Onset Of Raynaud's Phenomenon Research Articles

E31 Diffuse juvenile systemic sclerosis patients show distinct organ involvement, antibody pattern and have significantly more severe disease in the largest jSSc cohort of the world. Results from the juvenile scleroderma inception cohort

Abstract Introduction Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1 000 000 children. In adult patients there are significant differences between the clinical presentation of diffuse and limited subtypes. We reviewed clinical differences in presentation of subtypes in patients in the juvenile systemic scleroderma inception cohort (jSSc). Objectives To study the clinical presentation of jSSc patients with diffuse (djSSc) and limited (ljSSc) subtypes. Methods We reviewed the baseline clinical characteristics of the patients, who were recruited to the jSScC till December 2022. jSScC is a prospective cohort of jSSc patients, who developed the first non-Raynaud’s symptom before the age of 16 years and are under the age of 18 years at the time of inclusion. Results The JSScC included 232 patients, 68% (n = 159) had diffuse subtype. The median age at onset of Raynaud phenomenon was 10.4 years (7.3–12.9) and the median age at the first non-Raynaud symptom was 10.9 years (7.3–13.0). Median disease duration was 2.5 years (1.0–4.6). The female/male ratio was significantly lower in the djSSc subtype (3:1 vs 5:1, P < 0.001). Antibody profile was similar, with the exception of a significantly higher number of anticentromere positive patients in the ljSSc (10% vs 2%, P = 0.02). Decreased FVC < 80% was found in ∼30% and decreased DLCO < 80% was found in around 40% in both subtypes. Abnormal HRCT findings were found in 44% of patients. Pulmonary hypertension assessed by ultrasound was identified in ∼5% in both groups. Gastrointestinal involvement occurred in 43% of djSSc and 36% in ljSSc (P = 0.303). Patients with diffuse subtype had significantly higher modified Rodnan Skin Score (16 vs 4, P = 0.001), more frequently sclerodactyly (85% vs 55%, P < 0.001), a history of digital ulceration (62% vs 30%, P < 0.001), active ulceration (21% vs 8%, P = 0.021), telangiectasia (44% vs 22%, P = 0.002), a decreased Body Mass Index z scores ≤ -2 (20% vs 6%, P = 0.008) and decreased joint range of motion (64% vs 48%, P = 0.022). Patients with ljSSc had significantly higher rate of cardiac involvement (11% vs 3%, P = 0.007). Regarding patient related outcomes djSSc patients had more severe disease with respect to patient reported global disease activity by VAS 0–100 (40 vs 30, P = 0.024), patient reported global disease damage by VAS 0–100 (40 vs 25, P = 0.001), patient reported assessment of ulceration activity by VAS 0–100 (10 vs 0, P = 0.001) and patient reported Raynaud activity by VAS 0–100 (30 vs 15, P = 0.001). Regarding physician related outcomes the physician reported global disease activity by VAS 0–100 (30 vs 20, P = 0.001), physician reported global disease damage by VAS 0–100 (30 vs 20, P = 0.004), and physician assessed ulceration activity by VAS 0–100 (5 vs 0, P = 0.018) were significantly higher in djSSc. Conclusion In the largest jSSc cohort in the world, djSSc patients have a significantly more severe disease. Patients and physician related outcomes were significantly more severe in djSSc group. Interestingly, we found no differences regarding interstitial lung disease, pulmonary hypertension or gastrointestinal involvement, although the number of patients with decreased BMI < -2 z scores was significantly higher in the djSSc patients. Ethics Our work is approved by the IRB of the Ärztekammer Hamburg

Does early systemic sclerosis really exist?

Systemic sclerosis (SSc) is an autoimmune systemic disease of unknown origin, characterized by sclerosis of the skin and internal organs associated with endothelial dysfunction, immune dysregulation, and autoantibody [1]. The most common manifestations are Raynaud's phenomenon (RP), digital ulcers, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), gastrointestinal disorders, scleroderma renal crisis (SRC), heart problems, and musculoskeletal symptoms. Nevertheless, SSc may be a clinically heterogeneous disease that ranges from a milder form to more rapid widespread internal organ involvement with different clinical features at onset. This entity is easy to diagnose in the advanced stages, but the vascular and fibrotic involvement may have started years previously. Prompt detection of the various manifestations benefits prognosis [2], but this is challenging in the early stages of the disease when most of the typical signs and symptoms are absent. Consequently, an SSc diagnosis may be delayed for years following the onset of RP, and even after the appearance of the first non-RP symptom. Thus, treatment and prognosis may be delayed until systemic involvement is evident or even irreversible [3]. Conventional classification criteria are limited in identifying early-stage SSc patients. The ACR/EULAR classification criteria specify that patients with pre-scleroderma, as defined by LeRoy and Koenig, do not have to be classified as definite SSc. However, autoimmunity can precede clinical manifestations by years [4], and efforts have been made to detect this situation before frank disease develops [5]. Nevertheless, diagnosis of early SSc can still be a challenge despite the wealth of published data and available information.

Raynaud's Phenomenon: A Vascular Acrosyndrome That Requires Long-Term Care.

Some 5-10% of the German population are affected by Raynaud's phenomenon (RP). In around 10-20% of cases RP arises from an underlying disease, most commonly a connective tissue disease. This review encompasses the diagnosis and differential diagnosis of RP and examines the efficacy of the currently available pharmaceutical and non-pharmaceutical treatment options. We conducted a selective literature search in PubMed using the search terms "Raynaud's phenomenon", "Raynaud's syndrome," "vasospasm," "vascular acrosyndrome," and "systemic sclerosis," together with a search of the Cochrane Database of Systematic Reviews up to April 2020. Raynaud's phenomenon mainly affects the fingers or toes and is typically triggered by cold or emotional stressors. The most important diagnostic steps are demonstration of a tendency towards digital vasospasm, exclusion of occlusions in the afferent arteries and acral vessels, nail-fold capillaroscopy, and determination of autoantibody status. Tumor screening should be arranged in the presence of B symptoms or first manifestation of RP in old age. The onset of RP in childhood is a rare occurrence and points to a secondary origin. The principal options for treatment are protection against cold and administration of calcium antagonists, which reduces the occurrence of RP by around 20-40 %. The treatment of RP in patients with systemic sclerosis is described in the recommendations of the European League Against Rheumatism (EULAR). At onset or after years of latency, patients with Raynaud phenomenon may have an underlying disease (most commonly a connective tissue disease). Long-term specialist care is necessary for asymptomatic patients with risk factors and for those with clinically manifest symptoms of an underlying condition alike.

Circulating peroxisome proliferator-activated receptor γ is elevated in systemic sclerosis.

IntroductionSystemic sclerosis (SSc) is an autoimmune connective tissue disease with distinguished fibrosis of the skin and internal organs. Vascular damage, immune dysregulation and fibroblasts activation contribute to SSc pathogenesis. Peroxisome proliferator-activated receptor γ (PPAR-γ) can be a link between cell metabolism and fibrosis in SSc due to its anti-fibrotic and immunomodulatory properties.AimTo measure the serum level of PPAR-γ in SSc patients and correlate it with the SSc subtype, hs-CRP, disease duration, vascular and internal organ involvement.Material and methodsTwenty-two SSc patients (15 limited SSc, 7 diffuse SSc) matched with healthy controls were analysed. Clinical and laboratory data were collected including specific antibodies, interstitial lung disease, oesophageal involvement, digital pitting scars, disease duration, Raynaud’s phenomenon (RP) and modified Rodnan skin score (mRSS). PPAR-γ levels were analysed by ELISA. Statistical analysis was performed with χ2, Student’s t-test and Mann-Whitney-U test. Pearson and Spearman correlation analyses were used to establish variables association. The significance threshold was set at p < 0.05.ResultsPPAR-γ concentration was elevated in SSc patients in comparison to controls (p = 0.007) with the highest difference for diffuseSSc (p = 0.004) with significantly elevated mRSS. No association between PPAR-γ levels and hs-CRP, internal organ and vascular involvement, disease duration, autoantibodies and RP onset was found.ConclusionsThe present study revealed elevated serum PPAR-γ in SSc patients, in particular those with a diffuse form, presenting highest mRSS and lowest BMI. Whether circulating PPAR-γ originates from atrophic adipose tissue, reperfused vessels or ischemic tissues needs assessing. Also the biological meaning or effect of elevated serum PPAR-γ requires further studies.

Paradoxical pulmonary event under tocilizumab treatment for systemic sclerosis-associated usual interstitial pneumonia

We read with interest, the results of the faSScinate trial1 suggesting tocilizumab had a good safety profile in the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). SSc-ILD is, however,...

Etiological profile of secondary Raynaud's phenomenon in an internal medicine department. About 121 patients

Raynaud's phenomenon is a reversible episodic vasospastic disorder triggered by cold or emotion. Two types of Raynaud's phenomenon were distinguished: Raynaud's disease and secondary Raynaud's phenomenon. The purpose of this study was to determine the etiologic profile of secondary Raynaud's phenomenon in an internal medicine department. A descriptive retrospective study including patients with secondary Raynaud's phenomenon followed in a tertiary internal medicine department between 2000 and 2013. We included 121 patients. The sex ratio M/F was 0.16. The mean age at the onset of Raynaud's phenomenon was 41.7 years. The average age of patients at the time of the etiologic diagnosis was 47.3 years. The mean delay between Raynaud's phenomenon onset and the first consultation was 41.33 months. Raynaud's phenomenon involved hands in all cases and feet in 16.10% of cases with a typical form in most cases (41.4%). Complications (digital ulcers and scars) were noted in 32.23% of cases. Nail fold capillaroscopy showed scleroderma pattern in 49.52% of patients. Antinuclear antibodies were positive in 88.49% of patients. Interstitial lung disease was reported in 54.04% of cases. Connective tissue diseases were diagnosed in 86.77% of patients. Other secondary Raynaud's phenomenon causes were vasculitis (6.61%), atherosclerosis (1.65%) and medical or professional causes (1.65%). The most frequent one cause systemic sclerosis (n=61, 98%) followed by systemic lupus erythematosus (11.57%) and primary Sjögren syndrome (6.61%). In our study, the Raynaud's phenomenon was most frequently secondary to connective tissue diseases. This may be a selection bias because our department is a third-line unit where patients are often referred for systemic disease suspicion.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Gastrointestinal Involvement in Systemic Sclerosis: An Update.

Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study.

ObjectiveSystemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc.MethodsIn the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis.ResultsOf the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide<80% predicted (65%), DU (34%), cardiac involvement (32%), FVC<80% predicted (31%), increased PAPsys>40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis.ConclusionIn SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to ‘widen' the still very narrow ‘window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.

Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database

ObjectivesTo longitudinally map the onset and identify risk factors for skin sclerosis and digital ulcers (DUs) in patients with systemic sclerosis (SSc) from an early time point after the onset...

SAT0490 Vitamin D Serum Levels Correlate with Bone Mass Values in Postmenopausal Systemic Sclerosis Patients

BackgroundVitamin D is involved in both innate and adaptive immunity and in the regulation of bone turnover1. High prevalence of vitamin D deficiency has been reported in autoimmune disease including...

FRI0481 Microvascular Modifications in Very Early Systemic Sclerosis Patients

BackgroundGreat interest is devoted today to patients with very early diagnosis of systemic sclerosis (VEDOSS), characterized by the presence of Raynaud phenomenon (RP), puffy fingers, Antinuclear antibodies (ANA), plus the...

From Raynaud's Phenomenon to Very Early Diagnosis of Systemic Sclerosis- The VEDOSS approach.

Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that is very difficult to diagnose in the early phase, because of the low sensitivity of the classification criteria currently used to identify patients without skin involvement, with an important delay on the therapy that is often started when internal organ involvement has already irreversible. The biggest challenge in the fight against SSc is to detect valid predictors of disease so as to treat patients since the earliest stages of disease. Raynaud's phenomenon (RP), antinuclear antibodies (ANA) positivity, and puffy fingers have been recently indicated as the"red flags", the main elements to suspect SSc and then to perform further tests to confirm the diagnosis in particular nailfold video capillaroscopy and evaluation of specific disease antibodies (anticentromere and anti-topoisomerase I). Particularly, RP is the earliest, even if aspecific sign of SSc, and more and more attention should be paid to its early identification in order to reduce the diagnostic delay. Besides, the time gap between the onset of RP and the diagnosis should be considered as a "window of opportunity" for SSc patients, through which the physician can act with effective drugs able to block or at least slow the progression of the disease.

Aging and Scleroderma

Although rare in the general population, geriatricians and general practitioners should be aware of the clinical manifestations of systemic sclerosis (SSc) as it can present at an older age and may have unique patterns of organ involvement. Furthermore, recent important advances in treatment have improved survival among SSc patients resulting in a distinct population aging with SSc. Symptoms of SSc overlap frequently with those of the aging population (such as gastroesophageal reflux disease and cold sensitivity), however, specific features, such as the new onset of Raynaud phenomenon or the new onset of swelling of the hands and feet, should prompt an evaluation for SSc. Elderly-onset SSc patients may have higher rates of specific organ manifestations (such as pulmonary hypertension) but can present with the whole spectrum of SSc. The diagnosis and care of elderly patients with SSc present unique and challenging issues best approached by a multidisciplinary team focusing on each SSc-specific organ system.

PTPN22 R620W may affect age at onset and survival of SSC patients

Background and objectivesThe PTPN22 SNP rs2476601 (1858C→T, R620W) shows association with several autoimmune diseases including SSc. Here we analyse data from SSc patients concerning the time-dependent development of the disease...

Atypical clinical presentation of a subset of patients with anti-RNA polymerase III - non-scleroderma cases associated with dominant RNA polymerase i reactivity and nucleolar staining

IntroductionAnti-RNA polymerase III (RNAP III) antibodies are highly specific markers of scleroderma (systemic sclerosis, SSc) and associated with a rapidly progressing subset of SSc. The clinical presentation of anti-RNAP III positive patients, onset of Raynaud's phenomenon (RP) and SSc in unselected patients in a rheumatology clinic were evaluated.MethodsAutoantibodies in sera from 1,966 unselected patients (including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) in a rheumatology clinic were screened by radioimmunoprecipitation. Anti-RNAP III positive sera were also tested by immunofluorescence antinuclear antibodies and anti-RNAP III ELISA. Medical records of anti-RNAP III positive patients were reviewed.ResultsAmong 21 anti-RNAP III positive patients, 16 met the American College of Rheumatology (ACR) SSc criteria at the initial visit but 5 did not; diagnoses were vasculitis, early polyarthritis, renal failure with RP, interstitial lung disease, and Sjögren's syndrome. The first two patients developed rapidly progressive diffuse SSc. An additional case presented with diffuse scleroderma without RP and RP developed two years later. Anti-RNAP III antibodies in these 6 cases of atypical clinical presentation were compared with those in 15 cases of typical (SSc with RP) cases. Anti-RNAP III levels by ELISA were lower in the former group (P = 0.04 by Mann-Whitney test) and 3 of 6 were negative versus only 1 of 15 negative in the latter (P < 0.05 by Fisher's exact test). Three cases of non-SSc anti-RNAP III positive patients had predominant reactivity with RNAP I with weak RNAP III reactivity and had a strong nucleolar staining. Three anti-RNAP III patients, who did not have RP at the initial visit, developed RP months later. Scleroderma developed prior to RP in 5 out of 16 (31%) in the anti-RNAP III group, but this was rare in patients with other autoantibodies. The interval between the onset of RP to scleroderma was short in anti-RNAP III positive patients.ConclusionsAnti-RNAP III antibodies are highly specific for SSc; however, a subset of anti-RNAP III positive patients do not present as typical SSc. The interval between RP and scleroderma in this group is short, and 31% of patients developed scleroderma prior to RP in this group. Anti-RNAP III positive patients may not present as typical SSc and detecting anti-RNAP III may have predictive value.

Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors

Digital ulcers (DU) are a major complication in the course of systemic sclerosis (SSc). In recent years, efficacious, but expensive therapies (e.g. iloprost, sildenafil, bosentan) have been shown to improve healing or to reduce the recurrence of DU. For optimal management it would be useful to identify the risk factors for DU. Such statistical analyses have been rare because they require a high number of patients. To identify potential risk factors for DU in patients with SSc. We used the registry of the German Network for Systemic Scleroderma and evaluated the data of 1881 patients included by August 2007. We assessed potential risk factors for DU by comparing patients with (24.1%) and without active DU at time of entry (75.9%). Multivariate analysis revealed that male sex, presence of pulmonary arterial hypertension (PAH), involvement of the oesophagus, diffuse skin sclerosis (only when PAH was present), anti-Scl70 antibodies, young age at onset of Raynaud's phenomenon (RP), and elevated erythrocyte sedimentation rate (ESR) significantly impacted on the appearance of DU. Certain combinations increased the patients' probability of presenting with DU, with the highest probability (88%) for male patients with early onset of RP, ESR>30 mm h(-1), anti-Scl70 antibodies and PAH. Patients with DU developed RP, skin sclerosis and organ involvement approximately 2-3 years earlier than patients without DU. The results reveal possible risk factors for the occurrence of DU in SSc. As DU are prone to local complications, prophylactic vasoactive treatment for patients presenting with these factors may be justified.

Long‐term outcome of primary Raynaud's phenomenon and its conversion to connective tissue disease: a 12‐year retrospective patient analysis

Objectives: To determine the frequency of development of connective tissue disease (CTD) in patients considered to have idiopathic Raynaud's phenomenon (RP) >10 years.Patients and methods: Based on initial evaluation, 113 women and 29 men were divided into either ‘primary RP’ (n=109) or ‘possible secondary RP’ (n=33) groups and were re‐evaluated after a median follow‐up period of 12.4 years.Results: Overall 20 patients (14.1%) progressed to a definite CTD; 10 from ‘primary RP’ (9.2%) and 10 from ‘possible secondary RP’ (30.3%). Initial presence of antinuclear antibodies, thickening of fingers, higher age at onset of RP, and female sex seemed to be important determinants for a possible transition to a CTD.Conclusion: In RP‐patients, who are at risk of development of a CTD, serial clinical and laboratory controls are warranted for the decision to initiate therapy early.

No Evidence of an Association between Helicobacter pylori Infection and Raynaud Phenomenon

Background: Raynaud phenomenon (RP) is a vasospastic condition that manifests itself as cold-induced ischemic attacks of the fingers with skin color changes. It may be classified as primary (PRP) or secondary (SRP), if associated to other diseases, mainly connective-tissue diseases. Recently, the association between PRP and Helicobacter pylori infection has been reported. The aims of this study were to evaluate the prevalence of gastric H. pylori infection in a large group of patients affected by PRP and SRP and to assess whether it was more evident in patients with more recent onset of RP. Methods: Ninety-eight consecutive patients (93 F and 5 M), referring to our videocapillaroscopic service for the diagnosis of vascular and connective-tissue diseases, were evaluated. Forty-nine of them were affected by PRP and 49 by SRP. Patients were classified as having PRP on the basis of normal serological and immunological findings, normal videocapillaroscopic examination and exclusion of other conditions inducing RP. H. pylori infection was diagnosed by 13C-urea breath test (UBT). Two groups of 49 age-and sex-matched controls, respectively, were also evaluated. Results: Patients with SRP resulted significantly older than those with PRP (P < 0.006). UBT was found positive in 22/49 patients with PRP (45%) and in 29/49 patients with SRP (59%). The positivity of the respective control groups was 36% and 53% (P = NS). There was no higher prevalence of H. pylori infection in patients with RP lasting for less than 4 years. Conclusions: The results do not confirm the previously reported high prevalence of H. pylori infection in patients with PRP. A high association was not even found between the presence of the microorganism and SRP. There was no difference in the prevalence of H. pylori infection among the subgroups with more recent onset of both PRP and SRP.

Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases.

To summarize the current literature on the frequency, rates, types, and outcome predictors of secondary diseases that develop in patients with primary Raynaud phenomenon. A structured MEDLINE literature search with the MeSH heading "Raynaud's disease," which was crossed with (1) systemic sclerosis, (2) prognosis, (3) prospective studies, (4) follow-up studies, and (5) retrospective studies, was used to identify 910 articles for possible inclusion. Articles that identified patients with primary Raynaud phenomenon who were followed up and re-evaluated at the end of the study, and which used published classification criteria to assess the presence or absence of secondary disease were included. Patient-years of Raynaud disease, patient-years of follow-up, and rates and predictors of transition to secondary disease were calculated from the articles selected. The summary odds ratio and positive predictive value for evaluation criteria at entry were calculated from 2 x 2 tables generated for each variable. Ten articles identified a total of 639 patients with primary Raynaud phenomenon who were followed up for 2531 patient-years. Eighty-one patients (12.6%) developed a secondary disorder, 80 of which were connective-tissue diseases. Transitions occurred at a mean rate of 3.2 per 100 patient-years of observation. The mean time to develop a secondary disorder was 2.8 years from study entry and 10.4 years from the onset of Raynaud phenomenon. At entry, the best predictor of transition was an abnormal nailfold capillary pattern (positive predictive value, 47%). Antinuclear antibodies in these patients had a positive predictive value of only 30%. Although a variety of clinical and serological abnormalities can be found in patients with primary Raynaud phenomenon, only a small percentage of them develop a connective-tissue disease.

Early Detection of Connective Tissue Disease in Patients with Raynaud’s Phenomenon

Connective tissue diseases such as scleroderma frequently show an insidious onset. In their early stages a diagnosis of a specific CTD is hard to make, and the disorder may then be designated as "undifferentiated CTD." Raynaud's phenomenon (RP) is the first symptom in many cases and may precede the disease for many years. RP, however, is a common finding in the population, especially in young females. Thus, only a minority of patients with RP will develop a CTD. For reason of prognosis and early diagnosis and to get more insight in the initial pathophysiological processes, it is important to know which patients with RP will develop or are already evolving into a CTD. Patients referred to the clinician because of RP frequently (24-40%) show signs or symptoms of CTD, especially of scleroderma. Pulmonary function disturbances and esophageal hypomotility are asymptomatic in many cases, and should be sought for with sensitive methods. How can we distinguish patients with truly primary RP from those who will evolve into CTD (and thus should be screened for CTD and be followed)? The presence of antinuclear antibodies (ANA) and abnormalities at nailfold capillary microscopy (NCM) have proven to be early indicators of evolution into CTD, especially scleroderma and related disorders. The antigenic specificities of ANA indicate which syndrome the patient will develop, e.g., anti-CENP-B indicates the CREST-syndrome and anti-topoisomerase I diffuse scleroderma. Other factors of prognostic significance in patients with RP are age at onset and severity of RP: older age at onset and a highly severe RP represent risk factors for CTD. What do we know about the evolution of RP into CTD? Follow-up studies on patients referred because of RP have shown that some 15-20% of these patients have an insidious progress to limited cutaneous scleroderma including CREST. Risk factors have already been mentioned. From a pathophysiological point of view, studies in patients with early scleroderma have proved that microvascular changes are crucial in the disease process. These changes, demonstrated morphologically by NCM and functionally, e.g., by pulmonary function studies, are also reflected in increased levels of VIII antigen and in in vivo platelet activation. Both of these phenomena probably result from endothelial damage. There is increasing evidence that T-cells and their products are involved in vascular damage in early scleroderma. Future research should be directed to the elucidation of the target antigens for these T-cells.