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PubMed2003

Evaluation of caspase 1 and sFas serum levels in patients with systemic sclerosis: correlation with lung dysfunction, joint and bone involvement.

Recent studies point out at the role of apoptosis disturbances in the development of systemic sclerosis(SSc). The aim of our study was to examine caspase 1 and sFas serum levels in scleroderma patients and correlate the obtained results with skin involvement and internal organ changes. We studied 29 patients (14 with limited and 15 with diffuse SSc). The extension of skin involvement was measured using Total Skin Score (TSS). Internal organ involvement was assessed by specialist procedures. Serum caspase 1 and sFas levels were measured by enzyme-linked immunosorbent assay. We found correlation between sFas serum level and duration of Raynaud's phenomenon and TSS; caspase 1 serum level correlated only with TSS. Correlations between caspase 1 and lung dysfunction and sFas levels with joint and bone involvement in SSc patients were also observed. The obtained results revealed that disturbances of apoptosis might play a role in SSc pathogenesis. Caspase 1 and sFas serum levels correlate with the skin involvement severity, lung dysfunction, joint and bone changes.

Adolescent↗
PubMed2002

Low-dose ultraviolet A1 phototherapy for extragenital lichen sclerosus: results of a preliminary study.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin disease in which numerous therapies have been used, with only limited success. Because low-dose UVA1 phototherapy has been shown to be an effective treatment option for localized scleroderma, which shares several similar clinical and histologic features with LS, we initiated a clinical trial with this phototherapeutic modality in patients with LS. METHODS: Ten patients suffering from extragenital LS were treated with low-dose UVA1 phototherapy 4 times weekly with single UVA1 doses of 20 J/cm(2). Forty treatment sessions were performed within 10 weeks, resulting in a cumulative UVA1 dose of 800 J/cm(2). RESULTS: Low-dose UVA1 phototherapy resulted in a marked reduction of the clinical score and a significant (P <.05) decrease of ultrasonographically measured skin thickness as well as a highly significant (P <.001) increase of dermal density. The patients reported a remarkable softening and repigmentation of the affected skin. CONCLUSION: Analogous to the treatment results in localized scleroderma, low-dose UVA1 phototherapy seems to be an effective and well-tolerated treatment option for extragenital LS.

Adult↗
PubMed1998

Human autoantibodies reveal titin as a chromosomal protein.

Assembly of the higher-order structure of mitotic chromosomes is a prerequisite for proper chromosome condensation, segregation and integrity. Understanding the details of this process has been limited because very few proteins involved in the assembly of chromosome structure have been discovered. Using a human autoimmune scleroderma serum that identifies a chromosomal protein in human cells and Drosophila embryos, we cloned the corresponding Drosophila gene that encodes the homologue of vertebrate titin based on protein size, sequence similarity, developmental expression and subcellular localization. Titin is a giant sarcomeric protein responsible for the elasticity of striated muscle that may also function as a molecular scaffold for myofibrillar assembly. Molecular analysis and immunostaining with antibodies to multiple titin epitopes indicates that the chromosomal and muscle forms of titin may vary in their NH2 termini. The identification of titin as a chromosomal component provides a molecular basis for chromosome structure and elasticity.

Amino Acid Sequence↗
PubMed1991

Treatment of systemic sclerosis.

Proper classification of patients into diffuse cutaneous and limited cutaneous subsets and the anticipation of complications are the keys to the management of subjects with systemic sclerosis (scleroderma). Patients with early diffuse disease and rapidly progressive skin thickening are at highest risk of developing serious disease of the internal organs (intestine, lung, heart, kidney) and should be considered for disease modifying treatment. The targets of the disease and sites of possible intervention are vascular endothelium (vasoprotective agents), mononuclear cell subsets (immunosuppressive agents), and fibroblasts (colchicine, D-penicillamine). A number of new agents with sound scientific rationale are currently undergoing therapeutic trials. Much can be done to improve the lifestyle of those with scleroderma. The most dramatic recent development is the ability to reverse kidney disease by the prompt use of angiotensin converting enzyme inhibitors and modern methods of renal dialysis and transplantation. Scleroderma is not a hopeless disease.

Colchicine↗
PubMed1999

Efficacy evaluation of prostaglandin E1 against placebo in patients with progressive systemic sclerosis and significant Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon, due to connective tissue diseases, is difficult to treat successfully. Symptomatic improvement has been reported using nifedipine or iloprost, but adverse side effects may limit their use. The purpose of this study was to examine the effects of PGE1 (Alprostadil) in patients with scleroderma and severe Raynaud's disease. METHODS: Twelve females, aged 50-67 years, were included in the study with six of them receiving a 3-hour infusion of alprostadil at the standard dosage of 60 micrograms in 250 cc of physiological infusion for six consecutive days and the remaining six receiving placebo (250 cc of physiological infusion administered in the same manner). RESULTS: After infusion, blood flow, digitally measured by telethermography was increased only in patients treated with alprostadil. The number, frequency and severity of attacks recorded were reduced only in patients treated with alprostadil. No side effects were recorded during and after the infusion. CONCLUSION: In conclusion, alprostadil is effective in the management of Raynaud's phenomenon, due to scleroderma.

Alprostadil↗
PubMed1992

Rheological properties of blood in Raynaud's phenomenon.

Rheological tests were performed in four rigorously defined groups of patients with Raynaud's phenomenon: primary family-related (n = 21), primary family-unrelated (n = 30), 'possible scleroderma' (n = 26), and scleroderma (n = 19). Whole blood and plasma viscosity, and hematocrit were significantly higher in the 'possible scleroderma' group. We conclude that the contribution of central rheological abnormalities in the pathogenesis of Raynaud's phenomenon is limited.

Blood Viscosity↗
PubMed1989

Treatment of systemic sclerosis.

Proper classification of patients into diffuse cutaneous and limited cutaneous subsets and the anticipation of complications are the keys to the management of individuals with systemic sclerosis (scleroderma). Patients with early diffuse disease and rapidly progressive skin thickening are at highest risk to develop serious internal organ involvement (intestine, lung, heart, kidney) and should be considered for disease modifying therapy. The targets of the disease and sites of possible intervention are vascular endothelium (vasoprotection agents), mononuclear cell subsets (immunosuppressive agents), and fibroblasts (colchicine, D-penicillamine). A number of new therapeutic agents with sound scientific rationale are undergoing therapy trials. Much can be done to improve the lifestyle of the scleroderma sufferer. The most dramatic recent development is the ability to reverse kidney involvement with prompt use of angiotensin converting enzyme inhibitors and modern methods of renal dialysis and transplantation. Scleroderma is not a hopeless disease.

Humans↗
PubMed1987

Procollagen gene expression by scleroderma fibroblasts in culture. Inhibition of collagen production and reduction of pro alpha 1(I) and pro alpha 1(III) collagen messenger RNA steady-state levels by retinoids.

Recent studies have demonstrated that retinoids (synthetic vitamin A analogs) can modulate connective tissue metabolism in human skin fibroblast cultures. In this study, we examined the effects of 3 retinoids, all-trans-retinoic acid (RA), 13-cis-RA, and an aromatic retinoid, RO-10-9359, on collagen gene expression in scleroderma fibroblast cultures and matched control fibroblast cultures. The results indicated that all-trans-RA and 13-cis-RA significantly reduced procollagen production both in control and scleroderma fibroblast cultures in a dose-dependent manner. The reduction in procollagen production was paralleled by a similar decrease in steady-state levels of type I and type III procollagen messenger RNAs, which suggests that there is coordinate inhibition on the transcriptional level. In contrast, RO-10-9359 elicited only limited effects on collagen production, and such effects were variable. The results suggest that further development of retinoids might provide an effective means to counteract tissue deposition of collagen in scleroderma and other fibrotic diseases.

Adult↗
PubMed2004

Autoantibodies in SLE but not in scleroderma react with protein-stripped nucleosomes.

Autoantibodies against nucleosomes (ANuA) are known to be sensitive markers for systemic lupus erythematosus (SLE), but their clinical relevance seemed to be limited because sera from patients with progressive systemic sclerosis (PSS) also showed positive reactions with conventional ANuA ELISA test systems (anti-Nu1 ELISA). It was generally assumed thatANuA were associated with both diseases. Using discontinuous sucrose gradient centrifugation to generate pure nucleosomes, we discovered by chance that at the 30-50% sucrose interface an antigen (Nu2) banded which was demonstrably free of non-histone components and histone H1. The two different nucleosome preparations, Nu1 and Nu2, were used in parallel as antigenic substrates in standardised ELISA tests to analyse sera from SLE (295 patients), PSS (119) and patients with other rheumatic diseases (101). With Nu1, 62% of the SLE and 52% of the PSS sera showed positive reactions. Two sera from patients suffering from Sjögren's syndrome (SS) and one from polymyositis were also positive. Using the Nu2 preparation, 58% of the SLE but none of the PSS sera showed a positive reaction. One serum from a patient with SS was also positive. It could be shown that it was the PSS-specific autoantigen Scl-70 in the nucleosome preparation (Nu1) which contributed to the positive reactions of the PSS sera in conventional ANuA test systems, whereas in the Nu2 preparation no remaining Scl-70 was detectable. The present study definitely proved that ANuA are highly and specifically associated with SLE but not with PSS.

Antibodies, Antinuclear↗
PubMed1995

Tranilast inhibits collagen synthesis in normal, scleroderma and keloid fibroblasts at a late passage culture but not at an early passage culture.

We have previously reported that tranilast, an anti-allergic agent, specifically suppresses collagen synthesis in normal skin fibroblasts and to a greater extent in keloid fibroblasts. We found in this study that the specific suppression of collagen synthesis by tranilast was limited to the fibroblasts with a high passage number (passage 8-10). In normal skin fibroblasts with a low passage number (passage 1-2), tranilast exerted no significant effect on collagen synthesis. This was also observed with scleroderma and keloid fibroblasts. This result suggests that inhibition of collagen by tranilast will be dependent on in vitro cellular aging and that serial cell passages result in the loss of the cell phenotype resistant to tranilast effect.

Cells, Cultured↗
PubMed1999

Development and validation of a self-administered systemic sclerosis questionnaire (SySQ).

OBJECTIVE: To develop a self-administered systemic sclerosis questionnaire (SySQ) covering condition-specific functional limitation and symptoms. METHODS An initial item pool was generated by open patient interviews. A preliminary questionnaire was devised using 62 systemic sclerosis (SSc; scleroderma) patients. Factor analysis was used for further selection and grouping of items into distinct scales. The retrieved scales were tested for internal consistency and test-retest reliability. Spearman's rank correlation and Wilcoxon's rank sum test were used to examine hypothesized associations of the SySQ with various clinical and laboratory features. RESULTS: Altogether 32 SySQ items were selected and aggregated into 12 scales addressing 'pain', 'stiffness', 'coldness', 'complex functions', 'strength of hands', 'rising', 'walking', shortness of breath', 'upper airway symptoms', 'eating', 'swallowing' and 'heartburn/regurgitation'. Internal consistency ranged from 0.93 ('complex functions') to 0.73 ('heartburn/regurgitation'); Spearman's correlation coefficient for test retest reliability ranged from 0.93 to 0.73 (P < 0.001). While the scales were associated with corresponding functional impairments, there was generally less association with morphological impairments. CONCLUSION: The SySQ is a valid and reliable condition-specific measure in patients with SSc. Individually applicable scales cover a wide spectrum of general and organ-specific SSc symptoms and functional limitation. After further validation with respect to its ability to measure change, it may be used in clinical, health services and epidemiological research.

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↗
PubMed1987

[Update on the treatment of systemic scleroderma].

Renewed clinical trials of drugs used for many years and the availability of new symptomatic therapies allows selection of appropriate treatment for progressive systemic sclerosis. Colchicine damages intracytoplasmic microtubules and when administered at a dose of at least 1.5 mg per day during early stages of the disease reduces cutaneous sclerosis without improving other manifestations of scleroderma. D-penicillamine inhibits bridge formation during collagen maturation, acting mainly on cutaneous infiltration with more uncertain effects on visceral localizations of the disease. It can be effective against pulmonary lesions but, as with colchicine, must be prescribed early. Its action is delayed and its side effects limit its use. Corticoids are of very limited efficiency and although they may be useful for relief of muscular and articular localizations they have been accused of precipitating onset of renal insufficiency. Immunodepressants have until now been assessed as ineffective. The demonstration in patients with progressive systemic sclerosis of abnormal activation of immunity system cells suggested the use in this collagen disease of a new immunosuppressive agent, cyclosporine A, but clinical utility of this drug remains to be demonstrated. In systemic sclerosis efficacy of plasma exchange is mainly directed against vasomotor disorders and digital ulcerations, but study results are difficult to assess because of associated therapies. Constraints and risks of this treatment also considerably reduce its interest. The coagulation factor XIII acts as a stabilizing factor of collagen. It reduces cutaneous infiltration but its efficacy is based on results of a single controlled trial and its use is limited by the need for repeated intravenous injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1989

T lymphocyte subset abnormalities and HLA antigens in scleroderma (systemic sclerosis).

Studies of T lymphocyte subsets were carried out in a group of 50 scleroderma patients, of whom 46 were also HLA phenotyped. The total lymphocyte count was depressed in 22 patients, and CD4 (helper cells) numbers were normal. CD8 (suppressor-cytotoxic) cells were reduced in 27 patients, and the CD4/CD8 number ratio increased above normal in three additional patients, resulting in 30 patients being classified as CD8-deficient. In the 46 patients HLA phenotyped, DRw8 was significantly increased in the entire patient group, but when the patients were subdivided into CD8-deficient (n = 29) and CD8-normal (n = 17), the increase in DRw8 was confined to the CD8-deficient patients. B18 was also increased in patients with limited sclerosis, while DR4 and DRw53 were significantly decreased and DR5 significantly increased in patients with more extensive skin sclerosis. These findings suggest that scleroderma is a heterogeneous condition and that this heterogeneity is reflected in different HLA profiles in patients subtyped according to their clinical profile and subpopulations of T cells.

Adult↗
PubMedDate not supplied

Scleroderma in childhood: a 35-year history of cases and review of the literature.

Scleroderma is a connective tissue disease with a variety of clinical presentations. The purpose of our study was to review representative cases of scleroderma in childhood to determine the initial presentation, course of the disease, orthopaedic manifestations, and the necessity and success of surgical intervention. Records from the four medical centers were retrospectively reviewed to identify the patients who were diagnosed with scleroderma over the past 35 years. Data on disease presentation, course, treatment, and response were collected. Seventeen cases representing the variety of clinical presentations are presented. Scleroderma characteristically presents with asymmetric lesions involving the extremities and remains a diagnostic and therapeutic challenge. Treatment must be individualized to the patient and his or her specific limitations brought about by the disease. Early diagnosis, supportive care, and physical therapy combined with early orthopaedic surgical intervention to release joint contractures are among the most efficacious treatments.

Adolescent↗
PubMedDate not supplied

Association of CTLA-4 with systemic sclerosis in Japanese patients.

OBJECTIVE: The contribution of CTLA-4 alleles to the pathogenesis of systemic sclerosis (SSc) was studied in Japanese patients. METHODS: CTLA-4 typing in 2 dimorphic sites, +49 A/G and -308 C/T, was carried out in 62 SSc patients and 107 normal subjects by the PCR-RFLP (restriction fragment length polymorphism) method. HLA-DRB1*15 and *08 genotyping were carried out by the PCR-SSCP (simple-stranded DNA conformation polymorphism) method. RESULTS: In SSc the frequency of the +49A allele increased slightly (40.3%), but was not significant. In SSc with diffuse scleroderma and SSc with anti-topoisomerase I antibody, the +49A also increased (43.8%, and 48.0%, respectively) but again was not significant. A significant increase in the +49A was not observed in SSc with HLA-DRB1*1502 or ORB1*0802. In contrast, the +49A had significantly increased in SSc with the anti-RNP antibody [52.9%, p = 0.0337, Odds ratio (OR) = 2.27 (95% confidential interval (CI) = 1.09-4.71)]. HLA-DRB1*1502 and *0802 had no influence on the association of anti-RNP antibody with the +49A. The +49AA genotype increased significantly in SSc without lung fibrosis [31.8%, p = 0.0456, OR = 3.37 (CI = 1.16-9.87)], especially in limited SSc without lung fibrosis [33.3%, p = 0.0319, OR = 3.62 (CI = 1.16-11.29)]. The dimorphism at -308 did not associate with SSc. CONCLUSION: In Japanese scleroderma, the +49A allele of CTLA-4 increased in the presence of SSc with the anti-RNP antibody.

Abatacept↗
PubMed2003

European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria.

OBJECTIVE: To further assess the construct validity of the three European Scleroderma Study Group (EScSG) preliminary activity indices for systemic sclerosis (SSc): for SSc as a whole, for diffuse SSc (dcSSc), and for limited SSc (lcSSc). METHODS: 30/290 SSc clinical charts collected for the EScSG study used to develop activity criteria for SSc were selected and sent to four clinical experts in SSc. The experts ranked the charts from 1 to 30 (1=lowest activity, 30=highest activity). The relationships among the ranks given by each investigator and each of the three scores, and between any two of the ranks were investigated. RESULTS: A consistently significant correlation (r(s)=0.530-0.712) was found between the ranks given by each of the four investigators and the index for the entire patient group. A similar level of agreement was detected between each couple of the four experts (r(s)=0.428-0.720). Moreover, the ranks given in patients with an index >3 were significantly higher than those given for patients with an index < or =3. This cut off point had previously been shown to best discriminate patients with active disease. CONCLUSIONS: Of the originally developed activity indexes, the whole series index has been externally validated. The index comprises the first preliminary, but necessary, groundwork to improve the concept of disease activity in SSc, which is still ill defined. It can be used as a preliminary activity index in clinical investigational studies.

Humans↗