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PubMed2005

[Scleroderma-like lesions in the course of autoimmune hepatitis. Case report].

UNLABELLED: We present a case of a 31-year old man with a 17 year history of Raynaud's symptom and contractures of the both hands' interdigitalis joints, progressive skin sclerosis of the arms, forearms and hands, telangiectases on the face skin. Because of the painful leg ulcers on the outer surface of both shins and on the dorsal part of the right foot (they appeared almost 10 years ago) the patient finally was admitted to our Department. Physical examination revealed hepatosplenomegaly, in laboratory tests leukopenia, mild thrombocytopenia, elevated ESR, elevated serum levels of IgG, IgM, IgA, creatine kinase level and hypergammaglobulinaemia were found. Neither anti-HBV or anti-HCV or antiphospholipid antibodies were present. Immunofluorescence test (HEP-2 cells) revealed the presence of antinuclear antibodies in a titer of 1:2560 (homogenous and partially speckled pattern) and by immuno-diffusion-anti-Ro antibodies. Hepatosplenomegaly was diagnosed by USG examination. Endocrinological, neurological, surgical and pulmonological examinations gave no abnormalities. Liver biopsy showed features of chronic inflammation and autoimmune hepatitis was diagnosed. COMMENT: the presence of scleroedematous lesions of the skin accompanying chronic hepatic inflammation enabled us to establish the diagnosis of scleroderma-like lesions in the course of long lasting mild autoimmune hepatitis.

Adult↗
PubMed1978

Collagen in the cellular and fibrotic stages of scleroderma.

The collagen in localized and systemic scleroderma skin was studied by light microscopy with silver impregnation (50 patients), electron microscopy (14 patients), and immunofluorescence microscopy using specific antibodies against Type I and Type III collagens (12 patients). In the cellular stage, the dermis and adipose tissue revealed perivascular or diffuse cellular infiltrates (mostly lymphocytes, plasma cells, and macrophages), accompanied by deposition of Type III collagen. The lower dermis also showed an increase in Type III collagen. In the fibrotic stage, the papillary layer showed a reduction and/or clumping of Type III collagen as compared to normal skin. The lower dermis and the adipose tissue revealed compact collagen consisting exclusively of Type I collagen or a mixture of Type I and Type III collagen. The pattern of Type III collagen distribution was similar to that of reticulin, thus suggesting that at least some reticulin fibrils may represent Type III collagen.

Adipose Tissue↗
PubMed2002

Reproductive factors and the risk of scleroderma: an Italian case-control study.

OBJECTIVE: To investigate the association between scleroderma (systemic sclerosis; SSc) and reproductive factors in a hospital-based case-control study conducted at the University Hospital of Verona in Northeastern Italy. METHODS: Forty-six confirmed cases of SSc in women (42 with diffuse SSc and 4 with limited SSc) and 153 female control subjects with orthopedic disorders were recruited at the University Hospital. For each subject, information on age at first pregnancy, number of children and abortions, and use of oral contraceptives was obtained by means of a structured questionnaire, and information on the subject's occupational history and lifestyle factors was also sought. RESULTS: Parous women had a reduced risk of SSc (age-adjusted odds ratio [OR] 0.3, 95% confidence interval [95% CI] 0.1-0.8) compared with nulliparous women. The risk decreased with an increasing number of children: the age-adjusted OR was 0.6 (95% CI 0.2-1.7) for those women who had had 1 child, 0.3 (95% CI 0.1-0.7) for those having had 2 children, and 0.3 (95% CI 0.1-0.8) for those having had 3 or more children. Abortive pregnancies were inversely related to SSc risk: for women who had an abortion, the OR was 0.5 (95% CI 0.2-1.5) compared with women with no history of abortion. The overall history of any pregnancy (abortive or age-adjusted complete) was associated with a reduced risk of SSc (age-adjusted OR 0.3, 95% CI 0.1-0.7). CONCLUSION: Since the incidence of SSc is higher in women and has its peak after childbearing age, it has been hypothesized that immunobiologic modifications during pregnancy may be associated with SSc development. Our findings showing a reduced risk of SSc among parous women seem to exclude the possibility of pregnancy itself as a risk factor for SSc. The role of HLA compatibility between the mother and the fetus, however, should be evaluated in further research.

Abortion, Spontaneous↗
PubMed1986

Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis.

Ninety patients who fulfilled the ARA criteria for systemic sclerosis were divided into 6 groups on the basis of cutaneous areas of sclerosis. Anticentromere antibody (ACA) was found in 14 of 28 patients of the first 2 groups, the first group being pure sclerodactyly, and the second sclerodactyly plus minimal sclerotic lesions (eyelids, neck, armpits). In the other 4 groups (62 patients) in whom skin sclerosis was more diffuse, ACA was found in one case. Fluorescent antinuclear antibodies (FANA) with a diffusely grainy pattern, those with a nucleolar pattern and the anti-Scl-70 antibody were present in all 6 groups, but were significantly more frequent in the last 4 groups than in Groups 1 and 2. The cumulative survival rate as well as disease duration were found to be significantly longer in the first 2 groups designated "limited cutaneous systemic sclerosis," than in the 5th and 6th groups, i.e., patients in whom the trunk also was involved: "diffuse cutaneous systemic sclerosis." The cumulative survival rate and disease duration of patients with skin sclerosis of the face and limbs, but not of trunk, were not significantly different either from those of patients with limited cutaneous systemic sclerosis or from those of patients with diffuse cutaneous systemic sclerosis. Thus these patients show the same antibody pattern as diffuse cutaneous systemic sclerosis, but the prognosis not significantly different from the other 2 subsets. We suggest they constitute a distinct subset of systemic sclerosis for which we propose the name "intermediate cutaneous systemic sclerosis."

Adolescent↗
PubMed1995

Elevated procollagen type I carboxyterminal propeptide production in cultured scleroderma fibroblasts.

BACKGROUND: We recently reported that the serum concentration of procollagen type I carboxyterminal propeptide (P1CP) in patients with systemic sclereosis (SSc) was elevated. In the present study, we investigated collagen metabolism in in vitro cultured scleroderma fibroblasts by measuring P1CP levels in the culture medium. METHODS AND RESULTS: Spontaneous P1CP production was 4.2 times higher in fibroblast cultures from patients with SSc (n = 11) than in those from healthy controls (n = 10). P1CP production in fibroblasts derived from diffuse cutaneous SSc patients was significantly greater than that from limited cutaneous SSc patients. The serum P1CP level in SSc patients was correlated with the P1CP production of cultured fibroblasts (r = 0.815, p < 0.005). Transforming growth factor beta increased P1CP production, and gamma-interferon decreased P1CP production similarly in both SSc and normal fibroblasts. In contrast, histamine dihydrochloride increased P1CP production only in SSc fibroblasts but not in controls. CONCLUSION: These findings suggest that P1CP production in SSc fibroblasts is relevant to in vivo collagen synthesis in SSc patients.

Adolescent↗
PubMed2000

Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients.

OBJECTIVE: To describe the demographic, clinical, and laboratory features and natural history of patients with systemic sclerosis sine scleroderma (ssSSc), and to compare them with those of patients with SSc and limited cutaneous involvement (IcSSc). METHODS: The University of Pittsburgh Scleroderma Databank served as the data source. Patients were divided into those who had no skin thickening (ssSSc) and those who had skin thickening only distal to elbows or knees and/or of the face (IcSSc) during their disease course. These two groups were compared with regard to demographic characteristics, clinical, laboratory, and serologic features, and survival rates. Chi-square and Student's t-test analyses were performed, and Fisher's exact test was used as appropriate. RESULTS: Of 555 consecutive patients without diffuse cutaneous SSc, 48 (9%) had ssSSc and 507 (91%) had IcSSc. The ssSSc patients had a mean total disease duration of 18.6 years (15.1 years before study entry and 3.5 years of followup after study entry), and had not developed IcSSc or another connective tissue disease. Other than the absence of skin thickening, the ssSSc group had no significant differences in individual internal organ involvements, laboratory features, serum autoantibody type, or survival rate compared with patients with IcSSc. Within the category of lung involvement, patients with ssSSc had a significantly greater frequency of dyspnea with mild exertion or at rest, and a tendency toward reduced carbon monoxide diffusing capacity (<70% of predicted normal) and primary pulmonary arterial hypertension. Patients with IcSSc had significantly more frequent individual manifestations of digital pitting scars, digital-tip ulcers, telangiectasia, and calcinosis than those with ssSSc, in part related to increased time of observation. Puffy fingers and finger joint contractures were detected significantly more often in IcSSc patients. CONCLUSION: Systemic sclerosis sine scleroderma should be included in the spectrum of SSc with limited cutaneous involvement and should not be considered a distinct or separate disorder.

Adolescent↗
PubMed2006

Pulmonary involvement in systemic sclerosis.

Scleroderma, also known as progressive systemic sclerosis (SSc), is a multisystem autoimmune disorder characterized by inflammation and fibrosis involving the skin as well as internal organs such as the vasculature, esophagus, and the respiratory tract. Pulmonary involvement consists most often of interstitial fibrosis and pulmonary vascular disease leading to pulmonary arterial hypertension (PAH). Bronchiectasis is an uncommon pulmonary manifestation of systemic sclerosis. Pulmonary hemorrhage with acute renal failure and diffuse alveolar hemorrhage in the absence of a history of renal involvement or penicillamine intake have rarely been reported in patients with systemic sclerosis.On high resolution CT, evidence of interstitial disease is seen in approximately 90% of patients, the main findings being a fine reticular pattern involving the subpleural regions of the lower lobe. Other common findings include ground-glass opacities, honeycombing, and parenchymal micronodules. The most distinctive pulmonary histologic findings in patients with scleroderma are the vascular changes found in PAH in the absence of significant interstitial fibrosis.There is no strong evidence that any drug alters the course of the two main types of lung disease in systemic sclerosis. This apparent failure of therapy may reflect the fact that pulmonary involvement is usually identified at an established or late stage. It has been suggested that, for fibrosing alveolitis, corticosteroids are most effective if given in combination with cyclophosphamide. In some patients with SSc, PAH has been considered as a major cause of morbidity and mortality. Centrally infused prostacyclin (epoprostenol) and its subcutaneously infused analog treprostinil improve hemodynamics, as well as the quality of life and survival in these patients. Iloprost has also shown a positive effect on PAH in SSc patients. More recently, bosentan, an endothelin receptor antagonist, has proved effective in controlling PAH after 6 months' treatment. Sildenafil has been used as a selective pulmonary vasodilator in SSc patients with isolated PAH. This drug decreased mean pulmonary artery pressure and pulmonary vascular resistance, and increased cardiac output, with much improvement of the physical condition of the patients. Lung transplant can be considered as a last option.Clinicians must be aware of the possibility of lung disease in patients with SSc so that it can be treated as early as possible.

Endothelin Receptor Antagonists↗
PubMed2002

[How to recognize scleroderma].

Systemic sclerosis is a multisystem disorder characterized by the presence of connective tissue sclerosis, vascular abnormalities concerning small-sized arteries and the microcirculation, and autoimmune changes. This disease is usually preceded by Raynaud's phenomenon. Cutaneous changes are useful for diagnosis. Sclerosis is initially proeminent on hands with frequently pitted scars. Telangiectases and calcium deposits are mainly observed in a good prognosis subset of the disease (CREST) characterized by the association of limited skin involvement and anti-centromere antibodies with possible late onset of pulmonary hypertension. The bad prognosis subset is associated with diffuse cutaneous sclerosis, pulmonary fibrosis, gastrointestinal disease, myocardial involvement and anti-topo-isomerase I antibodies. Histological skin changes are similar to those observed in morphea. In morphea, there is only localized sclerosis of the skin with highly variable aesthetic disability. The condition may be subdivided clinically into the following types: circumscribed plaques, linear morphea and frontoparietal lesions. The last two forms may be associated with atrophy of the underlying anatomic structures. Many other diseases may have a scleroderma-like appearance. In these diseases, nail folds abnormalities, visceral involvement and immunological changes are usually different from those observed in systemic scleroderma.

Diagnosis, Differential↗
PubMed1999

[Synthetic glucocorticoid in the treatment of connective tissue diseases].

Synthetic glucocorticoids are the most potent anti-inflammatory and immunosuppressive drugs, which have been used for almost 50 years as a core drug for the treatment of connective tissue diseases. The mechanism of action of glucocorticoids as anti-inflammatory or immunosuppressive drug is considered as the repression of inflammatory cytokines, receptors of cytokines, and adhesion molecules. When 60 mg of prednisolone is administered in 3 divided doses, the plasma concentrations are around 20-30 micrograms/dl during the day time, in which condition around 90% of GC receptors are occupied. However, the concentration will decrease almost to 0 microgram/dl in the next early morning. In case of methyl prednisolone pulse therapy, about 40 micrograms/dl of the steroid is present in the next morning. These kinetics are important when we consider the glucocorticoid therapy. In the treatment of connective tissue diseases, the combination of the steroid therapy with the immunosuppressive therapy should always be considered. In diffuse proliferative lupus nephritis, glucocorticoid dosage, started at high level to suppress the clinical activity of SLE, decrease rather rapidly while cytotoxic drugs are administered at least for 2 years. In the treatment of systemic sclerosis, normotensive scleroderma kidney is treated with moderate dose of glucocorticoid and cytotoxic drugs. It is our clinical impression that low dose glucocorticoid is quite effective in the treatment of rheumatoid arthritis. However, low dose glucocorticoid therapy is effective for the patient's sense of well-being, but is scarsely effective for the articular symptoms itself and shows intense rebound phenomenon when glucocorticoid is withdrawn.

Connective Tissue Diseases↗
PubMed1996

Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous involvement: association with serum anti-U3RNP antibody.

OBJECTIVE: To describe a group of patients with systemic sclerosis (SSc) and diffuse cutaneous (dc) involvement with isolated pulmonary hypertension (IPHT) and to compare them to 2 other SSc patient groups, i.e., one with limited cutaneous (lc) involvement with IPHT and another with dcSSc without IPHT. METHODS: The Pittsburgh Scleroderma Databank was screened to identify appropriate patients. SSc specific serum autoantibodies were determined using published methods. Chi-squared tests and Kaplan-Meier survival analysis were performed. RESULTS: During the period 1975-92, 60 of 580 (10%) consecutive new patients with lcSSc and 14 of 677 (2%) with dcSSc have developed IPHT (p < 0.0001). The patients with IPHT did not differ from their parent dc or lc groups by age, race, sex, or cutaneous manifestations. All 14 patients with dcSSc IPHT had minimal or no pulmonary interstitial fibrosis on chest radiograph. The 12 tested had a striking reduction in DLCO (mean 50% of predicted normal), similar to results for patients with lcSSc with IPHT. Of note, 5 of these 14 patients had survived "scleroderma renal crisis" 1.3 to 10.7 (mean 5.5) years before onset of IPHT. Six of 13 (46%) patients with dcSSc with IPHT were positive for serum anti-U3RNP antibody by immunoprecipitation, and one had the typical nucleolar staining pattern of anti-U3RNP, but was not tested for U3RNP by immunoprecipitation. In contrast, only 13 (6%) of the 244 patients with dcSSc without IPHT (p < 0.0001) had anti-U3RNP antibody. Survival from the first reported symptom consistent with pulmonary hypertension (usually dyspnea on exertion) was uniformly poor in both IPHT groups, with the vast majority of patients dying during the first 2 years. CONCLUSION: Patients with SSc with dc involvement can develop severe, fatal isolated pulmonary arterial hypertension. This complication occurs disproportionately more often in patients with serum anti-U3RNP antibody.

Adult↗
PubMed2001

Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway.

OBJECTIVE: To explore the role of reactive oxygen species (ROS) in the in vitro activation of skin fibroblasts from patients with systemic sclerosis (SSc). METHODS: Fibroblasts were obtained from involved skin of patients with limited or diffuse SSc. Oxidative activity imaging in living cells was carried out using confocal microscopy. Levels of O2- and H2O2 released from fibroblasts were estimated by the superoxide dismutase (SOD)-inhibitable cytochrome c reduction and homovanilic acid assays, respectively. To verify NADPH oxidase activation, the light membrane of fibroblasts was immunoblotted with an anti-p47phox-specific antibody. Fibroblasts were stimulated with various cytokines and growth factors to determine whether any of these factors modulate ROS generation. Cell proliferation was estimated by 3H-thymidine incorporation. Northern blot analysis was used to study alpha1 and alpha2 type I collagen gene expression. RESULTS: Unstimulated skin fibroblasts from SSc patients released more O2- and H2O2 in vitro through the NADPH oxidase complex pathway than did normal fibroblasts, since incubation of SSc fibroblasts with diphenylene iodonium, a flavoprotein inhibitor, suppressed the generation of ROS. This suppression was not seen with rotenone, a mitochondrial oxidase inhibitor, or allopurinol, a xanthine oxidase inhibitor. Furthermore, the cytosolic component of NADPH oxidase, p47phox, was translocated to the plasma membrane of resting SSc fibroblasts. A transient increase in ROS production was induced in normal but not in SSc fibroblasts by interleukin-1beta (IL-1beta), platelet-derived growth factor type BB (PDGF-BB), transforming growth factor beta1 (TGFbeta1), and H2O2. Treatment of normal and SSc fibroblasts with tumor necrosis factor a (TNFalpha), IL-2, IL-4, IL-6, IL-10, interferon-alpha (IFNalpha), IFNgamma, granulocyte-macrophage colony-stimulating factor (GM-CSP), G-CSF, or connective tissue growth factor (CTGF) had no effect on ROS generation. Constitutive ROS production by SSc fibroblasts was not inhibited when these cells were treated with catalase, SOD, IL-1 receptor antagonist, or antibodies blocking the effect of TGFbeta1, PDGF-BB, and other agonists (IL-4, IL-6, TNFalpha, CTGF). In contrast, treatment of SSc fibroblasts with the membrane-permeant antioxidant N-acetyl-L-cysteine inhibited ROS production, and this was accompanied by decreased proliferation of these cells and down-regulation of alpha1(I) and alpha2(I) collagen messenger RNA. CONCLUSION: The constitutive intracellular production of ROS by SSc fibroblasts derives from the activation of an NADPH oxidase-like system and is essential to fibroblast proliferation and expression of type I collagen genes in SSc cells. Our results also exclude O2-, H2O2, IL-1beta, TGFbeta1, PDGF-BB, IL-4, IL-6, TNFalpha, or CTGF as mediators of a positive, autocrine feedback mechanism of ROS generation.

Acetylcysteine↗
PubMed1996

Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders.

Connective tissue growth factor (CTGF) is a novel peptide that exhibits platelet-derived growth factor-like activities and is produced by skin fibroblasts after activation with transforming growth factor-beta. Coordinate expression of transforming growth factor-beta followed by CTGF during wound repair suggests a cascade process for control of tissue regeneration. We recently reported a significant correlation between CTGF mRNA expression and histologic sclerosis in systemic sclerosis. To confirm the relation between CTGF and skin fibrosis, we investigated CTGF gene expression in tissue expression in tissue sections from patients with localized scleroderma, keloid, other sclerotic skin disorders using nonradioactive in situ hybridization. In localized scleroderma, the fibroblasts with positive signals for CTGF mRNA were scattered throughout the sclerotic lesions with no preferential distribution around the inflammatory cells or perivascular regions, whereas the adjacent nonaffected dermis was negative for CTGF mRNA. In keloid tissue, the fibroblasts positive for CTGF mRNA were diffusely distributed, especially in the peripheral expanding lesions. In scar tissue, however, the fibroblasts in the fibrotic lesions showed partially positive signals for CTGF mRNA. In eosinophilic fasciitis, nodular fasciitis, and Dupuytren's contracture, CTGF mRNA was also expressed partially in the fibroblasts of the fibrotic lesions. Our findings reinforce a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-beta plays an important role in the pathogenesis of fibrosis, as it is the only inducer for CTGF identified to date.

Adolescent↗