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PubMed1979

Skin thickness and collagen content in progressive systemic sclerosis and localized scleroderma.

Skin biopsies of uniform location and surface area (7 mm diameter) were obtained from the extensor aspect of the forearm of 147 patients with progressive systemic sclerosis (PSS) (107 with diffuse scleroderma, 40 with the CREST syndrome variant) and 58 individuals with normal skin. After careful removal of all subcutaneous fatty tissue, the skin cores were weighed and their water and hydroxyproline content determined. Despite recent claims to the contrary, it was found that there is a marked and highly significant increase in the thickness of the skin during the indurative phase of PSS, and that this is associated with a proportionate increase in total dermal collagen content. A similar degree of thickening was found in the skin of patients with eosinophilic fasciitis and acromegaly. A close correlation was observed between clinical estimation of the degree of skin thickening and the weight of the skin biopsy cores. Change in the weight of skin cores was observed during the course of illness of the patients with PSS and may serve as a useful measurement of alteration in the degree of skin thickening.

Acromegaly↗
PubMed2003

Update on disease-modifying antirheumatic drugs in the treatment of systemic sclerosis.

Treatment of systemic sclerosis has been somewhat haphazard and treatment has often been "borrowed" from the experience gained from treating other connective tissue diseases. There was a period of time that was focused mainly on organ-specific manifestations of systemic sclerosis and some advance in preventing vital organ damage (such as renal crisis) was achieved. The vast improvement in mortality from the use of ACE inhibitors raises one's hopes for other effective therapeutic interventions. At this juncture, the evidence is strong that the ACE inhibitors that are used in scleroderma renal crisis are disease-modifying, even without proving it by a randomized controlled trial. The evidence is strong that the use of epoprostenol for primary pulmonary hypertension is life-saving; however, whether epoprostenol is life-saving in the pulmonary hypertension in scleroderma remains to be proven. There are suggestions that bosentan (for the pulmonary hypertension of scleroderma), cyclophosphamide (for SSc alveolitis), stem cell transplant, interferon-gamma (for interstitial pulmonary fibrosis), and methotrexate (for the skin thickening of diffuse scleroderma) may improve organ function or functional activities, but whether they are truly disease-modifying remains to be proven. As we increase our understanding of the pathophysiology of systemic sclerosis and we learn how better to design trials for systemic sclerosis, we may be more successful in developing optimal disease-modifying therapy. Although the treatment of systemic sclerosis remains difficult, there are an increasing number of potentially effective regimens that are undergoing clinical investigations. A rational approach to therapy seems possible, based on a hypothesis of the pathogenesis of systemic sclerosis. Thus, there is accumulating evidence that supports the use of prostacyclin derivatives to treat systemic sclerosis, some evidence that antifibrotic regimens may be effective, and moderate evidence that immunosuppression also may be effective in certain stages of this disease.

Antirheumatic Agents↗
PubMedDate not supplied

[Studies of the mechanism of disorders of the natural killer cell activity in patients with systemic scleroderma].

The NK activity of peripheral blood mononuclear cells (PBMC) was evaluated in 90 patients with various subsets of systemic scleroderma (SSc). The NK activity, as performed with K-562 as target cell, was found to be significantly lowered in patients with diffuse scleroderma, but did not differ from the healthy control in patients with acrosclerosis. The lowest values in the NK activity assay were obtained in patients with most extensive skin involvement and severe internal organ changes. The NK activity of healthy donors' PBMC was significantly decreased by addition of SSc patients PBMC (50:1) to the cytotoxicity assay, but was not influenced by the patients sera.

Cytotoxicity, Immunologic↗
PubMed1989

[The Scl-70 antibody and its clinical significance].

In the review of the literature on the Scl-70 antigen, methods of detection of the Scl-70 antibody, the correlation between its presence and the clinical, genetic and immunological parameters are presented. It is emphasized that the Scl-70 antibody which is regarded as a marker of diffuse scleroderma, may have a prognostic significance. In indirect immunofluorescence on HEp-2 cells the Scl-70 antibody gives a characteristic pattern described as diffuse fine speckles with dotted nucleolus. A somewhat different but distinct staining pattern on hamster liver described by the authors was found to be characteristic of that antibody. The fluorescence associated with Scl-70 antibody is designated as nucleolar-reticular mixed staining with nucleolus predominating. It is suggested that hamster liver substrate which is easily available may replace the expensive HEp-2 cells for detecting Scl-70 antibody.

Antibodies, Antinuclear↗
PubMed1997

Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis.

The observation that revelation of immunocryptic epitopes in self antigens may initiate the autoimmune response has prompted the search for processes which induce novel fragmentation of autoantigens as potential initiators of autoimmunity. The reversible ischemia reperfusion which characterizes scleroderma has focused attention on reactive oxygen species as molecules which might induce autoantigen fragmentation. We demonstrate that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by reactive oxygen species, in a metal-dependent manner. Multiple features of the fragmentation reaction and its inhibition indicate that these autoantigens possess metal-binding sites, which focus metal-catalyzed oxidation reactions (and consequent fragmentation) to specific regions of the antigens. These data suggest that the autoantibody response in scleroderma is the immune marker of unique protein fragmentation, induced by ischemia reperfusion in the presence of appropriate metals, and focus attention on abnormal metal status as a potential pathogenic principle in this disease.

Autoantigens↗
PubMed2001

Esophageal hypomotility in systemic sclerosis: close relationship with pulmonary involvement.

PURPOSE: Esophageal motility was assessed in patients with systemic sclerosis (SSc) by scintigraphy and compared with (i) extent of scleroderma, (ii) duration of disease, (iii) index of anti-topoisomerase I antibody (topo I), and (iv) pulmonary involvement. METHODS: A multiple-swallow test was performed in 47 patients with SSc in the supine position with 99mTc-DTPA. A region of interest on the entire esophagus was defined and the retention ratio (RR) was calculated from a time-activity curve. RESULTS: Patients with diffuse scleroderma had higher RRs than those with limited scleroderma (48.8% vs. 30.0%; p < 0.05). There was no correlation between the RRs and the duration of disease. Patients with positive topo I had higher RRs than those who were negative (53.8% vs. 29.7%; p < 0.05). Patients with reduced % diffusion capacity for carbon monoxide (%DLCO) had higher RRs than those with normal %DLCO (40.5% vs. 19.6%; p = 0.03). Patients with reduced % vital capacity (%VC) had higher RRs than those with normal %VC (54.6% vs. 25.0%; p < 0.005). Patients with pulmonary fibrosis had higher RRs than those who were negative (58.5% vs. 20.3%; p < 0.00005). CONCLUSION: Esophageal dysfunction in patients with SSc showed a correlation with the extent of scleroderma, positive topo I, and pulmonary involvement. The RR can be an objective clinical marker for the severity of organ fibrosis.

Adolescent↗
PubMed1989

Progressive systemic sclerosis: Part 1--The disease and medical management.

The incidence of scleroderma is approximately 700,000 people in the United States. Pathologic changes occur in a variety of body systems and can alter lifestyle, especially for people with diffuse scleroderma. Information from clinical practice and research concerning the nature, incidence, pathophysiology, complications, and medical management is discussed. Although there is no known cure for scleroderma, life expectancy has improved as management of renal hypertensive crisis and renal failure has improved.

Education, Nursing, Continuing↗
PubMed1989

[The PM-Scl (polymyositis-scleroderma) autoantibody and its nucleolar fluorescence pattern].

By indirect immunofluorescence studies of antinuclear antibodies on hamster liver imprints as a substrate performed to determine the nuclear staining pattern of sera from patients with connective tissue diseases 10 sera showed a distinct homogeneous nucleolar staining pattern associated with weaker speckled or homogeneous nucleoplasmic fluorescence. In all 10 cases the antibodies revealed the PM-Scl specificity in immunodiffusion. Clinically 9 patients had an acrosclerosis, in 56% overlapped with symptoms of polymyositis. Only one patient had a diffuse scleroderma. The homogeneous nucleolar immunofluorescence pattern of PM-Scl should be distinguished from mixed nucleolar and diffuse reticular nucleoplasmic pattern of Scl-70.

Antibodies, Antinuclear↗
PubMed1993

Systemic sclerosis (scleroderma) associated with discoid lupus erythematosus.

Six patients with systemic sclerosis (SS) and discoid lupus erythematosus (DLE) were studied to determine whether such cases have some common clinical and laboratory findings. DLE preceded SS in all cases. Three patients had diffuse scleroderma with lung and esophagus involvements and the others limited scleroderma. Three patients had anti-topoisomerase-I and antiribonucleoprotein antibodies, 2 had either of them and the remaining anticentromere antibodies. Four had DLE located on the scalp, leading to alopecia. The other 2 had DLE on the face and extremities. No case fulfilled criteria for systemic lupus erythematosus (SLE). The present cases with SS and DLE, but without SLE, indicate that this type of systemic-cutaneous collagen disease overlap does exist and may be not so rare.

Adult↗
PubMed1997

Role of metal-catalyzed oxidation reactions in the early pathogenesis of scleroderma.

The observation that revelation of immunocryptic epitopes in self-antigens may initiate the autoimmune response has prompted the search for processes that induce novel autoantigen structure as potential initiators of autoimmunity. Recent studies have demonstrated that the autoantigens targeted in diffuse scleroderma are unified by their enrichment in nucleolini and by their susceptibility to fragmentation in a novel metal-dependent reaction that requires the generation of reactive oxygen species. Several other studies highlight the importance of reactive oxygen species as mediators of damage during ischemia-reperfusion and present evidence for increased generation of these radicals in patients with scleroderma. Together, these studies suggest a model for the pathogenesis of scleroderma in which metals and free radicals play a central, autoamplifying role.

Autoantibodies↗
PubMed2002

U3 snoRNP associates with fibrillarin a component of the scleroderma clumpy nucleolar domain.

Serum from patients with scleroderma recognizes the clumpy autoantigen. The present studies addressed the issue as to whether the clumpy nucleolar autoantigen recognized by scleroderma serum is fibrillarin-U3 snoRNP. Clones encoding for clumpy autoantigen were immunodetected from a lambdagt11 HeLa cell random-primed library with the serum from a patient with diffuse scleroderma and autoautoantibodies against clumpy autoantigen. Sequences from the recombinant phages were amplified by PCR and subcloned into a pCRII vector. The DNA was sequenced by a dideoxy termination reaction. Ten lambdagt11 clumpy clones were detected by immunoscreening. One containing the glycine-rich and RNP2 fibrillarin domains was expressed in lysogenic bacteria. The recombinant proteins were used to elicit antibodies in rabbits, and these exhibited clumpy nucleolar reactivity. The recombinant fibrillarin tested by ELISA was recognized by the clumpy scleroderma serum from the majority of patients. In situ hybridization assays showed that the fibrillarin tagged by the elicited antibodies was colocalized with U3 snoRNP in the nucleolus in a clumpy manner and coprecipitated the U3 snoRNP. In conclusion, the fibrillarin-U3 snoRNP complex is the major component of the clumpy subcellular domain. Therefore these molecules constitute an important target of scleroderma autoantibodies.

Autoantigens↗
PubMed1992

Lower extremity amputation in scleroderma.

Scleroderma or Systemic Sclerosis (SSC) is a disorder characterized by fibrosis of the skin and multiple internal organs. The pathological lesion is a triad of small artery intimal proliferation, medial thinning and adventitial scarring. Autoamputation of fingers and toes is often seen, but only a few cases of limb amputation in scleroderma patients have been reported. The Pittsburgh Scleroderma databank includes 1,030 patients with SSC. Among these were seven patients who sustained lower limb amputation. There were four patients with the CREST variant of SSC, two with diffuse scleroderma, and one who had SSC/rheumatoid arthritis/polymyositis overlap who sustained limb amputation. Of the seven, three were male and five had a significant smoking history. Ages ranged from 46 to 71 years. All patients underwent amputation for nonhealing ulcerations. No problems with postoperative wound healing were seen. Pathologic changes typical of SSC in addition to atherosclerotic peripheral vascular disease were described in one case. Three patients were successfully fitted with prostheses and became independent ambulators. Four patients could not be fitted with prostheses. No skin problems were reported related to prosthetic use. Our review demonstrates that SSC patients who undergo amputation can become successful prosthetic users and should be considered for prosthetic prescription.

Aged↗
PubMed1996

Cardiac involvement in scleroderma.

In summary, cardiac involvement in systemic sclerosis can be manifested as myocardial disease, pericardial disease, conduction system disease, or arrhythmias. Clinical cardiac involvement is a poor prognostic factor. Asymptomatic cardiac abnormalities are frequent, and all cardiac abnormalities are seen more often in diffuse scleroderma. Unlike other organs, the role of vascular involvement is unclear. At present, treatment of cardiac scleroderma is essentially symptomatic and empiric. The role of vasodilation and immunosuppression needs further exploration.

Arrhythmias, Cardiac↗
PubMed1988

Comparison between counterimmunoelectrophoresis and double radial immunodiffusion in the detection of antibodies to topoisomerase I in sera from scleroderma patients.

Sera from 146 patients with progressive systemic sclerosis have been submitted to the detection of anti-Scl 70 antibodies by both double radial immunodiffusion (ID) and counterimmunoelectrophoresis (CIE). CIE detected a significantly higher number of positive sera from patients with diffuse scleroderma, while no difference between the two techniques was noted in sera from patients with CREST variant. CIE increases the diagnostic importance of the serologic investigation in systemic sclerosis and gains a better distinction between subgroups of patients with different clinical expressions of this disease.

Autoantigens↗
PubMed2000

Pathogenesis of telangiectasia in scleroderma.

Scleroderma (progressive systemic sclerosis) is a systemic autoimmune disorder characterised by skin sclerosis, calcinosis and changes in microvasculature. The etiology of the disease is unknown but both genetic and environmental factors have been implicated. Telangiectasia (macroscopically visible dilated skin vessels) occurring primarily on the hands and face, are a prominent feature in scleroderma and are present in the majority of patients. Similarly, telangiectasia are found in patients with hereditary hemorrhagic telangiectasia (HHT), a mutational disorder of the germline genes endoglin and ALK-1, members of the TGFbeta receptor family, expressed on endothelial cells. Our study investigated the number, distribution and microscopic characteristics of telangiectasia in both limited (n = 29) and diffuse scleroderma (n = 9) and compared findings with 3 patients with HHT. In limited scleroderma, the mean number of telangiectasia (hand and face) was 36 (0-150) compared with 23 (0-135) in diffuse scieroderma. A significant correlation was observed between the number of telangiectasia on the face and on the hands (p = 0.014). The total number of telangiectasia correlated significantly with the disease duration (p = 0.009). The spatial distribution of the telangiectasia appeared to be random on both hands and foreface in contrast with the distribution of subcutaneous calcification of the hands which occurred predominantly on the distal and flexor surfaces of the first, second and fifth digits. Nailfold microscopic capillaroscopy was performed on 12 patients. No significant correlation was observed between capillary diameter or density and with total number of telangiectasia observed macroscopically. The distribution and microscopic appearance of telangiectasia in scleroderma appeared very similar to those observed in HHT. In view of these similarities we therefore conclude that telangiectactic development in scleroderma may be associated with disorders of the TGFb receptor family proteins found on the microvasculature.

Adult↗
PubMed1990

Early detection of connective tissue disease in patients with Raynaud's phenomenon.

Connective tissue diseases such as scleroderma frequently show an insidious onset. In their early stages a diagnosis of a specific CTD is hard to make, and the disorder may then be designated as "undifferentiated CTD." Raynaud's phenomenon (RP) is the first symptom in many cases and may precede the disease for many years. RP, however, is a common finding in the population, especially in young females. Thus, only a minority of patients with RP will develop a CTD. For reason of prognosis and early diagnosis and to get more insight in the initial pathophysiological processes, it is important to know which patients with RP will develop or are already evolving into a CTD. Patients referred to the clinician because of RP frequently (24-40%) show signs or symptoms of CTD, especially of scleroderma. Pulmonary function disturbances and esophageal hypomotility are asymptomatic in many cases, and should be sought for with sensitive methods. How can we distinguish patients with truly primary RP from those who will evolve into CTD (and thus should be screened for CTD and be followed)? The presence of antinuclear antibodies (ANA) and abnormalities at nailfold capillary microscopy (NCM) have proven to be early indicators of evolution into CTD, especially scleroderma and related disorders. The antigenic specificities of ANA indicate which syndrome the patient will develop, e.g., anti-CENP-B indicates the CREST-syndrome and anti-topoisomerase I diffuse scleroderma. Other factors of prognostic significance in patients with RP are age at onset and severity of RP: older age at onset and a highly severe RP represent risk factors for CTD. What do we know about the evolution of RP into CTD? Follow-up studies on patients referred because of RP have shown that some 15-20% of these patients have an insidious progress to limited cutaneous scleroderma including CREST. Risk factors have already been mentioned. From a pathophysiological point of view, studies in patients with early scleroderma have proved that microvascular changes are crucial in the disease process. These changes, demonstrated morphologically by NCM and functionally, e.g., by pulmonary function studies, are also reflected in increased levels of VIII antigen and in in vivo platelet activation. Both of these phenomena probably result from endothelial damage. There is increasing evidence that T-cells and their products are involved in vascular damage in early scleroderma. Future research should be directed to the elucidation of the target antigens for these T-cells.

Antibodies, Antinuclear↗
PubMed1990

Functional and phenotypic analysis of T lymphocytes cloned from the skin of patients with systemic sclerosis.

Activated T lymphocytes often accumulate in the lower dermis of patients with systemic sclerosis (scleroderma) and may play a role in the development of dermal fibrosis. We propagated and cloned these cells directly from skin biopsies in four of eight cases of early, untreated systemic sclerosis with diffuse scleroderma. The cloning frequency estimates were f = 0.20 and f = 0.48 for T cells derived from the skin of two patients versus f = 0.68 and f = 0.96 for autologous blood T lymphocytes. All but one of 24 skin-derived scleroderma clones were CD4+. Clonal analyses performed with CD4+ clones from patients and normal controls showed that all but one skin-derived clones synthesized either interferon-gamma (60%), glycosaminoglycan-stimulatory factor (26%) or both (9%) when induced in vitro by a mitogen, concanavalin A, but not by autologous dermal fibroblasts. In contrast, blood-derived clones had a different functional phenotype. All skin-derived clones produced tumour necrosis factor-alpha. Our results demonstrate that T lymphocytes obtained from the skin of patients with systemic sclerosis synthesized cytokines which could modulate functions of human dermal fibroblasts.

Adult↗
PubMed1982

[Anticentromere antibodies. Diagnostic and prognostic value].

The results of investigations for antinuclear antibodies in scleroderma and other connective diseases are reported. An indirect fluorescence method on Hep-2 cell smears was used. Antibodies directed against chromosomal centromeres were detected in 25 cases: 19 sera of patients with diffuse scleroderma, 2 cases of Raynaud's disease, 2 cases of rheumatoid arthritis and 1 case each of lupus and dermatomyositis. A significant correlation was found between the presence of anticentromere antibodies and benign forms of scleroderma, notably the CREST syndrome.

Antibodies, Antinuclear↗