Contribution to the peripheral vasculopathy and endothelial cell dysfunction by CXCL4 in Systemic Sclerosis.

BACKGROUND: CXCL4, a chemokine with anti-angiogenic property, is involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). OBJECTIVE: To investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, and the effect of CXCL4 on endothelial cell dysfunction and the potential signaling. METHODS: We measured the plasma CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls (HCs). Then, CXCL4 concentrations were correlated with clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort. Moreover, we studied the anti-angiogenic effects of CXCL4 and the underlying downstream signaling in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: Circulating CXCL4 levels were 103.62 % higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, which were confirmed in two independent cohorts. CXCL4 levels were associated with digital ulcers (DU) and nailfold videocapillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were inhibited by CXCL4 or SSc derived plasma, which reversed by CXCL4 neutralizing antibody, but failed by CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor-1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -ß or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs. CONCLUSIONS: CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.

Clinical features and outcomes of the patients with anti-glycyl tRNA synthetase syndrome.

OBJECTIVE: To analyze the clinical features and outcomes of the patients with anti-glycyl tRNA synthetase (anti-EJ) syndrome in a large Chinese cohort. METHODS: The medical records, imaging, and serologic data of patients with anti-EJ antibodies from the China-Japan Friendship Hospital database were retrospectively investigated. Anti-EJ antibodies were identified using immunoblot assay. Long-term follow-up was conducted. RESULTS: Anti-EJ antibodies were present in 46 (19.7%) of the 234 patients with antisynthetase syndrome (ASS), preceded by anti-Jo-1 and anti-PL-7 antibodies. The mean age of disease onset was 51.2 ± 15.9 years, and 69.6% of these patients were female. The most prevalent clinical feature was interstitial lung disease (ILD) (96.7%), which was also the most common initial manifestation, followed by fever (60.9%), mechanic's hands (56.5%), muscle involvement (50%), and Raynaud phenomenon (8.7%). Ten (21.7%) patients developed rapidly progressive ILD (RP-ILD). Organizing pneumonia (OP) on high-resolution computed tomography (HRCT) scans (OR = 37.5, p = 0.006) and a higher C-reactive protein-to-albumin ratio (CAR) (OR = 28.3, p = 0.01) were independent risk factors for RP-ILD. Muscular pathological features were heterogeneous. Concomitant infection was noted in 63.0% of the patients during the disease course. Hypoalbuminemia (OR = 0.759, p = 0.002) was an independent risk factor for concomitant infection. Patients responded well to glucocorticoid therapy. The 5- and 10-year survival rates of the patients with anti-EJ were 97.8% and 88%, respectively. CONCLUSION: Anti-EJ syndrome was found to be a relatively common ASS subtype, with a favorable outcome. A notable proportion of the patients experienced RP-ILD, which was prone to OP on HRCT and a higher CAR, and needed aggressive management. Key Points • ILD was the most common initial manifestation of anti-glycyl tRNA synthetase syndrome. • RP-ILD was notable in anti-EJ positive patients. • Anti-EJ positive patients possessed a favorable long-term prognosis, but easily relapsed.

Nailfold Capillaroscopy Characteristics of Antisynthetase Syndrome and Possible Clinical Associations: Results of a Multicenter International Study.

OBJECTIVE: To describe nailfold videocapillaroscopy (NVC) features of patients with antisynthetase syndrome (AS) and to investigate possible correlations with clinical and serological features of the disease. METHODS: We retrospectively analyzed NVC images of 190 patients with AS [females/males 3.63, mean age 49.7 ± 12.8 yrs, median disease duration 53.7 mos (interquartile range 82), 133 anti-Jo1 and 57 non-anti-Jo1-positive patients]. For each patient, we examined number of capillaries, giant capillaries, microhemorrhages, avascular areas, ramified capillaries, and the presence of systemic sclerosis (SSc)-like pattern. Finally, we correlated NVC features with clinical and serological findings of patients with AS. Concomitantly, a historical cohort of 75 patients with antinuclear antibody-negative primary Raynaud phenomenon (RP) and longterm followup was used as a control group (female/male ratio 4.13/1, mean age 53.9 ± 17.6 yrs) for NVC measures. RESULTS: NVC abnormalities were observed in 62.1% of AS patients compared with 29.3% of primary RP group (p < 0.001). An SSc-like pattern was detected in 67 patients (35.3%) and it was associated with anti-Jo1 antibodies (p = 0.002) and also with a longer disease duration (p = 0.004). Interestingly, there was no significant correlation between the presence of SSc-like pattern and RP, and only 47% of patients with SSc-like pattern had RP. CONCLUSION: NVC abnormalities are commonly observed in AS, independently from the occurrence of RP. The presence of an SSc-like pattern could allow identification of a more defined AS subtype, and prospective studies could confirm the association with clinical and serological features of AS.

Case of primary Sjogren's syndrome preceded by dystonia.

There are only six cases in literature that describe development of dystonia with Sjogren's syndrome (SS). We describe a case of a 43-year-old woman who presented with symptoms including movement disorder, sensory neurogenic bladder, sensory loss and neuropathic pain, migraine like headaches, musculoskeletal pain, Raynaud's phenomenon and dysautonomia. Symptoms started in 2000, with weakness that progressed to dystonia in 2003. Diagnostic work-up was inconclusive with negative inflammatory serologies, cerebrospinal fluid and MRI for many years. After patient developed sicca syndrome with dry eyes and mouth in 2009, her rheumatoid factor titre was elevated (550 IU/mL), erythrocyte sedimentation rate, anti-Sjogrens syndrome-related antigen A (anti-Ro/SSA) and anti-SSB/La: anti-Sjogrens syndrome-related antigen B (anti-La/SSB) became positive. Lip biopsy confirmed diagnosis of SS. She was diagnosed with primary SS with neurological involvement. Her symptoms responded well to intravenous methylprednisolone. Symptoms stabilised with trials of immune-suppressive therapy. This is a case that demonstrates the delay of diagnosing SS with preceding unique neurological association.

Prevalence and spectrum of symptomatic pulmonary involvement in primary Sjögren's syndrome.

OBJECTIVES: The present cross-sectional study aimed to estimate the prevalence of chronic respiratory symptoms in primary Sjögren's syndrome (pSS) and define the clinical, functional and imaging characteristics of symptomatic pulmonary disease in pSS. METHODS: Four hundred and fourteen consecutive pSS patients were interviewed for the presence of chronic respiratory complaints (cough and/or dyspnea). Symptomatic pSS patients without respiratory or other comorbidities underwent further investigation with clinical evaluation and assessment with pulmonary functional testing (PFTs) and chest high resolution CT (hrCT) on inspiratory and expiratory phase. Comparison of clinical and laboratory features between symptomatic and asymptomatic pSS patients was also performed. RESULTS: Prevalence of chronic respiratory symptoms in pSS was estimated at 21.5% (89/414). Symptoms were attributed to underlying comorbidities in approximately one third of cases (30/89). Thirty nine of the remaining 59 patients were finally assessed with PFTs and hrCT. Small airway disease was diagnosed in 20 individuals with an obstructive pattern in PFTs and/or compatible radiological signs. Seven patients were diagnosed with interstitial lung disease, while in the remaining 12 pSS patients, with normal PFTs and hrCT, symptoms were attributed to xerotrachea. Raynaud's phenomenon occurred more frequently in symptomatic than asymptomatic patients (p=0.024). CONCLUSIONS: Approximately one fifth of a large cohort of pSS patients presented chronic respiratory symptoms. Small airway disease was the most commonly recognized pulmonary disorder among symptomatic pSS patients, followed by xerotrachea and interstitial lung disease.

Systemic lupus erythematosus and systemic sclerosis: All roads lead to platelets.

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are two phenotypically distincts inflammatory systemic diseases. However, SLE and SSc share pathogenic features such as interferon signature, loss of tolerance against self-nuclear antigens and increased tissue damage such as fibrosis. Recently, platelets have emerged as a major actor in immunity including auto-immune diseases. Both SLE and SSc are characterized by strong platelet system activation, which is likely to be both the witness and culprit in their pathogenesis. Platelet activation pathways are multiple and sometimes redundant. They include immune complexes, Toll-like receptors activation, antiphospholipid antibodies and ischemia-reperfusion associated with Raynaud phenomenon. Once activated, platelet promote immune dysregulation by priming interferon production by immune cells, providing CD40L supporting B lymphocyte functions and providing a source of autoantigens. Platelets are actively implicated in SLE and SSc end-organ damage such as cardiovascular and renal disease and in the promotion of tissue fibrosis. Finally, after understanding the main pathogenic implications of platelet activation in both diseases, we discuss potential therapeutics targeting platelets.

An Autoimmune Basis for Raynaud's Phenomenon: Murine Model and Human Disease.

OBJECTIVE: Raynaud's phenomenon (RP) is common in anti-RNP-positive patients with rheumatic diseases but is not itself known to be caused by autoimmunity. The aim of this study was to assess autoantibodies that could mediate this process. METHODS: Antibodies derived from patient sera and from murine models of anti-RNP autoimmunity were screened for the ability to induce RP-like tissue ischemia and endothelial cell apoptosis in murine models and in vitro systems. RESULTS: RNP-positive sera from RP patients and murine sera from RNP-positive B cell adoptive transfer recipients induced RP-like tissue ischemia and endothelial cell apoptosis. Proteomic analysis identified cytokeratin 10 (K10) as a candidate autoantigen in RP. Monoclonal anti-K10 antibodies reproduced patterns of ischemic tissue loss and endothelial cell apoptosis; K10 knockout or depletion of anti-K10 activity in serum was protective. Cold exposure enhanced K10 expression and in vivo tissue loss. CONCLUSION: Anti-K10 antibodies are sufficient to mediate RP-like ischemia in murine models and are implicated in the pathogenesis of RP in patients with anti-RNP autoimmunity.

Antiphosphatidylserine/prothrombin (aPS/PT) antibodies are associated with Raynaud phenomenon and migraine in primary thrombotic antiphospholipid syndrome.

Objectives Antibodies to phosphatidylserine/prothrombin complex (aPS/PT) detectable in sera of some patients with antiphospholipid syndrome (APS) have been shown to correlate with thrombosis. However, associations of aPS/PT antibodies with APS related disorders remain unclear. Aim To evaluate whether there are any associations between aPS/PT antibodies and Raynaud phenomenon, migraine and/or valvular lesions in primary thrombotic APS (PAPS). Methods We enrolled 67 consecutive patients (56 women) with thrombotic PAPS (VTE in 80.6%), aged 46.2 ± 13.5 years. The exclusion criteria were: acute coronary syndromes or stroke within preceding 6 months, cancer, severe comorbidities and pregnancy. The IgG and IgM aPS/PT antibodies were determined by ELISA with the cut-off of 30 units. We recorded Raynaud phenomenon, migraine and valvular lesions. Results Positive IgM or/and IgG aPS/PT antibodies were observed in 29 patients (43.3%), with a higher prevalence of IgM antibodies ( n = 27, 40.3%) compared with IgG isotype ( n = 12, 17.9%, p = 0.014). aPS/PT antibodies were observed most commonly in patients with triple aPL ( n = 12, 85.7%) compared with those with double ( n = 5, 35.7%) or single aPL antibodies (n = 12, 30.8%, p = 0.03), with no association with demographics, the ANA titre, the type of thrombotic events or medications. Raynaud phenomenon, migraine and valvular lesions were observed in 15% ( n = 10), 30% ( n = 20) and 18% ( n = 12) of the patients, respectively. Raynaud phenomenon and migraine, but not valvular lesions, were markedly more frequent in PAPS patients presenting with positive aPS/PT antibodies ( n = 10, 34.5% vs. n = 0, 0%; p = 0.0001). Conclusions In PAPS patients aPS/PT antibodies are related to the occurrence of both Raynaud phenomenon and migraine.

Anti-CENP-B and anti-TOPO-1-containing sera from systemic sclerosis-related diseases with Raynaud's phenomenon induce vascular endothelial cell senescence not via classical p53-p21 pathway.

Raynaud's phenomenon (RP) is the earliest and most common clinical manifestation in patients with systemic sclerosis (SSc) and its related diseases containing anti-TOPO-1 and/or anti-CENP-B autoantibodies in the sera. However, the cause-effect relationship between the two autoantibodies and RP remains elucidation. Sera containing anti-CENP-B and anti-TOPO-1 autoantibodies were obtained from SSc-related diseases manifesting RP. The polyclonal auto-antibodies were purified from pooled sera by affinity chromatography. Mouse monoclonal anti-CENP-B and anti-TOPO-1 were purchased. Calf pulmonary arterial endothelial cells (CPAE) were incubated with 40% patient sera, purified polyclonal antibodies or mouse monoclonal antibodies for 1-6 days. The vascular endothelial biomarkers von Willebrand factor (vWF), thrombomodulin (CD141) and 6-keto-prostaglandin F1α (6-keto-PGF1α), cell viability marker ATP, and cell necrosis/lysis marker LDH in the culture supernatants were measured by ELISA. The cell senescence biomarker ß-galactosidase and telomere content in the cells were stained by the respective kit. The classical p53-p21 senescence pathway was detected by Western blot. We found that 40% anti-CENP-B or anti-TOPO-1-containing sera without heat-inactivation and mouse monoclonal antibodies suppressed 6-keto-PGF1α production, increased ß-galactosidase, and decreased relative telomere content. The cell senescence effects were proved not via p53-p21 pathway. The pathognomonic anti-CENP-B and anti-TOPO-1 autoantibodies in SSc-related diseases accelerate vascular endothelial cell senescence and functional impairment inducing RP. The real signaling pathway for autoantibody-induced cell senescence remains exploration.

Chronic inflammation predicts long-term mortality in patients with Raynaud's phenomenon.

BACKGROUND: Subclinical chronic inflammation could be the driving force behind the recently revealed association between abnormal nailfold capillaries as well as autoantibodies and long-term mortality in patients with incipient Raynaud's phenomenon. Whether laboratory markers that reflect a chronic inflammatory process are directly related to mortality in Raynaud's phenomenon is not known. METHODS: In total, 2958 patients with incipient Raynaud's phenomenon without previously known connective tissue disease (CTD) were enrolled. At their initial presentation, laboratory tests for C-reactive protein (CRP), leucocytes, fibrinogen and the haemoglobin concentration were obtained. In addition, nailfold capillaries and antinuclear antibodies (ANA) were assessed. Patients' mortality was recorded through a median follow-up period of 9.3 years. RESULTS: Baseline CRP, fibrinogen and haemoglobin concentration were associated with long-term mortality in an individual analysis of patients with incipient Raynaud's phenomenon. In a multivariable model including patients' age, nailfold capillaries and ANA, a low haemoglobin concentration remained independently related to future mortality. Amongst potential predictors for mortality in patients with Raynaud's phenomenon, a low haemoglobin concentration was most strongly related to patients' mortality risk. CONCLUSION: In Raynaud's phenomenon, laboratory markers that can be attributed to a chronic inflammatory state independently yield prognostic information in addition to the presence of abnormal nailfold capillaries and ANA. Amongst all prognostic markers, the haemoglobin concentration is most strongly related to patients' mortality in Raynaud's phenomenon.

Outcomes, rates and predictors of transition of isolated Raynaud's phenomenon: a systematic review and meta-analysis.

QUESTIONS: Published studies lack clear indicators of risk and predictors of transition from Raynaud's phenomenon (Rp) to connective tissue diseases (CTDs). Therefore, we aimed to study the outcomes, rates and predictors of transition to CTDs in patients with Rp. METHODS: A sensitive search was developed in Medline and Embase. Observational studies reporting incidence and risk factors of transition from Rp to a CTD were analysed by two independent reviewers. The main outcome was the rate of transition to a CTD; the secondary outcome was the evaluation of predictors. RESULTS: Of 856 articles captured, 7 selected studies met the inclusion criteria. A total of 4051 patients with primary Rp (pRp) and 1220 transitions to overt CTDs were recorded. The mean incidence rate of transition from pRp to a CTD was 2.65/100 person-years (standard error [SE] 1.2, 95% confidence interval [CI] 0.44-5.73). A total of 657 patients with suspected secondary Rp (ssRp) had antinuclear antibodies (ANAs) and/or capillary abnormalities; 188 transitions to CTDs were recorded, the mean incidence rate of transition from ssRp to CTD was 11.01/100 person-years (SE 4.0, 95% CI 0.11-22.12), and 135 transitions to systemic sclerosis (SSc), giving a mean incidence rate of transition from ssRp to SSc of 5.7/100 person-years (SE 2.19, 95% CI 1.02-13.19). With respect to patients with pRp, having ANAs without capillary abnormalities was associated with a risk for developing a CTD (pooled relative risks [RR] 7.63, 95% CI 2.87-20.29), whereas capillary abnormalities without ANAs resulted in a weaker risk of CTD transition (RR 5.53, 95% CI 1.45-21.06). The coexistence of ANAs and abnormal capillaroscopy significantly increased the risk of transition to CTD (RR 16.96, 95% CI 6.61-43.55). CONCLUSIONS: A low incidence rate of transition from pRp to overt CTD was found. In spite of a possible study selection bias, ssRp appears to have a strong risk of transition to a CTD when there is concomitant presence of ANAs and abnormal capillaroscopy.

Very early and early systemic sclerosis in the Spanish scleroderma Registry (RESCLE) cohort.

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.

Tendonitis and Tendon Rupture After Treatment With Rituximab: A Case Series.

CLINICAL DATA: Rituximab is a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody used to treat cancer and autoimmune conditions. Side effects of rituximab include fever, rash, cytopenia and hypotension, back pain, arthralgia, and myalgia. Here, we report on 3 patients who developed moderate to severe tendonitis after the second infusion of rituximab. THERAPEUTIC CHALLENGE: We report 3 patients who developed tendonitis after the second infusion of rituximab. These patients were undergoing treatment for connective tissue diseases. All 3 patients received 2 rituximab infusions, 2 weeks apart. The 3 cases developed clinical tendonitis that was confirmed by magnetic resonance imaging in 2 cases. INTERPRETATION: This is the first case series reporting new onset tendonitis in patients with connective tissue diseases after rituximab therapy. All 3 cases developed tendonitis 1 week after receiving the second dose of rituximab. Clinical features of tendonitis resolved 3-4 months in all cases. The underlying pathogenic mechanism by which rituximab causes tendonitis is not clear, but tendonitis and tendon rupture have been reported after using other medications such as quinolones. The tendon damage was progressive leading to tendon rupture in 1 patient, highlighting the importance of early recognition. It is plausible that there is a cause-effect relation between tendonitis and administration of rituximab in our 3 cases, since none of these cases had previous history of tendonitis; however, more data are needed to confirm this observation.

Chronic granulomatous disease as a risk factor for cutaneous lupus in childhood.

Chronic granulomatous disease (CGD) is a primaryimmunodeficiency disorder that affects the phagocyticcells of the innate immune system. It is characterizedby recurrent or persistent infections with granulomaformation. Lupus-like lesions have been reported incarriers of CGD and less frequently, in patients withCGD. Immunological study in these patients areusually negative. We describe the case of an 8-yearoldboy with CGD who developed chronic and acutecutaneous lupus erythematous with angular cheilitis,oral ulcers, Raynaud phenomenon, and positiveserologies for antinuclear, anticentromere, and anti-Saccharomyces cerevisiae antibodies.

Mixed connective tissue disease-enigma variations?

In 1972, Sharp et al. described a new autoimmune rheumatic disease that they called MCTD, characterized by overlapping features of SSc, SLE, PM/DM, high levels of anti-U1snRNP and low steroid requirements with good prognosis. MCTD was proposed as a distinct disease. However, soon after the original description, questions about the existence of such a syndrome as well as disputes over the features initially described began to surface. The conundrum of whether MCTD is a distinct disease entity remains controversial. We undertook a literature review, focusing on the articles reporting new data about MCTD published in the last decade, to determine whether any new observations help to answer the conundrum of MCTD. After reviewing recent data, we question whether the term MCTD is appropriately retained, preferring to use the term undifferentiated autoimmune rheumatic disease.

Aberrant immune response with consequent vascular and connective tissue remodeling - causal to scleroderma and associated syndromes such as Raynaud phenomenon and other fibrosing syndromes?

PURPOSE OF REVIEW: Scleroderma and other autoimmune-induced connective tissue diseases are characterized by dysfunctions in the immune system, connective tissue and the vasculature. We are focusing on systemic sclerosis (SSc)-associated pulmonary hypertension, which remains a leading cause of death with only a 50-60% of 2-year survival rate. RECENT FINDINGS: Much research and translational efforts have been directed at understanding the immune response that causes SSc and the networked interactions with the connective tissue and the vasculature. One of the unexpected findings was that in some cases the pathogenic immune response in SSc resembles the immune response to helminth parasites. During coevolution, means of communication were developed which protect the host from over-colonization with parasites and which protect the parasite from excessive host responses. One explanation for the geographically clustered occurrence of SSc is that environmental exposures combined with genetic predisposition turn on triggers of molecular and cellular modules that were once initiated by parasites. SUMMARY: Future research is needed to further understand the parasite-derived signals that dampen the host response. Therapeutic helminth infection or treatment with parasite-derived response modifiers could be promising new management tools for autoimmune connective tissue diseases.

A New Way of Thinking about Systemic Sclerosis: The Opportunity for a Very Early Diagnosis.

Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that it is extremely difficult to diagnose in the early phase, resulting in a critical delay in therapy which is often begun when internal organ involvement is already irreversible. The ACR or LeRoy criteria have a low sensitivity for the early phases; these criteria were replaced by the ACR/EULAR 2013 criteria which improved the disease classification. Therefore, the SSc diagnosis may be delayed for several years after the onset of Raynaud's phenomenon (RP) and even after the onset of the first non-RP symptom. RP, antinuclear antibodies (ANA) positivity, and puffy fingers were recently indicated as "red flags" (by the VEDOSS project)--that is, the main elements for suspicion of SSc in the very early phase of the disease. Confirming the diagnosis requires further tests, particularly nailfold videocapillaroscopy and evaluation of specific disease antibodies (anti-centromere and anti-topoisomerase I). In this way, the VEDOSS project identified patients in the very early phase of disease enabling a "window of opportunity" whereby the physician can act with effective drugs to block or at least slow the progression of the disease. The principal challenge in the fight against SSc is to detect valid predictors of disease evolution in order to treat patients in the early stage of disease. While waiting to find valid predictors, a close follow-up of the patients with the VEDOSS red flags is essential, as is a close collaboration between rheumatologists and general practitioners in order to identify all potential SSc patients as soon as possible.