Nailfold Abnormalities Research Articles

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

ObjectiveThe 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of...

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

ObjectiveThe 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.MethodsUsing consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma‐like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc.ResultsIt was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc‐related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus‐based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.ConclusionThe ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

OP0034 Performance of the New EULAR/ACR Classification Criteria for Systemic Sclerosis in Clinical Practice

BackgroundThe preliminary classification criteria for systemic sclerosis (SSc) developed in 1980 lack sensitivity for early and mild SSc patients. Therefore, the ACR-EULAR committee developed new classification criteria for SSc (1)....

The pathogenesis, diagnosis and treatment of Raynaud phenomenon

The past 10 years have seen the publication of results from several multicentre clinical trials in primary and systemic sclerosis (SSc)-related Raynaud phenomenon. The publication of these studies has occurred as a result of new insights into the pathogenesis of Raynaud phenomenon, which are directing new treatment approaches, and increased international collaboration between clinicians and scientists. Although the pathogenesis of Raynaud phenomenon is complex, abnormalities of the blood vessel wall, of neural control mechanisms and of intravascular (circulating) factors are known to interact and contribute. Key players relevant in drug development include nitric oxide, endothelin-1, alpha adrenergic receptor activation, abnormal signal transduction in vascular smooth muscle, oxidative stress and platelet activation. The main advances in diagnosis have been a clearer understanding of autoantibodies and of abnormal nailfold capillary patterns as independent predictors of SSc, and widespread use and increased availability of capillaroscopy. The ultimate aim is to translate the advances made in the pathophysiology and early diagnosis into development of treatments to prevent and reverse digital vascular dysfunction and injury. This Review provides an update of the pathogenesis, diagnosis and treatment of Raynaud phenomenon. Current and future treatment approaches are discussed, and some key unanswered questions are highlighted.

A Novel Dermato-Pulmonary Syndrome Associated With MDA-5 Antibodies

Melanoma differentiation-associated protein 5 (MDA-5) is a novel autoantibody frequently characterized by interstitial lung disease and a distinct cutaneous phenotype with palmar papules, ulceration, and rash. Virtually all patients have underlying dermatomyositis, but many lack the characteristic clinical myopathy associated with it. In the setting of amyopathic disease, the absence of clinically available biomarkers or clear pathologic diagnosis can complicate effective prognostic and therapeutic intervention. Until recently the presence of MDA-5 antibody associated dermato-pulmonary syndrome was described only in Asian populations. We present 2 cases of MDA-5-associated dermato-pulmonary syndrome and provide a comprehensive review of available literature.

Interreader Reliability in Assessment of Nailfold Capillary Abnormalities by Beginners: Pilot Study of an Intensive Videocapillaroscopy Training Program

To test the learning curve of rheumatologists with different experience in videocapillaroscopy (VCP) attending an intensive training program focused on interpretation of the main capillary nailfold abnormalities, the scleroderma (systemic sclerosis, SSc) pattern, and the normal pattern, and to determine their interreader agreement with an experienced investigator. Five investigators (1 senior, 1 junior, and 3 beginners) participated in the exercise. The study was composed of 2 steps. First, an independent investigator selected representative VCP images of normal patterns and capillary abnormalities. The second step included the training program, which ran 4 hours per day for 7 days. The senior rheumatologist taught investigators to recognize and interpret the normal pattern, the capillary abnormalities, and the different types of SSc pattern. These abnormalities were considered: homogeneously enlarged capillaries, giant capillaries, irregularly enlarged capillaries, microhemorrhages, neoangiogenesis, avascular areas, and capillary density. A total of 300 VCP images were read from all the investigators. Both κ values and overall agreement percentages of qualitative and quantitative assessments showed progressive improvement from poor to excellent from the beginning to the end of the exercise. The sensitivity and specificity of the participants in the assessment of SSc pattern at the last lecture session were high. Our pilot study suggests that after an intensive 1-week training program, novice investigators with little or no experience in VCP are able to interpret the main capillary abnormalities and SSc pattern and to achieve good interreader agreement rates.

Items for developing revised classification criteria in systemic sclerosis: Results of a consensus exercise

Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated. Our objective was to select a set of items potentially useful for the classification of SSc using consensus procedures, including the Delphi and nominal group techniques (NGT). Items were identified through 2 independent consensus exercises performed by the Scleroderma Clinical Trials Consortium and the European League Against Rheumatism Scleroderma Trials and Research Group. The first-round items from both exercises were collated and redundancies were removed, leaving 168 items. A 3-round Delphi exercise was performed using a 1-9 scale (where 1 = completely inappropriate and 9 = completely appropriate) and a consensus meeting using NGT was conducted. During the last Delphi round, the items were ranked on a 1-10 scale. In round 1, 106 experts rated the 168 items. Those with a median score of <4 were removed, resulting in a list of 102 items. In round 2, the items were again rated for appropriateness and subjected to a consensus meeting using NGT by European and North American SSc experts (n = 16), resulting in 23 items. In round 3, SSc experts (n = 26) then individually scored each of the 23 items in a last Delphi round using an appropriateness score (1-9) and ranking their 10 most appropriate items for the classification of SSc. Presence of skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern, and Raynaud's phenomenon ranked highest in the final list that also included items indicating internal organ involvement. The Delphi exercise and NGT resulted in a set of 23 items for the classification of SSc that will be assessed for their discriminative properties in a prospective study.

Report from the EULAR ACR Scleroderma Classification Criteria Committee

Classification criteria for SSc are being updated as previous ACR preliminary classification criteria did not include some lcSSc patients and early SSc.Objectives. Items from two large European and NA surveys were reduced by experts using Delphi and nominal group techniques that resulted in 23 items. The face, discriminant and construct validity were studied using many databases in Europe and NA. Further item reduction occurred ranking 20 cases of SSc and mimickers by experts with variable probabilities of having SSc and weighing items relative to each other after agreeing on further item reduction using the 1000 minds exercise.Results. In the Delphi exercise, skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern, RP and some organ involvement ranked highest. Compared with diseases that mimic SSc in multiple databases, SSc patients are more likely to have skin thickening (OR = 427), telangiectasias (OR = 91), RNA polymerase III (OR = 75), puffy fingers (OR = 35), finger flexion contractures (OR = 29), tendon/bursal friction rubs (OR = 27), topo I (OR = 25), RP (OR = 24), finger tip ulcers/pitting scars (OR = 19), anti-centromere (OR = 14), abnormal nailfold capillaries (OR = 10), GERD (OR = 8) and ANA, calcinosis, dysphagia, oesophageal dilation (all OR = 6), ILD/pulmonary fibrosis (OR = 5) and PM-Scl antibody (OR = 2). Low DL CO and FVC and PAH had OR <2. Renal crisis and digital pulp loss/acro-osteolysis did not occur in SSc mimickers. The 1000 minds exercise had experts ranked 20 cases and eliminated some of the 23 items. A scoring system found variable weighting of several items.Future direction. Thousand minds cases will be rescored by experts and then further item reduction will occur by consensus and statistical item reduction for redundant criteria, with validation in databases and prospectively collected patients with standardized case report forms at multiple sites of cases and mimickers.

Nailfold capillaroscopy in Behçet’s disease, analysis of 128 patients

The aims of this study were to find the characteristics and prevalence of nailfold capillary changes in a large series of patients with Behçet's disease (BD) and to analyze their possible relation to other clinical characteristics of the disease. We performed nailfold capillaroscopy in 128 randomly selected patients fulfilling the international classification criteria for BD. Capillaroscopy was done in eight fingers with a x3.2 microscopy. All patients were questioned for history of Raynaud's phenomenon, ischemic ulcers, smoking, and hypertension. A computerized form including demographic, clinical, and para-clinical features was used to collect data. Univariate and multivariate logistic regressions were used to analyze the relation between capillaroscopic findings and disease characteristics. Odds ratio and a confidence interval at 95% (CI) were calculated for each item. The mean age of the patients was 37 +/- 10 years, and the male to female ratio was 1.56:1. Capillaroscopy was abnormal in 51 patients (40%, CI 8.5). Enlarged capillaries were seen in 33 patients (26%, CI 7.6), hemorrhages in 21 (16%, CI 6.4), and capillary loss only in one patient. In univariate logistic regression analysis, the presence of enlarged capillaries was associated with lower age at disease onset (OR = 0.9, CI 0.9-1; p = 0.04), hypertension (OR = 4.2, CI 1.5-11.4; p = 0.006), superficial phlebitis (OR = 5.5, CI 1.2-24.4; p = 0.03), and negative pathergy test (OR = 0.4, CI 0.2-0.9; p = 0.04). The presence of hemorrhages tended to be associated with articular symptoms (p = 0.05). Multivariate analysis also confirmed the association of enlarged capillaries with lower age at disease onset (p = 0.01), hypertension (p = 0.001), and superficial phlebitis (p = 0.03). Nailfold abnormalities, mainly enlarged capillaries, are frequent in patients with BD. Our results suggest that these abnormalities may be related to other vascular features of the disease such as superficial phlebitis, but it does not seem to confer special risk for any other specific clinical symptom of the disease.

Predicting the course of juvenile dermatomyositis: Significance of early clinical and laboratory features

Juvenile dermatomyositis (DM) is a rare chronic inflammatory disease of childhood. The clinical course of juvenile DM appears to be variable, and little is known about predictors of the disease course. The aims of this study were to describe the clinical course of juvenile DM and to determine whether early clinical and laboratory features can be used to predict the time to remission and/or the disease course. Clinical and laboratory data from a cohort of 84 patients with juvenile DM were prospectively entered into a database (1990-2005). Remission was defined as a clinical state of no active skin rash, weakness, or elevated muscle enzyme levels for 6 months off medication. The disease course was defined as monophasic, polyphasic, or chronic. Data were reviewed at the time of diagnosis and at 3 months and 6 months after the diagnosis to determine predictors of the time to remission and/or the disease course. The median time to remission was 4.67 years. Sixty percent of patients had a chronic course, 37% a monophasic course, and 3% a polyphasic course. The presence of rash (most strongly indicated by Gottron's papules) at 3 months was the earliest predictor of a longer time to remission (relative risk [RR] 0.55 [95% confidence interval (95% CI) 0.37-0.81], P = 0.002). At 6 months, the presence of nailfold abnormalities and rash also predicted a longer time to remission (RR 0.35 [95% CI 0.14-0.74], P = 0.003). We were unable to determine a prediction model of disease course. The majority of patients in our cohort had a chronic disease course. The persistence of Gottron's papules and nailfold abnormalities early in the disease course was associated with a longer time to remission.

Anti-Ro52 antibodies, antisynthetase antibodies, and antisynthetase syndrome

We present a case of antisynthetase syndrome manifesting with interstitial lung disease, mechanic's hands, nailfold abnormalities, and subclinical myositis, in the presence of antibodies to the aminoacyl tRNA synthetase PL-12 and also to Ro52. Antibodies to Ro52 have been recently associated with idiopathic inflammatory myositis, but there have only been occasional reports of this antibody occurring in association with aminoacyl tRNA synthetases, including PL-12. Our case adds to the descriptions of the concurrence of antibodies to PL-12 and Ro52. The mechanism for the coupling of antibody response remains elusive but is likely to play a fundamental role in disease pathogenesis.

Unique Characteristics of Systemic Sclerosis Sine Scleroderma-Associated Interstitial Lung Disease

To describe the characteristics of systemic sclerosis sine scleroderma (ssSSc)-associated interstitial lung disease (ILD) presenting as idiopathic interstitial pneumonia (IIP). Retrospective review of six patients with ssSSc-associated ILD diagnosed after referral for evaluation of IIP. All patients were white, their mean age was 56 years (range, 37 to 86), and gender was evenly divided. Sclerodactyly, skin thickening, and digital edema were absent in all patients. All patients had scattered telangiectasia, and four patients had Raynaud phenomenon with abnormal nailfold capillaroscopy findings. All described gastroesophageal reflux, and three patients had esophageal dysmotility by esophagography. All had restrictive pulmonary physiology and a reduced diffusion capacity. High-resolution CT revealed nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) radiographic patterns. Of the three patients who underwent surgical lung biopsy, two patients had NSIP and one patient had UIP pathologic patterns. Five patients had asymptomatic pericardial effusions and elevated pulmonary artery pressures by echocardiography. All patients had nucleolar-staining anti-nuclear antibodies (ANAs), and one patient was anti-Scl-70 positive. All five anti-Scl-70-negative patients were anti-Th/To positive, and the anti-Scl-70-positive patient was anti-Th/To negative. In the presentation of an IIP, the presence of a nucleolar-staining ANA, telangiectasia, Raynaud phenomenon with abnormal capillaroscopy findings, gastroesophageal reflux, or pericardial disease suggests underlying systemic sclerosis. These findings should aid clinicians in the evaluation and treatment of patients with otherwise undefined ILD.

Raynaud's phenomenon in children: a retrospective review of 123 patients.

To examine the clinical presentation and disease associations of Raynaud's phenomenon (RP) in children and adolescents. A systematic retrospective chart review was conducted of 123 cases drawn from 2 computerized databases at the Children's Hospital of Boston. Participants aged <19 years with episodic reversible color changes in the extremities were examined. Case records were analyzed for clinical presentation, disease associations, and physical examination and laboratory findings. In contrast to the findings of smaller pediatric series reported to date, the large majority of our patients-approximately 70%-did not have a recognized underlying connective tissue disease. For both primary and secondary RP, approximately 80% of patients were female, and mean age of onset was similar in the 2 groups. Biphasic or triphasic color changes were less common than monophasic changes and were no more common in secondary than primary RP. Findings predictive of secondary RP were limited to the presence of antinuclear antibodies and abnormal nailfold capillaries. Antiphospholipid antibodies were found at some time in at least 21% of patients with both primary and secondary RP. RP in children, as in adults, principally affects girls and is frequently free of association with connective tissue disease. Antinuclear antibody positivity and abnormal nailfold capillaries correlate with secondary disease. Antiphospholipid antibodies are surprisingly common, a new finding of uncertain implications.

Women's health after plastic surgery

Allegations that exposure to endogenous silicone, especially related to breast implants, might be causally related to connective tissue disease originated from case studies. More recent comparative studies have implied no such increased risk. The aims of the present study were to compare the prevalence and/or incidence of autoimmune and connective tissue disorders in a population-based cohort of female Sydney residents stratified by augmentation mammoplasty status. In this population-based retrospective cohort study, the health status of female Sydney residents who had augmentation mammoplasty for cosmetic reasons between 1979 and 1983 was compared with that of female Sydney residents who had non-silicone-associated plastic surgery over the same period. Both groups were matched for age (+/- 5 years), year of plastic surgery (+/- 2 years), plastic surgeon, anaesthetist and mode of anaesthesia. Outcome measures comprised rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, sicca symptoms polymyositis/ dermatomyositis, connective tissue disease overlap, digital vasospasm, abnormal nailfold capillaroscopy, elevated antinuclear antibody titre, carpal tunnel syndrome, tendonitis, osteoarthritis, psoriatic arthritis, livedo reticularis, thyroid disease, multiple sclerosis, axillary lymphadenopathy, fibromyalgia and breast carcinoma. There was no difference in the occurrence of connective tissue diseases or connective tissue disease-related parameters, thyroid disorders, fibromyalgia or multiple sclerosis between cohorts. However, axillary adenopathy and low titre positive antinuclear antibody (ANA) occurred with a significantly greater frequency in the exposed cohort (odds ratio (OR) = 3.50, 95% confidence interval (CI) = 2.10-5.84 and OR = 1.29, 95% CI = 1.03-1.62, respectively). Axillary adenopathy correlated with capsular contracture (relative risk (RR) = 2.07, 95% CI = 1.22-3.51) and also the self-reported development of digital vasospasm (RR = 3.20, 95% CI = 1.46-7.03) after breast augmentation. No association was found between augmentation mammoplasty exposure and various connective tissue diseases and/or their related features. However, axillary adenopathy and low titre ANA were detected more frequently in the exposed cohort. Women with axillary adenopathy were more likely to have breast capsular contracture and report digital vasospasm post-dating surgery. Given comparable frequencies of higher titre ANA of both cohorts, the finding of elevations of low titre ANA is of dubious clinical significance.

Quantitative analysis of nailfold capillary abnormalities in patients with connective tissue diseases.

Nailfold capillary microscopy has been shown to reflect microvascular disturbances mainly in connective tissue diseases including systemic sclerosis (SSc). Nailfold capillary abnormalities were analyzed with a light microscope under immersion oil at magnifications of x60 and x400. Abnormal nailfold capillary pattern in SSc was different from that of systemic lupus erythematosus (SLE) and normal controls, but not from dermatomyositis (DM). Seventy-two per cent of patients with Raynaud's phenomenon showed an abnormal nailfold capillary pattern. In primary Raynaud's phenomenon, 12% of subjects developed undifferentiated connective tissue disease. In undifferentiated connective tissue disease, 23% developed SSc. The apical limb width, capillary width and capillary length of subjects who developed SSc were significantly larger than in those who did not. With regard to the clinicolaboratory findings, the occurrence rate of an abnormal apical limb width, abnormal capillary width, abnormal capillary length, and antinuclear antibody in patients who developed SSc was significantly higher than in those who did not. An abnormal capillary pattern correlated with an elevated pulmonary artery resistance. All the patients with pulmonary arterial hypertension showed an abnormal capillary pattern, decreased diffusion capacity for carbon monoxide, and elevated pulmonary vascular resistance. Nailfold capillary abnormalities show a close relation to pulmonary arterial hypertension. Nailfold capillary abnormalities are useful for detecting vascular abnormality in clinical practice. These facts stress the importance of nailfold capillary abnormalities in SSc.

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.

Raynaud's Phenomenon: State of the Art 1998: EDITORIAL REVIEW

Raynaud's Phenomenon (RP) is a relatively common problem which may be troublesome and difficult to treat in a minority of patients. The state of the art in 1998 focusses on three key areas: the clinical spectrum of RP; its progression and prognosis; and its treatment. RP is a systemic disease, with a multifactorial aetiology and vasospasm affects not just the digits and skin but also major organs including the heart, lungs and kidneys. It is important to distinguish primary from secondary RP. RP may predate an associated connective tissue disease by many years and markers for this include severe RP symptoms with trophic skin changes, serological abnormalities and abnormal nailfold capillaries. Repeated attacks of vasospasm may cause ischaemic reperfusion injury to the endothelium, resulting in a vicious and self propagating cycle of cause and effect. Nifedipine remains the "gold standard" of treatment but a number of new and promising drugs, eg relaxin, are currently under investigation. "Vasodilator-plus" drugs, with the ability to also modulate some of the haemorrheological abnormalities in RP, are the drugs that are going to have a major clinical impact on the disease and hold promise for the future.

Early expression of E-selectin, tumor necrosis factor alpha, and mast cell infiltration in the salivary glands of patients with systemic sclerosis.

To assess the predictive value of early endothelial E-selectin and tumor necrosis factor alpha (TNF alpha) expression, as well as mast cell infiltration, in the subsequent progression to systemic sclerosis (SSc) in patients with Raynaud's phenomenon (RP) and abnormal nailfold capillaroscopic findings. Clinical criteria were evaluated, and immunostaining was performed on lip biopsy samples from 22 patients with RP and abnormal capillaroscopic results. None of these patients initially fulfilled the American College of Rheumatology criteria for SSc. E-selectin, TNF alpha, and mast cell infiltration were found in 9, 10, and 8 of 11 patients, respectively, whose disease progressed to SSc, and in 0, 2, and 1 of 11 patients, respectively, whose disease did not progress to SSc (P < 0.001, P < 0.01, and P < 0.01, respectively). E-selectin, TNF alpha, and mast cell infiltration are detectable in the very early stages of SSc, prior to the onset of skin changes.

Association of anticardiolipin antibodies and abnormal nailfold capillaroscopy in patients with systemic lupus erythematosus.

Anticardiolipin antibodies (aCL) are found in about 40-50% of patients suffering from systemic lupus erythematosus (SLE) and their presence carries an increased risk of thromboembolism. Since there is a high prevalence of nailfold capillary abnormalities in patients with SLE, we studied the relationship between aCL and skin microcirculatory changes or vascular symptoms in 51 consecutive patients with SLE (49 women, 2 men, 34.8 +/- 13.7 years). Twenty-two patients (43.1%) had positive aCL (IgG 22 (5-60) GPL; IgM 5 (3-16.5) MPL; median titre and range) and 12 (54.5%) of them had abnormal capilloscopic findings. By contrast, among the 29 patients without aCL, only six (20.7%) had an abnormal capillaroscopy (P = 0.027). There was no correlation between either aCL or capillaroscopy and Raynaud's phenomenon. These results show a relationship between aCL and nailfold capillary changes in patients with SLE, suggesting a direct damage of the vascular endothelium by aCL.

Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions.

Connective tissue diseases (CTDs) frequently present as undifferentiated disorders that may or may not develop into one of the well defined CTDs. The natural evolution of the early undifferentiated CTDs is not well known. Some years ago a cooperative study was started on 410 patients with early CTD; within this group, 48 patients had early scleroderma. Raynaud's phenomenon has been recognized as an early sign of CTD. Several studies on Raynaud's phenomenon patients have shown that abnormal nailfold capillary patterns have prognostic significance for evolution to a CTD, particularly scleroderma. Mixed connective tissue disease (MCTD) is the prototype of an overlap syndrome. The relevance of defining MCTD as a separate disease entity has been challenged. Follow-up studies show that many patients originally diagnosed with MCTD develop a definite CTD, particularly scleroderma or systemic lupus erythematosus, within a few years. In patients with MCTD, primary pulmonary hypertension is an important cause of death. This condition seems to be associated with anticardiolipin antibodies. A number of case reports suggest that immunosuppressive treatment is of benefit in this almost always fatal condition. The main reason for describing MCTD as a separate entity is its association with antibodies to U1-RNP. Recent studies have suggested that the production of anti-U1-RNP is an antigen-driven process, but the nature of the trigger for its production has not been elucidated. Retroviral proteins do not appear to be involved. Antibodies to the protein part of the U1-RNP complex and antibodies to the RNA component have been described. Levels of anti-RNA antibodies seem to parallel disease activity in MCTD patients.(ABSTRACT TRUNCATED AT 250 WORDS)