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PubMed2001

[Anti-proteinase 3 antibodies in diffuse systemic sclerosis (SSc) with normotensive renal impairment: is it suggestive for an overlapping between SSc and idiopathic vasculitis? ]

OBJECTIVE: To test the prevalence of anti-neutrophil cytoplasmic antibodies (ANCA) in systemic sclerosis (SSc) and to verify a possible association of ANCA with normotensive renal involvement in SSc. PATIENTS AND METHODS: 51 patients affected by SSc, 35 with diffuse scleroderma (dSSc) and 16 with limited scleroderma (lSSc), were tested for ANCA by indirect immunofluorescence (IIF) on human ethanol and formalin-acetone-fixed granulocytes (before and after DNase treatment), by conventional enzyme linked immuno-sorbent assay (ELISA) and by capture-ELISA. RESULTS: Six out of 51 selected SSc patients had ANCA by IIF (11.7%) and five presented a perinuclear/nuclear atypical ANCA pattern. In all cases we only found anti-proteinase3 (aPR3) antibodies. All ANCA positive patients had diffuse form of SSc (17.1%), all were anti-Scl70 positive (aScl70), five patients had proteinuria, three had microscopic haematuria. All ANCA positive patients were normotensive with normal renin plasma levels, the mean erythrocyte sedimentation rate (ESR) was higher in this group compared to the other SSc patients. CONCLUSIONS: Our study shows that aPR3 is not rare in dSSc. According to the clinical and serological findings and to the recent literature, we can hypothesise that when ANCA are found in SSc, an overlapping of scleroderma with systemic necrotizing vasculitis should be suspected.

Journal Article↗
PubMed1990

Specificity of anti-Scl-70 antibodies in scleroderma: increased sensitivity of detection using purified DNA topoisomerase I from calf thymus.

A large scale purification of DNA topoisomerase I from calf thymus was obtained using the combinations of 62% ammonium sulfate precipitation, Biorex 70, hydroxylapatite and phenylagarose chromatography. Silver staining of the preparation separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed 2 bands of apparent molecular weight of 70 and 60 kDa. Immunoblotting with a serum of anti-Scl-70 specificity also recognized both proteins. Anti-Scl-70 antibodies were detected in 24/32 (75%) patients with diffuse scleroderma by ELISA and 28/32 (87%) had the ability to neutralize the topoisomerase I activity. All of 14 sera with anticentromere antibodies did not react with DNA topoisomerase I by both assays. The presence of anti-Scl-70 antibodies remained disease specific despite the increase in sensitivity of both assays.

Animals↗
PubMed1982

Immune complexes in progressive systemic sclerosis (scleroderma).

Serum immune complexes were measured in 92 patients with progressive systemic sclerosis, and elevated levels were found as follows: Raji cell assay 72% (59% after pronase treatment of Raji cell), agarose gel electrophoresis 52%, and C1q binding 24%. Forty-three (47%) had abnormal results on two or more of these tests, but only 17 (18%) had normal results by all three assays. Computer-assisted analysis of immune complex results and extensive clinical and laboratory data compiled on these patients revealed that the patients with abnormal Raji cell assays more often had diffuse scleroderma, tendon friction rubs, and positive serum antinuclear antibody tests than did patients with negative results on Raji cell assays. Individuals with immune complexes detected by C1q binding had evidence of pulmonary involvement and positive serum rheumatoid factor more frequently than did patients whose C1q tests were negative.

Adolescent↗
PubMed1990

Autoantibodies to nucleolar antigens in systemic scleroderma: clinical correlations.

Indirect immunofluorescence(IIF) and double immunodiffusion (DID) were performed on the sera of 64 patients who had a nucleolar immunofluorescence pattern on HEp-2 cells. Forty-nine of the sera were from 296 patients with systemic scleroderma (SSc) and 15 sera were from 214 patients with systemic lupus erythematosus (SLE). A homogeneous nucleolar staining pattern was found in 45 of the 64 sera (70.3%), a clumpy fluorescence associated with fibrillarin antibody in 14 (21.8%) and a speckled pattern was found in five of the sera (7.8%). There was a clear correlation between the sera which showed a homogeneous nucleolar staining pattern with symptoms of the polymyositis/scleroderma overlap syndrome that differed from SSc with concomitant myositis. The clumpy pattern was mainly associated with diffuse scleroderma and the speckled pattern with limited scleroderma (previously called acrosclerosis).

Adult↗
PubMed1999

[From Thibierge-Weissenbach syndrome (1910) to anti-centromere antibodies (1980). Clinical and biological features of scleroderma].

G. Thibierge and M.R.J. Weissenbach reported during the 1st July 1910 session of the Hospital Medical Society the first case report of what was later called in 1964 in the English literature a CRST syndrome. This patient had progressive systemic sclerosis (PSS) with Raynaud's phenomenon, recurrent cutaneous calcinosis and face and trunk telangiectasiae. Since this first description, progressive systemic sclerosis has been split in various subtypes according to the extent of cutaneous and visceral involvement. Preliminary classification criteria have been edicted by the American College of Rheumatology (ACR) in 1980. Various antinuclear autoantibodies have been associated with the prognosis of the different subtypes of PSS: anticentromere antibodies are detected in 50% of patients with CREST syndrome which has a better vital prognosis than diffuse scleroderma. This later form is associated with either anti-Scl 70 (topoisomerase I) antibodies (20 to 30%) or anti-RNA polymerase III (20%).

Antibodies, Antinuclear↗
PubMed2003

A comparison between anti-Th/To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement.

OBJECTIVE: To compare anti-Th/To-positive and anticentromere antibody (ACA)-positive patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: We reviewed the medical records of 107 anti-Th/To-positive patients and 365 ACA-positive patients who were first evaluated during 1985-2000. ACA was detected by indirect immunofluorescence on HEp-2 cell substrate, and anti-Th/To was detected by RNA immunoprecipitation with K562 cell extracts. Patients were included if they had a clinical diagnosis of lcSSc, and excluded if they had >1 SSc-associated serum autoantibody. RESULTS: The final study groups comprised 87 lcSSc patients with anti-Th/To antibodies and 306 with ACAs. Anti-Th/To-positive patients were younger (P < 0.04) and had a shorter disease duration at their first evaluation (P < 0.003). Patients with anti-Th/To antibodies had more subtle skin changes, less severe vascular involvement, and less frequent distal esophageal hypomotility. Both groups had a higher frequency of "intrinsic" pulmonary hypertension than has been previously reported in the literature (28% and 19% of anti-Th/To-positive and ACA-positive patients, respectively), perhaps due to referral bias. Patients in the anti-Th/To group more often had radiographic evidence of interstitial lung disease (48% versus 13% of the ACA group; P < 0.0001). Scleroderma renal crisis was uncommon (4 cases), but occurred exclusively in the anti-Th/To group. Survival among the anti-Th/To-positive patients was reduced compared with that in the ACA group (P < 0.02). CONCLUSION: Patients with anti-Th/To and those with ACA most often develop lcSSc and have a high frequency of "intrinsic" pulmonary hypertension. Compared with the ACA patients, anti-Th/To lcSSc patients have more subtle cutaneous, vascular, and gastrointestinal involvement, but more often have certain features typically seen in diffuse scleroderma, such as pulmonary fibrosis and scleroderma renal crisis, as well as reduced survival.

Adult↗
PubMed1988

Theophylline-resistant and theophylline-sensitive "active" and "total" E rosette-forming lymphocytes in patients with systemic scleroderma.

Using the E rosette test and its modification with theophylline, we have studied T regulatory lymphocytes in various forms of systemic scleroderma. Mean percentages of active rosette-forming cells (ARFC) as well as the fraction resistant to theophylline incubation (ARFC-res) were significantly decreased, irrespective of the variety of the disease, compared to the age-matched controls. Late ("cold") rosette-forming fractions were unimpaired. The theophylline-sensitive fraction of total rosette-forming cells (TRFC-sens), which contains mainly cells from the suppressor circuit, was found to be lowered in all patients groups studied, whereas the ARFC-sens fraction was significantly decreased only in patients with diffuse scleroderma over 50 years of age, in whom there was a tendency to a more severe course, as manifested by pronounced systemic organ involvement. The lowered values of E rosette tests were found in a majority of SSc patients and were correlated with the appearance in the sera of factors capable of inhibiting ARFC formation by normal human peripheral blood T lymphocytes. Normal values of the E rosette test were related to the presence in the patients' sera of factors stimulating ARFC formation by normal lymphocytes. We surmise from the results that in SSc patients the T-cell defect is not only restricted to T suppressor cells but also refers to the active theophylline-resistant fraction containing mainly T inducer and T cytotoxic cells.

Adult↗
PubMed1993

Identification of a subset of patients with scleroderma with severe pulmonary and vascular disease by the presence of autoantibodies to centromere and histone.

OBJECTIVES: The role of autoantibodies in the investigation and management of rheumatic diseases is well recognised. The objective of this study was to determine the clinical significance of the co-occurrence of antibodies to centromere and histone in serum samples from patients investigated for systemic rheumatic diseases. METHODS: Serum samples from 1316 consecutive patients were screened for antinuclear antibodies and the clinical findings in patients with antibodies to centromere alone were compared with those with antibodies to both centromere and histone. RESULTS: Twenty six patients had antibodies to centromere. Fourteen patients had antibodies to centromere alone and 12 patients had antibodies to centromere and histone. Four of the 12 patients with antibodies to centromere and histone had diffuse scleroderma with severe pulmonary or vascular disease. CONCLUSIONS: A subset of patients with scleroderma with antibodies to centromere and histone has been identified retrospectively, who have severe pulmonary or vascular disease. It will be of interest to follow up the clinical course of other patients with scleroderma who have both antibodies for the development of pulmonary or vascular disease.

Adult↗
PubMed1988

Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma).

Immunofluorescence on rat liver sections was used to select high-titer antinucleolar antibodies (ANoA) in the sera of patients with systemic sclerosis (scleroderma). In 646 patients, 53 ANoA sera (8%) were identified, and of these, 46 were available in sufficient quantities for further analysis. The complex of RNA polymerase I was immunoprecipitated by 7 sera (15%), which uniformly produced punctate nucleolar staining. The PM-Scl antigen, a particle consisting of 11 polypeptides, was immunoprecipitated by 8 sera (17%), all of which displayed homogeneous nucleolar staining. A 34-kd nucleolar protein (fibrillarin) of the U3 RNP complex was positive in immunoblotting of 22 sera (48%), which characteristically produced clumpy nucleolar staining. Antibodies against RNA polymerase I were associated with diffuse scleroderma of short duration, which was characterized by a high prevalence of internal organ involvement, including renal crisis. Anti-U3 RNP antibodies had a high prevalence in men with significantly less joint involvement, compared with ANoA-negative patients. Anti-PM-Scl antibodies identified a group of scleroderma patients with a high prevalence of concomitant myositis and renal involvement.

Antibodies, Antinuclear↗
PubMed2000

Long-term outcomes of scleroderma renal crisis.

BACKGROUND: Although scleroderma renal crisis, a complication of systemic sclerosis, can be treated with angiotensin-converting enzyme (ACE) inhibitors, its long-term outcomes are not known. OBJECTIVE: To determine outcomes, natural history, and risk factors in patients with systemic sclerosis and scleroderma renal crisis. DESIGN: Prospective observational cohort study. SETTING: University program specializing in scleroderma. PATIENTS: 145 patients with scleroderma renal crisis who received ACE inhibitors and 662 patients with scleroderma who did not have renal crisis. MEASUREMENTS: Among patients with renal crisis, the four outcomes studied were no dialysis, temporary dialysis, permanent dialysis, and early death. Demographic, clinical, and laboratory data were compared to identify risk factors for specific outcomes. Follow-up was 5 to 10 years. RESULTS: 61% of patients with renal crisis had good outcomes (55 received no dialysis, and 34 received temporary dialysis); only 4 of these (4%) progressed to chronic renal failure and permanent dialysis. More than half of the patients who initially required dialysis could discontinue it 3 to 18 months later. Survival of patients in the good outcome group was similar to that of patients with diffuse scleroderma who did not have renal crisis. Some patients (39%) had bad outcomes (permanent dialysis or early death). CONCLUSIONS: Renal crisis can be effectively managed when hypertension is aggressively controlled with ACE inhibitors. Patients should continue taking ACE inhibitors even after beginning dialysis in hopes of discontinuing dialysis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Connective tissue disease and autoantibodies in the kindreds of 63 patients with systemic sclerosis. The United Kingdom Systemic Sclerosis Study Group.

Systemic sclerosis (SSc) tends to occur in a sporadic fashion and familial occurrence of the disease is unusual. Nevertheless, reports of related connective tissue diseases (CTD), autoantibodies, or both in family members together with associations of certain HLA class II phenotypes with SSc suggest that genetic factors might play a part in susceptibility to the disease. Because of the relative rarity of SSc only a small number of family pedigrees have been studied previously. This report represents the largest study to date, to our knowledge, of family members of patients with scleroderma, and provides the opportunity to investigate the relative importance of genetic and environmental factors operating in the disease. The family pedigrees of 63 patients with systemic sclerosis were examined with respect to clinical, serologic, and immunogenetic features. Multiple cases of SSc were seen only in 1 family, in which the disease affected a father and daughter. Disease expression in these 2 individuals was very similar both clinically and serologically; relatives with other connective tissue diseases were found in 9 families, and nonspecific features of CTD such as Raynaud phenomenon, and arthralgia or arthritis, occurred commonly, especially in female relatives. Antinuclear antibodies (ANA) were also detected more frequently in relatives than in controls. However, antibodies previously demonstrated to have a high degree of specificity for SSc were confined to patients with this disease. Probands had an increase in the frequency of HLA-DR3, DR5, and C4AQO. Patients with diffuse scleroderma had an increased frequency of HLA-DR3, while those with the limited form of the disease had an increased frequency of HLA-DR5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

[Antiendothelial antibodies in systemic scleroderma and Raynaud's disease].

Using ELISA on fixed endothelial hybridoma (EAhy.926) cells we investigated the occurrence of antiendothelial antibodies (AEA) in the sera from patients with scleroderma systematica (SS) (n = 70) and Raynaud's disease (RD) (n = 19). The mean IgG and IgA-AEA levels were significantly higher in the SS patients than RD patients (p < 0.001) and controls (p < 0.001). We have detected circulating IgG-AEA in 64.2% of patients with SS, 35.2% of SS sera were positive for IgA-AEA. In patients with RD, the frequency of AEA corresponded to that of the random population sample. We have found a high incidence of Raynaud's phenomenon, myositis, telangiectasia and marked digital ischaemia (digital ischemic pulp ulcers, digital scars, osteolysis and autoamputation) among AEA positive patients with SS. AEA-positive patients were characterized by high extent and severity of Raynaud's phenomenon and higher average nailfold capillary microscopy scores. No correlations were found between AEA and different clinical or laboratory parameters, including the type of scleroderma (diffuse and limited), the presence of anti-Scl-7O and anticentromere antibodies and the clinical features of SS (lungs, kidneys and heart involvement, esophageal dysfunction, calcinosis, Sjogren's syndrome). There was no significant correlation between the AEA level and patient age, extent of skin involvement (skin score). Thus, in SS, AEA is associated with a peripheral vasculopathy and represent a useful marker for the diagnosis of endothelial dysfunction.

Adolescent↗
PubMed1996

Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype.

OBJECTIVE: To investigate a high prevalence of systemic sclerosis (SSc; scleroderma) in a well-defined population of 21,255 Choctaw Indians residing in 8 southeastern Oklahoma counties who were "users" of Indian Health Services. METHODS: A case-control study of 12 SSc cases and 48 matched non-SSc controls (4 per case) was conducted to investigate potential occupational, residential, and infectious exposures, as well as genetic factors which might predispose to SSc. HLA class II alleles were determined by DNA oligotyping, and class I and III alleles were defined serologically. RESULTS: The prevalence of SSc in full-blooded Choctaws was at least 8/1,704, or 469/100,000 (95% confidence interval [95% CI] 203-930) over the 4-year interval 1990-1994 and was significantly higher than that among non-full-blooded Choctaws (6/19,551, or 31/100,000) (P = 0.00001, odds ratio [OR] = 15.4, 95% CI 4.9-49.8). The overall prevalence of SSc in Oklahoma Choctaws (66/100,000) also was significantly higher than that in other Native Americans in Oklahoma (9.5/100,000) (P = 10(-6), OR = 6.95, 95% CI 3.3-13.7), who showed a prevalence similar to that reported for whites (2.1-25.3/100,000). Among the SSc cases, there was striking homogeneity of disease expression with the majority exhibiting diffuse scleroderma, pulmonary fibrosis, and autoantibodies to topoisomerase I. No environmental exposures were found to be in excess among cases versus controls. The strongest risk factor for SSc in cases (100%) versus controls (54%) was an HLA haplotype bearing the alleles B35, Cw4, DRB1*1602 (DR2), DQA1*0501, and DQB1*0301 (DQ7) (P = 0.002, Pcorr = 0.036, OR = 21, 95% CI 2.9-437). Survey of another group of Choctaws residing in another state revealed no cases of SSc despite a high frequency of the same HLA haplotype. CONCLUSION: Full-blooded Choctaw Native Americans living in southeastern Oklahoma have the highest prevalence of SSc yet found in any population. A major risk factor for disease is a uniquely Amerindian HLA haplotype; however, additional genes and/or an as-yet-unidentified environmental exposure seem likely.

Adult↗
PubMed1998

Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis.

OBJECTIVE: To determine whether the initiation of corticosteroids or other types of therapy affects the development of scleroderma renal crisis (SRC). METHODS: Using a case-control study, 110 patients with systemic sclerosis who developed SRC between 1981 and 1993 were closely matched with controls on sex, race, age, disease duration, skin score, levels of creatine phosphokinase, and presence of tendon friction rubs. Corticosteroid use was determined prior to the onset of SRC in cases or prior to the first visit in controls. Cases were compared with matched controls using McNemar's matched-pair analysis and conditional logistic regression analysis. The effects of other drugs, including D-penicillamine, nonsteroidal antiinflammatory drugs (NSAIDs), calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors, were also evaluated. RESULTS: In the 6 months prior to SRC onset or to the first visit, high-dose corticosteroids (> or =15 mg/day prednisone or equivalent) were administered significantly more frequently in SRC patients (36%) than in the controls (12%) (McNemar's odds ratio 4.37, 95% confidence interval 2.03-9.43, P < 0.0001). New use of low-dose steroids, continuous use of any steroid dose, NSAIDs, calcium channel blockers, and ACE inhibitors were not associated with an increased risk of SRC. Antecedent D-penicillamine therapy may have been protective against the development of SRC in controls. CONCLUSION: This retrospective case-control study has shown a significant association between antecedent high-dose corticosteroid therapy and the development of SRC. These results should discourage the use of high-dose corticosteroids in patients with early diffuse scleroderma who are at increased risk of developing SRC.

Acute Kidney Injury↗
PubMed1993

Antinuclear antibody profile in UCD line 200 chickens: a model for progressive systemic sclerosis.

The fully blown disease of human progressive systemic sclerosis (PSS, scleroderma) is serologically associated with the emergence of several types of autoantibodies, some of them regarded as more specific for scleroderma (e.g. Scl-70, anti-centromere) and some common also to other connective tissue diseases (e.g. anti-ssDNA). Since most patients suffering from PSS are not under medical control until clinical manifestations are fully established, only scarce data are available on the dynamics and clinical significance of autoantibodies in the very early stages of this systemic fibrotic disease. The University of California at Davis line 200 (UCD 200) of chickens spontaneously develop a PSS-like disorder with an acute inflammatory stage around 60 days after hatching, leading to fibrosis with fast progression. In order to address a possible correlation between the occurrence and titer of autoantibodies and the initial disease activity, we have chronologically investigated the presence and titer of autoantibodies directed against several human nuclear antigens in this animal strain. In UCD-200 chickens, we found a progressive increase in autoantibodies to histones, to ssDNA and--to a lesser degree--dsDNA with peaks at the age of 60 and 120 days, to poly(I) and poly(G) with a peak at 120 days and an elevation in anti-cardiolipin antibodies. Total immunoglobulin concentrations, anti-Ro, anti-La and anti-Sm showed no significant differences as compared to negative results in healthy normal controls. Our data reveal parallels in the antinuclear antibody (ANA) spectrum between UCD-200 chickens and human autoimmune collagen diseases, but do not reflect the typical ANA spectrum found in the foudroyant form of diffuse scleroderma.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗