Scleroderma Spectrum Disorders Research Articles

Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH. We performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations. The key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present. We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.

Serum levels of tenascin‐C in collagen diseases

Tenascins are a family of large multimetric extracellular matrix (ECM) proteins. Among them, large molecular weight variant tenascin-C is known to be specifically expressed in pathological conditions. However, no link between tenascin-C and collagen diseases has been established. The aim of our study was to determine the serum tenascin-C levels in patients with various collagen diseases, and to evaluate the possibility that serum levels of tenascin-C can be a useful marker for collagen diseases, correlating with the pathogenesis. Serum tenascin-C levels of 33 patients with scleroderma (SSc), 10 patients with scleroderma spectrum disorder (SSD), 15 patients with localized scleroderma (LSc), 12 patients with dermatomyositis (DM), 10 patients with systemic lupus erythematosus (SLE) and 15 healthy controls were measured with specific enzyme-linked immunosorbent assays. Serum tenascin-C levels were significantly elevated in patients with SSc, SSD and LSc than in healthy controls. Significantly higher total skin thickness score or higher incidence of pitting scars/ulcers and diffuse pigmentation were observed in SSc patients with elevated tenascin-C levels than in those with normal levels. Our study suggests that serum tenascin-C levels are increased in fibrotic conditions, and that tenascin-C contributes to the pathogenesis of vascular damage as well as fibrosis in SSc patients. Clarifying the role of tenascin-C in the pathogenesis of collagen diseases may lead to a new therapeutic approach.

Capillaroscopy abnormalities in relation to disease activity in juvenile systemic lupus erythematosus

Juvenile-onset systemic lupus erythematosus (jSLE) has a more severe disease onset and clinical course in comparison with the adult SLE. The aims of this study were to investigate in jSLE the prevalence of capillaroscopic patterns, to assess any association between capillaroscopy and clinical parameters and, to monitor the capillaroscopy changes over time. A total of 62 SLE patients, 35 jSLE (mean age 13.2years) and 27 adult-onset SLE (mean age 29.1years) were studied. In this study non-specific capillary abnormalities were observed in the majority of jSLE patients and the severity of the overall capillaroscopic abnormalities seems to be related to disease activity. Moreover, this longitudinal study allowed the observation of the dynamic feature of capillaroscopic pattern in these patients. Particularly, the presence of a scleroderma-like capillaroscopic pattern should be considered a red flag for the potential development of clinical manifestations suggestive for scleroderma spectrum disorders. Capillaroscopy may be considered a useful examination in an overall clinical assessment and an additional help in the assessment of disease activity in these patients.

Serum levels of leptin receptor in patients with systemic sclerosis.

Microvascular damage is one of the primary pathologic components of systemic sclerosis (SSc). Serological abnormalities of angiogenic and angiostatic factors in SSc have previously been described. Like these factors, the plasma levels of leptin were significantly elevated in patients with SSc in comparison to normal controls. However, leptin receptor has not been examined in patients with SSc. The current study used sandwich ELISA to evaluate the serum levels of leptin receptor in patients with SSc. Serum samples were obtained from 36 patients with SSc. Samples were also obtained from 12 healthy control subjects and 10 patients with scleroderma spectrum disorder (SSD) who did not fulfill the criteria for SSc but who had the potential to develop SSc. Mean serum leptin receptor levels were significantly higher in patients with SSD than in patients with SSc (255.7 ng/mL vs. 184.6 ng/mL, p < 0.05 according to a Mann-Whitney test). There were no statistically significant differences between healthy control subjects and patients with SSc. Clinical parameters were evaluated, and the frequency of esophageal reflux was significantly lower in patients with elevated serum leptin receptor levels than in those with reduced levels (6.3% vs. 35.3%, p < 0.05). In summary, these results suggest that the serum levels of leptin receptor are a clinically useful marker of SSD, and measurement of serum leptin receptor over time in patients with SSD may lead to early detection of SSc.

Arterial Imaging in Digital Gangrenes Associated with Scleroderma-Spectrum Disorders

Objectives: Digital refractory gangrene is rarely found in collagen diseases, including systemic sclerosis and is possibly caused by similar underlying vascular damage in peripheral arterial disease (PAD) such as arteriosclerosis obliterans (ASO) and/or thromboangiitis obliterans (TAO) by unclarified mechanisms other than vasculitis and thrombosis. This study evaluated the radiological imaging in patients with digital gangrene associated with collagen disease and compared the images with those of PAD based on the results of laboratory and histopathological examinations. Methods: Angiography, MR angiography and/or CT angiography were performed on 6 patients with refractory gangrene or extensive ulcers accompanied by scleroderma-spectrum disorders; 3 with diffuse systemic sclerosis, 1 with limited systemic sclerosis, 1 with overlap syndrome and 1 with Sj?gren’s syndrome. Results: Although the vascular alterations in collagen diseases were similar to those in PAD, the abnormal image findings (occlusion or stenosis of the arteries with smooth vessel walls) found in collagen diseases did not include atheromatous plaque, which are worm-like vessels that are characteristic of those observed in PAD. Conclusions: Some cases of digital gangrene seen in collagen diseases show similar vascular imaging patterns to those of PAD and comprehensive examinations including arterial imaging can be useful for the diagnosis of these unrecognized vascular changes other than vasculitis or digital thrombosis.

Nailfold capillaroscopic report: qualitative and quantitative methods

Nailfold capillaroscopy (NVC) is a simple and non-invasive method used for the assessment of patients with Raynaud's phenomenon (RP) and in the differential diagnosis of various connective tissue diseases. The scleroderma pattern abnormalities (giant capillaries, haemorrages and/or avascular areas) have a positive predictive value for the development of scleroderma spectrum disorders. Thus, an analytical approach to nailfold capillaroscopy can be useful in quantitatively and reproducibly recording various parameters. We developed a new method to assess patients with RP that is capable of predicting the 5-year transition from isolated RP to RP secondary to scleroderma spectrum disorders. This model is a weighted combination of different capillaroscopic parameters (giant capillaries, microhaemorrages, number of capillaries) that allows physicians to stratify RP patients easily using a relatively simple diagram to deduce prognosis.

Scleroderma pattern of nailfold capillary changes as predictive value for the development of a connective tissue disease: a follow-up study of 3,029 patients with primary Raynaud’s phenomenon

To assess the prognostic value of scleroderma pattern of nailfold capillary changes for the development of connective tissue diseases (CTD) in subjects with primary Raynaud's phenomenon (RP). The study included 3,029 consecutive patients with primary RP who had been followed at 6-month intervals during the mean of 4.8 years. The pathological features of nailfold capillaroscopy were recorded in all patients who had neither clinical nor serological signs of a CTD. In patients who developed CTD, capillary changes obtained 6 months prior to diagnosis were analyzed. A possible relationship between capillary changes and the presence of associated CTD was assessed. At the end of follow-up, 1,660 (54,8%) patients have still the primary RP, 246 (8,1%) had suspected secondary RP, and 1,123 (37,1%) patients developed CTD (363 undifferentiated CTD, 263 systemic sclerosis, 143 systemic lupus erythematosus, 106 rheumatoid arthritis, 102 Sjögren's syndrome, 61 overlap syndrome, 30 vasculitides, 24 mixed CTD, 19 polymyositis, 7 dermatomyositis, and 5 primary antiphospholipid syndrome). Scleroderma pattern were significantly associated with the development of systemic sclerosis [P = .00001, sensitivity 94%, specificity 92%, positive predictive value 52%, negative predictive value 99%, and odds ratio 163 (95% CI, 97,9-271,5)], as well as dermatomyositis (P = .0004), overlap syndrome with signs of systemic sclerosis (P = .0001), and mixed connective tissue disease (P = .007). Capillary microscopy is effective method for differentiation between primary and secondary RP and useful tool for the prediction of scleroderma spectrum disorders in RP patients.

Circulating miR-142-3p levels in patients with systemic sclerosis

Recently, increased evidence has shown that serum micro (mi)RNA levels are a useful biomarker for the diagnosis, prognosis and therapeutic value of various diseases. However, serum miRNA has not been investigated in patients with systemic sclerosis (SSc), to our knowledge. To investigate the possibility that serum levels of Homo sapiens miR-142 stem-loop (hsa-miR-142-3p), one of the miRNAs regulating the expression of integrin αV, could be a specific disease marker for SSc. Serum samples were obtained from 61 patients with SSc and 20 healthy controls. Patients with systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma spectrum disorder (SSD), who did not fulfil American College of Rheumatology criteria for SSc but might develop SSc in the future, were included as disease controls in this study. miRNAs were purified from serum, and miR-142-3p levels were measured with a quantitative real-time PCR assay. Serum miR-142-3p levels in patients with SSc were significantly higher than in patients with SSD, SLE or DM, and healthy control groups. Patients with increased miR-142-3p levels tended to have a short sublingual frenulum. Our data indicate that serum levels of miR-142-3p may be elevated specifically in patients with SSc, correlating with the severity of this disease, and may be useful diagnostic markers for the presence of SSc and for the differentiation of SSc from SSD.

Dermoscopy findings of nail fold capillaries in connective tissue diseases

Nail fold (video) capillaroscopy is a well-established technique to assess patients with Raynaud's phenomenon, in whom specific abnormalities of capillaries are predictive of underlying systemic sclerosis and its related diseases (scleroderma spectrum disorder). The typical abnormalities are also found in patients with dermatomyositis and those findings are useful for the assessment of vascular injury and the evaluation of therapeutic effect in patients with scleroderma spectrum disorder and dermatomyositis. Recently, it has been suggested that dermoscopy can replace the capillaroscopy in significant part for detection of nail fold capillary abnormalities. In this review, I summarized the established capillaroscopy findings in connective tissues diseases and tried to apply the findings of dermoscopy to the findings and classification of capillaroscopy.

Serum levels of soluble CD163 in patients with systemic sclerosis

Macrophages may play a role in the pathogenesis of systemic sclerosis (SSc), and CD163-positive M2 macrophages are potentially important source for fibrosis-inducing cytokines. However, no link between M2 macrophages and SSc has been established. The aim is to evaluate the possibility that serum levels of soluble CD163 (sCD163) can be a useful marker for SSc, reflecting M2 activation of macrophages in this disease. Serum sCD163 levels of 43 patients with SSc, 10 patients with scleroderma spectrum disorder (SSD), and 12 healthy controls were measured with specific enzyme-linked immunosorbent assays. SSc patients had significantly higher serum sCD163 levels than healthy controls. The sCD163 levels in SSD patients were higher than healthy controls and lower than SSc patients. Significantly higher right ventricular systolic pressure and lower % DLco levels, and shorter duration of disease were seen in SSc patients with elevated serum sCD163 levels than those with normal levels. These results suggest that sCD163 levels may be increased in proportion to the progression of this disease, indicating the involvement of CD163 in the pathogenesis of SSc. Furthermore, serum sCD163 levels may be a marker of pulmonary hypertension at the early stage in patients with SSc.

Exercise‐induced pulmonary hypertension associated with systemic sclerosis: Four distinct entities

Exercise-induced pulmonary hypertension (PH) may represent an early but clinically relevant phase in the spectrum of pulmonary vascular disease. There are limited data on the prevalence of exercise-induced PH determined by right heart catheterization in scleroderma spectrum disorders. We undertook this study to describe the hemodynamic response to exercise in a homogeneous population of patients with scleroderma spectrum disorders at risk of developing pulmonary vascular disease. Patients with normal resting hemodynamics underwent supine lower extremity exercise testing. A classification and regression tree (CART) analysis was used to assess combinations of variables collected during resting right heart catheterization that best predicted abnormal exercise physiology, applicable to each individual subject. Fifty-seven patients who had normal resting hemodynamics underwent subsequent exercise right heart catheterization. Four distinct hemodynamic groups were identified during exercise: a normal group, an exercise-induced pulmonary venous hypertension (ePVH) group, an exercise out of proportion PH (eoPH) group, and an exercise-induced PH (ePH) group. The eoPH and ePVH groups had higher pulmonary capillary wedge pressure (PCWP) than the ePH group (P < 0.05). The normal and ePH groups had exercise PCWP ≤18 mm Hg, which was lower than that in the ePVH and eoPH groups (P < 0.05). During submaximal exercise, the transpulmonary gradient and pulmonary vascular resistance (PVR) were elevated in the ePH and eoPH groups as compared with the normal and ePVH groups (P < 0.05). CART analysis suggested that resting mean pulmonary artery pressure (mPAP) ≥14 mm Hg and PVR ≥160 dynes/seconds/cm(-5) were associated with eoPH and ePH (positive predictive value 89% for mPAP 14-20 mm Hg and 100% for mPAP >20 mm Hg). We characterized the exercise hemodynamic response in at-risk patients with scleroderma spectrum disorders who did not have resting PH. Four distinct hemodynamic groups were identified during exercise. These groups may have potentially different prognoses and treatment options.

Circulating miR-29a levels in patients with scleroderma spectrum disorder

Systemic sclerosis (SSc) or scleroderma is an acquired disorder which typically results in fibrosis of the skin and internal organs [ 1 Korn J.H. Immunologic aspects of scleroderma. Curr Opin Rheumatol. 1989; 1: 479-484 Crossref PubMed Scopus (40) Google Scholar , 2 Mauch C. Krieg T. Fibroblast-matrix interactions and their role in the pathogenesis of fibrosis. Rheum Dis Clin North Am. 1990; 16: 93-107 PubMed Google Scholar , 3 Jelaska A. Arakawa M. Broketa G. Korn J.H. Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts: increased proportion of high collagen-producing cells in systemic sclerosis fibroblasts. Arthritis Rheum. 1996; 39: 1338-1346 Crossref PubMed Scopus (103) Google Scholar ]. The pathogenesis of tissue fibrosis may include inflammation, autoimmune attack and vascular damage, resulting in the activation of fibroblasts to produce excessive amounts of various collagens, mainly type I collagen which consists of α1(I) and α2(I) collagen [ [4] LeRoy E.C. Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast. J Clin Invest. 1974; 54: 880-889 Crossref PubMed Scopus (492) Google Scholar ]. However, the mechanism underlying the dysregulation of type I collagen in SSc is still unknown.

Noninvasive imaging techniques in the assessment of scleroderma spectrum disorders

Systemic sclerosis (SSc) affects both microvascular structure and function. Laser Doppler imaging (LDI) and thermal imaging can be used to measure cutaneous blood vessel function. Nailfold capillaroscopy (NC) measures capillary morphology. The aim of this study was to investigate the relationship between capillary morphology and blood flow, and to determine which combination of techniques allows the best discrimination between patients with SSc, primary Raynaud's phenomenon (RP), and healthy controls. NC was performed in 16 patients with SSc, 14 patients with primary RP, and 16 healthy controls. In addition, participants underwent cold stimulus with cold water. Hands were imaged to monitor rewarming and reperfusion. Nailfold morphologic features were measured and baseline images and rewarming curves were analyzed. Significant differences were found between groups (analysis of variance) for capillary morphologic features and rewarming curve characteristics. A correlation (P < 0.001) was found between LDI and thermal imaging at baseline (0.667) and maximum (0.729) blood flow and skin temperature, and for the areas under the rewarming curves (0.684). Receiver operating characteristic curves indicated that NC, thermal imaging, and LDI allowed 89%, 74%, and 72%, respectively, of SSc patient data to be correctly classified versus primary RP patients and controls. NC, LDI, and thermal imaging each independently provide good discrimination between patients with SSc and those with primary RP and healthy controls (NC being the most suitable technique for classifying patient groups). However, a combination of all 3 techniques improves classification. LDI and thermal imaging give equivalent information on dynamic changes in the cutaneous microcirculation; however, these only weakly correspond to capillary morphology.

Guttate morphea in a scleroderma spectrum disorder patient with anticentromere antibody

Auteur(s) : Masayoshi Yamanaka, Osamu Ishikawa Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan Guttate morphea is a rare varient of localized scleroderma and accounts for only 0.13%-1.2% of patients with morphea [1, 2]. We herein present a case of guttate morphea in a scleroderma spectrum disorder (SSD) [3, 4] with ACA. A 38-year-old Japanese woman presented with a 4-year history of erythematous skin lesions [...]

Correlation of Biomarkers of Endothelium Dysfunction and Matrix Remodeling in Patients with Systemic Sclerosis

Systemic sclerosis (SSc) is a multisystem disease characterized by microvascular dysfunction and excessive fibrosis. However, the relationship between these 2 features remains unclear. Endothelial dysfunction can be assessed by quantifying plasma asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase. Matrix remodeling can be assessed by quantifying serum tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Both biomarkers are elevated in patients with SSc. Our objective was to test whether plasma ADMA is correlated with serum TIMP-1. We enrolled 91 subjects, 39 patients with SSc, 28 patients with primary Raynaud's phenomenon (RP), and 24 healthy volunteers. Plasma ADMA concentrations were measured by liquid chromatography-tandem mass spectrometry. Serum TIMP-1 concentrations were determined by ELISA. Mean ADMA concentrations were higher in patients with SSc (0.68 microM +/- 0.12) than in patients with primary RP or healthy volunteers (respectively, 0.56 microM +/- 0.14 and 0.62 microM +/- 0.12; p = 0.002). Median serum TIMP-1 concentrations were increased in patients with SSc compared to primary RP and healthy volunteers [12 (9-15), 11 (8-13), and 10 (7-13) nM, respectively; p = 0.05]. In the SSc group, we observed a statistically significant correlation between plasma ADMA and serum TIMP-1 (r = 0.34, p = 0.035). These data are consistent with our hypothesis of an association of endothelial dysfunction and matrix remodeling in scleroderma spectrum disorders.

Prognostic Model Based on Nailfold Capillaroscopy for Identifying Raynaud's Phenomenon Patients at High Risk for the Development of a Scleroderma Spectrum Disorder: PRINCE (Prognostic Index for Nailfold Capillaroscopic Examination)

Prognostic Model Based on Nailfold Capillaroscopy for Identifying Raynaud's Phenomenon Patients at High Risk for the Development of a Scleroderma Spectrum Disorder: PRINCE (Prognostic Index for Nailfold Capillaroscopic Examination)

Dapsone Treatment for Eosinophilic Fasciitis

A previously healthy 38-year-old woman was seen regarding severe skin stiffness and thickening. Previous findings are summarized. The patient originally saw her primary care practitioner with a 3-month history of limb aches, ankle swelling, and malaise. She was taking no medication. Findings showed an increased serum C-reactive protein level (80 mg/L [to convert to nanomoles per liter, multiply by 9.524]), mild anemia (hemoglobin level, 11.3 g/dL [to convert to grams per liter, multiply by 10.0]), elevated plasma viscosity (1.74 mPa·s), eosinophilia (eosinophil count, 2.92 10/μL[toconvert tovalue 10/L,multiplyby10]), and low serum ferritin and folate levels. A gastroenterologic consultation to investigate suspected malabsorption excluded celiac disease, parasitic infection of the bowel, and a gastrointestinal or gynecological malignant neoplasm. Computed tomography of the abdomen showed only a thickened proximal jejunal loop. Because of persisting eosinophilia (eosinophil count, 4.77 10/μL and 6.97 10/μL on 2 further occasions), hypereosinophilic syndrome was considered. The jejunal abnormalities were presumed to represent eosinophilic enteritis, but this condition was excluded histologically. Because of increasing symmetrical arthralgias, the patient was seen in the rheumatology department. Generalized tightening and tautness of the skin, restricted joint movement (particularly the elbow and metacarpophalangeal [MCP] joints), and a positive prayer sign (inability to oppose the palms of the hands) were documented. A negative result for rheumatoid factor and normal autoimmune screening findings and complement levels made scleroderma spectrum disorders unlikely. A polyclonal increase in -globulins (mainly IgG) was found. In the dermatology department, the stiff induration and predominantly distal limb distribution of skin tethering, together with significant blood eosinophilia, were viewed as highly suggestive of eosinophilic fasciitis (EF). A deep incisional biopsy to the fascia, from the right forearm, supported this diagnosis. Septae between fat lobules were thickened by fibrosis, and a mononuclear infiltrate including numerous eosinophils was seen. Overlying skin appeared normal. Treatment with oral prednisolone was started, initially at 40 mg/d. After 2 weeks, some symptomatic improvement and a reduction of skin edema were apparent, so the prednisolone dose was reduced to 30 mg/d. At review some weeks later, however, there had been little, if any, further improvement.

Prognostic model based on nailfold capillaroscopy for identifying Raynaud's phenomenon patients at high risk for the development of a scleroderma spectrum disorder: PRINCE (Prognostic Index for Nailfold Capillaroscopic Examination)

To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud's phenomenon (RP) to RP secondary to scleroderma spectrum disorders (SSDs). The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1-8 years. Six variables were examined because of their potential prognostic relevance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries). The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P = 0.008) and microhemorrhages (HR 2.33, P = 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physicians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

Incidence and natural history of Raynaud phenomenon: a long-term follow-up (14 years) of a random sample from the general population

Because the natural history of primary Raynaud phenomenon (RP) is unclear, we undertook this long-term (14 years) follow-up of an epidemiologic study on RP to investigate the incidence, remittance rate, and transition rate toward systemic sclerosis and other scleroderma spectrum disorders in a population-based sample of subjects. In 1988 and 1989, 296 subjects obtained from a random sample of the general population of the Alpine valley of Tarentaise (southeast France) completed a cross-sectional study on RP. Of these, 78 met the diagnostic criteria for RP (RP+). From April 2002 to March 2003, we were able to get follow-up information on 292 people (dropout rate, 1.4%). Eighteen subjects (6.1%) had died, and the remaining 274 were successfully contacted. They were first evaluated by a standardized phone interview regarding their cold sensitivity, digital color changes, and RP. If any significant medical changes related to RP and/or suggesting scleroderma were reported, these subjects were invited for a medical evaluation. Mortality was similar in RP+ and RP- subjects, and no death was due to an RP-related condition. Seven cases of new RP were diagnosed in the RP- group, which corresponds to an annual incidence rate of 0.25%. Among the 72 RP+ subjects and the 7 subjects with a new RP available for follow-up, none developed clinical features of scleroderma. A disappearance of RP attacks for 2 winters or more was reported by 24 RP+ subjects (33%). These results show that, in the general population, RP is most often a benign condition and may disappear in a substantial proportion of subjects.

The Prognostic Value of Nailfold Capillary Changes for the Development of Connective Tissue Disease in Children and Adolescents with Primary Raynaud Phenomenon: A Follow‐up Study of 250 Patients

To assess the prognostic value of capillaroscopy findings for the development of connective tissue disease in children and adolescents with Raynaud phenomenon, we followed up a group of 250 (mean age 15 years) for 1 to 6 years after the first capillaroscopy was performed. Every 6 months they were screened for signs and symptoms of connective tissue disease. Analysis was performed on capillary changes registered 6 months before the development of connective tissue disease. Capillary changes were classified into three types: normal, nonspecific, and sclerodermatous. At the end of the follow-up period, 191 (76%) subjects had primary Raynaud phenomenon, 27 (10.8%) were diagnosed as having undifferentiated connective tissue disease, and 32 (12.8%) fulfilled the criteria for a diagnosis of a specific connective tissue disease. Systemic lupus erythematosus was found in nine (3.6%) patients, rheumatoid arthritis in 10 (4%) patients (six of them with juvenile onset rheumatoid arthritis), and scleroderma spectrum disorders in 13 (5.2%). The mean time for the evolution of Raynaud phenomenon into undifferentiated connective tissue disease or a form of the disease was 2 years. Most of the subjects with primary Raynaud phenomenon (173/191, 91%), undifferentiated connective tissue disease (22/27, 81%), juvenile onset rheumatoid arthritis/rheumatoid arthritis (7/10, 70%), and systemic lupus erythematosus (6/9, 67%) had normal capillary findings. Nonspecific capillary changes occurred in 3 of 10 (30%) patients with rheumatoid arthritis, 2 of 9 (22%) with systemic lupus erythematosus, 4 of 27 (15%) with undifferentiated connective tissue disease, and 18 of 191 (9%) with primary Raynaud phenomenon. Of all the subjects, only 10 (4%) showed sclerodermatous disease type capillary changes 6 months before the expression of a particular disease: eight (62%) of these developed scleroderma spectrum disorders, one expressed systemic lupus erythematosus, and one had undifferentiated connective tissue disease. We concluded that there were no specific capillary changes predictive for future development of systemic lupus erythematosus, juvenile onset rheumatoid arthritis/rheumatoid arthritis, and undifferentiated connective tissue disease in children and adolescents with Raynaud phenomenon. Most of our study subjects with Raynaud phenomenon who developed these diseases had normal capillary findings or nonspecific changes. Children and adolescents who developed scleroderma spectrum disorders showed a sclerodermatous type of capillary changes 6 months before the expression of the disease, indicating that this type of capillary changes in children and adolescents with Raynaud phenomenon highly correlated with further development of scleroderma spectrum disorders.