A new computerized method for the assessment of skin lesions in localized scleroderma

OBJECTIVE: Up to now, no validated tools are in use for the assessment of the skin lesions in localized scleroderma (LS). The aim of this study is to evaluate the performance of a new computerized skin score (CSS) method for the measurement of circumscribed lesions in LS. METHODS: The study consisted of three phases: set up of the CSS technique, measurement of target lesions of LS patients, assessment of intra- and inter-rater reliability. The CSS technique consists in delimitating the indurate lesion on an adhesive transparent film, transferring it over a cardboard and then calculating the affected area with a specifically created software. The technique was explained to a panel of 10 physicians with different expertise in LS (three paediatric rheumatologists, two dermatologists, five paediatric residents). All participants, singularly and blindly to the others, examined 10 consecutive patients twice after a time interval of at least 6 h. The intra-observer variability was evaluated by the repeatability coefficient and the inter-rater reliability by the intra-class correlation coefficient (ICC). RESULTS: The repeatability coefficients were good, ranging between 1.90 and 7.03. The mean values of skin scores were not significantly different among the examiners. The ICC for indurate area calculation were high in both the experts (0.97) and the residents (0.91-0.94). CONCLUSIONS: CSS has shown to be a reliable method to assess the skin lesions in patients with LS. It is reproducible, easy to use and, with the support of the CSS software, applicable worldwide.     

Cellular infiltrates in scleroderma skin

The purpose of this study was to determine the frequency, distribution, and nature of cellular infiltrates in 108 skin biopsies from patients with systemic scleroderma (SS) and localized scleroderma (LS). Cellular infiltrates, perivascular or diffuse, were noted in 49% of SS and 84% of LS patients and consisted of lymphocytes, plasma cells, and macrophages. No correlation was noted between the presence or severity of skin cellular infiltrates and serum serologic abnormalities.     

Spontaneous skin regression and predictors of skin regression in Thai scleroderma patients

Skin tightness is a major clinical manifestation of systemic sclerosis (SSc). Importantly for both clinicians and patients, spontaneous regression of the fibrosis process has been documented. The purpose of this study is to identify the incidence and related clinical characteristics of spontaneous regression among Thai SSc patients. A historical cohort with 4 years of follow-up was performed among SSc patients over 15 years of age diagnosed with SSc between January 1, 2005 and December 31, 2006 in Khon Kaen, Thailand. The start date was the date of the first symptom and the end date was the date of the skin score ≤2. To estimate the respective probability of regression and to assess the associated factors, the Kaplan–Meier method and Cox regression analysis was used. One hundred seventeen cases of SSc were included with a female to male ratio of 1.5:1. Thirteen patients (11.1%) experienced regression. The incidence rate of spontaneous skin regression was 0.31 per 100 person-months and the average duration of SSc at the time of regression was 35.9 ± 15.6 months (range, 15.7–60 months). The factors that negatively correlated with regression were (a) diffuse cutaneous type, (b) Raynaud’s phenomenon, (c) esophageal dysmotility, and (d) colchicine treatment at onset with a respective hazard ratio (HR) of 0.19, 0.19, 0.26, and 0.20. By contrast, the factor that positively correlated with regression was active alveolitis with cyclophosphamide therapy at onset with an HR of 4.23 (95% CI, 1.23–14.10). After regression analysis, only Raynaud’s phenomenon at onset and diffuse cutaneous type had a significantly negative correlation to regression. A spontaneous regression of the skin fibrosis process was not uncommon among Thai SSc patients. The factors suggesting a poor predictor for cutaneous manifestation were Raynaud’s phenomenon, diffuse cutaneous type while early cyclophosphamide therapy might be related to a better skin outcome.     

Blood hyperviscosity with reduced skin blood flow in scleroderma

The vascular complications of scleroderma have previously been attributed to the progressive obliteration of small vessels. Our study was carried out to determine whether abnormalities of blood viscosity occur in this disease, thereby contributing to the ischaemic process. Blood viscosity was measured in 20 patients using a rotational viscometer. At a high rate of shear, blood hyperviscosity was found in 35% of the patients and at a low rate of shear, in 70%. In addition there was a significant increase in the plasma viscosity which implicates changes in plasma proteins (fibrinogen, immunoglobulins) as causing the hyperviscosity. Measurement of the hand blood flow by venous occlusion plethysmography showed reduced flow at 32 degrees , 27 degrees , and 20 degrees C. A unique finding was a delayed recovery of the blood flow after cooling. These observations suggest that the increased resistance to blood flow in skin affected by scleroderma may be caused by an interaction between the occlusive vascular lesion and blood hyperviscosity. In addition, blood flow patterns and hyperviscosity could help distinguish scleroderma from primary Raynaud's disease.     

Systemic and cell type-specific gene expression patterns in scleroderma skin

We used DNA microarrays representing >12,000 human genes to characterize gene expression patterns in skin biopsies from individuals with a diagnosis of systemic sclerosis with diffuse scleroderma. We found consistent differences in the patterns of gene expression between skin biopsies from individuals with scleroderma and those from normal, unaffected individuals. The biopsies from affected individuals showed nearly indistinguishable patterns of gene expression in clinically affected and clinically unaffected tissue, even though these were clearly distinguishable from the patterns found in similar tissue from unaffected individuals. Genes characteristically expressed in endothelial cells, B lymphocytes, and fibroblasts showed differential expression between scleroderma and normal biopsies. Analysis of lymphocyte populations in scleroderma skin biopsies by immunohistochemistry suggest the B lymphocyte signature observed on our arrays is from CD20+ B cells. These results provide evidence that scleroderma has systemic manifestations that affect multiple cell types and suggests genes that could be used as potential markers for the disease.     

Platelet gel in the treatment of severe scleroderma skin ulcers

Systemic sclerosis (SSc) is characterized by microvascular damage and fibrosis of the skin and internal organs. Non-healing skin ulcers, mainly non-venous leg ulcers, represent one of the most challenging complications. Platelet gel (PG) is a hemocomponent containing numerous growth factors, potentially useful for tissue reparation. This pilot open study aimed to evaluate the effect of PG in 12 SSc patients with skin ulcers resistant to conventional therapies from at least 6?months. PG was applied in the wound bed twice weekly for 2?weeks, then once a week for 12?weeks; in all cases, the ongoing treatments remained unchanged at the time of PG applications. Skin ulcers were evaluated at 0, 12 and 24?weeks; the patient’s quality of life was also evaluated using the visual analogical scale (VAS) and the health assessment questionnaire (HAQ). During the 6-month follow-up, the skin ulcers consistently improved in 10/12 patients, with complete healing in 4. At the last evaluation, wound size reduced from 23.4?±?14.9 SD to 2.3?±?2.2 SD cm² (p?<?0.0001). Patient’s quality of life markedly improved: VAS decreased from 87.08?±?13.5 to 57.9?±?12.6; p?<?0.0001 and HAQ from 0.73?±?0.43 to 0.57?±?0.22; p?<?0.0001. PG may represent a novel therapeutic option for SSc skin ulcers refractory to conventional treatments.     

Localized scleroderma in childhood is not just a skin disease

OBJECTIVE: Juvenile localized scleroderma is usually considered a disease that is confined to the skin and subcutaneous tissue. We studied the prevalence and clinical features of extracutaneous manifestations in a large cohort of children with juvenile localized scleroderma. METHODS: Data from a multinational study on juvenile scleroderma was used for this in-depth study. Clinical features of patients with extracutaneous manifestations were compared with those of patients who had exclusively skin involvement. RESULTS: Seven hundred fifty patients entered the study. One hundred sixty-eight patients (22.4%) presented with a total of 193 extracutaneous manifestations, as follows: articular (47.2%), neurologic (17.1%), vascular (9.3%), ocular (8.3%), gastrointestinal (6.2%), respiratory (2.6%), cardiac (1%), and renal (1%). Other autoimmune conditions were present in 7.3% of patients. Neurologic involvement consisted of epilepsy, central nervous system vasculitis, peripheral neuropathy, vascular malformations, headache, and neuroimaging abnormalities. Ocular manifestations were episcleritis, uveitis, xerophthalmia, glaucoma, and papilledema. In more than one-fourth of these children, articular, neurologic, and ocular involvements were unrelated to the site of skin lesions. Raynaud's phenomenon was reported in 16 patients. Respiratory involvement consisted essentially of restrictive lung disease. Gastrointestinal involvement was reported in 12 patients and consisted exclusively of gastroesophageal reflux. Thirty patients (4%) had multiple extracutaneous features, but systemic sclerosis (SSc) developed in only 1 patient. In patients with extracutaneous involvement, the prevalence of antinuclear antibodies and rheumatoid factor was significantly higher than that among patients with only skin involvement. However, Scl-70 and anticentromere, markers of SSc, were not significantly increased. CONCLUSION: Extracutaneous manifestations of juvenile localized scleroderma developed in almost one-fourth of the children in this study. These extracutaneous manifestations often were unrelated to the site of the skin lesions and sometimes were associated with multiple organ involvement. The risk of developing SSc was very low. This subgroup of patients with juvenile localized scleroderma should be evaluated extensively, treated more aggressively, and monitored carefully.     

Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts

OBJECTIVE: Scleroderma is characterized by excessive synthesis and accumulation of matrix proteins in lesional tissues. Transforming growth factor beta (TGFbeta) plays a central role in the pathogenesis of fibrosis by inducing and sustaining activation of fibroblasts; however, the underlying mechanisms are poorly understood. We undertook this study to examine the expression and function of SMADs, recently characterized intracellular effectors of TGFbeta signaling, in scleroderma fibroblasts. METHODS: Primary dermal fibroblasts obtained from 14 patients with scleroderma and from 4 healthy adult volunteers were studied. Northern analysis was used to determine the expression of endogenous SMAD messenger RNA (mRNA), and Western analysis was used to determine SMAD protein expression. Intracellular compartmentalization of cellular SMAD proteins in the presence and absence of TGFbeta was studied by antibody-mediated immunofluorescence confocal microscopy. The effect of TGFbeta blockade on SMAD subcellular distribution was determined using anti-TGFbeta antibodies as well as a dominant-negative TGFbeta receptor type II (TGFbetaRII) vector to disrupt TGFbeta responses. SMAD-regulated luciferase reporter expression was examined to investigate the potential functional significance of activation and nuclear accumulation of endogenous SMADs in scleroderma fibroblasts. RESULTS: Protein and mRNA levels of SMAD3, but not of SMAD4 or SMAD7, were variably elevated in scleroderma fibroblasts compared with those from healthy controls. In sharp contrast to control fibroblasts, which displayed predominantly cytoplasmic localization of SMAD3/4 in the absence of exogenous TGFbeta, in scleroderma fibroblasts SMAD3 and SMAD4 consistently showed elevated nuclear localization. Furthermore, phosphorylated SMAD2/3 levels were elevated and nuclear localization of phosphorylated SMAD2/3 was increased, suggesting activation of the SMAD pathway in scleroderma fibroblasts. Blockade of autocrine TGFbeta signaling with antibodies or by expression of dominant-negative TGFbetaRII failed to normalize SMAD subcellular distribution, suggesting that elevated nuclear SMAD import was due to alterations downstream of the TGFbeta receptors. The activity of a SMAD-responsive minimal promoter-reporter construct was enhanced in transiently transfected scleroderma fibroblasts. CONCLUSION: This study is the first to demonstrate apparently ligand-independent constitutive activation of the intracellular TGFbeta/SMAD signaling axis in scleroderma fibroblasts. SMAD signaling may be a mechanism contributing to the characteristic phenotype of scleroderma fibroblasts and playing a role in the pathogenesis of fibrosis.     

Stiff skin syndrome versus scleroderma: a report of two cases

Stiff skin syndrome is a rare cutaneous disease, scleroderma-like disorder that presents in infancy or early childhood with rock-hard skin, limited joint mobility, and mild hypertrichosis. Normally, it occurs in the absence of visceral or muscle involvement. Patients do not present immunologic abnormalities or vascular hyperactivity. We describe two adults who initially were diagnosed suffering from scleroderma but fit criteria for stiff skin syndrome. A review of the clinical range of this disorder and discussion of the differential diagnosis with scleroderma is presented.