47.2). Conclusions The classification of early forms of scleroderma identifies patients with different prognostic risk of progression. The evolution to definite SSc is more frequent in early than in very early SSc patients. Digestive involvement is a risk factor of progression. An active assessment of organ damage in preclinical stages allows a correct classification and risk stratification, with implications for monitoring and treatment. [ABSTRACT FROM AUTHOR]

Introduction: The term scleroderma derives from the Greek words skleros, which means hard, and derma, which means skin. It refers to an acquired systemic inflammatory disease of the connective tissue –also known as systemic sclerosis (SSc)– characterized by excessive collagen deposition in the skin and the internal organs that results in fibrosis. The typical vascular lesion in SSc leads to narrowing of the vessel lumen, intimal thickening, medial hypotrophy, and adventitial fibrosis of small muscular vessels, collagen deposition in the other matrix components of interstice, and the Raynaud phenomenon secondary to these widespread microvascular abnormalities. All these characteristics lead to a connective tissue re-modeling. Discussion: Several clinical studies utilize the American Rheumatology Association’s 1980 classification. However, these diagnostic criteria are unsatisfactory because they fail to take into consideration part of the disease spectrum. Early-phase SSc is characterized by the Raynaud phenomenon (in 90% of all patients), sclerodactyly, and positivity for SSc-specific autoantibodies (antinuclear antibodies, anti-topoisomerase I antibodies, anti-RNA polymerase I and III antibodies, anti-centromere antibodies, anti-fibrillarin antibodies, anti-PM-SCL antibodies).. It is necessary to reduce delays in the diagnosis of SSc. Conclusions: Patients with red-flag positivity (Raynaud phenomenon and digital edema) require Phase I SSc screening, which consists in capillaroscopic assessment of possible microvascular abnormalities. The work-up will then focus on inflammatory indices, renal function tests, and internal organ involvement (echocardiography, high-resolution computed tomography of the chest, diffusing capacity of the lungs for carbon monoxide).

Immune activation is a hallmark of systemic sclerosis (SSc). However, the immunological alterations that occur in preclinical and non-fibrotic SSc and that differentiate these subjects from those with primary Raynaud's phenomenon (PRP) or healthy controls (HC) are poorly defined. We isolated CD56 + (NK/NKT-like) cells from HC, patients with PRP, early SSc (EaSSc) and definite SSc without skin or lung fibrosis. Cytokine production upon different activating stimuli was measured via a multiplex immuno assay. Clearly discriminative patterns among the different stages of SSc were most markedly observed after TLR1/2 stimulation, with increased IL-6, TNF-α and MIP-1α/CCL3 production in definite SSc patients as compared to HC and/or PRP. Initial alterations were observed in EaSSc patients with an intermediate secretion pattern between HC/PRP and definite SSc. CD56 + cells from patients at different stages of SSc differentially respond to TLR stimulation, highlighting the relevance of natural immunity in the developmental and pre-fibrotic SSc. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is characterized by microvasculopathy (Raynaud's phenomenon and fibrointimal proliferation), presence of autoantibodies and collagen deposition in skin (scleroderma) and internal organs. Microvasculopathy, detected by nailfold capillaroscopy, and disease-specific autoantibodies (anti-topoisomerase I, anti-centromere, anti-RNA polymerase III antibodies) usually appear earlier, even years before scleroderma. At that stage of the disease, immune activation with T cells and B cells promote fibrosis. Diagnosis of SSc has been relied on scleroderma, and by this time, internal organs may have developed fibrosis, a lethal feature with no available treatment. The new EULAR/ACR 2013 criteria for the classification of SSc will help identify SSc patients before fibrosis of internal organs. The early diagnosis of SSc, before the development of fibrosis in internal organs, will allow the introduction of immunosuppressive medications in these patients in a controlled setting (randomized trials). It is anticipated that this approach will change the hitherto grim prognosis of SSc for the better. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is associated with secondary malignancies. Previous studies have suggested that mutated cancer proteins, such as RNA polymerase III, are autoantigens promoting an inflammatory response in SSc. However, it has never been previously investigated whether non-neoplastic tissue in SSc harbors mutations which may play a role in SSc pathogenesis. Skin biopsies were obtained from 8 sequential patients with a progressive form of early stage SSc (with severe skin and/or lung involvement). Areas of dermal fibrosis were microdissected and analyzed with deep, whole exome sequencing. Gene mutation patterns were compared to autologous buccal mucosal cells as a control. SSc skin biopsies were hypermutated with an average of 58 mutations/106 base pairs. The mutational pattern in all samples exhibited a clock-like signature, which is ubiquitous in cancers and in senescent cells. Of the 1997 genes we identified which were mutated in at least two SSc patients, 39 genes represented cancer drivers (i.e. tumor suppressor genes or oncogenes) which are commonly found in gynecological, squamous and gastrointestinal cancer signatures. Of all the mutations, the most common mutated genes were important in regulating pathways related to epigenetic histone modifications, DNA repair and genome integrity. Somatic hypermutation occurs in fibrotic skin in patients with early progressive SSc. Cancer driver gene mutations may potentially play a fundamental role in the pathogenesis of SSc. • Non-synonymous genomic mutations are common in the dermis of patients with early systemic sclerosis. • Genomic mutations have a clock-like signature, which is commonly present in cancer. • Many mutated genes are important in the maintenance of genomic integrity. [ABSTRACT FROM AUTHOR]

Introduction. Raynaud's phenomenon (RP) can be idiopathic, benign, or associated with a series of causes among which the most reserved prognosis have the systemic autoimmune diseases. Autoimmune Raynaud's is frequently an early sign of scleroderma spectrum diseases (SSD), associated with a high morbidity. Nailfold capillaroscopy (NC) can identify a specific pattern in SSD, reflecting the early microvascular involvement. Objectives. To evaluate the ability of NC to differentiate non-immune RP from immune-associated RP (immune RP) and to reveal the role of NC in the early etiological diagnosis of RP. Materials and methods. This transversal descriptive study included all the patients with unclassified RP who visited the clinic between October 2009 -- May 2011. The etiology of RP was established through clinical, paraclinical assessment and NC. The statistical analysis used the chi-square test and logistic regression. Sensitivity (Se), specificity (Sp), negative predictive value (NPV) and positive predictive value (PPV) for immune RP were calculated for each capillaroscopic parameter studied, as well as for the exam itself. Results. 49 patients were included, 41 women (83,7%) and 8 men (16,3%), aged 18-71 years (mean±SD 41.46 ± 15.02 years); 11 patients with non-immune RP and 29 with immune RP were identified. The etiology was diverse: overlap syndromes (n = 10; 20.4%), early systemic sclerosis (n = 7; 14.3%), undifferentiated connective tissue disease (n = 5; 10.2%), systemic lupus erythematosus and rheumatoid arthritis (2 cases each, 4.1%), dermatomyositis, Sjogren's syndrome and other autoimmune diseases (1 case each, 2%). Pathologic NC, megacapillaries and microhaemorrhages were significantly associated with immune RP. Logistic regression showed the association between the same parameters and immune RP (odds ratio, p): pathologic NC (5.75; 0.014), megacapillaries (8; 0.039) and microhaemorrhages (8; 0.039). NC exam had Se = 79.3%, Sp = 63.6%, PPV = 85% and NPV = 53.8% in the diagnosis of immune RP. The parameters with the highest specificity and PPV were architectural derangement, reduced capillary density and ramified capillaries, followed by megacapillaries and microhaemorrhages. Conclusions. NC can efficiently discriminate between non-immune RP and immune RP, facilitating the early diagnosis of underlying systemic conditions. The capillaroscopic examination of RP patients identified not only early scleroderma cases, but also a significant number of other connective tissue diseases. [ABSTRACT FROM AUTHOR]

Objective. To assess internal organ involvement in early SSc at presentation.Methods. One hundred and fifteen patients admitted to a tertiary centre because of RP, who did not present any routinely detectable scleroderma-related internal organ involvement, were investigated for ANA and videocapillaroscopy, and underwent history and physical examination to detect symptoms/signs suggestive of SSc. Patients were then subdivided into three groups: (i) early SSc, constituted by patients without clinical manifestations other than RP, but with scleroderma marker autoantibodies and/or typical capillaroscopic abnormalities; (ii) probable SSc, constituted by patients with the same autoantibody and/or capillaroscopic status as early SSc patients, but with any of the following manifestations: digital ulcers/scars, puffy fingers, arthritis, telangiectasia, dysphagia/heartburn, shortness of breath; (iii) UCTD, constituted by patients with a specific (i.e. disease antibody marker) ANA and capillaroscopic findings plus any disease manifestation. All patients were investigated by lung functional study and B-mode echo-Doppler-cardiography. Patients who consented underwent oesophageal manometry.Results. An inverted mitral E : A ratio (i.e. early scleroderma cardiac involvement) and/or a diffusing lung capacity for CO <80% of the predictive value (i.e. early lung involvement) and/or basal low oesophageal sphincter pressure <15 mmHg (i.e. early oesophageal involvement) were detected in 37/51 probable SSc patients (72%), 8/19 early SSc patients (42%) and 12/45 UCTD patients (27%).Conclusion. A scleroderma-related internal organ involvement was detected in patients from each group and, more importantly, was pre-clinical in a number of cases. [ABSTRACT FROM AUTHOR]

Summary: Introduction: The term scleroderma derives from the Greek words skleros, which means hard, and derma, which means skin. It refers to an acquired systemic inflammatory disease of the connective tissue --also known as systemic sclerosis (SSc)-- characterized by excessive collagen deposition in the skin and the internal organs that results in fibrosis. The typical vascular lesion in SSc leads to narrowing of the vessel lumen, intimal thickening, medial hypotrophy, and adventitial fibrosis of small muscular vessels, collagen deposition in the other matrix components of interstice, and the Raynaud phenomenon secondary to these widespread microvascular abnormalities. All these characteristics lead to a connective tissue re-modeling. Discussion: Several clinical studies utilize the American Rheumatology Association''s 1980 classification. However, these diagnostic criteria are unsatisfactory because they fail to take into consideration part of the disease spectrum. Early-phase SSc is characterized by the Raynaud phenomenon (in 90% of all patients), sclerodactyly, and positivity for SSc-specific autoantibodies (antinuclear antibodies, anti-topoisomerase I antibodies, anti-RNA polymerase I and III antibodies, anti-centromere antibodies, anti-fibrillarin antibodies, anti-PM-SCL antibodies).. It is necessary to reduce delays in the diagnosis of SSc. Conclusions: Patients with red-flag positivity (Raynaud phenomenon and digital edema) require Phase I SSc screening, which consists in capillaroscopic assessment of possible microvascular abnormalities. The work-up will then focus on inflammatory indices, renal function tests, and internal organ involvement (echocardiography, high-resolution computed tomography of the chest, diffusing capacity of the lungs for carbon monoxide). [Copyright &y& Elsevier]

Classification criteria for systemic sclerosis evolved over the last three decades, allowing an earlier classification. In the late 2000s, the EULAR Scleroderma Trials and Research Group validated very early and early systemic sclerosis criteria. Raynaud phenomenon, anti-nuclear antibody positivity and the puffy fingers are "Red flags" that must lead to refer the patient to a specialist and benefit from a capillaroscopy and the specific autoantibodies. At the stage of very early systemic sclerosis, pulmonary, cardiac and digestive involvements may be present and must be screened. Herein, we detail very early and early systemic sclerosis criteria, as well as the predictive factors of evolution towards a systemic sclerosis., (Copyright © 2019 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)