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PubMed2003

Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis.

Our objective was to study the presence of microchimerism in a series of 47 female Spanish patients with scleroderma (SSc) and to compare with a control group. Polymerase chain reaction was used to identify Y-chromosome sequences in DNA extracted from peripheral blood cells. Y-chromosome sequences were found in DNA from peripheral blood cells in four out of 47 (8.5%) patients with scleroderma (two limited and two diffuse) and in two out of 40 (5%) healthy women (no statistical differences were found). When we compared SSc patients and healthy controls who had had at least one male child, four out of 29 (13.7%) and two out of 26 (7.6%) had microchimerism respectively (no statistically significant differences were found). Patients with both scleroderma and persistent microchimerism had had a male offspring. Foetal microchimerism does not seem to play a major role in most cases of female Spanish patients with SSc.

Adult↗
PubMed2005

Correlation of the degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis: results from the Scleroderma Lung Study.

OBJECTIVE: To determine whether baseline self-assessment measures of health status and physiologic indices of disease severity in alveolitis-positive patients with systemic sclerosis (SSc) correlate with the severity of their dyspnea, and to quantify functional impairment in patients with scleroderma lung disease and compare it with that in patients with chronic obstructive pulmonary disease (COPD). METHODS: SSc patients (n = 138) with diffuse (n = 81) or limited (n = 57) cutaneous disease and active alveolitis (determined by bronchoalveolar lavage and/or high-resolution computed tomography) who participated in the National Heart, Lung, and Blood Institute-sponsored, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial of oral cyclophosphamide for treatment of SSc-associated interstitial lung disease were evaluated. Pearson's univariate correlations were determined between the Short Form 36 (SF-36) physical component summary (PCS) and mental component summary (MCS) scales, functional questionnaires, and physiologic parameters of breathing (forced vital capacity [FVC] and single-breath diffusing capacity for carbon monoxide [DLCO]). Student's t-test was used to compare subgroups. Scores from 2 instruments for self-assessment of breathlessness, Mahler's baseline dyspnea index (BDI) and a visual analog scale (VAS) for breathing, were divided at the median. Values for the DLCO and FVC (% predicted) were divided based on the American Thoracic Society guidelines for mild (>70% of predicted), moderate (50-70% of predicted), and severe (<50% of predicted) physiologic impairment. RESULTS: Scores on the BDI and VAS for breathing were highly correlated (r = -0.61). The PCS and MCS were able to differentiate patients with more breathlessness (measured by BDI and VAS for breathing) and more abnormal physiologic measures (FVC and DLCO). In SSc patients with alveolitis, all 8 domains of the SF-36 were significantly impaired as compared with the healthy population and were similar to those reported by patients with COPD. CONCLUSION: The SF-36 was able to discriminate between scleroderma lung disease patients with more severe and less severe breathlessness, the primary symptom of active alveolitis. The SF-36 complements the BDI and VAS scores for breathing in scleroderma lung disease and is variably correlated with results of pulmonary function tests, suggesting that the SF-36 should be included as an outcome measure in intervention trials in this population.

Carbon Monoxide↗
PubMed2003

Molecular mechanisms of interleukin-4-induced up-regulation of type I collagen gene expression in murine fibroblasts.

OBJECTIVE: There is evidence that interleukin-4 (IL-4) plays a major role in the induction of extracellular matrix protein synthesis in fibrotic disease. We therefore examined the effect of IL-4 on collagen synthesis in primary fibroblasts isolated from normal and TSK/+ mice, which spontaneously develop a scleroderma-like syndrome characterized by diffuse cutaneous hyperplasia. METHODS: Expression of the IL-4 receptor was determined by flow cytometry and Western blotting. The IL-4 signal transduction cascade was analyzed by Western blotting. We assessed the role of signal transducer and activator of transcription 6 (STAT-6) in IL-4 induction of alpha2(I) collagen promoter activity and message levels via luciferase reporter assay and real-time polymerase chain reaction. The activation status of the transcription factors activator protein 1 (AP-1) and Sp-1 upon stimulation with IL-4 in normal and TSK/+ fibroblasts was examined by electrophoretic mobility shift assay. RESULTS: Flow cytometry and Western blotting showed that IL-4 receptor alpha expression was elevated in TSK/+ fibroblasts compared with normal fibroblasts. After IL-4 stimulation, janus-activated kinase 1 (JAK-1) and JAK-2 were phosphorylated to a greater degree in TSK/+ fibroblasts than in C57BL/6 fibroblasts. TSK/+ fibroblasts appeared to be hyperresponsive to IL-4, displaying increased synthesis of alpha1(I) collagen messenger RNA (mRNA), collagen protein, and activity of a luciferase reporter construct containing the -300 to +54 murine alpha2(I) collagen promoter. Overexpression of STAT-6 enhanced this effect, whereas expression of a dominant-negative STAT-6 abrogated the ability of IL-4 to induce alpha1(I) collagen mRNA in TSK/+ fibroblasts. Moreover, IL-4 induced increased DNA binding activity of transcription factors that are important for collagen synthesis. CONCLUSION: Our observations indicate that IL-4 has a profound effect on several factors that have been identified as playing major roles in the regulation of collagen synthesis and suggest that IL-4 increases the expression of type I collagen through a mechanism involving the activation of transcription factors that bind to and activate collagen promoter.

Animals↗
PubMedDate not supplied

[Variability of the clinical picture and the classification of progressive systemic scleroderma].

Fiftythree patients with progressive systemic sclerosis were studied. Four of them (3 males) had the diffuse form of the disease. The skin manifestation of this clinical picture is characterized by diffuse progression of the cutaneous sclerosis over almost the whole body surface, except for the hands where it eventually may appear late. The prognosis for these patients it especially poor. Fortyfive patients (44 females) had acrosclerosis in the widest sence. Twentyseven of these ("acrosclerosis stricto sensu") had cutaneous sclerosis of the hands, face, and often other parts of the body, but not on the abdomen, arms or thighs. The remaining 18 patients had sclerotic alterations on these surfaces also. In this syndrome (which the authors call "the intermediary syndrome"), i.e. where the abdomen, arms, and thighs also are affected, certain internal organs and the joints are more involved than in "acrosclerosis stricto sensu". With rare exceptions, a symptomatic tetrade (REST-syndrome) occurred in acrosclerosis and all the intermediary syndromes. This consisted of Raynaud's syndrome (R), esophagopathy (E), cutaneous sclerosis (S), and telangectasia (T). Fifty % of the patients in addition had calcinosis (C), either subcutaneous or para-articular. The tetrade "REST syndrome" becomes in these cases the pentade "CREST syndrome". The addition of calcinosis to the other four phenomena of the REST syndrome does not alter the frequency of internal organ involvement or the prognosis of the disease. The term "REST syndrome" and its variant "CREST syndrome" should replace the conservative term "acrosclerosis" because they add to the purely cutaneous phenomena other characteristic manifestations of the disease. Two patients could neither be classified under the REST syndrome nor the progressive diffuse syndromes. Two other patients had no cutaneous phenomena ("scleroderma sine scleroderma").

Adolescent↗
PubMed1992

Oropharyngeal and esophageal interrelationships in patients with nonobstructive dysphagia.

Normal swallowing requires the close functional coordination of the mouth, pharynx, and esophagus, and if one of these components becomes functionally impaired, it is likely that the others may be affected. Using videofluoroscopy and manometry in this study, we examined the esophageal phase of swallowing in 12 patients with oropharyngeal dysphagia (group A) and the oropharyngeal components of swallowing in 29 patients with esophageal motor dysfunction and nonobstructive dysphagia (group B). A wide range of esophageal function abnormalities was seen in the first group, including delayed esophageal body peristalsis, spontaneous or simultaneous (tertiary) contractions, esophageal body dilation, proximal bolus redirection, and poor lower esophageal sphincter relaxation. Manometrically, 92% of group A patients were classified as having nonspecific esophageal motility disorder (NSEMD). In a similar fashion, group B patients exhibited many oropharyngeal function abnormalities on videofluorography including disturbed lingual peristalsis, slowed pharyngeal transit time with poor constriction of pharyngeal muscles, and laryngeal vestibular and tracheal bolus penetration. Manometrically, group B patients were classified as having NSEMD, achalasia, diffuse esophageal spasm, nutcracker esophagus, scleroderma, and chronic intestinal pseudoobstruction. In conclusion, oropharyngeal function is significantly altered in patients with esophageal motility disorders and dysphagia, and esophageal motor dysfunction occurs in patients with oropharyngeal dysphagia. These changes may represent either a compensatory mechanism or concomitant involvement of the oropharynx or the esophagus by the underlying neuromotor disorder. We suggest that assessment by esophageal motility and videofluoroscopy of both the oropharyngeal and esophageal phases of swallowing may improve diagnosis and therapy in patients with nonobstructive dysphagia.

Adult↗
PubMed2002

A review of oesophageal manometry testing in a district general hospital.

Although several modalities are available to investigate oesophageal motility disorders, manometry is the gold standard. The procedure is increasingly available in district general hospitals but the clinical utility of this investigation in this setting remains unclear. The aim in this study was to evaluate the use and outcome of oesophageal manometry in a district general hospital. Data on 100 consecutive oesophageal manometry procedures were analysed, taking into account the referral pattern, indications, and results. The indications were gastro-oesophageal reflux disease (preoperative assessment before fundoplication) (58), dysphagia (28), chest pain (12), and epigastric pain (2). Diagnoses were made using predefined standard criteria and were as follows: normal (41), non-specific motility disorder (NSMD) (38), achalasia (15), diffuse oesophageal spasm (4), and scleroderma (2). Of the 58 patients who had undergone manometry as a preoperative assessment of oesophageal motility, 27 (47%) were abnormal. Twenty five (43%) had NSMD and two (3%) had achalasia. Forty eight of these preoperative cases were combined with 24 hour pH recording, which confirmed acid reflux in 35 (73%). The experience reported here reflects the published evidence that the use of manometry is changing. It is now more commonly used for assessment before antireflux surgery and for dysphagia, and the use in the assessment of chest pain is declining. The findings confirm the importance of eliminating achalasia before inappropriate antireflux surgery.

Adolescent↗
PubMed2006

Use of endoluminal ultrasound to evaluate gastrointestinal motility.

The use of high-frequency ultrasound transducers in the gastrointestinal tract (GI) has already yielded remarkable findings concerning the anatomy, physiology and pathophysiology of the GI tract and of various motility disorders. These transducers have made completely invisible portions of the GI tract (the longitudinal smooth muscle, muscles of the upper esophageal sphincter, components of the gastroesophageal junction high-pressure zone, and the muscle of the anal sphincter complex) accessible to investigation. Use of simultaneous ultrasound and manometry has allowed the exploration of the normal physiology of peristaltic contraction. The components of the high-pressure zone of the distal and proximal esophagus have been isolated and the movement of these components has been studied individually and as a group. Various esophageal motility disorders have been investigated including achalasia, scleroderma, Barrett's esophagus and diffuse esophageal spasm. The possible etiology of the symptoms of esophageal chest pain and heartburn (sustained esophageal contractions of the longitudinal smooth muscle), have been studied. The possible underlying pathophysiology of GERD (the missing gastric clasp and sling fiber pressure profile) has been explored. Three-dimensional high-frequency ultrasound imaging has allowed the peristaltic contraction sequence to be viewed in a completely new and unique manner. The biomechanics of both esophageal contraction and the gastroesophageal junction high-pressure zone have been investigated and the mechanical advantage of esophageal shorting has been studied. The mechanism of action of standard surgical and newer endoscopic therapies for GERD has been defined. Future applications of this technology are limited only by our imagination.

Endosonography↗
PubMed1979

[Functional disorders of the esophagus. Diagnosis and therapy].

Functional disorders of the esophagus may be divided into alterations of the pharyngeal and upper esophageal sphincter motor function, malfunction of the tubular esophagus and disorders of the lower esophageal sphincter. Radiology, endoscopy and manometry are essential in the evaluation of the individual patient, in lower esophageal sphincter insufficiency with reflux disease acid clearance, reflux provocation test, acid perfusion and pH metry should be added. Conservative vs. operative therapy has to be critically evaluated. The diagnostic criteria of the most common functional disturbances like idiopathic diffuse esophageal spasm, achalasia and scleroderma are presented and therapeutic efforts discussed.

Antacids↗
PubMed1968

Evaluation of 100 esophageal motility studies at a university medical center.

100 esophageal motility studies on 88 consecutive patients referred to the University of California Medical Center were analyzed. Diagnoses of achalasia, diffuse spasm of the esophagus, scleroderma, hiatal hernia and other conditions were made from the motility tracings. The motility tests have been found to be most helpful in differentiating various disorders of swallowing and thoracic pain of unknown cause.

Esophageal Diseases↗
PubMed1998

Classification and epidemiology of scleroderma.

Scleroderma is classified as two separate but related entities, a localized form and a systemic form. The classification scheme for morphea presented here is that of Peterson et al, which divides morphea into five categories: plaque, generalized, bullous, linear, and deep. Using this system, these authors estimated the incidence rate of localized scleroderma to be 27 new cases per million population per year. Overall survival was similar to that of the general population. There was a preponderance of female cases (approximately 3:1) for all forms of morphea except for linear scleroderma, which had an even sex distribution. Systemic scleroderma is divided into limited and diffuse disease based on the extent of skin involvement. Recent estimates have placed the incidence rate of systemic sclerosis in the United States at 19 new cases per million adults per year, with an overall prevalence of 240/million adults. The female-to-male ratio is approximately 5:1. The prevalence of scleroderma varies by geographic region and ethnic background and is higher in the United States than in Europe or Japan. Although systemic sclerosis survival has improved over the past two decades, with 5-year survival over 80%, long-term survival is significantly lower than expected, and morbidity is considerable.

Adult↗
PubMed1982

Immune response to connective tissue components of the basement membrane.

The immune response to connective tissue components of basement membrane (type IV collagen and laminin) and to interstitial collagen (type I) has been examined in human and murine systems. We also examined the role that immunologic sensitization to autologous connective tissue components might play in inducing an inflammatory response resulting in pathologic sequelae. Mice receiving a single subcutaneous injection of 5 micrograms type IV or type I murine collagens, or murine laminin in complete Freund's adjuvant mount a delayed-type hypersensitivity response characterized by a mononuclear cell infiltrate when challenged in the footpad with the sensitizing antigen. Cell-mediated immunity to these connective tissue antigens can be transferred to normal syngeneic mice with sensitized T-lymphocytes. In addition, repeated immunizations with these homologous connective tissue components elicit antibody responses in mice. Our data demonstrate the immunogenic nature of types IV and I collagen, and of laminin in a syngeneic murine model. We have demonstrated autoantibodies to the basement membrane and interstitial collagens in the sera of patients with scleroderma (systemic sclerosis); ELISA ratios correlate directly with the extent of pulmonary fibrosis in these patients. Anti-type IV collagen autoantibodies were found to be primarily IgM and anti-type I collagen antibodies, primarily IgG. An antibody response to autologous connective tissue antigens could lead to complement activation, immune complex formation, and deposition of the complexes along vascular endothelium with recruitment of blood monocytes in situ, mirroring the early scleroderma lesion (perivascular mononuclear cell filtrates). In vitro we examined the role of human peripheral blood mononuclear cells in the activation of fibroblasts. Adherent human blood monocytes release mediators which stimulate fibroblast proliferation and collagen deposition. A model is presented for the induction of immunity to autologous connective tissue components, leading to mononuclear cell inflammation, fibroblast activation and fibrosis. Selective immunity to basement membrane collagens may influence the clinical expression of diffuse connective tissue syndromes such as scleroderma (systemic sclerosis).

Animals↗
PubMed1977

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.

Adolescent↗
PubMed1978

Diffuse fasciitis with eosinophilia.

The recently described syndrome of diffuse fasciitis with eosinophilia consists of scleroderma-like cutaneous changes in the absence of Raynaud's phenomenon and without visceral involvement. Peripheral blood eosinophilia and hypergammaglobulinemia occur in the majority of patients. The biopsy specimen is characteristic and shows a diffusely thickened fascia with a noticeable inflammatory infiltrate. The etiology and pathogenesis of the entity are unknown. The majority of the cases have been reported to respond to corticosteroids. Pulmonary function abnormalities and rheumatoid factor elevation in one of our patients suggests that this syndrome may be a variant scleroderma or may have previously unrecognized systemic manifestations. The patients' objective responses to corticosteroids were minimal.

Adrenal Cortex Hormones↗
PubMed1976

Treatment of scleroderma heart by D-penicillamine.

A case of severe diffuse systemic sclerosis with cardiomegaly and cardiac failure is described. Treatment with D-penicillamine caused a pronounced decrease in heart size, together with clinical improvement. The use of penicillamine in scleroderma heart has not previously been reported.

Adult↗
PubMed1996

Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients.

A retrospective chart review was carried out on 344 patients with systemic sclerosis (SSc) followed prospectively for the occurrence of pulmonary hypertension (PHT). Seventeen patients (4.9%) were found to have PHT. Eight patients had isolated PHT, while in nine PHT was associated with restrictive lung disease (RLD). The subset with RLD developed PHT earlier, but had longer survival than patients with isolated PHT. Patients with limited scleroderma tend to develop isolated PHT, while in those with diffuse disease PHT is associated with RLD. Irrespective of disease type, PHT in SSc has an extremely poor prognosis with a median survival of 12 months following diagnosis.

Adult↗
PubMed2006

Right heart function in scleroderma: insights from myocardial Doppler tissue imaging.

To use Doppler tissue imaging to evaluate heart function and to predict rehospitalization rate in progressive systemic sclerosis, we studied 40 patients (limited in 24 patients, diffuse in 16 patients) with chest roentgenography, pulmonary function test, routine echocardiography, and myocardial Doppler tissue. Another 45 volunteers without any sign of heart failure served as the control group. Significant difference of echocardiographic parameters was found in peak transmitral early diastolic velocity, right ventricular (RV) ejection fraction (EF) (RVEF), pulmonary artery systolic pressure, and Doppler tissue parameters of the RV and septum (peak transmitral early diastolic velocity, P = .012; RVEF, P < .0001; pulmonary artery systolic pressure, P < .0001). The parameters derived by pulsed wave Doppler tissue decreased in RV, including peak systolic myocardial velocity (Sm), early diastolic velocity, late diastolic velocity, and myocardial performance index. RVEF and left ventricular EF were estimated by Simpson's method. RV-Sm could be used to identify RV failure. Receiver operating characteristic area under the curve for RV-Sm was 0.935. RV-Sm less than 11 cm/s indicted RVEF less than 40% with sensitivity of 87% and specificity of 86%. Contrary to expectation, pulmonary artery systolic pressure was not so well correlated with RV function. The frequency of admission was reverse correlated with decrement of RV-Sm in patients with RV-Sm less than 12 cm/s. We conclude that in progressive systemic sclerosis, RV systolic dysfunction is common and appears to be a result of pulmonary hypertension, disturbance of myocardial microcirculation, and myocardial fibrosis. Pulmonary hypertension was not well correlated with RV dysfunction; it suggested pulmonary hypertension was not the only cause of RV failure. Primary right heart involvement was the other possible cause. By myocardial Doppler tissue imaging, we can predict the frequency of hospitalization; it suggests simultaneous involvement of heart, skin, lung, and other organs. RV-Sm more than 12 cm/s predicted a decreased likelihood of readmission to the hospital.

Adult↗
PubMed2005

Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum.

Chronic cutaneous graft-versus-host disease (GVHD) is classically divided into two major clinical categories--lichenoid and sclerodermoid. Although diffuse areas of sclerosis as in scleroderma characterize the more advanced stages of the sclerodermoid form, the initial circumscribed plaques would be more correctly described as morpheaform. Eosinophilic fasciitis (EF) (a fibrosing disorder related to deep morphea) and lichen sclerosus (LS) have also been reported as manifestations of sclerodermoid GVHD. However, these two presentations of GVHD have not been emphasized in the dermatologic literature. We describe 6 patients, all of whom developed LS and two of whom also developed EF in the context of chronic GVHD. Each patient presented clinically with hypopigmented plaques that exhibited wrinkling, scaling, and follicular plugging. These lesions demonstrated the classic histologic features of LS including epidermal atrophy; a subepidermal zone of pale-staining, homogenized collagen; and a bandlike lymphocytic infiltrate. Although all patients eventually developed morpheaform and/or sclerodermoid GVHD, LS was a prominent part of the initial presentation of chronic cutaneous GVHD in every case. The LS lesions tended to occur on the neck and upper to mid aspect of the trunk, whereas morpheaform lesions favored the lower aspect of the trunk. EF involved the extremities (sparing the hands and feet), and was characterized clinically by an acute onset of pain and edema followed by induration with a rippled appearance. This case series serves to expand the spectrum of sclerodermoid GVHD, with LS as the most superficial and EF as its deepest manifestation.

Adult↗