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PubMed1998

Clinical approach to scleroderma.

Systemic sclerosis (SSc) is a heterogenous disease with a morbidity and mortality that varies widely. Nonetheless, the future clinical course of an individual patient can be estimated based on the severity of skin and internal organ involvement within the first several years of the disease. Patients with limited cutaneous SSc (ISSc) have skin thickening below the elbows or knees and may have face and neck involvement. Patients with this subtype of SSc have Raynaud's phenomenon, digital ulcers, and esophageal dysfunction. Significant morbidity and mortality arises in those patients with ISSc who develop interstitial lung disease or pulmonary artery hypertension. Patients with diffuse cutaneous SSc (dSSc) have skin thickening above the elbows and knees or on the trunk. These patients have a more abrupt onset of disease, often with constitutional symptoms and arthalgias. Severe heart, lung, gut, and renal involvement, if it occurs, tends to develop within the first 5 years of disease, especially within the first several years. Patients with significant internal organ involvement have a poorer prognosis than patients who do not. The goals of the initial history and physical and laboratory examinations are to classify the type of scleroderma as ISSc or dSSc, to estimate disease duration, and to define the extent and severity of organ involvement. Treatment of SSc is organ based. Treatment may reduce morbidity associated with Raynaud's phenomenon, digital ulcers, esophageal dysmotility, esophageal reflux, gut dysmotility, arthralgias, myositis, and pulmonary artery hypertension. Therapy may stabilize lung function in patients with interstitial lung disease with alveolitis and stabilize renal function in patients with renal crisis. The overall prognosis for patients with SSc appears to be improving. Patients with early dSSc should be considered for enrollment onto protocol testing of potential disease-modifying therapies.

Arthralgia↗
PubMedDate not supplied

Thrombin-mediated cellular events in pulmonary fibrosis associated with systemic sclerosis (scleroderma).

The vascular hypothesis for the pathogenesis of systemic sclerosis was perhaps Professor LeRoy's most important scientific contribution. One early and important consequence of vascular injury is the release of activated thrombin. In this manuscript we present our data and review the current understanding of the role played by thrombin in the process of fibrosis, particularly as it relates to scleroderma lung disease. Thrombin's cellular effects are intimately involved in promoting myofibroblast differentiation, endothelial cell activation, extracellular matrix protein deposition, and the induction of important profibrotic factors. Such studies confirm that thrombin is one of the major mediators in the development and progression of pulmonary fibrosis. Therefore, targeting the major receptor of thrombin, PAR-I, and its downstream signaling molecules may lead to novel therapeutic approaches for the management of scleroderma lung fibrosis. We are indebted to Dr LeRoy for his many contributions to the field of scleroderma, and for all that he did to stimulate our interest in these studies.

Apoptosis↗
PubMed2002

[Cardiac and pulmonary involvement in scleroderma].

Systemic sclerosis is a connective tissue disease characterised by microvascular involvement and fibrosis affecting skin, lung, heart and intestinal tract. Sixty percent of deaths are secondary to heart or lung involvement and (or) to pulmonary hypertension. Clinical expression of these complications is present only in patients with the most severe problems. Therefore, it is appropriate to systematically and repeatedly look for these complications, even in asymptomatic patients. Heart involvement can present as cardiomyopathy, pericarditis, conduction or repolarisation abnormalities and arrhythmia, sometimes leading to sudden death. Pulmonary hypertension is due either to direct involvement of pulmonary arteries or is secondary to lung fibrosis. Doppler echocardiography and lung function tests are systematically and repeatedly proposed to screen patients for pulmonary hypertension at initial diagnosis and during follow-up. Right heart catheterisation ascertains the diagnosis of pulmonary hypertension. Chronic pulmonary interstitial fibrosis is the most frequent manifestation of lung involvement. High resolution computed tomography is the method of choice to make the diagnosis and to assess the severity of the lesions. Treatment is not completely standardised. However, a severe and rapidly progressing lung involvement is probably a good indication of immunosuppressive agents, such as cyclophosphamide.

Diagnosis, Differential↗
PubMed1976

Progressive systemic sclerosis (scleroderma). First case report in a Nigerian.

The first case of progressive systemic sclerosis in a Nigerian is described. In addition to the typical features of the disease, the case shows affection of the peripheral nerves, a very rare complication. The latter led to a mistaken diagnosis of leprosy. The reasons for the rarity of this disorder in the indigenous Africans and its differentiating features from leprosy are discussed.

Adult↗
PubMed1999

Monocytes of patients wiht systemic sclerosis (scleroderma spontaneously release in vitro increased amounts of superoxide anion.

It has been suggested that toxic oxygen free radicals can be involved in the pathogenesis of systemic sclerosis (scleroderma) (SSc). Because the cells that contribute to the generation of free radicals are not known, our aim was (i) to evaluate the ability of unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes and polymorphonucleate neutrophils of SSc patients to generate superoxide anion (O2*-); and (ii) to investigate whether the O2*- produced by these cells involved the activation of nicotinamide-adenine dinucleotide diphosphate oxidase biochemical pathway. Employing the superoxide dismutase-inhibitable reduction of cytochrome c to evaluate the generation of O2*-, unmanipulated monocytes of SSc patients generated more O2*- than primary Raynaud's phenomenon patients and normal control monocytes (p = 0.0001), and the release was higher in patients with diffuse cutaneous involvement and 5 y or less disease duration (p = 0.02). The involvement of nicotinamide-adenine dinucleotide diphosphate oxidase in the enhanced 02*- production was demonstrated by the finding that the cytosolic components of the enzyme, p47phox and p67phox, were both translocated to the plasma membrane of enriched but otherwise unmanipulated monocytes of SSc patients. The involvement of mitochondrial oxidases was excluded by the lack of inhibition of O2*- production when monocytes were incubated in the presence of rotenone, a mitochondrial oxidase inhibitor. Upon stimulation with phorbol 12-myristate 13-acetate, monocytes of SSc patients produced more O2*- than controls. In SSc patients untreated polymorphonucleate neutrophils generated significantly less O2*- than monocytes (p = 0.0001) and only slightly more than polymorphonucleate neutrophils of primary Raynaud's phenomenon patients and normal controls (p = 0.03). In conclusion, we demonstrate that in patients with scleroderma, unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes release in vitro increased amounts of superoxide anion through the activation of nicotinamide-adenine dinucleotide diphosphate oxidase and, thus, contribute to the oxidative stress found in this disease.

Adult↗
PubMed1986

Long-term ranitidine in progressive systemic sclerosis (scleroderma) with gastroesophageal reflux.

Eighteen patients with progressive systemic sclerosis and symptomatic gastroesophageal reflux were studied for 20 weeks. All patients were initially treated with ranitidine for a 6-week period. From the 7th week the patients were randomized to further treatment with either ranitidine or placebo. Heartburn and dysphagia, the endoscopic appearance of the esophageal mucosa, the esophageal motility, and gastroesophageal reflux were assessed during the study. The efficacy of ranitidine was maintained during the 20-week period. A shift to placebo was recognized by the patients almost immediately and caused heartburn and esophageal mucosal inflammation to increase significantly.

Adult↗
PubMed1977

Histocompatibility antigens in progressive systemic sclerosis (scleroderma).

A study was undertaken to determine the distribution of major histocompatibility (HLA) antigens in progressive systemic sclerosis (PSS) (scleroderma). A total of 106 patients with PSS and 208 normal controls were tested for the presence of 18 different HLA antigens by the microcytotoxicity technique. These patients were equally divided between patients with classical diffuse scleroderma (53 patients) and those with the CREST syndrome variant of the disease (53 patients). When the P values were multiplied by 18, to correct for the number of antigens studied, no significant alteration in the frequency of any HLA antigen was found for the entire group of scleroderma patients or for either of the two subpopulations.

Calcinosis↗
PubMed1999

Systemic sclerosis (scleroderma) in two iron ore mines.

Six males with systemic sclerosis were observed in the work forces of two iron ore mines. The usual spectrum of clinical features encountered in systemic sclerosis patients were present. Histologic examination of pulmonary tissue was performed on three of the cases and showed features of both silicosis and scleroderma but to different degrees and stages of development. Exposure to high levels of silica-containing dusts had occurred in all six cases.

Adult↗
PubMedDate not supplied

A five-year followup of hand function and activities of daily living in systemic sclerosis (scleroderma).

The purpose of this study was to identify hand factors that change over a five-year period that may be risk factors for the development of functional disability in persons with systemic sclerosis (scleroderma). Sixty individuals with scleroderma were administered assessments of grip and pinch strength, joint range of motion, and pain, and were observed for the presence of digital ulcers, digital scars, calcium deposits, puffy fingers, and tendon friction rubs. Matched-pairs chi square analyses and Fisher's exact tests were performed to compare variables at year 1 and five years later. Grip and pinch strength increased as did joint motion except for the wrist and thumb carpometacarpal joint. There were also significant increases in the presence of scars, friction rubs, calcium deposits, and puffy fingers. Regression analysis was done to determine which variables predicted functional ability. Only puffy fingers predicted functional disability. In conclusion, hand impairment persisted over time while functional ability decreased.

Activities of Daily Living↗
PubMed1998

Mortality and causes of death of 344 Danish patients with systemic sclerosis (scleroderma)

OBJECTIVE: To determine survival, mortality and causes of death in Danish patients with systemic sclerosis (scleroderma), and to analyse how these parameters are influenced by demographic variables and the extent of skin involvement. METHODS: A cohort of 344 patients with incident systemic sclerosis (SSc) after 1 January 1960 was retrospectively identified, representing 3716 patient-years of follow-up. The vital status at the end of the study ultimo 1996 was established by reviewing the clinical charts and by contacting the Danish Central Person Register. The causes of death were based on information obtained from the hospital charts and the autopsy reports (80%) and death certificates (20%). The extent of skin sclerosis was described by means of a two-subset model (limited and diffuse involvement) and a three-subset model (digital, extremity and truncal involvement) in all patients. Expected numbers of deaths were calculated by means of age- and sex-specific mortality rates of the general Danish population. RESULTS: Crude mortality rates were 6.5 and 3.9%/yr, respectively, in men and women. The standardized mortality ratio (SMR) was 2.9 (95% CI 2.5-3.4) and was not significantly influenced by sex or age at disease onset. Mortality rates were significantly increased in patients with diffuse skin sclerosis (SMR 4.5, 95% CI 3.5-5.7) and patients under the age of 35 yr (SMR 13, 95% CI 2.7-37). Of the 160 patients who died during the study, 41 deaths (26%) were SSc related, accounting for one-third of the excess mortality. CONCLUSION: We found a significantly increased mortality in patients with SSc, particularly in the subset of patients with diffuse skin sclerosis and in young patients. The excess mortality was due to an increase in both the SSc-related mortality and the unrelated mortality. However, all other subsets also had a significantly increased risk of death, mainly due to an increased risk of death due to causes unrelated to SSc, cancer among others. The fact that the unrelated mortality in SSc was found to be 2-fold increased suggests that the excess mortality that was classified as unrelated should more appropriately be termed indirectly SSc related.

Adolescent↗
PubMed1985

Systemic sclerosis (scleroderma) and esophageal adenocarcinoma: Is increased patient screening necessary?

An increased risk of esophageal carcinoma has been reported in systemic sclerosis (scleroderma). Periodic endoscopic or radiologic surveillance, or both, of systemic sclerosis patients with gastroesophageal reflux symptoms has been recommended for early detection of Barrett's mucosa and esophageal adenocarcinoma. A review of 680 closely followed systemic sclerosis patients for esophageal carcinoma of all types, and of a 22-yr experience with esophageal and esophagogastric junction adenocarcinoma and undifferentiated carcinoma, did not reveal a significant increase in the frequency of esophageal carcinoma in systemic sclerosis. Regular surveillance for Barrett's esophagus and esophageal adenocarcinoma would not appear to be cost-effective because of the rarity of carcinoma, increased patient discomfort and expense, and the questionable benefit for long-term survival.

Adenocarcinoma↗
PubMed1999

Clinical and laboratory manifestations of systemic sclerosis (scleroderma) in Black South Africans.

A retrospective study of systemic sclerosis (SSc) in Blacks attending a tertiary hospital on the Witwatersrand, South Africa, was undertaken. The female:male ratio of the 63 patients was 4.6:1 and the mean age of onset of SSc was 36.1 yr. Four of the 11 males were ex-goldminers and nine females resided close to goldmines. Forty-one patients had diffuse cutaneous SSc (dcSSc), 18 had limited cutaneous SSc (lcSSc) and four were unclassified. Overall, 56% had pulmonary fibrosis, 37% had myositis and 98% were antinuclear antibody (ANA) positive, with a notable absence of anti-centromere antibodies. Subset comparisons showed myositis and a reduced forced vital capacity to be significantly more common with dcSSc than lcSSc. The only significant sex differences were that arthralgia/arthritis was more common in women, while calcinosis occurred more frequently in men. Seven of the eight known deaths occurred in patients with dcSSc. These findings, particularly the age of disease onset, predominance of the dcSSc subset, inflammatory features of myositis and a raised erythrocyte sedimentation rate, and absence of anti-centromere antibodies, are similar to those reported previously in African-Americans.

Adolescent↗
PubMed2000

Detection of activated complement complex C5b-9 and complement receptor C5a in skin biopsies of patients with systemic sclerosis (scleroderma).

OBJECTIVE: Upregulated matrix synthesis is a hallmark of systemic sclerosis (SSc). There are indications that growth factors such as platelet derived growth factor (PDGF) are involved in proliferative pathways in SSc lesions. As activated complement releases PDGF from endothelial cells, we searched for activated complement and the complement receptor for C5a (C5aR) in skin biopsies of patients with SSc. METHODS: Snap frozen sections of 8 patients with early SSc and 5 patients with longterm SSc were examined. Using monoclonal antibodies against activated complement complex C5b-9 and the C5aR, skin biopsies derived from both clinically involved and non-involved skin were examined by APAAP immunohistochemistry. RESULTS: A pattern of activated complement C5b-9 and the CSaR could be detected in SSc microvasculature. Eleven of the 13 patients (7/8 patients with early SSc) showed positive staining for C5b-9. The CSaR was detected in 6 of the 8 patients with early SSc. In 3 patients with longterm disease, C5aR expression could also be detected in non-involved skin. CONCLUSION: Activated complement and complement receptors could be detected in early and late stages of SSc skin lesions. The presence of complement receptors in non-involved skin may indicate preclinical activation of pathways resulting in growth factor dependent matrix synthesis.

Antigens, CD↗
PubMedDate not supplied

The arthropathy of systemic sclerosis (scleroderma); comparison with mixed connective tissue disease.

Arthritis in systemic sclerosis (PSS) can be prominent and an overlap with rheumatoid arthritis (RA) has sometimes been queried. We therefore analysed the pattern of joint involvement of hands and wrists in 34 patients (1 male) with PSS and compared it with that of 9 patients with mixed connective tissue disease (MCTD), a condition with distinct overlap features. Although MCTD patients were younger, disease duration was similar in both groups. Extra-articular radiological findings such as calcinosis, pulp atrophy and tuft resorption were present in over half the patients with PSS but were less frequent in MCTD. Marginal erosions occurred in over 50% and ulnar styloid erosions in 35% of the PSS patients. Erosions of the 1st CMC joint were seen in one-third of them and were unrelated to age. Erosions did not correlate with clinical synovitis, the presence of rheumatoid factor which was present in 26% of PSS patients or the presence of anti-centromere or anti-Scl-70 antibodies. Erosions in MCTD patients occurred frequently and were more destructive and rapidly progressive. Correlation between erosions, rheumatoid factor and clinical arthritis was high. We conclude that erosions in PSS are frequent. Their pattern is varied but usually discrete and seldom destructive. They are not related to arthritis or serological abnormalities and may be due to several mechanisms aside from synovitis. In contrast, erosions in MCTD are more frequently destructive and related to arthritis and rheumatoid factor, suggesting a true overlap.

Adult↗
PubMed1975

Chromosomal abnormalities in progressive systemic sclerosis (scleroderma) with consideration of radiation effects.

An increased frequency of cytogenetic aberrations was observed in 63 patients with progressive systemic sclerosis (PSS, scleroderma). The most striking finding was the appearance of compound aberrations (chromosomal fragments and rearrangements) in PSS patients, while none were found in the control subjects. The aberrations were nonspecific in nature. The frequency of aberrations in the PSS patients was elevated above that of other patients receiving similar diagnostic radiation exposure (less than 1 R to greater than 10 R), but showed no relation to the amount of irradiation. The dose-response relation may have been obscured by the narrow range of exposures or by a "breakage factor" newly reported in such patients. It appears that in PSS patients the increased chromosomal breakage is not associated with an elevated frequency of leukemia or other neoplasms such as has been reported to be associated with other nonspecific breakage syndromes.

Adult↗
PubMed1989

Anti-IgE autoantibodies in systemic sclerosis (scleroderma).

An enzyme immunoassay was used to determine the prevalence of anti-IgE auto-antibodies in 66 patients with systemic sclerosis (scleroderma) stratified according to extent and duration of disease. Serum IgG anti-IgE antibodies were detected in 14 (21%) patients and IgM anti-IgE antibodies in nine (14%) patients. The overall prevalence of IgG or IgM isotypes was 21/66, (32%). Anti-IgE autoantibodies were not found in six patients with undifferentiated connective tissue disease or two patients with eosinophilic fasciitis. Attempts to demonstrate histamine release from basophils in vitro by using serum samples containing high titre anti-IgE antibody were unsuccessful. By multivariate analysis the presence of anti-IgE antibody was not associated with duration of systemic sclerosis; extent of scleroderma; specific visceral features, including heart, lung, renal, and gastrointestinal involvement; or mortality.

Autoantibodies↗
PubMed1993

The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).

HLA class II alleles were determined using the PCR-RFLP method in Japanese systemic sclerosis (scleroderma) patients with (n = 28) or without (n = 34) anti-topoisomerase I antibodies (anti-topo I). Either the DQB1*0601 or *0301 allele was recognized in all anti-topo I positive patients, compared with 44% of anti-topo I negative patients (P < 0.00001, relative risk [RR] > 41) or 58% of Japanese healthy control subjects (P < 0.00001, RR > 24). Tyrosine at position 26 in the second hypervariable region in the beta 1 domain of the DQB1 gene is common to these two alleles and is not present in any other known DQB1 alleles. We also examined immunoreactivities of anti-topo I positive sera to four different autoantigenic B cell epitopes of topo I molecule that were expressed as recombinant fusion proteins. One major B cell epitope, located within the region corresponding to amino acid residues 74-248, was perfectly associated with the amino acid sequence FLEDR at positions 67-71 in the beta 1 domain of the DRB gene. Two other epitopes, corresponding to 316-441 or 658-700, were associated with the serologically defined HLA-DR52 antigen. Patients with both FLEDR and DR52 demonstrated higher anti-topo I antibody titers. These results suggest that the HLA-DR and DQ genes together control the autoimmune response to topo I in systemic sclerosis.

Amino Acid Sequence↗